Clinical trial NCT02971293
Conditions: Chronic Obstructive Pulmonary Disease COPD
Keywords: AZD8871 long-acting muscarinic antagonist (LAMA) long-acting β2-agonist (LABA) inhaled long-acting bronchodilator pharmacokinetics safety tolerability efficacy Phase IIa Muscarinic receptor antagonist β2 adrenoceptor agonist (MABA)
Sponsor: AstraZeneca
Start date: 2016-12-15; Completion date: 2017-08-18
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a study to evaluate the effects of AZD8871 in patients with COPD. Adult male or female patients with moderate to severe COPD, who agree to be in this study, will receive 3 treatments, i.e. 2 different doses of AZD8871 and placebo (dummy medication containing no drug) at once a day for 2 weeks, in a random order. To make the comparison between AZD8871 and placebo as fair as possible, this study is "double blinded." This means that neither patient nor the study doctor will know in which order the 3 treatments will be given. This study will include patients who are between 40 and 80 years of age. In total there will be 42 patients participating in this study at two study centers in the United Kingdom and Germany. The study will have a total of 12 visits for each patient spanning for a period of 4 to 6 months. The study is anticipated to run for approximately 8 months and should not exceed 10 months.

Detailed description:
This is 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 and placebo, administered using a dry powder inhaler (DPI) device once daily, for 2 weeks, in patients with moderate to severe COPD. AZD8871 is a new chemical entity 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.

The objective of the study is to assess the efficacy, safety and PK of AZD8871 after a 14-day treatment period at 2 different doses 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. The crossover design has been chosen to avoid inter-patient variability and optimize sample size. 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. The proposed dose levels of AZD8871 in this study are 100 and 600 µg of AZD8871 given by inhalation once daily for 14 days through a single dose DPI. Doses have been selected based on the safety, tolerability, PK and pharmacodynamics (PD) information generated in previous clinical trials with AZD8871. The wash-out period proposed for this current study is a minimum of 28 days and up to 35 days in order to avoid any carry over effect between periods. The broad dose range selected (6 fold range from 100 to 600 µg) has been chosen to span the likely therapeutic dose and facilitate the dose selection for future studies. Considering the expected efficacy in patients with COPD and the available data to date, it is anticipated the benefits will outweigh the risks and support the continued investigation of AZD8871 in clinical studies.

Arms: arm 1: The subjects will receive AZD8871 100 µg once daily, by dry powder inhaler (DPI) device. The treatment will be administered via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products. arm 2: The placebo will be administered via single dose DPI that is an adaptation of the commercially available Genuair® with a smaller internal volume to enable delivery of single doses. To maintain blinding, each patient will receive one inhaled dose from placebo DPI provided to him/her on each day of the treatment period. arm 3: The subjects will receive AZD8871 600 µg once daily by DPI device via single dose DPI that is an adaptation of the multi-dose Genuair™ used in approved inhalation products.
Interventions: intervention 1: AZD8871 100 µg intervention 2: AZD8871 600 µg intervention 3: Placebo
Intervention descriptions: intervention 1: The subjects will receive one dose of AZD8871 100 µg single dose DPI. intervention 2: The subjects will receive AZD8871, 600 µg single dose DPI. intervention 3: The subject will receive Placebo single dose DPI.

Protocol documents:
Prot_000.pdf: 
 
Clinical Study Protocol (CSP), ANGEL 
Version 17.0 
Template Form Doc ID: LDMS_001_00026737 
Parent Doc ID: SOP AZDoc0018580 
 
Clinical Study Protocol  
 
Drug Substance 
AZD8871 
 
Study Code 
D6640C00004 
 
Version 
3.0  
 
Date 
16 December 2016 
 
A phase IIa, randomised, multi-centre, double-blind, placebo-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 
EudraCT number:  2016-002863-32 
Sponsor: 
AstraZeneca AB, 151 85 Södertälje, Sweden 
 
 
 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
2 (107) 
VERSION HISTORY 
Version 3.0, 16 December 2016 
Changes to the protocol are summarised below 
1) Section 3.2 (Exclusion criteria) was updated to add 2 exclusion criteria to specify that 
patients who had 2 or more exacerbations of COPD within the last year prior to Screening and 
patients who were placed in an institution due to a regulatory or court order were not to be 
included in the study. 
2) Section 3.9 (Discontinuation of investigational product) was updated to add study-specific 
withdrawal criteria (based on measurable parameters for vital signs, laboratory results, 
electrocardiograms, lung function, and worsening of COPD.  
3) Appendix C (Actions Required in Cases of Increases in Liver Biochemistry and Evaluation 
of Hy’s Law) was updated to align with the update to Section 3.9. 
 
Version 2.0, 22 September 2016 
Changes to the protocol are summarised below 
1) Protocol synopsis, Section 1.2 (Rationale for study design, doses and control groups), 
Section 1.4 (Study design), Section 3.5 (Methods for assigning treatment groups), Section 7.1 
(Identity of investigational product(s)), Section 7.2.2 (Treatment periods), and Section 8.2 
(Sample size estimate), and Section 8.5.3 (Analysis of the primary efficacy variable): The 
high dose level was changed from 900 μg to 600 μg based on the exposure levels seen in the 
Phase I Study D6640C00003. 
2) Protocol synopsis and Section 7.1 (Identity of investigational product(s)): Dosage form for 
300 μg was removed as this is no longer required (due to the change in the high dose from 
900 μg to 600 μg). 
3) Protocol synopsis and Section 7.1(Identity of investigational product(s)): The requirement 
of 2 dry powder inhaler s (DPIs) per administration was changed to one DPI per 
administration (due to the change in the high dose from 900 μg to 600 μg). 
4) Section 1.2 (Rationale for study design, doses and control groups) and Section 1.3 
(Benefit/risk and ethical assessment): Newly available data from a previously reported study 
(D6640C00003) were added. Typo-error in the study number (D6640C00003) was corrected. 
5) Section 6.3.6 (Adverse events based on examinations and tests) and Section 6.4 (Reporting 
of serious adverse events): The serious adverse event reporting process was updated in 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
3 (107) 
alignment with the update on Sponsor’s processes. 
6) Section 4.2.3 (Visit 5, 8 and 11 (Treatment Day 14) and Section 5.3 (Other assessments): 
Additional text was added for the instruction on timing of taste assessment, for clarity. 
7) Protocol synopsis: Typo-error regarding the number of treatments in the study was 
corrected from 4 to 3.  
 
Version 1.0, 09 August 2016 
Initial creation 
 
 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
4 (107) 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 
 


 
5 (107) 
PROTOCOL SYNOPSIS 
 
A phase IIa, randomised, multi-centre, double-blind, placebo-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 
 
 
Co-ordinating Investigator 
 
 
 
 
 
 
Study site(s) and number of patients planned 
It is planned that approximately 42 patients with moderate to severe chronic obstructive 
pulmonary disease (COPD) will be randomised into the study. 
The study will be conducted at 2 sites in Germany and the United Kingdom (UK).  Estimated 
study duration is 6 months. 
Study period 
 
Phase of development 
Estimated date of first patient enrolled 
Q4 2016 
IIa 
Estimated date of last patient completed 
Q2 2017 
 
 
Study design 
This is a proof-of-concept, randomised, double-blind, 3-way complete crossover William’s 
design, multiple dose study of 2 dose levels of AZD8871 and placebo administered by a dry 
powder inhaler (DPI) device.  Approximately 42 male and non-childbearing female patients 
with moderate to severe COPD as per the Global Initiative for Chronic Obstructive Lung 
Disease (GOLD 2016) guidelines will be randomised into the study.  A subset of 20 patients, 
Redacted


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
6 (107) 
who will have specifically consented for pharmacokinetics (PK), will undergo PK 
assessments.  The aim is to ensure at least 30 patients complete the study. 
The study will consist of a Screening period, 3 treatment periods (each separated by a 
wash-out period), and a Follow-up Visit.  
Screening period: This will last up to 28 days and consists of a Screening Visit (Visit 1), 
Visit 2, and a run-in period.  
Patients will be withdrawn from their usual COPD therapy after signing the informed consent 
form (ICF) at Visit 1 and maintained on their usual inhaled corticosteroid (ICS) therapy, if 
any.  Those patients that were taking any long-acting muscarinic antagonist (LAMA), they 
will be maintained with ipratropium (following the approved dosage and regimen) between 
Visit 1 and Visit 2.  In addition, salbutamol will be administered as rescue medication during 
the study as needed (salbutamol will be discontinued 6 hours previous 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: 
x ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed 
x Reversibility test with salbutamol and spirometry (confirm inclusion criteria #6 and 
#7): These must be performed at Visit 2.  
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. 
Run-in period: 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 following the approved dosage and regimen (must be discontinued 
8 hours prior to previous any pulmonary function test).  
After the run-in period patients who fulfil all inclusion and none of the exclusion criteria will 
be randomised at Visit 3 to receive each of the 3 treatments (AZD8871 or placebo). 
Treatment periods:  The duration of each treatment period will be 14 days.  In each 
treatment period, patients will receive one 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: 


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
7 (107) 
x AZD8871 100 μg once daily (double-blind) 
x AZD8871 600 μg once daily (double-blind) 
x Placebo (double-blind) 
Each of the 3 treatment periods will include 2 overnight stays at the study site and one 
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 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. 
Drug 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 20 patients will undergo PK assessments.  Blood samples will be 
collected pre-dose and up to 24 hours post-dose.  
From treatment period 2 onwards, on Day 1 of every new treatment period, 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).  
Drug administration compliance will be recorded in the e-Diary of the patient when the patient 
is not at the site. 
Wash-out periods: Between each treatment period, there will be a wash-out period of 28 to 
35 days. During this period, all patients will receive ipratropium following the approved 
dosage and regimen (must be discontinued 8 hours before any pulmonary function test). 
Follow-up Visit:  Patients will come to the site for a Follow-up Visit, 28 days (up to 35 days) 
after the last investigational product (IP) administration, for adverse events (AEs) assessment, 
safety laboratory, electrocardiogram (ECG), vital signs and physical examination.   


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
8 (107) 
Objectives 
Primary Objective: 
Outcome Measures: 
To evaluate the efficacy of inhaled AZD8871 
in patients with moderate to severe COPD 
Primary 
• Change from baseline in Trough FEV1 on Day 15 
Secondary 
• 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 8 to Day 15) 
• Change from baseline in Peak FEV1 over 
treatment duration (Day 8 to Day 14) 
• 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 after treatment, from Day 8 to Day 14 after 
treatment and during the whole treatment duration 
• Rescue medication use 
 


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
9 (107) 
Secondary Objective: 
Outcome Measures: 
To investigate the PK of AZD8871 and its 
metabolites 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 
metabolites LAS191861 and LAS34850 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: 
Outcome Measures: 
To evaluate the safety and tolerability of 
inhaled AZD8871 in patients with moderate to 
severe COPD 
• AEs/Serious Adverse Events (SAEs) 
• Vital signs 
• ECG 
• Clinical laboratory assessments 
 
Exploratory Objective: 
Outcome Measure: 
To evaluate the taste of inhaled AZD8871 in 
patients with moderate to severe COPD 
• Taste assessment 
 
Target patient population 
The study will be performed in adult male and non-childbearing female patients 40 to 80 years 
of age with moderate to severe COPD. 


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
10 (107) 
Duration of treatment 
Each of the 3 treatment periods will last for 14 days and will be followed (except the last one) 
by a wash-out period of 28 days (up to 35 days).  The entire study period is scheduled to take 
from a minimum of 4.5 months (140 days) to a maximum of 5.6 months (175 days) for each 
individual patient. 
Investigational product, dosage and mode of administration 
Investigational product 
Investigational product 
Dosage form and strength 
Manufacturer 
AZD8871 
Powder for inhalation administered 
via single dose DPI 
100 and 600 μg/inhalation 
Industrias Farmacéuticas Almirall 
S.A. 
 
 
Placebo 
Powder for inhalation administered 
via single dose DPI 
Industrias Farmacéuticas Almirall 
S.A. 
 
 
DPI=Dry powder inhaler. 
 
Product dosage and mode of administration 
Study treatment 
IP administration 
Comments 
AZD8871 100 μg 
100 μg single dose DPI  
1 inhalation QD 
AZD8871 600 μg 
600 μg single dose DPI 
1 inhalation QD 
Placebo 
Placebo single dose DPI 
1 inhalation QD 
DPI=Dry powder inhaler; QD=Once a day. 
All investigational products will be administered by oral inhalation.  Patients will be provided with 1 single dose 
DPI per day during the treatment periods.  
Statistical methods 
Sample size 
The study will be powered to demonstrate superiority of AZD8871 100 μg and 600 μg versus 
placebo for the primary efficacy endpoint.  With a total of 30 patients, there is 80% power to 
detect a difference between actives and placebo for the change from baseline to trough FEV1 
at Day 15 equal to 100 mL, assuming a within-patient standard deviation (SD) of 135 mL, 
2-sided 5% significance level and a normal distribution.  Assuming an approximate 25% 
dropout, the total sample size will be approximately 42 (multiple of 6 sequences).  From 
previous studies, the screening failure rate is estimated to be approximately 55%, therefore 
approximately 93 screened patients will be required to achieve the goal of approximately 
42 randomised patients. 
Redacted
Redacted


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
11 (107) 
Due to the exploratory nature of the study, there will be no adjustment for multiple 
comparisons. 
Statistical analyses 
The analysis of all the efficacy variables will be performed on the Full Analysis Set 
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 20 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; 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 each period will be included as a covariate. 
Analyses of secondary variables: 
Efficacy analyses 
All continuous variables defined as change from baseline or observed values will be analysed 
using mixed models. 
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 
sequence. 


Clinical Study Protocol Synopsis 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
12 (107) 
Categorical variables will be analysed descriptively. 
Pharmacokinetic analyses 
Plasma concentrations and PK parameters will be listed and summarised for AZD8871 and its 
metabolites per treatment and day using appropriate descriptive statistics. 
Product 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).  A linear mixed-effect model will be used with 
the logarithm of the PK parameters as the response variable and dose, day and dose by day 
interaction as fixed effects.  
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. 
Exploratory analyses 
Each question of the taste questionnaire will be analysed using descriptive statistics.  In 
addition, the overall evaluation of taste will be compared among treatment groups using an 
analysis of variance (ANOVA) model for crossover designs.  
 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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TABLE OF CONTENTS 
PAGE 
 
TITLE PAGE ........................................................................................................... 1 
VERSION HISTORY .............................................................................................. 2 
PROTOCOL SYNOPSIS ......................................................................................... 5 
TABLE OF CONTENTS ....................................................................................... 13 
1. 
INTRODUCTION ................................................................................................. 22 
1.1 
Background and rationale for conducting this study ............................................. 22 
1.2 
Rationale for study design, doses and control groups ............................................ 23 
1.3 
Benefit/risk and ethical assessment ....................................................................... 25 
1.4 
Study design ........................................................................................................... 26 
2. 
STUDY OBJECTIVES .......................................................................................... 30 
2.1 
Primary objective ................................................................................................... 30 
2.2 
Secondary objectives ............................................................................................. 30 
2.3 
Safety objectives .................................................................................................... 31 
2.4 
Exploratory objectives ........................................................................................... 31 
3. 
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 31 
3.1 
Inclusion criteria .................................................................................................... 31 
3.2 
Exclusion criteria ................................................................................................... 33 
3.3 
Patient enrolment and randomisation ..................................................................... 36 
3.4 
Procedures for handling incorrectly enrolled or randomised patients ................... 37 
3.5 
Methods for assigning treatment groups ................................................................ 38 
3.6 
Methods for ensuring blinding ............................................................................... 38 
3.7 
Methods for unblinding .......................................................................................... 38 
3.8 
Restrictions ............................................................................................................ 39 
3.9 
Discontinuation of investigational product ............................................................ 40 
3.9.1 
Procedures for discontinuation of a patient from investigational product ............. 43 
3.10 
Criteria for withdrawal ........................................................................................... 43 
3.10.1 
Screen failures ........................................................................................................ 43 
3.10.2 
Withdrawal of the informed consent ...................................................................... 44 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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3.11 
Discontinuation of the study .................................................................................. 44 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 44 
4.1 
Enrolment/Screening period .................................................................................. 49 
4.1.1 
Visit 1 – Screening ................................................................................................. 49 
4.1.2 
Visit 2 – Reversibility testing ................................................................................ 50 
4.2 
Treatment period .................................................................................................... 50 
4.2.1 
Visit 3 - Randomisation and Visits 6 and 9 (Treatment Day 1) ............................. 50 
4.2.2 
Visits 4, 7 and 10 (Treatment Day 8) ..................................................................... 52 
4.2.3 
Visit 5, 8 and 11 (Treatment Day 14) .................................................................... 52 
4.3 
Follow-up Visit (Visit 12) ...................................................................................... 54 
4.4 
Premature discontinuation visit .............................................................................. 54 
5. 
STUDY ASSESSMENTS ..................................................................................... 55 
5.1 
Efficacy assessments .............................................................................................. 55 
5.1.1 
Pulmonary function test (spirometry) .................................................................... 55 
5.1.2 
Reversibility testing ............................................................................................... 56 
5.1.3 
FEV1 and clinical stability check ........................................................................... 57 
5.1.4 
Breathlessness, cough, and sputum scale ............................................................... 57 
5.1.5 
Rescue medication use ........................................................................................... 57 
5.2 
Safety assessments ................................................................................................. 58 
5.2.1 
Laboratory safety assessments ............................................................................... 58 
5.2.2 
Physical examination ............................................................................................. 61 
5.2.3 
Electrocardiogram .................................................................................................. 61 
5.2.4 
Vital signs .............................................................................................................. 62 
5.2.4.1 
Heart rate and blood pressure ................................................................................ 62 
5.2.4.2 
Body temperature ................................................................................................... 63 
5.2.5 
Adverse events ....................................................................................................... 63 
5.2.6 
Unscheduled tests ................................................................................................... 63 
5.2.7 
Repeated tests ......................................................................................................... 63 
5.3 
Other assessments .................................................................................................. 63 
5.4 
Pharmacokinetics ................................................................................................... 63 
5.4.1 
Collection of samples ............................................................................................. 63 
5.4.2 
Determination of drug concentration ..................................................................... 64 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................ 64 
5.5 
Pharmacodynamics ................................................................................................ 64 
5.6 
Pharmacogenetics................................................................................................... 64 
5.7 
Biomarker analysis ................................................................................................. 64 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 65 
6.1 
Definition of adverse events .................................................................................. 65 
6.2 
Definitions of serious adverse event ...................................................................... 65 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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6.3 
Recording of adverse events .................................................................................. 66 
6.3.1 
Time period for collection of adverse events ......................................................... 66 
6.3.2 
Follow-up of unresolved adverse events ................................................................ 66 
6.3.3 
Variables ................................................................................................................ 66 
6.3.4 
Causality collection ................................................................................................ 67 
6.3.5 
Adverse events based on signs and symptoms ...................................................... 67 
6.3.6 
Adverse events based on examinations and tests ................................................... 68 
6.3.7 
Hy’s Law ................................................................................................................ 68 
6.3.8 
Disease progression ............................................................................................... 68 
6.4 
Reporting of serious adverse events....................................................................... 68 
6.5 
Overdose ................................................................................................................ 69 
6.6 
Pregnancy ............................................................................................................... 70 
6.6.1 
Maternal exposure .................................................................................................. 70 
6.6.2 
Paternal exposure ................................................................................................... 70 
6.7 
Management of IP related toxicities ...................................................................... 71 
6.8 
Study governance and oversight ............................................................................ 71 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 71 
7.1 
Identity of investigational product(s) ..................................................................... 71 
7.2 
Dose and treatment regimens ................................................................................. 72 
7.2.1 
Run-in period ......................................................................................................... 72 
7.2.2 
Treatment periods .................................................................................................. 72 
7.2.3 
Wash-out periods ................................................................................................... 73 
7.3 
Labelling ................................................................................................................ 73 
7.4 
Storage ................................................................................................................... 73 
7.5 
Compliance ............................................................................................................ 73 
7.6 
Accountability ........................................................................................................ 73 
7.7 
Concomitant and other treatments ......................................................................... 74 
7.7.1 
Other concomitant treatment .................................................................................. 76 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................ 76 
8.1 
Statistical considerations ........................................................................................ 76 
8.2 
Sample size estimate .............................................................................................. 77 
8.3 
Definitions of analysis sets .................................................................................... 77 
8.3.1 
Full analysis set ...................................................................................................... 77 
8.3.2 
Safety analysis set .................................................................................................. 77 
8.3.3 
Pharmacokinetic analysis set ................................................................................. 78 
8.3.4 
Per-protocol analysis set ........................................................................................ 78 
8.3.5 
Protocol deviations ................................................................................................. 78 
8.4 
Outcome measures for analyses ............................................................................. 78 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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8.4.1 
Primary efficacy variable ....................................................................................... 78 
8.4.2 
Secondary variables ............................................................................................... 79 
8.4.2.1 
Efficacy variables ................................................................................................... 79 
8.4.2.2 
Pharmacokinetic variables ..................................................................................... 79 
8.4.3 
Safety variables ...................................................................................................... 81 
8.4.4 
Exploratory variable ............................................................................................... 81 
8.5 
Methods for statistical analyses ............................................................................. 81 
8.5.1 
Demographic and baseline characteristics ............................................................. 81 
8.5.2 
Concomitant and rescue medication ...................................................................... 83 
8.5.3 
Analysis of the primary efficacy variable .............................................................. 83 
8.5.4 
Analysis of the secondary variables ....................................................................... 83 
8.5.4.1 
Analysis of the efficacy variables .......................................................................... 83 
8.5.4.2 
Analysis of pharmacokinetic variables .................................................................. 84 
8.5.5 
Sensitivity analysis ................................................................................................. 85 
8.5.6 
Exploratory analysis ............................................................................................... 85 
8.5.7 
Analyses of safety variables ................................................................................... 86 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA .......................... 87 
9.1 
Training of study site personnel ............................................................................. 87 
9.2 
Monitoring of the study ......................................................................................... 88 
9.2.1 
Source data ............................................................................................................. 88 
9.2.2 
Study agreements ................................................................................................... 88 
9.2.3 
Archiving of study documents ............................................................................... 88 
9.3 
Study timetable and end of study ........................................................................... 88 
9.4 
Data management by PAREXEL ........................................................................... 89 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 90 
10.1 
Ethical conduct of the study ................................................................................... 90 
10.2 
Patient data protection ............................................................................................ 90 
10.3 
Ethics and regulatory review ................................................................................. 90 
10.4 
Informed consent ................................................................................................... 91 
10.5 
Changes to the protocol and Informed Consent Form ........................................... 92 
10.6 
Audits and inspections ........................................................................................... 92 
11. 
LIST OF REFERENCES ....................................................................................... 93 
 
LIST OF TABLES 
Table 1 
Study Plan detailing the procedures ......................................................... 45 
Table 2 
Laboratory safety variables ...................................................................... 59 


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Version 3.0 
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Table 3 
Drugs of abuse and alcohol parameters .................................................... 60 
Table 4 
Medications allowed as concomitant medications ................................... 74 
Table 5 
Medications prohibited as concomitant medications ............................... 75 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ....................................................................................... 29 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Information .................................................................. 94 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document ................................................................................. 96 
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 97 
Appendix D 
Breathlessness, Cough Sputum Scale ..................................................... 101 
Appendix E 
Taste questionnaire ................................................................................. 102 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
%Fluctuation 
Fluctuation index during a dosing interval 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Code 
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 
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 
CPMP 
Committee for Proprietary Medicinal Products 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 


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Abbreviation or 
special term 
Explanation 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DES 
Data entry site 
DGR 
Dangerous goods regulations 
DILI 
Drug-induced liver injury 
DMP 
Data Management Plan 
DPI 
Dry powder inhaler 
DVS 
Data Validation Specification 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
ERS 
European Respiratory Society 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GMP 
Good Manufacturing Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
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 
IP 
Investigational Product  
LABA 
Long-acting β2-agonist 


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Abbreviation or 
special term 
Explanation 
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 
MedDRA 
Medical Dictionary for Regulatory Activities 
NA 
Not applicable 
ND 
Not determined 
PD 
Pharmacodynamic(s) 
PDF 
Portable Document Format 
PHL 
Potential Hy’s Law 
PI 
Principal Investigator  
PK 
Pharmacokinetic(s) 
PP 
Per-protocol 
PRO 
Patient-reported outcome 
QD 
Once a day (quaque die) 
QID 
Four times a day (quarter in die) 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected using Bazett formula 
QTcF 
QT interval corrected using Fridericia’s formula 
Rac 
Accumulation ratio 
Rac(AUC0-24) 
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 


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Version 3.0 
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Abbreviation or 
special term 
Explanation 
SD 
Standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
Standard error 
SOP 
Standard Operating Procedure 
TBL 
Total bilirubin 
TCS 
Tata Consultancy Services 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time to reach maximum plasma concentration  
UK 
United Kingdom 
ULN 
Upper limit of normal 
 


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Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
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 with alpha-lactose monohydrate 
and delivered by dry powder inhaler (DPI) that allows delivery of a single dose of the study 
drug. 
COPD is a significant cause of morbidity and mortality worldwide (Global Initiative for 
Chronic Obstructive Lung Disease 2009 [GOLD 2016]).  It is a common, preventable and 
treatable disease characterised by persistent airflow limitations.  The disease is usually 
progressive and associated with and enhanced chronic inflammatory response in the airways 
and the lung to noxious particle or gases (GOLD 2016).  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 2016 
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 
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 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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profile.  A muscarinic receptor antagonist and β2 adrenoceptor agonist (MABA) compound 
will represent an important treatment option for patients with COPD. 
1.2 
Rationale for study design, doses and control groups 
The objective of the study is to assess the efficacy, safety and pharmacokinetics (PK) of 
AZD8871 after a 14-day treatment period at 2 different doses 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.” 
The crossover design has been chosen to avoid inter-patient variability and optimize sample 
size.  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). 
The proposed dose levels of AZD8871 in this study are 100 and 600 μg of AZD8871 given by 
inhalation once daily during 14 days through a single dose DPI.  Doses have been selected 
based on the safety, tolerability, PK and pharmacodynamics (PD) information generated in 
previous clinical trials with AZD8871. At the time of writing of this document, 2 clinical 
studies are ongoing with AZD8871, studies D6640C00001 and D6640C00003. 
Study D6640C00001 is a 2-part placebo-controlled study in asthmatic and COPD patients.  
Part 1 of the D6640C00001 was the first time in human study with AZD8871. This part has 
been completed and is in the reporting phase. Part 1 was a single ascending dose safety, 
tolerability, PK and PD investigation in 16 male, mild asthmatic patients. Single doses ranging 
from 50 to 2100 μg of AZD8871 were administered and were found to be safe and 
well-tolerated. Pharmacokinetic data generated for AZD8871 showed dose proportionality 
increase for systemic exposure parameters (maximum plasma concentration [Cmax] and area 
under the plasma concentration-curve from time 0 to the time of last quantifiable 
concentration [AUClast] and linear PK). Maximum exposure limits predefined in the protocol 
were not reached (Mean preliminary Cmax and area under the plasma concentration-curve from 
time 0 to 24 hours post-dose [AUC(0-24)] achieved for AZD8871 after 2100 μg represented 
68% and 84%, respectively of the predefined human exposure limits. Mean terminal half-lives 
found in the study for AZD8871 (calculated over 36 hours) ranged from 16 to 23 hours. The 
active metabolite, LAS191861, was also measured and systemic exposure represented about 
23% of the parent compound exposure. Significant and sustained PD (bronchodilation) dose-


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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response effect with peak and trough FEV1 reaching a plateau of around 500-600 mL and 
300-400 mL, respectively at doses of ≥400 μg) was observed. 
Part 2 of study D6640C00001 is a randomised, single dose, placebo- and active 
comparator-controlled 5-way complete crossover investigation in 38 moderate to severe 
COPD patients. The last patient, last visit for this study has been completed; data analysis  is 
currently ongoing and final results are expected to be reported in December 2016. Two dose 
levels of AZD8871 (400 and 1800 μg) are being compared against placebo and 2 active 
reference agents (indacaterol 150 μg and tiotropium 18 μg). These dose levels were selected 
based on safety and exposure obtained in the first part of the study.  At the time of writing this 
document between 28 to 30 patients had received these 2 doses of AZD8871. 
Study D6640C00003 is a Phase I, randomised, multiple ascending dose study to investigate 
safety, tolerability and PK of AZD8871 administered for 12 days to healthy male subjects.  
This study entitles 3 dose levels: 300 μg (cohort 1), 600 μg (cohort 2) and up to 1800 μg 
(cohort 3, exact dose is to be decided). Data from the first 2 cohorts of subjects dosed with 
300 μg and 600 μg of AZD8871 have been generated and both the dose levels were found to 
be safe and well tolerated. Preliminary interim results generated at 300 μg and 600 μg dose 
levels demonstrated time independent kinetics of AZD8871 and steady-state achievement for 
AZD8871 after 5 days of once daily dosing. There was evidence of accumulation of AZD8871 
in plasma based on AUC(0-24) with geometric mean accumulation ratios ranging from 1.5 to 
1.7. No accumulation was observed for Cmax. Based on a sampling scheme of up to 96 hour 
post-dose, mean preliminary estimates for the terminal elimination half-life of AZD8871 
ranged from 64.4 to 78.8 hours, after 12 days of repeated administration.  Mean AZD8871 
steady-state Cmax and AUC(0-24) achieved after 600 μg represented 55 and 78% of the 
predefined human exposure limits. Preliminary PK data have been also generated for the 
active metabolite LAS191861 after repeated administration of AZD8871. There was evidence 
of accumulation of LAS191861 in plasma with a geometric mean accumulation ratios for 
AUC(0-24) ranging from 2.4 to 3.5 and for Cmax from 1.9 to 2.7. Mean metabolite AUC(0-24) 
after 12 days of daily treatment represented approximately 23% of the parent compound 
AUC(0-24), being the ratios significantly lower than those observed in preclinical species. Mean 
metabolite terminal half-lives observed after repeated administration ranged from 116 to 
138 hours.  
Based on the information of terminal elimination half-lives observed for AZD8871 and 
LAS191861 in MAD study (D6640C00003), the wash-out period proposed for this current 
study is a minimum of 28 days and up to 35 days in order to avoid any carry-over effect 
between periods. 
In light of the safety, tolerability and PK data generated in studies D6640C00001 and 
D6640C00003, the proposed doses for study D6640C00004 are anticipated to be well 
tolerated. The broad dose range selected (6-fold range from 100 to 600 μg) has been chosen to 
span the likely therapeutic dose and facilitate the Phase 2b study dose selection. 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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1.3 
Benefit/risk and ethical assessment 
A detailed assessment of the overall benefit/risk of AZD8871 is discussed in the Investigator’s 
Brochure (IB). 
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 adverse effects (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. 
Among the 16 patients included in Part 1 of Study D6640C0001, 14 patients reported 
16 treatment emergent adverse events (TEAEs), all of them were mild to moderate in 
intensity. None of these TEAEs led to study discontinuation and all were resolved by the end 
of each period. Among the different TEAEs, 4 episodes of headache in the same patient and 
1 episode of dizziness were assessed by the investigator as related to AZD8871. The most 
frequently reported TEAEs were headache and nasopharyngitis. Only 2 potential 
anticholinergic events were reported in the Part 1 of the Study D6640C00001: pre-syncope 
was observed in one patient (placebo group) and dizziness was reported in 2 patients (one 
each, in the 200 μg and placebo groups).  No positive dose-response was observed with any 
specific TEAE during the exposure of AZD8871 in the part 1 of this study. No paradoxical 
bronchospasm or any TEAE with fatal outcome were reported in any of the doses level tested. 
No clinically relevant ECG abnormalities or laboratory abnormalities were observed in this 
first part of the trial.  
For Study D6640C00003, data from the first 2 cohorts of subjects have been generated: 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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x 
First dose level (300 μg) of study D6640C00003 tested in 8 healthy volunteers during 
12 days was well tolerated. There were 5 subjects that reported TEAEs (one moderate 
toothache, one moderate headache, and one mild headache in the 300 μg group; and in 
the placebo group, one subject experienced a mild bruise from venepuncture site on 
left arm and the other subject experienced mild dry cough, mild sore throat, and mild 
runny nose).  None of these TEAEs led to study discontinuation and all were resolved 
by the end of each period. Among the TEAEs, no serious adverse events (SAEs) and 
no severe AEs were reported by this cohort. No relevant laboratory or ECG 
abnormalities were reported by this cohort. 
x 
Second dose level (600 μg) of study D6640C00003 tested in 8 healthy volunteers 
during 12 days was well tolerated. Two subjects reported TEAEs. One subject in the 
600 μg group had a moderate headache; one subject in the placebo group had a mild 
upper back pain. None of these TEAEs led to study discontinuation and both events 
were resolved by the end of each period. Among the TEAEs, no SAEs and no severe 
AEs were reported by this cohort. No relevant laboratory or ECG abnormalities were 
reported by this cohort. 
To limit the risks for the patients enrolled in this study D6640C00004 and who will be 
required to stop their usual COPD therapy and to assess investigational product (IP) efficacy, 
patients will maintain their usual inhaled corticosteroid (ICS), if any.  They will also be 
provided with salbutamol to be used as rescue medication. In addition, those patients that were 
taking any LAMA, they will be maintained with ipratropium between Visit 1 and Visit 2.  All 
patients will receive ipratropium (following the approved dosage and regimen) during run-in 
and wash-out period to ensure stability of the patient.  
Considering the expected efficacy in patients with COPD and the available data to date, it is 
anticipated the benefits will outweigh the risks and support the continued investigation of 
AZD8871 in clinical studies. 
1.4 
Study design 
This is 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 and placebo, administered using a DPI device once 
daily, for 2 weeks, in patients with moderate to severe COPD. 
This multi-centre study will be conducted at 2 sites in Europe (Germany and United Kingdom 
[UK]).  It is planned that approximately 42 men and women of non-childbearing potential 
aged 40 to 80 years (both inclusive) with moderate to severe COPD will be randomised to the 
study.  A subset of 20 patients, who will have specifically consented, will also undergo PK 
assessments.  The entire study period is scheduled to take from a minimum of 4.5 months 
(140 days) to a maximum of 5.6 months (175 days) for each individual patient.  The study is 
anticipated to run for approximately 8 months and should not exceed 10 months. 


Clinical Study Protocol 
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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Patients will be provided with salbutamol as rescue medication to be used as needed 
throughout the study and with ipratropium to be used according to the approved dosage and 
regimen during the run-in and wash-out periods. 
The study will consist of a Screening period, 3 treatment periods (each separated by a 
wash-out period), and a Follow-up Visit.  
Screening period: This will last up to 28 days and consists of a Screening Visit (Visit 1), 
Visit 2, and a run-in period.   
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: 
x ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed 
x Reversibility test with salbutamol and spirometry (confirm inclusion criteria #6 and 
#7): These must be performed at Visit 2. 
Only patients who fulfil the reversibility criterion (improvement of FEV1 ≥12% and 200 mL 
after administration of salbutamol) and fulfil FEV1 predicted values (FEV1 ≥40% and <80% 
from predicted normal value and FEV1/forced vital capacity (FVC) ratio <70%) 
post-salbutamol at Visit 2, will be started on the run-in period to assess clinical stability. 
If the reversibility criteria or FEV1 predicted values are not met, the tests may be repeated at 
the latest, up to Day-14.  If any of these 2 criteria are not achieved at the repeat attempt, the 
patient will not be randomised. 
The duration of run-in period will be between a minimum of 14 and a maximum of 28 days. 
During the run-in period, all patients will receive ipratropium following the approved dosage 
and regimen (must be discontinued 8 hours before any pulmonary function test). 
During the randomised treatment period of the study, each patient 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.  Patient will receive one of the 3 following possible 
treatments in any given period, in a randomised manner: 
x 
AZD8871 100 μg once daily 
x 
AZD8871 600 μg once daily 
x 
Placebo 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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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 
28 up to 35 days, during which patients will receive ipratropium following the approved 
dosage and regimen (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 pre-best test review 
([BTR]; details on BTR are presented in Section 5.1.1). 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).  If the FEV1 stability criterion is not met, an additional 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, 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 28 up to 35 days after last 
administration of the IP. 
 


Clinical Study Protocol 
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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Figure 1 
Study flow chart 
 
d=day; FU=follow-up; V=visit. 
During periods 1 to 3 of the treatment period, each patient will randomly receive one of the 3 possible treatments (AZD8871 at the doses of 100 μg or 600 μg 
or placebo). 
 


Clinical Study Protocol 
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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measures: 
To evaluate the efficacy of inhaled AZD8871 
in patients with moderate to severe COPD 
Primary 
• Change from baseline in Trough FEV1 on Day 15 
Secondary 
• 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 8 to Day 15) 
• Change from baseline in Peak FEV1 over 
treatment duration (Day 8 to Day 14) 
• 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 after treatment, from Day 8 to Day 14 after 
treatment and during the whole treatment duration 
• Rescue medication use 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measures: 
To investigate the PK of AZD8871 and its 
metabolites 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 
metabolites LAS191861 and LAS34850 when 
applicable: 
Day 1: Cmax, tmax, area under the plasma 
concentration-curve (AUC)last, 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 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
31 (107) 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measures: 
To evaluate the safety and tolerability of 
inhaled AZD8871 in patients with moderate to 
severe COPD 
• AEs/SAEs 
• Vital signs 
• Electrocardiogram (ECG) 
• Clinical laboratory assessments 
 
2.4 
Exploratory objectives 
Exploratory Objective: 
Outcome Measures: 
To evaluate the taste of inhaled AZD8871 in 
patients with moderate to severe COPD 
• Taste assessment 
 
3. 
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
3.1 
Inclusion criteria 
For inclusion in the study patients should fulfil the following criteria: 
1. 
Patient who provided of informed consent prior to any study-specific procedures 
2. 
Male or female 40 to 80 years of age (both inclusive) at Screening (Visit 1).  A 
female is eligible to enter and participate in the study if she is of non-childbearing 
potential. 
Note: A female is considered to be of non-childbearing potential if she meets one of 
the following criteria: 
• 
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 


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Study Code D6640C00004 
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• 
Post-menopausal; aged ≥50 years and amenorrhoeic for 12 months or more, 
following cessation of all exogenous hormonal treatments 
3. 
Male patient should use a condom and spermicide 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. 
4. 
COPD Diagnosis: Patient with an established clinical history of COPD for more 
than 1 year at Screening, according to the GOLD 2016 COPD guidelines. 
5. 
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)xnumber 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. 
a. 
Patient smoking other tobacco types will not be allowed, unless he/she 
meets the cigarette criterion as well. 
6. 
Patient with post-bronchodilator FEV1/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. 
7. 
Patient with post-bronchodilator FEV1 that must be ≥40% and <80% predicted 
normal value at Visit 2.  If criterion is not met, the test can be repeated at the latest, 
up to Day -14. 
8. 
Patient who fulfils reversibility criteria to salbutamol at Visit 2.  Reversibility is 
defined as ≥12% and ≥200 mL increase in FEV1 after inhalation of 4 puffs of 
salbutamol (400 μg).  If the criterion is not met, the test can be repeated at the latest, 
up to Day -14. 
9. 
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 up Visit 11. 
10. 
Patient is free from any clinically active 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. 
11. 
Patient is willing to remain at the study centre as required per protocol to complete 
all visit assessments. 


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Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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12. 
Patient with body mass index (BMI) <40 kg/m2 at the time of Screening. 
3.2 
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Patient previously enrolled in the present study. 
2. 
Patient has significant diseases other than COPD, ie, disease or condition or an 
abnormality in laboratory, ECG, medical history or physical examination 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. 
3. 
Childbearing potential female, pregnant or lactating. 
4. 
Patient who, in the opinion of the Investigator, has a current diagnosis of asthma. 
5. 
Patient has alpha-1 antitrypsin deficiency as the cause of COPD. 
6. 
Patient has other active pulmonary disease such as active tuberculosis, lung cancer, 
bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary 
pulmonary hypertension, or uncontrolled sleep apnoea.  Allergic rhinitis is not 
exclusionary. 
7. 
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). 
8. 
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.  
9. 
Patient who had 2 or more exacerbations of COPD (moderate or severe in intensity) 
within the last year prior to Screening (see Section  3.9 for definition of 
exacerbation of COPD). 
10. 
Patient has been hospitalised due to poorly controlled COPD within 3 months of 
Screening. 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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11. 
Patient has acute worsening of COPD that requires treatment with corticosteroids or 
antibiotics in the 6 week interval prior to Screening (Visit 1), or during the 
Screening Period (between Visits 1 and 3). 
12. 
Patient has had lower respiratory tract infections that required antibiotics within 
6 weeks prior to Screening. 
13. 
Patient cannot perform acceptable spirometry, ie, meet American Thoracic Society 
(ATS)/European Respiratory Society (ERS) acceptability criteria. 
14. 
Patient has changed their smoking status (ie, start or stop smoking) or initiation of a 
smoking cessation program within 6 weeks of Screening. 
15. 
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. 
Cardiac disease: 
16. 
Patient with 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 meaning which has required changes in 
the pharmacological therapy or other intervention within 12 months prior to 
Screening Visit (Visit 1), or newly diagnosed arrhythmia within the previous 
3 months prior to Screening Visit (Visit 1). 
 
Second degree atrio-ventricular block. 
 
Patient with clinically significant conduction or ECG abnormalities. 
 
Coronary artery disease. 
 
Use of pacemaker. 
 
Hospitalisation within 12 months prior to Screening Visit (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”. 
17. 
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). 


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Study Code D6640C00004 
Version 3.0 
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18. 
Patient with heart rate <50 bpm. 
19. 
Patient has clinically significant uncontrolled hypertension as assessed by the 
Investigator. 
Neurological: 
20. 
Patient with seizures or history of seizures requiring anticonvulsants within 
12 months prior to Screening. 
21. 
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: 
22. 
Patient with symptomatic bladder neck obstruction, acute urinary retention or 
symptomatic non-stable prostate hypertrophy. 
23. 
Patient with a serum potassium value <3.5 mmol/L at Screening and on repeat 
testing.  Note: however potassium replacement and rescreening is allowed if serum 
potassium concentration was <3.5 mmol/L at Screening.  
Others: 
24. 
Any laboratory abnormality or suspicion of any clinically relevant disease or 
disorder (on history or examination), including uncontrolled diabetes, 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, or any other safety concerns in the opinion of the 
Investigator. 
25. 
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. 
26. 
Patient with known narrow-angle glaucoma. 
27. 
Patient has a history of hypersensitivity to β2-agonists, muscarinic anticholinergics 
or lactose/milk protein.  Lactose intolerance is not an exclusion criterion. 
28. 
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 prior to 
randomisation.  


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Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Note: However, 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. 
29. 
Patient who, in the opinion of the Investigator, would be unable to abstain from 
protocol-defined prohibited medications during the study. 
30. 
Patient who 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. 
31. 
Patient involved in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site). 
32. 
Patient treated with investigational drug or device in another clinical trial within the 
last 30 days or 5 half-lives (whichever is longer) prior to Screening. 
Note: Patient participation in observational studies (ie, studies that do not require 
change to medication or an additional intervention) is not exclusionary. 
33. 
Patient who donated or lost >500 mL of blood and plasma within the previous 
3 months prior to Screening. 
34. 
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. 
35. 
Patient with known human immunodeficiency virus (HIV) infection or chronic 
hepatitis B or C infection. 
36. 
Patient who has been placed in an institution due to a regulatory or court order. 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4. 
3.3 
Patient enrolment and randomisation 
Investigator(s) should keep a record, the patient screening log, of patients who entered 
pre-study screening. 
At Visit 3, approximately 42 patients will be randomly assigned to one of the 3 possible 
treatment sequences, according to a William’s design for crossover studies and using a 
balanced 1:1:1 randomisation ratio.  Thus, 7 patients will be assigned to each treatment 
sequence.  To ensure random allocation, each patient will be given the IP bearing the lowest 
available randomisation number at the site. 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Prior to initiating the study, a computer generated randomisation schedule will be prepared to 
assign a treatment sequence to a randomisation number by PAREXEL through AZRand 
according to the relevant Standard Operating Procedure (SOP).  The randomisation schedule 
will describe the link between the randomly assigned sequences of 3 treatments to each 
randomisation number.  The block size will be determined in agreement with the Clinical Trial 
Manager and the Statistician, and will not be communicated to the Investigators. 
The Investigator(s) will: 
1. 
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed. 
2. 
Assign a 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 electronic Case Report 
Form (eCRF). 
3. 
Determine patient eligibility.  See Section 3. 
4. 
For patients fulfilling the eligibility criteria at Visit 3, the Investigator will assign a 
unique randomisation number following chronological ascending order. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. 
Randomisation data will be kept strictly confidential, accessible only to authorised persons, 
until the time of unblinding of the allocated treatment of all study patients after locking the 
database upon termination of the study.  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. 
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation. 
3.4 
Procedures for handling incorrectly enrolled or randomised 
patients 
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive study medication.  There can be no exceptions to this rule.  Patients 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment, and must be withdrawn from the study. 
Where 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 


Clinical Study Protocol 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment.  The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented. 
3.5 
Methods for assigning treatment groups 
PAREXEL will be responsible for generating the randomisation scheme through AZRand. 
The choice of treatment sequences was determined according to William’s design and 
sequences are balanced.  Patients will be allocated to the 3 treatment groups in a 1:1:1 ratio. 
 
Treatment Period 1 Treatment Period 2 
Treatment Period 3 
Sequence A (n=7) 
AZD8871 100 μg 
AZD8871 600 μg 
Placebo 
Sequence B (n=7) 
AZD8871 100 μg 
Placebo 
AZD8871 600μg 
Sequence C (n=7) 
AZD8871 600 μg 
AZD8871 100 μg 
Placebo 
Sequence D (n=7) 
AZD8871 600 μg 
Placebo 
AZD8871 100μg 
Sequence E (n=7) 
Placebo 
AZD8871 100 μg 
AZD8871 600μg 
Sequence F (n=7) 
Placebo 
AZD8871 600 μg 
AZD8871 100μg 
 
The randomisation numbers will be grouped in blocks.  The block size will not be 
communicated to the Investigators. 
The randomisation list will only be provided to Almirall personnel responsible for study 
medication preparation and to Covance Bioanalytical group responsible for PK analyses. 
3.6 
Methods for ensuring blinding 
This study will be performed in a double-blind manner.  All IPs will be supplied in identical 
packaging to enable double-blind conditions. 
Placebo-containing DPI devices will be present with the same external appearance and the 
same composition as the AZD8871-containing devices, except for the active ingredient. 
Supplies of salbutamol and ipratropium will be open-label. 
3.7 
Methods for unblinding 
Individual treatment codes, indicating the treatment randomisation for each randomised 
patient, will be available to the Investigator(s) or pharmacists at the study site. 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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The treatment 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 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.  Treatment 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. 
3.8 
Restrictions 
Patients enrolled in the study should adhere to the following restrictions from 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 at the 
study centre during their entire stay at each treatment visit.  No food intake will be 
allowed between meals. 
2. 
On Day 1, Day 8, and Day 14, 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 dose administration on Days 1 and 14, but only up to 
1 hour on Day 8.  Meals should not include any xanthine-containing compounds (ie, 
caffeine) or grapefruit-containing foods or beverages.  During the 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’ residency at the study centre, standardised meals will be served according 
to the study centre’s standard practice. 
4. 
Exposure to dust or polluted air should be avoided for at least 1 hour before each 
visit until completion of all study procedures. 
5. 
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. 
6. 
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. 
7. 
Patients must abstain from any of the following: 


Clinical Study Protocol 
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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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 
Alcohol from 72 hours before each visit to the study centre and during 
residency 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 residency at the study centre.  Decaffeinated drinks will be 
acceptable to be consumed during the study. 
 
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, Seville oranges (also called bitter orange, 
including marmalade) consumption from 48 hours prior to administration of the 
IP at Visit 3 and until the final Follow-up Visit at the end of the study. 
 
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. 
 
Strenuous physical activity, which is not within the patient’s normal daily 
routine, as from 72 hours before the Screening Visit until the Follow-up Visit at 
the end of the study. 
 
Blood or plasma donation 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 7.7. 
3.9 
Discontinuation of investigational product 
Patients may be discontinued from IP at any time but once dosing has occurred every attempt 
should be made to continue assessments to ensure the safety of the patient.  Specific reasons 
for withdrawing a patient will be: 
x 
Patient withdrawal:  The patient is free to discontinue treatment at any time, without 
prejudice to further treatment.  A patient who decides to discontinue the IP will always 
be asked about the reason(s) and the presence of any AEs.  If possible, they will be 


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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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seen and assessed by an Investigator(s).  Adverse events will be followed up (See 
Section 6.3) and all study drugs should be returned by the patient. 
x 
AE: If a patient experiences an AE, their premature discontinuation will be considered 
at the discretion of either the Investigator or the patient regardless of the causal 
relationship to the IP.  AE should be indicated as the reason for discontinuation. 
x 
Protocol deviation: After randomisation, any protocol deviations detected should be 
corrected when possible and the patient should be allowed to continue.  The following 
will lead to discontinuation of treatment: protocol deviations that could affect patient’s 
safety (eg, illness requiring treatment(s) which in the clinical judgement of the 
Investigator [or after discussion with the trial monitor] might invalidate the trial by 
interfering with the IP); deviations due to patient non-compliance with the study 
protocol. 
x 
Failure to meet randomisation criteria: Violations of inclusion and/or exclusion criteria 
detected after randomisation.  See Section 3.4 for patients not fulfilling 
inclusion/exclusion criteria but detected after randomisation. 
x 
Lost to follow-up: Non-attendance.  In these cases, every effort should be made by the 
Investigator to ascertain the reason and to assure patient’s attendance as soon as 
possible.  Every effort (at least 3 documented attempts) should be made to contact the 
patient and documented in the medical records.  If patient could not be reached after 
that, a registered mail letter will be sent to the patient and documented in the medical 
records. 
x 
Pregnancy: In case of pregnancy the female patient will be immediately discontinued 
from the study. 
x 
Clinical/FEV1 stability criteria not fulfilled during the treatment periods. 
x 
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. 
(a) 
Vital signs 
 
Systolic blood pressure (SBP) increase of >40 mmHg from baseline (ie, before 
first dose of study drug) and SBP >180 mmHg at any time within the 12-hour 
interval after taking study drug. 


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(b) 
Laboratory findings (any time after randomisation; test must be repeated to 
confirm that withdrawal criterion has been met) 
x 
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.  
x 
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. 
x 
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 the study. 
(c) 
ECG (within 4 hours of post-IP dosing):  
 
Symptomatic bradycardia defined as heart rate <45 beats per minute (bpm) or 
asymptomatic bradycardia defined as resting supine pulse <30 bpm while 
awake, persisting for at least 10 minutes. 
 
Heart rate of >120 bpm and an increase of >40 bpm during the first 4 hours 
post-dose, persisting for at least 10 minutes. 
 
QTcF interval prolongation exceeding >500 ms during the treatment period or 
>60 ms change from baseline (within 4 hours post-dose), persisting for at least 
5 minutes. 
(d) 
Lung function 
x 
FEV1 decrease by>20% from baseline (ie, before first dose of study drug) on 
2 consecutive spirometry assessments obtained at least 15 minutes apart with 
associated symptoms of dyspnoea at any time within the first 2-hour interval 
after taking study drug. 


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(e) 
COPD worsening 
x 
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 color 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 hospitalization or death. 
 
Moderate: Exacerbations that require treatment with systemic steroids and/or 
antibiotics, and do not result in hospitalization or death. 
 
Severe: Exacerbations that result in hospitalization or death. 
x 
Other: Study cancellation or any other reason not described above. 
x 
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. 
3.9.1 
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A patient that decides 
to discontinue IP will always be asked about the reason(s) and the presence of any AE.  If 
possible, they will be seen and assessed by an Investigator(s).  Adverse events will be 
followed up (See Section 6); e-Diary, paper diary and all study drugs should be returned by 
the patient. 
If a patient is withdrawn from study, see Section 3.10. 
3.10 
Criteria for withdrawal 
3.10.1 
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Screen Failure’ (ie, patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not randomised 
patients). 


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3.10.2 
Withdrawal of the informed consent 
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigator will follow-up AEs outside of the clinical study.  The patient will 
return the e-Diary and paper diary. 
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Withdrawn patients will not be replaced. 
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the eCRF.  All reasons for withdrawal of 
consent must be documented. 
3.11 
Discontinuation of the study 
The study will be stopped if: 
x 
The PI/Co-ordinating Investigator and the Sponsor assessed that the type; number 
and/or severity of AEs justify discontinuation of the trial 
x 
In the judgement of AstraZeneca, trial patients are placed at undue risk because of 
clinically significant findings that: 
 
Are assessed as causally related to study drug 
 
Are not considered to be consistent with continuation of the study 
x New safety information emerges, which raise concern about the safety of the study drug 
and continuation would pose potential risk to the patient. 
x The Sponsor decides to discontinue the study: For instance, if there is at least one case of 
fatal SAE considered related to AZD8871 or at least 2 cases of SAEs considered related to 
AZD8871. 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
The Study Plan detailing the procedures at Screening, during the treatment period and during 
follow-up is presented in Table 1. 


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Table 1 
Study Plan detailing the procedures 
 
Screening period 
Treatment periods (Period 1-Period 3) 
 
 
Visit 
1a 
2a 
3, 6, 9b, d 
4, 7, 10c 
5, 8, 11b, d 
Follow-
up/early 
termination 
Visit 
For details 
see Protocol 
Section 
Treatment Day 
-28 to -14 
-28 to -14 
1 
Overnight 
stay 
8 
14 
Overnight 
stay 
After 28 up 
to 35 days of 
Visit 11 (or 
last IP 
admin) 
 
Signed Informed Consent 
X 
 
 
 
 
 
10.4 
Inclusion/exclusion criteria 
X 
X 
X (Visit 3) 
 
 
 
3.1 and 3.2 
Demography 
X 
 
 
 
 
 
4.1.1 
Smoking history 
X 
 
 
 
 
 
4.1.1 
Medical/surgical history 
X 
 
 
 
 
 
4.1.1 
Concomitant medications 
X 
X 
X 
X 
X 
X 
7.7 
Height/weighte 
X 
 
 
 
 
X 
4.1.1 
Physical examinationf 
X 
 
X 
 
X 
X 
5.2.2 
Vital signs (BP)g 
X 
 
X 
X 
X 
X 
5.2.4 
Inhaler trainingh 
 
 
X 
 
 
 
4.2.1 
Safety laboratory testsi 
X 
 
X 
 
X 
X 
5.2.1 
Drugs of abuse and alcohol 
Screenj 
X 
 
Xk (Visit 3) 
 
 
 
 
Urine pregnancy test in 
women 
X 
 
 
 
 
 
4.1.1 


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Date 16 December 2016 
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Table 1 
Study Plan detailing the procedures 
 
Screening period 
Treatment periods (Period 1-Period 3) 
 
 
Visit 
1a 
2a 
3, 6, 9b, d 
4, 7, 10c 
5, 8, 11b, d 
Follow-
up/early 
termination 
Visit 
For details 
see Protocol 
Section 
Treatment Day 
-28 to -14 
-28 to -14 
1 
Overnight 
stay 
8 
14 
Overnight 
stay 
After 28 up 
to 35 days of 
Visit 11 (or 
last IP 
admin) 
 
i-STAT measurementl 
 
 
X 
 
X 
 
5.2.1 
Clinical stability check 
 
X 
X 
 
 
 
5.1.3 
FEV1 stability check 
 
 
Xm 
 
 
 
 
Spirometryn 
 
X 
X 
X 
X 
 
5.1.1 
Reversibility testingo 
 
X 
 
 
 
 
5.1.2 
12-lead ECGp 
X 
 
X 
X 
X 
X 
5.2.3 
Ipratropium dispensationq 
X 
X 
 
 
X 
 
7.2 
Salbutamol dispensation 
X 
X 
X 
X 
X 
 
4.1.1 
Randomisation 
 
 
X (Visit 3) 
 
 
 
4.2.1 
IP administration and IP 
kit dispensationr 
 
 
X 
X 
X 
 
7.2 
AEs 
X 
X 
X 
X 
X 
X 
6 
BCSS questionnaire 
 
X 
X 
X 
X 
 
5.1.4 
Taste questionnaire  
 
 
 
 
X 
 
4.2.3 
Dispense/Check 
 
X 
X 
X 
X 
 
4 


Clinical Study Protocol 
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Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
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Table 1 
Study Plan detailing the procedures 
 
Screening period 
Treatment periods (Period 1-Period 3) 
 
 
Visit 
1a 
2a 
3, 6, 9b, d 
4, 7, 10c 
5, 8, 11b, d 
Follow-
up/early 
termination 
Visit 
For details 
see Protocol 
Section 
Treatment Day 
-28 to -14 
-28 to -14 
1 
Overnight 
stay 
8 
14 
Overnight 
stay 
After 28 up 
to 35 days of 
Visit 11 (or 
last IP 
admin) 
 
e-Diary/paper diarys 
PK blood collectiont 
 
 
X 
X 
X 
 
5.4 
AE=Adverse event; aPTT=Activated partial thromboplastin time; BCSS=Breathlessness, Cough, Sputum Scale; BP=Blood pressure; 
ECG=Electrocardiogram, FEV1=Forced expiratory volume in 1 second; INR=International normalised ratio; IP=Investigational Product; 
PK=Pharmacokinetics; PTT=Partial thromboplastin time. 
 
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) 
ICF: This must be completed at Visit 1 before any study-specific assessments are performed.  
(ii) 
Reversibility test with salbutamol and spirometry (confirm inclusion criteria #6 and #7): These 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 28 up to 35 days (from the last IP use).  
e. 
Height will be measured at Visit 1; weight will be measured at Visit 1 and at Follow-up Visit. 
f. 
Physical examination will be complete examination at Visit 1 and at Follow-up Visit.  Brief physical examination will be performed at rest of visits 
during the study (Visits 3, 5, 6, 8, 9 and 11). 
g. 
Vital signs: Blood pressure will be assessed pre-dose and 1, 2, 4, and 24 hours 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 Follow-up Visits. Heart rate will be assessed 
by ECG. 


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h. 
Inhaler training will be done before starting IP treatment on Day 1 at each treatment period. 
i. 
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, coagulation parameters (INR, PTT and 
aPTT) will be assessed at Visit 1 and at Follow-up Visit. 
j. 
Alcohol screen could be performed using a urine sample or a breath test. 
k. 
Drugs of abuse and alcohol screen will be performed at Visit 3 prior to randomisation. 
l. 
i-STAT for glucose and potassium measurements will be done pre-dose and then 1, 2, 4 and 24 hours post-dose on Visits 3, 5, 6, 8, 9 and 11.  i-STAT 
will be done after 4 hours of fasting. 
m. 
FEV1 stability will be performed at Visits 6 and 9 based on the pre-BTR. 
n. 
Spirometry measurements will be done at -1 h and -15 min pre-dose and then 15 min, 30 min, 1, 2, 4, 8, 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. 
o. 
Reversibility test includes a pre-salbutamol spirometry and then at 20-30 minutes post-salbutamol.  If reversibility criterion is not fulfilled, a second 
spirometry can be performed up to 60 minutes post-salbutamol administration. 
p. 
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 
measurements will be done at 1 and 4 hours post-dose.  ECG should be performed before spirometry. 
q. 
All patients will receive ipratropium (following the approved dosage and regimen) during the run-in and wash-out periods.  In addition, those patients 
that were taking any LAMA, they 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). 
r. 
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 doses will be taken at home. 
s. 
E-Diary will be used to collect daily BCSS questionnaire and daily use of rescue medication (salbutamol) during the run-in and 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. 
t. 
PK blood samples will be collected from patients who will have specifically consented to the PK assessments at pre-dose and at 30 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. 
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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4.1 
Enrolment/Screening period 
This period will start with the signature of the ICF at the Screening Visit (Visit 1), and will 
end at pre-dose on Visit 3, Day 1 (randomisation).  No study-specific procedures will be 
performed prior to signing ICF.  All the screening assessments can be performed at Visit 1 
or Visit 2, based on the site's preference, except for the following: 
x 
ICF: This must be completed at Visit 1 before any study-specific assessments are 
performed.  
x 
Reversibility test with salbutamol and spirometry (confirm inclusion criteria #6 and 
#7): These 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. 
4.1.1 
Visit 1 – Screening 
Screening procedures will be performed according to the Study Plan (Table 1).  Any test can 
be repeated once within 28 days to re-confirm eligibility. 
At Screening, to verify the eligibility of patients, the following evaluation will be performed: 
1. 
Obtain informed consent. 
2. 
Assess inclusion/exclusion criteria. 
3. 
Review medical/surgical history, demographics (age, sex, race, and BMI), and 
smoking information (date of smoking initiation, former smoker, date of smoking 
cessation, and total pack-years). 
4. 
Assess prior and current COPD medications and switch to ICS mono-component if 
applicable; if patient currently taking LAMA, provide them with ipratropium. Other 
current COPD therapy (other than usual ICS and use of ipratropium as specified in 
this protocol) should be stopped at this visit.  Record all current medication usage 
and any medications taken during the previous 15 days.  
5. 
Perform the 12-lead ECG. The ECG readings will be assessed by the Investigator. 
6. 
Collect vital signs (including temperature) and perform complete physical 
examination, including body weight (in light indoor clothes, without shoes), and 
height. 
7. 
Safety laboratory, urine pregnancy, and serology tests. 
8. 
Test for drugs of abuse and alcohol screen 


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9. 
Dispense rescue medication (salbutamol) to all patients and ipratropium if 
applicable. 
4.1.2 
Visit 2 – Reversibility testing 
1. 
Review inclusion/exclusion criteria 
2. 
Assess the use of concomitant and rescue medications since previous visit.  Confirm 
daily use of ICS mono-component, and ipratropium, if applicable  
3. 
Assess AEs 
4. 
Perform reversibility test and confirm clinical stability 
5. 
Confirm inclusion criteria #6 and #7 with post-bronchodilator spirometry 
6. 
Dispense the e-Diary and paper diary and instruct the patient how to use them.  
7. 
Instruct the patient to record their use of rescue medication (salbutamol) and to 
complete the BCSS questionnaire on e-Diary every evening. 
8. 
Instruct the patient to record AEs and concomitant medication during run-in and 
wash-out periods on the paper diary. 
9. 
Dispense rescue medication (salbutamol) and ipratropium to all patients 
If the reversibility criterion is not fulfilled or if inclusion criteria #6 and #7 are not confirmed, 
one repetition of pulmonary function tests, at the latest, up to Day -14 is allowed. 
4.2 
Treatment period 
4.2.1 
Visit 3 - Randomisation and Visits 6 and 9 (Treatment Day 1) 
These visits will include an overnight stay at the study centre, and should last approximately 
25 hours. 
Visits 6 and 9 should occur after a wash-out period of 28 up to 35 days after last 
administration of IP. 
Pre-dose assessments: 
1. 
Test for drugs of abuse and alcohol screen prior to randomisation 
2. 
Review inclusion/exclusion criteria (only at Visit 3, prior to randomisation) 
3. 
Confirm clinical stability 
4. 
At visit 3 only, randomise the patient if their eligibility is confirmed (assign the 
lowest available randomisation number) 


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5. 
Train the patient on the use of the DPI 
6. 
Confirm the patient has not taken rescue medication (salbutamol) during the past 
6 hours and ipratropium during the past 8 hours prior to pre-dose spirometry 
7. 
Assess the use of concomitant medications since previous visit 
8. 
Assess AEs since previous visit 
9. 
Review completion of the e-Diary for BCSS questionnaire and rescue medication 
intake 
10. 
Perform the 12-lead ECG 
11. 
Collect vital signs (blood pressure) and perform brief physical examination 
12. 
Collect blood for safety laboratory tests 
13. 
Measure glucose and potassium (i-STAT) 
14. 
Obtain pre-dose PK sample in the subset of 20 patients who specifically consented 
to this 
15. 
Perform pre-dose spirometry at 60 min and 15 min prior to IP administration 
(reference value for subsequent visits for the stability criterion) 
Administration of IP: 
Patients will take the IP at the study site at 9:00 AM±2 hours. 
Post-dose assessments: 
The following assessments should be conducted: 
1. 
Check vital signs (blood pressure) at 1, 2, 4, and 24 hours postdose 
2. 
Perform brief physical examination at 24 hours post-dose 
3. 
Perform the 12-lead ECG at 1, 2, 4, and 24 hours post-dose 
4. 
Perform spirometry at 15 and 30 min, and at 1, 2, 4, 8, 23 and 23:45 hours post-dose 
5. 
Measure glucose and potassium (i-STAT) at 1, 2, 4 and 24 hours post-dose 
6. 
Obtain PK samples at 30 min and 1, 2, 4, 6, 8, 12, and 24 hours post-dose in the 
subset of 20 patients who specifically consented to this 


Clinical Study Protocol 
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7. 
Dispense the IP kit for Treatment Days 1 to 7 for the corresponding period (IP will 
be taken on site on Day 1 and Day 2) 
8. 
Check and instruct the patient to record on e-Diary daily IP intake, rescue 
medication (salbutamol), and BCSS questionnaire every evening. 
9. 
Dispense rescue medication (salbutamol) if needed 
4.2.2 
Visits 4, 7 and 10 (Treatment Day 8) 
These visits will be ambulatory and should last approximately 5 hours.  Patients should take 
the IP at the study site within±1 hour of dosing time of Day 1 and between 7 am and 11 am.  
The following assessments should be conducted: 
1. 
Review completion of the e-Diary for IP compliance, BCSS questionnaire and 
rescue medication (salbutamol) intake 
2. 
Assess AEs since previous visit 
3. 
Assess the use of concomitant medications since previous visit 
4. 
Perform the 12-lead ECG at 1 and 4 hours post-dose 
5. 
Check vital signs (blood pressure) pre-dose and at 1 and 4 hours post-dose 
6. 
Obtain PK samples pre-dose and 1 hours post-dose in the subset of 20 patients who 
specifically consented to this 
7. 
Perform spirometry at -60 min and -15 min pre-dose and at 15 and 30 min, and at 1, 
2, and 4 hours post-dose 
8. 
Dispense the IP kit for Treatment Days 8 to 14 for the corresponding treatment 
period (IP will be taken on site on Day 8 and Day 14) 
9. 
Dispense rescue medication (salbutamol) if needed 
All attempts should be made to ensure that the patient visits the site on the scheduled date.  In 
case of any unexpected change to the schedule, -1 day (minus one day) window may be 
allowed after consultation with the Sponsor for these visits.  
4.2.3 
Visit 5, 8 and 11 (Treatment Day 14) 
These visits will include an overnight stay at the study centre, and should last approximately 
25 hours.  The following assessments should be conducted: 


Clinical Study Protocol 
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Pre-dose assessments: 
1. 
Instruct the patient on how to complete the taste questionnaire and ask him/her to 
complete this at Visits 5, 8 and 11. All questions must be completed within 15 
minutes after IP intake, except the question on the last page. The last page of the 
questionnaire must be completed by the patient within 2 hours after IP intake. 
2. 
Review completion of the e-Diary for IP compliance, BCSS questionnaire and 
rescue medication (salbutamol) intake 
3. 
Assess AEs since previous visit 
4. 
Assess the use of concomitant medications since previous visit 
5. 
Confirm the patient has not taken rescue medication during the past 6 hours to 
pre-dose spirometry  
6. 
Perform the 12-lead ECG. 
7. 
Collect vital signs (blood pressure) and perform brief physical examination 
8. 
Measure glucose and potassium (i-STAT) 
9. 
Obtain pre-dose PK sample in the subset of 20 patients who specifically consented 
to this 
10. 
Perform pre-dose spirometry at 60 min and 15 min prior to IP administration 
Administration of IP: Patients will take the IP at the study site at 9:00 AM ±2 hours.  
Post-dose assessments 
The following assessments should be conducted: 
1. 
Check vital signs (blood pressure) at 1, 2, 4, and 24 hours post-dose 
2. 
Perform brief physical examination at 24 hours post-dose 
3. 
Perform safety laboratory tests at 24 hours post-dose 
4. 
Perform the 12-lead ECG at 1, 2, 4, and 24 hours post-dose 
5. 
Perform spirometry at 15 and 30 min, and at 1, 2, 4, 8, 23 and 23:45 hours post-dose 
6. 
Measure glucose and potassium (i-STAT) at 1, 2, 4 and 24 hours post-dose 
7. 
Obtain PK samples at 30 min and 1, 2, 4, 6, 8, 12, and 24 hours post-dose in the 
subset of 20 patients who specifically consented to this 


Clinical Study Protocol 
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Study Code D6640C00004 
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Date 16 December 2016 
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8. 
Check e-Diary for recording of IP intake, rescue medication, and BCSS 
questionnaire to be completed every evening 
9. 
Taste questionnaire must be completed by the patient within 15 minutes after IP 
intake (all questions except the question on the last page). The last page of the 
questionnaire must be completed by the patient within 2 hours after IP intake. 
10. 
Dispense rescue medication (salbutamol) and ipratropium (except at Visit 11). 
All attempts should be made to ensure that the patient visits the site on the scheduled date for 
these visits.  In case of any unexpected change to the schedule, -1 day (minus one day) 
window may be allowed after consultation with the Sponsor for Visits 5, 8 and 11. 
4.3 
Follow-up Visit (Visit 12) 
The Follow-up Visit should occur 28 up to 35 days after the last visit of the treatment period.  
The following assessments should be conducted: 
1. 
Perform the safety laboratory tests 
2. 
Perform the 12-lead ECG 
3. 
Collect vital signs (including temperature) and perform complete physical 
examination, including body weight (in light indoor clothes, without shoes) 
4. 
Assess the use of concomitant medications since previous visit 
5. 
Assess AEs 
4.4 
Premature discontinuation visit 
This visit should occur as soon as possible and no later than 35 days after the last 
administration of the IP.  The following assessments should be conducted: 
1. 
Perform the safety laboratory tests 
2. 
Perform the 12-lead ECG 
3. 
Collect vital signs (including temperature) and perform complete physical 
examination, including body weight (in light indoor clothes, without shoes) 
4. 
Assess the use of concomitant and rescue medications since previous visit 
5. 
Assess AEs 


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5. 
STUDY ASSESSMENTS 
An Electronic Data Capture (EDC) system will be used for data collection and query handling.  
The Investigator will ensure that data are recorded on the eCRFs as specified in the study 
protocol and in accordance with the instructions provided. 
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA).  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site. 
5.1 
Efficacy assessments 
Efficacy measurements will be made at the time indicated in the Study Plan (Table 1). 
5.1.1 
Pulmonary function test (spirometry) 
A centralised spirometry company (ERT) will provide the spirometers and all necessary 
equipment (computer, calibration syringe, printer, paper, ink, etc.), a detailed study manual 
and training to the technicians and PI (as needed) in charge of conducting the spirometry for 
this clinical study.  Spirometer will measure: 
x 
FVC (maximal volume of air exhaled with maximally forced expiratory effort from a 
position of maximal inspiration).  
x 
FEV1 (volume of air expressed in litres exhaled during the first second of performance 
of the FVC). 
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 ATS and ERS guidelines should be followed to provide accurate and comparable 
spirometric data. Spirometer will be configured to meet ATS/ERS recommendations for 
accuracy and precision (Miller et al, 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 some deviations from 
some ATS/ERS requirements. However, the technician must ensure that tests are performed 
with the correct technique, manually deselecting efforts which do not meet minimum 
standards. The technician must use their judgement 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-steps quality control: 


Clinical Study Protocol 
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x 
“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. 
x 
“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 then, allow 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 minutes prior to the test and comfortable; tight 
clothing should be loosened to allow the thorax to move freely. Each manoeuvre comprises 
1 “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 1 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. 
5.1.2 
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.  If the reversibility criterion is not fulfilled, spirometry can be repeated up to 
60 min post-salbutamol administration. 
The reversibility test will be considered positive if patients show improvement of FEV1 ≥12% 
and 200 mL after administration of salbutamol. 


Clinical Study Protocol 
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If the reversibility criteria are not fulfilled, the pulmonary function test can be repeated once, 
at the latest, up to Day -14. 
5.1.3 
FEV1 and clinical stability check 
FEV1 stability check will be performed at Visits 6 and 9 (Day 1 of treatment periods 2 and 3).  
It is not an outcome measure.  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 
measurement could be taken within 30 min of the second pre-dose measurement, and the 
mean of the last 2 measurement 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, 
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: 
x 
No relevant respiratory signs/symptoms that modify the patient’s baseline daily 
activities 
x 
Not meeting criteria of COPD exacerbation (as per Investigator’s clinical judgement) 
x 
No SAEs 
x 
No relevant AEs that potentially modify the absorption, distribution, metabolism, and 
excretion of IP 
5.1.4 
Breathlessness, cough, and sputum scale 
The BCSS (Leidy et al, 2003) questionnaire is a 3-item, patient-reported outcome (PRO) 
measure.  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. 
5.1.5 
Rescue medication use 
Patients will be provided with salbutamol, to be used as needed, as a rescue medication.  
Patients will be provided with an e-Diary to collect their daily use of rescue medication during 
the run-in and treatment periods. 
Salbutamol should be held at least 6 hours before any pulmonary function tests. 


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5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in the Study Plan (see Section 4).  The results of tests 
performed at Visit 1 will be regarded as baseline data. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
The clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to the Investigator site.  Sample tubes and sample sizes may vary depending on 
laboratory method used and routine practice at the site. 
The following laboratory variables will be measured: 


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Table 2 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
B-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 
Coagulation parameters (INR, PTT and aPTT)a 
S/P-Calcium, total 
 
S/P-Chloride 
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 
 
U-Ketones 
 
U-Nitrites 
 
ALP=Alkaline phosphatase; ALT=Alanine transaminase; aPTT=Activated 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; PTT=Partial 
thromboplastin time. 
a. Coagulation parameters will be assessed at Screening and Follow-up Visits only.  
 
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 6.3. 


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NB.  In case a patient shows an AST or ALT ≥3×ULN or TBL ≥2×ULN please refer to 
Appendix C, for further instructions. 
As per AstraZeneca standards, during the course of the study the Investigator will remain 
vigilant for increases in liver biochemistry.  The Investigator is responsible for determining 
whether a patient meets potential Hy’s Law (PHL) criteria at any point during the study.  Hy’s 
Law guidance for the Investigator is included in Section 6.3.7 and Appendix C. 
The following laboratory tests will be performed only at the Screening Visit to check the 
eligibility of the patient for participation in the study: 
x 
Serology tests: 
 
HIV I and II antibodies, 
 
Hepatitis B surface antigen 
 
Hepatitis B core (HBc) immunoglobulin antibodies (IgM) 
 
Hepatitis C antibodies  
x 
Urine pregnancy test in women 
x 
Women aged less than 50 years (see inclusion criterion #2): Serum/plasma FSH and 
LH 
Drugs of abuse and alcohol screen will be performed at Screening and Visit 3 (prior to 
randomisation) at the site. Alcohol screen could be performed using a urine sample or a breath 
test. 
Table 3 
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 
Cotinine 
a 
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. 
 


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5.2.2 
Physical examination 
A complete physical examination will be performed at Screening (Visit 1) and at Follow-up 
Visit and will include an assessment of the following: general appearance, eye, ears, nose, 
throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, 
musculoskeletal/extremities, dermatological/skin, thyroid/neck, lymph nodes, 
neurological/psychiatric and throat. 
Brief physical examination will be performed at other visits including 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 Visit 1 (Screening) for calculation of BMI.  
Patients should be in light indoor clothes without shoes. 
5.2.3 
Electrocardiogram 
Standard 12-lead ECG evaluations will be recorded after approximately 5 minutes resting in 
supine position before any blood sampling and spirometry test. 12-lead ECGs will be recorded 
preferably always by the same technician for each patient. 
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 according to the 
recommendations of the supplier. 
Electrocardiogram will be performed at the times presented in the Study Plan (Table 1). 
Individual ECG analysis will be performed 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).  At least 
3 complete evaluable complexes per lead will be recorded.  The following ECG parameters 
will be determined: 
x 
Heart rate 
x 
RR interval: Duration in milliseconds between 2 R peaks of 2 consecutive 
x 
QRS complexes 
x 
PR interval: Duration in milliseconds from the beginning of wave P to onset of 
ventricular depolarisation (Q and R) 


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x 
QRS interval: Duration in milliseconds of the QRS complex 
x 
QT interval: Duration in milliseconds from the beginning of Q wave to the end of the 
T wave 
x 
QTc interval: QT interval corrected by heart rate: 
 
QTcB interval: QT interval corrected using Bazett formula 
(QT[msec]/RR[sec]1/2) 
 
QTcF interval: QT interval corrected using Fridericia’s formula 
(QT[msec]/RR[sec]1/3) 
At Visit 1, 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 of Visit 1. 
Any abnormal finding in the ECG tracing (rhythm, ectopy, conduction, morphology, 
myocardial infarction, ST segment, T wave and U wave observations) will be evaluated by the 
Investigator and will be specifically documented 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 6.3. 
In case of technical problems, the Investigator considers any result is clinically relevant or 
doubtful, additional 12-lead ECGs may be performed, using the same equipment, within a 
reasonable time. 
5.2.4 
Vital signs 
For information on how AEs based on vital signs should be recorded and reported, see Section 
6.3. 
5.2.4.1 
Heart rate and blood pressure 
Heart rate will be assessed by ECG (Section 5.2.3). Systolic and diastolic blood pressure (SBP 
and DBP) (in mmHg) will be measured after at least 5 minutes resting, and also, before taking 
any blood sample and conducting any spirometry.  Measurements will be carried out with 
patient in the supine position and preferably always on the same arm.  Data will be recorded 
on the eCRF. 
If there is any suspicion of unreliable measurement, blood pressure will be measured again.  
The value obtained on the second measurement will be considered as definitive and will be the 
one recorded on the eCRF. 


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Throughout the study, clinically relevant new findings or worsening of a pre-existing finding 
in the medical history/physical examination/blood pressure must be considered an AE and 
must be recorded on the AE form of the eCRF. 
5.2.4.2 
Body temperature 
Patient’s body temperature will be measured at Visit 1 (Screening) and Follow-up Visit 
(Visit 12). 
5.2.5 
Adverse events 
Procedures for recording and assessing AEs are included in Section 6.3. 
5.2.6 
Unscheduled tests 
As deemed necessary by the Investigator, additional safety test(s) can be performed at any 
time during the study in order to follow-up the progress of any clinically relevant abnormal 
finding, or to investigate any potential new AE.  These additional tests out of the initial 
schedule of the study will be called “unscheduled tests” and will not be associated with any 
study visit. 
5.2.7 
Repeated tests 
Any safety test may be repeated at the Investigator’s discretion when there is any kind of 
problem with the first test (ie, technical problem with the ECG machine, blood sample 
haemolysed, presence of artefacts, etc.).  The Investigator should repeat the individual test as 
soon as possible, prior to the next visit. 
At Visits 3, 6 and 9 (Day 1), the pre-dose assessments can be rescheduled (and therefore 
repeated on another date) for technical reasons, if FEV1 stability criterion is not met or if 
rescue medication is taken before the IP administration.  Also, any laboratory test(s) meeting a 
withdrawal criterion should be repeated as soon as possible, prior to withdrawing the patient. 
The repeated tests will be called “re-test” and will be identified with the same visit identifier 
as the first attempt. 
5.3 
Other assessments 
Taste assessment after intake of IP: The patient will record responses to taste questionnaire 
(Appendix E) on a paper questionnaire within 15 minutes of IP intake (all questions, except 
the question on the last page). The last page of the questionnaire must be completed by the 
patient within 2 hours after IP intake. This questionnaire will be completed only on Day 14 of 
each treatment period (ie, Visits 5, 8 and 11) and will be transcribed in the eCRF.  
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
Blood samples for determination of AZD8871 and its primary metabolites LAS191861 and 
LAS34850 in plasma will be taken at the times presented in the Study Plan (Table 1).  Blood 


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draw volume will be of 4 mL at all time points, for a total of 240 mL.  A total of 20 patients 
will participate in the PK sampling. 
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual. 
5.4.2 
Determination of drug concentration 
Samples for determination of AZD8871 and its metabolites, LAS191861 and LAS34850 
concentrations in plasma will be analysed by Covance on behalf of AstraZeneca, using 2 
different, validated bioanalytical methods, one for AZD8871 and LAS191861, and another for 
LAS34850 quantification.  Full details of the analytical method used will be described in a 
separate Bioanalytical Report. 
Results will be only reported for samples shipped within a timeframe for which the stability of 
AZD8871 and its metabolites, LAS191861 and LAS34850, in the samples has been validated 
and shown to be acceptable. 
Placebo samples will not be analysed unless specified. 
5.4.3 
Storage and destruction of pharmacokinetic samples 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization 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 PK samples to further 
evaluate and validate the analytical method.  Any results from such analyses may be reported 
separately from the clinical study report (CSR). 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report. 
5.5 
Pharmacodynamics 
Pharmacodynamic samples will not be taken during the study. 
5.6 
Pharmacogenetics 
Pharmacogenetic samples will not be taken during the study. 
5.7 
Biomarker analysis 
There will be no biomarker analysis in the study. 


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


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For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 
6.3 
Recording of adverse events 
6.3.1 
Time period for collection of adverse events 
Adverse events will be collected from the time of signature of informed consent throughout 
the treatment period and including the follow-up period (28-35 days after last dose of IP). 
6.3.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the patient’s last AE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the eCRF.  AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary. 
6.3.3 
Variables 
The following variables will be collected for each AE: 
x 
AE (verbatim) 
x 
The date and time when the AE started and stopped 
x 
Intensity 
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the IP (yes or no) 
x 
Action taken with regard to IP 
x 
AE caused patient’s withdrawal from study (yes or no) 
x 
Outcome 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for SAE 
x 
Date Investigator became aware of SAE 
x 
AE is serious due to 
x 
Date of hospitalisation 
x 
Date of discharge 


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x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 
x 
Causality assessment in relation to Study procedure(s) 
x 
Causality assessment in relation to other medication 
x 
Description of AE 
For grading the intensity of an AE, the following intensity rating scale will be used: 
1. Mild: awareness of sign or symptom, but easily tolerated (acceptable) 
2. Moderate: discomfort sufficient to cause interference with normal activities 
(disturbing) 
3. Severe: incapacitating, with inability to perform normal activities (unacceptable) 
Adverse Events will be collected only once with its maximum intensity. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2.  On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2. 
6.3.4 
Causality collection 
The Investigator will assess causal relationship between 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 IP?’ 
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A to the Clinical 
Study Protocol. 
6.3.5 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 


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were last asked?’, or revealed by observation will be collected and recorded in the eCRF.  
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
6.3.6 
Adverse events based on examinations and tests 
The results from protocol-mandated laboratory tests and vital signs will be summarised in the 
CSR.  Medical disorders present at the time of signing the informed consent that are part of 
the patient’s medical history will only be considered AEs if they worsen after this time. 
Relevant abnormalities detected before first IP administration in physical examination, 
laboratory value/vital sign, ECGs will not be considered AEs if already known as part of the 
medical history or in relation to prior medical conditions, and will be recorded in the eCRF 
history/physical examination form/page.  However, relevant abnormalities detected in 
Screening/run-in/ baseline tests, thought to be due to a study procedure, will be considered 
AEs and recorded in eCRF. 
During the study, abnormalities (newly occurring or worsening of previously known 
abnormalities) detected in laboratory values, vital signs, ECGs and physical examination 
which are considered clinically relevant by the Investigator or which require an intervention or 
a diagnosis test, or may result in the IP discontinuation, should be reported as AEs. 
In addition, when an AE meets the criteria of seriousness (SAE), it must also be recorded in 
the eCRF and reported following the defined timelines (see Section 6.4). 
6.3.7 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with total bilirubin ≥2xULN may need to 
be reported as SAEs.  Please refer to Appendix C for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law. 
6.3.8 
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, (ie, COPD in this study).  Events, which are 
unequivocally due to disease progression, should not be reported as an AE during the study. 
6.4 
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 Investigator 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. 


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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. Investigator 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 Investigator or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the Investigator or other study site personnel reports 
an SAE to the appropriate AstraZeneca representative by fax or email. 
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. The reference document for definition of expectedness is the IB for the AstraZeneca 
drug. 
6.5 
Overdose 
An overdose of AZD8871 is likely to lead to exaggerated pharmacological effects typical of 
β2-adrenergic stimulants (ie, tachycardia, hypertension, hypotension, palpitations, ventricular 
arrhythmias, tremor, muscle cramps, headache, nausea, vomiting, nervousness, drowsiness, 
insomnia, fatigue, malaise, metabolic acidosis, hypokalaemia, hyperglycaemia, etc.) and 
anticholinergics (ie, dry mucous membranes, mydriasis, increased heart rate, increased 
intraocular pressure, hypertension, urinary retention, constipation, hypoactive bowel sounds, 
flushed skin, confusion, disorientation, agitation, ataxia, etc.). 
Supportive and symptomatic treatment is indicated.  In serious cases, patients should be 
hospitalised. 
Reporting an overdose: 
x 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE forms in the eCRF and on the Overdose form. 
x 
An overdose without associated symptoms is only reported on the Overdose form. 
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 DES. 


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For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days. 
6.6 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca using the 
Pregnancy form. 
6.6.1 
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 DES within 1 or 5 calendar 
days for SAEs (see Section 6.4) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
6.6.2 
Paternal exposure 
Male patients should use a condom and spermicide to prevent pregnancy and drug exposure of 
a partner regardless of the gender or childbearing potential of the partner and refrain from 
donating sperm or fathering a child from 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 effective 
method of contraception should be used with female partners of childbearing potential. 
In case of pregnancy of the patient’s partners, 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. These pregnancies will be 
also followed up, and the outcome of the pregnancy (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should if possible be 
obtained and documented. 


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6.7 
Management of IP related toxicities 
There is no plan for dose reduction in this study. 
6.8 
Study governance and oversight 
There will be no steering committee, data monitoring committee or scientific advisory 
committee. 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Investigational product 
These are the proposed dose strengths. 
Investigational product 
Dosage form and strength 
Manufacturer 
AZD8871 
Powder for inhalation administered 
via single dose DPI 
100 and 600 μg/inhalation 
Industrias Farmacéuticas Almirall 
S.A. 
 
 
Placebo 
Powder for inhalation administered 
via single dose DPI 
Industrias Farmacéuticas Almirall 
S.A. 
 
 
DPI=Dry powder inhaler. 
 
Product dosage and mode of administration 
Study treatment 
IP administration 
Comments 
AZD8871 100 μg 
100 μg single dose DPI  
1 inhalation QD 
AZD8871 600 μg 
600 μg single dose DPI 
1 inhalation QD 
Placebo 
Placebo single dose DPI 
1 inhalation QD 
DPI=Dry powder inhaler: QD=Once a day. 
All investigational products will be administered by oral inhalation. 
 
The planned dose of AZD8871 or placebo will be administered via single dose DPI that is an 
adaptation of the commercially available Genuair® with a smaller internal volume to enable 
delivery of single doses.  To maintain blinding, each patient will receive one inhaled dose 
from the AZD8871 or placebo DPI provided to him/her on each day of the treatment period.  
Redacted
Redacted


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Doses taken at Day 1, Day 2, Day 8 and Day 14 of each treatment period will be taken at the 
study site, while doses on other treatment days will be taken at patient’s home. 
The IP manufacturing, labelling, packaging and release will be conducted following Good 
Manufacturing Practice (GMP) by Almirall.  Each DPI will be packed in an Aluminium Pouch 
including desiccant. 
Patient kit for each treatment period will include IP to cover treatment from Day 1 to Day 7 or 
from Day 8 to Day 14 (2 kits for each treatment period).  Further information will be provided 
in the Investigator drug manual. 
The Almirall Qualified Person will provide a certificate of analysis as well as appropriate 
certificate of release.  Batch numbers will be indicated in the CSR. 
For training purposes, each patient will receive an empty DPI that will be used on Visit 3, 6 
and 9 if considered necessary. 
7.2 
Dose and treatment regimens 
At Visit 1, patients will be provided with salbutamol, to be used as rescue medication during 
the study, until the Follow-up Visit.  Salbutamol should be held at least 6 hours before any 
pulmonary function tests. 
7.2.1 
Run-in period 
At Visit 2, if the reversibility test and FEV1 predicted values are fulfilled, the patient will start 
a run-in period for 14 to 28 days.  All patients will receive ipratropium following the approved 
dosage and regimen during the run-in period.  
7.2.2 
Treatment periods 
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.  
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). 
The Day 2 dose of IP will also be taken on site.  Doses from Day 3 to Day 7 will be taken at 
home.  IP administration on Day 8 and Day 14 will be done at the site and the rest of the doses 
(Day 9 to Day 13) will be taken at home. 
During each treatment period, each patient will receive one of the 3 possible treatments, with 
every patient receiving placebo in one of the treatment periods.  Patients will receive 2 kits 
(one to cover treatment from Day 1 to Day 7 and one to cover treatment from Day 8 to 
Day 14) containing IP for one of the 3 following treatments for 14 days in any given period: 
x 
AZD8871 100 μg 
x 
AZD8871 600 μg 


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x 
Placebo 
Further information regarding IP kit will be provided in the Investigator drug manual. 
7.2.3 
Wash-out periods 
Wash-out periods of 28 up to 35 days will occur between each treatment period (after last 
administration of IP).  All patients will receive ipratropium following the approved dosage 
and regimen during the wash-out periods.  
7.3 
Labelling 
Labels will be prepared in accordance with GMP and local regulatory guidelines.  The labels 
will fulfil GMP Annex 13 requirements for labelling.  Label text will be translated into local 
language. 
The IP will be provided in individual patient kit labelled with study-specific label. 
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 bag 
labels and inhaler labels. 
Patients participating in the study will be provided with an identification card where the 
Investigator’s details including telephone number are included and will be instructed to keep 
this identification card with them at all times. 
7.4 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The IP 
label on the study drug specifies: “No special storage conditions.  Do not refrigerate or 
freeze”. 
Further information regarding IP storage at the site will be provided in the Investigator drug 
manual. 
7.5 
Compliance 
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the eCRF (date, time, number of inhalations). 
Patients will be provided with an e-Diary to record their intake of the IP on a daily basis. 
7.6 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study personnel will account for all study drugs dispensed to and returned from the 
patient. 


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All used and unused supplies of the IP will be destroyed by PAREXEL at the end of the study.  
The certificate of delivery and destruction must be signed, in accordance with instructions by 
AstraZeneca.  Destruction must not take place unless the responsible person at AstraZeneca 
has approved it. 
7.7 
Concomitant and other treatments 
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 
maintained on their usual ICS therapy, if any.  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 during the entire experimental phase 
of the study. 
Table 4 and Table 5 summarise different possible treatments for COPD and other indications 
which are allowed and prohibited, respectively, with example of medication and applicable 
restrictions. 
Table 4 
Medications allowed as concomitant medications 
Medications 
Restrictions 
Oral anti-histamines, intranasal corticosteroids 
and sympathomimetics and intranasal 
anticholinergics 
Allowed but avoid for 12 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 all study duration 
Rescue medication: Salbutamol 100 μg (2 puffs) 
Allowed but avoid for 6 hours prior to any 
spirometry test for the study 
Ipratropium at the approved dosage and regimen 
Mandatory during run-in and wash-out periods 
but should be held at least 8 hours before Visits 3, 


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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; QID=Four times a day. 
 
Table 5 
Medications prohibited as concomitant medications 
Drug Class 
Medications 
Restrictions 
ANTICHOLINERGICS 
Oral or parenteral 
- 
Wash-out of 72 hours required 
before Visit 2 
Inhaled short-acting, SAMAs 
Oxitropium 
Wash-out of 12 hours required 
before Visit 2 
Inhaled long-acting, LAMAs 
Tiotropium 
Wash-out of 72 hours before Visit 2 
Β2-ADRENERGIC AGONISTS 
Inhaled short-acting, SABAs 
(except Salbutamol-rescue 
medication) 
Fenoterol, Terbutaline 
Wash-out of 6 hours before starting 
first pulmonary function test at each 
study visit 
Inhaled long-acting, LABAs (BID 
or QD) 
Formoterol, Salmeterol, 
Vilanterol, Indacaterol 
BID: Wash-out of 48 hours required 
before Visit 2 
QD: Wash-out of 7 days required 
before Visit 2. 
Oral short-acting 
Terbutaline, 
Metaprotenerol 
Wash-out of 24 hours required 
before Visit 2 
COMBINATIONS (INHALED) 
LABA + ICS fixed-dose 
combinations 
- 
Interrupt combination at least 
48 hours before Visit 2. Must be 
switched to ICS mono-component at 
Visit 1 
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 
Theophylline, 
Aminophylline 
Patients with these medications 
should not be enrolled into the study 
Mast cell stabilisers 
Cromolyn 
sodium/nedocromil 
sodium 
Wash-out of 5 days required before 
Visit 2 


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Drug Class 
Medications 
Restrictions 
Leukotriene modifiers 
Montelukast, Zafirlukast, 
Zileuton 
Wash-out of 48 hours required 
before Visit 2 
Selective and non-selective β-
blocking agents (oral or topical 
including eye drops) 
Acebutolol, Celiprolol, 
Xamoterol, Practolol, 
Propanolol 
Patients with these medication 
should not be enrolled into the study 
 
Phosphodiesterase IV inhibitors 
Roflumilast 
Wash-out of 4 weeks required 
before Visit 2 
Anti-IgE and anti-IL-5 antibody 
therapies 
Omalizumab, 
Mepolizumab 
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 
Loperamide 
Wash-out of 5 days required before 
Visit 2 
Live attenuated vaccine 
 
Wash-out of 30 days before 
Screening 
Inactivated vaccine 
Inactivated influenza 
vaccination, 
pneumococcal 
vaccination, or any other 
inactivated vaccine 
Wash-out of 7 days before 
Screening or randomisation Visit 
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; LAMA=Long-acting muscarinic antagonist; QID=Four times a 
day; SABA=Short-acting β2-agonist; SAMA=Short-acting muscarinic antagonist. 
 
7.7.1 
Other concomitant treatment 
Other medication other than that described above, which is considered necessary for the 
patient’s safety and well-being, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF. 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
8.1 
Statistical considerations 
All data analyses will be performed by the Global programming lead from AstraZeneca except 
the derivation of the PK parameters, which will be performed by Covance. 


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A fully detailed Statistical Analysis Plan (SAP) will be prepared by the Global Project 
Statistician from AstraZeneca before the database lock. 
All results will be presented by treatment with descriptive statistics appropriate to the nature 
of the variables.  Demographic and baseline characteristics will be presented.  For continuous 
variables, the number of non-missing observations, mean, standard deviation (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 PDF 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. 
8.2 
Sample size estimate 
The study will be powered to demonstrate superiority of AZD8871 100 μg and 600 μg versus 
placebo for the primary efficacy endpoint.  With a total of 30 patients, there is 80% power to 
detect a difference between actives and placebo for the change from baseline to trough FEV1 
at Day 15 equal to 100 mL, assuming a within-patient SD of 135 mL, 2-sided 5% significance 
level and a normal distribution.  Assuming an approximate 25% dropout, the total sample size 
will be approximately 42 (multiple of 6 sequences).  From previous studies, the screening 
failure rate is estimated to be approximately 55%, therefore approximately 93 screened 
patients will be required to achieve the goal of approximately 42 randomised patients. 
Due to the exploratory nature of the study, there will be no adjustment for multiple 
comparisons. 
8.3 
Definitions of analysis sets 
8.3.1 
Full analysis set 
The Full Analysis Set (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 and analysed according to the intent to treat principle. 
8.3.2 
Safety analysis set 
The safety analysis set consists of all randomised patients who received at least one dose of 
IP.  Patients will be analysed according to the randomised treatment assignment in each 


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period.  Any important deviations from the randomised treatment assignment will be listed 
and considered when interpreting the safety data. 
8.3.3 
Pharmacokinetic analysis set 
The PK analysis set is defined as all randomised patients participating in the subset of PK 
patients, who took at least one dose of IP and have at least one 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 study medication received).  All protocol deviations 
that occur during the study will be considered for their severity/impact and will be taken into 
consideration when patients are assigned to the PK analysis sets. 
The exclusion of any patients or time points from the calculation of the PK parameters will be 
documented by the PK scientist including the reason(s) for exclusion.  The available 
concentration data and PK parameter data for any patients excluded from the PK analysis set 
will be listed only, and presented in the individual figures of concentration-time plots. 
8.3.4 
Per-protocol analysis set 
The Per-Protocol (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). 
8.3.5 
Protocol deviations 
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 set and/or other 
analysis sets.  Deviations will be defined before database hard lock and unblinding.  Important 
deviations will include the following:  
x 
Violation of inclusion and/or exclusion criteria. 
x 
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. 
8.4 
Outcome measures for analyses 
8.4.1 
Primary efficacy variable 
The primary efficacy variable is the change from baseline in trough FEV1 at Day 15 (ie, after 
14 days of treatment). 


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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, just the available value will be used as trough. 
8.4.2 
Secondary variables 
8.4.2.1 
Efficacy variables 
The secondary efficacy variables are the following: 
x 
Change from baseline in Trough FEV1 on Day 2, and Day 8 
x 
Change from baseline in Peak FEV1 on Day 1, Day 8, and Day 14 
x 
Change from baseline in Trough FEV1 over treatment duration (Day 8 to Day 15) 
x 
Change from baseline in Peak FEV1 over treatment duration (Day 8 to Day 14) 
x 
Change from baseline in Total Score BCSS questionnaire and cough, breathlessness 
and sputum individual domain scores from Day 1 to Day 8 after treatment, from Day 8 
to Day 14 after treatment and during the whole treatment duration 
x 
Rescue medication use 
8.4.2.2 
Pharmacokinetic variables 
When possible, the following PK parameters will be assessed for AZD8871 and its 
metabolites, LAS191861 and LAS34850 on plasma concentrations: 
x 
Day 1: 
 
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 
 
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 


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x 
Day 14: 
 
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  
 
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 
 
Cmax/D - Observed maximum concentration divided by dose  
 
AUC0-24/D - Area under the concentration-time curve 0 to 24 h divided by the 
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. 
Calculation or derivation of the pharmacokinetic parameters 
The PK analyses of the plasma concentration data for AZD8871 and its metabolites will be 
performed at Covance, UK, 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. 
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 


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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. 
8.4.3 
Safety variables 
The safety variables are: 
x 
AEs/SAEs 
x 
Vital signs 
x 
ECG 
x 
Clinical laboratory assessments 
8.4.4 
Exploratory variable 
x 
Taste assessment 
8.5 
Methods for statistical analyses 
8.5.1 
Demographic and baseline characteristics 
Analyses of demographic and baseline characteristics will be performed on the Safety 
population. 
Demographic characteristics to be assessed are age, sex, race, height, weight and BMI. 
Baseline characteristics to be assessed include:  
x 
Smoking status (current and former smokers), smoking duration (years) and smoking 
consumption (total pack-years) at Screening. 
x 
Medical history and physical findings classified by system organ class and preferred 
term. 
x 
COPD duration (years). 


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x 
COPD severity.  COPD severity will be based on the post-bronchodilator FEV1 at 
Screening and will be defined as follows: 
 
Stage II (Moderate): FEV1/FVC < 0.70 and 50% ≤ FEV1 <80% predicted 
 
Stage III (Severe): FEV1/FVC < 0.70 and 30% ≤ FEV1 <50% predicted 
x 
Absolute values of the FEV1 and FVC (pre- and post-bronchodilator test) at Screening. 
x 
Percent of predicted FEV1 and FVC (pre- and post-bronchodilator test) at Screening. 
x 
Ratio FEV1/FVC (post-bronchodilator test) at Screening. 
x 
Mean bronchodilator reversibility (change from pre-bronchodilator test value) at 
Screening. 
x 
Percentage of bronchodilator reversibility (% increase over pre-bronchodilator test 
value) at Screening. 
x 
Number of patients who meet the reversibility criteria (at least 12% increase in FEV1 
post-bronchodilator and at least 200 mL increase from pre-test in FEV1). 
x 
Time since last exacerbation (days) during last 12 months. 
x 
The number and percentage of patients who used any prior medication (14 days before 
ICF) will be summarised overall by Anatomical Therapeutic Code (ATC) code (to a 
maximum of 3rd level), and preferred name. (Including also those medications taken 
before the ICF administration and continue afterwards, this will be classified in both 
prior and concomitant medication groups).  Patients with multiple drug usage in the 
same preferred name will be counted only once. 
x 
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; ICS, LABA, LABA+ICS combination, LAMA, 
short-acting β2-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. 
Screening values for ECGs, laboratory assessments, and blood pressure will not be presented 
in the tables corresponding to demographic and Screening characteristics but together with the 
corresponding assessments after baseline and with the changes from baseline to ease the 
interpretation of these safety outcomes. 
Appropriate descriptive statistics according to the nature of each variable will be provided for 
these variables.  No statistical tests will be performed. 


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8.5.2 
Concomitant and rescue medication 
The number and percentage of patients with: 
x 
Any medication taken during wash-out periods (those medications being taken after 
24 h of IP intake on Day 14 and before the following treatment period). 
x 
Any medication taken during the treatment periods (those medications being taken 
between the first IP administration and 24 h after the last IP administration of each 
treatment period) will be tabulated by ATC code (third level), preferred term and 
treatment. 
x 
Any rescue medication (ie, salbutamol) taken during the treatment periods. 
Additionally, the number and percentage of patients with any of these medications versus 
those not taking medication will be tabulated by treatment.  Listings with concomitant 
medication will also be produced. 
Concomitant medication will be summarised for the Safety population.  Additionally, the 
number and percentage of patients with any of these medications versus those not taking 
medication will be tabulated by treatment for each study part.  Listings with prior, 
concomitant and reliever medication will also be produced. 
8.5.3 
Analysis of the primary efficacy variable 
The primary efficacy variable 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 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: 
x 
AZD8871 100 μg versus Placebo  
x 
AZD8871 600 μg versus Placebo 
Treatment comparisons among active treatments will be also explored. 
8.5.4 
Analysis of the secondary variables 
8.5.4.1 
Analysis of the efficacy variables 
All secondary efficacy variables will be analysed using the same mixed model as that for the 
primary efficacy variable adjusting for the corresponding baselines. 


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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 
sequence. 
Peak FEV1 will be defined as the maximum value from 0 to 4 hours. 
The same treatment comparisons as those for the primary variable will be performed for the 
secondary variables. 
8.5.4.2 
Analysis of pharmacokinetic variables 
Descriptive statistics 
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 
metabolites concentrations, and comments will be provided. 
Plasma concentrations will be summarised by dose level of AZD8871 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 analysis 
set. 
For descriptive statistics for plasma concentrations that are below the LLOQ will be handled 
as follows: 
x 
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. 
x 
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. 
x 
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. 
x 
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 analysis set will be included in the data listings, but 
not in the summaries or in the inferential statistics. 
Individual plasma concentrations versus actual time will be plotted in linear and 
semi-logarithmic scale, with separate plots for each patient and concentrations for Day 1 and 


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Day 14 (where applicable) overlaid on the same plot.  Combined individual plasma 
concentration per dose level of AZD8871 will also be presented in linear and semi-logarithmic 
scale with separate plots for each dose level and day (Day 1 and Day 14). 
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 metabolites. 
Additional graphical presentations of PK data may be added at the discretion of the PK 
Scientist.  More details will be provided in the SAP. 
Analysis of accumulation 
Product 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).  A linear mixed-effect model will be used with 
the logarithm of the PK parameters as the response variable and dose, day and dose by day 
interaction as fixed effects.  Day will be treated as a repeated effect within-patient.  From 
these models, 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. 
8.5.5 
Sensitivity analysis 
The primary efficacy variable is the change from baseline in trough FEV1 at Day 15 (ie, after 
14 days of treatment). 
A sensitivity analysis will be performed 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 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. 
8.5.6 
Exploratory analysis  
Each question of the taste questionnaire will be analysed using descriptive statistics. In 
addition, the overall evaluation of taste will be compared among treatment groups using an 
analysis of variance (ANOVA) model for crossover designs adjusting for sequence, patient 
within sequence, period, and inhaler type as fixed effects factors. The difference in taste 
between devices (estimated by differences between LS means), the SE and 95% CI will be 
presented. 


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8.5.7 
Analyses of safety variables 
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 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 occurs during a wash-out 
period will be associated to the last treatment taken.  An AE that occurs more than 30 days 
after the last IP administration will not be counted as a TEAE.  TEAEs 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, and 24 h, respectively) on Days 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. 


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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. 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
9.1 
Training of study site personnel 
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study-specific procedures and system(s) 
utilised. 
The PI will ensure that appropriate training relevant to the study is given to all of these staff, 
and that any new information relevant to the performance of this study is forwarded to the 
staff involved. 
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other staff). 


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9.2 
Monitoring of the study 
During the study, a PAREXEL representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the Investigator(s). 
x 
Confirm that facilities remain acceptable. 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
being performed. 
x 
Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to the 
study) including verification of informed consent of participating patients.  This will 
require direct access to all original records for each patient (eg, clinic charts). 
x 
Ensure withdrawal of informed consent to the use of the patient’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, 
and the action is documented, and reported to the patient. 
The PAREXEL representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
9.2.1 
Source data 
Refer to the CSA for location of source data. 
9.2.2 
Study agreements 
The PI at each/the centre should comply with all the terms, conditions, and obligations of the 
CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail. 
Agreements between AstraZeneca and the PI should be in place before any study-related 
procedures can take place, or patients are enrolled. 
9.2.3 
Archiving of study documents 
The Investigator follows the principles outlined in the CSA. 
9.3 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last patient undergoing the study’. 


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The study is expected to start in Quarter 4, 2016 and to end by Quarter 2, 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with AZD8871. 
9.4 
Data management by PAREXEL 
Data management of the study will be performed by PAREXEL and supervised by Data 
Management at AstraZeneca. 
The main data management activities and procedures will be described in the Data 
Management Plan (DMP), created by PAREXEL using the AstraZeneca 
 template. 
Database and Data Validation 
DataLabs (an EDC system) will be used to collect and manage clinical data. 
The Data Validation Specification (DVS) will contain details of consistency and structural 
checks to be run against the data as well as listings required for PAREXEL data cleaning and 
review. The DVS will be created by PAREXEL to meet Sponsor requirements and standards. 
Automated edit checks with DataLabs are available once the data have been entered.  
Additional queries may also be identified during the study via further edit checks, listing 
review by PAREXEL personnel, data coding, etc. 
Database, edit checks, listings (programmed for data review) and any programming implying 
data conversions will be appropriately validated by PAREXEL. 
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail. 
The data will be validated as defined in the DMP.  Quality control procedures will be applied 
to each stage of data handling to ensure that all data are reliable and have been processed 
correctly. 
Clinical Coding 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the WHO-Drug Enhanced plus Herbal Dictionary.  
Classification coding will be performed by PAREXEL. 
Redacted


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Serious adverse event (SAE) reconciliation 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data Mapping 
Data will be collected during the study execution and will be mapped into Study Data 
Tabulation Model (SDTM) datasets in an ongoing basis. 
Transfers of SDTM datasets will be periodically received at Sponsor during the study and 
after database lock.  Frequency of these transfers will be agreed between Sponsor and 
PAREXEL and documented within the DMP. 
Management of external data 
In addition to the eCRF data, PAREXEL will receive electronic records for external data 
processed by vendors (Covance for PK, and ERT for e-Diary, and local laboratory for safety 
laboratory tests).  A reconciliation process will be performed by PAREXEL of eCRF data and 
against the rest of the data sources to ensure consistency of the common data. 
Audit trail of all databases will be maintained in order to protect the authenticity and integrity 
of the clinical data. 
When all data have been coded, validated, and electronically signed, the database will be 
locked.  Any treatment revealing data (such as the treatment information and the PK data) will 
be added to the set of data to be transferred after the database has been locked and the 
populations’ definition has been completed. 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the AstraZeneca policy on Bioethics and Human Biological Samples. 
10.2 
Patient data protection 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final version 
of the ICF and any other written information and/or materials to be provided to the patients.  


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The Investigator will ensure the distribution of these documents to the applicable EC, and to 
the study site staff. 
The opinion of the EC should be given in writing.  The Investigator should submit the written 
approval to AstraZeneca before enrolment of any patient into the study. 
The EC should approve all advertising used to recruit patients for the study. 
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements. 
If required by local regulations, the protocol should be re-approved by the EC annually. 
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national Regulatory 
Authorities. 
AstraZeneca will provide Regulatory Authorities, ECs and PIs with safety updates/reports 
according to local requirements. 
Each PI is responsible for providing the ECs with reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the IP.  AstraZeneca will provide 
this information to the PI so that he/she can meet these reporting requirements. 
10.4 
Informed consent 
The PI(s) at each centre will: 
x 
Ensure each patient is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
x 
Ensure each patient is notified that they are free to discontinue from the study at any 
time 
x 
Ensure that each patient is given the opportunity to ask questions and allowed time to 
consider the information provided 
x 
Ensure each patient provides signed and dated ICF before conducting any procedure 
specifically for the study 
x 
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
x 
Ensure a copy of the signed ICF is given to the patient 


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x 
Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described in 
the ICF that is approved by an EC. 
10.5 
Changes to the protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Co-ordinating 
Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant EC and if applicable, also the national 
regulatory authority, before implementation.  Local requirements are to be followed for 
revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each PI(s).  For distribution to EC see Section 10.3. 
If a protocol amendment requires a change to a centre’s ICF, AstraZeneca and the centre’s EC 
are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC. 
10.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an EC may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre. 


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11. 
LIST OF 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. 
GOLD 2016 
Global strategy for the diagnosis, management and prevention of chronic obstructive lung 
disease updated 2016.  Available from http://www.goldcopd.org.  Accessed on 07 July 2016 
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. 
Levey et al, 2009 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al.  A new 
equation to estimate glomerular filtration rate.  Ann Intern Med. 2009; 150(9):604-12. 
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. 


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


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x 
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? 
x 
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? 
x 
De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug? 
x 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
x 
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
x 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship. 
In difficult cases, other factors could be considered such as: 
x 
Is this a recognized feature of overdose of the drug? 
x 
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 judgement.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


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


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Appendix C 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law (HL).  It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.  Specific guidance on the managing liver 
abnormalities can be found in Section 6.3.7 of the protocol. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether 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 IP. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AE) and serious adverse events (SAE) according to the outcome of 
the review and assessment in line with standard safety reporting processes. 
Definitions 
Potential Hy’s Law (PHL) 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x Upper Limit of 
Normal (ULN) together with total bilirubin (TBL) ≥2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).  
Hy’s Law (HL) 
AST or ALT ≥3x ULN together with TBL ≥2xULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
Identification of Potential Hy’s Law Cases 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
x 
ALT ≥3xULN 


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x 
AST ≥3xULN 
x 
TBL ≥2xULN 
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met and will: 
x 
Notify the AstraZeneca representative 
x 
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits. If the 
criteria are met, assess if the patient meets study-specific withdrawal criteria 
(Section 3.9). 
x 
Promptly enter the laboratory data into the laboratory eCRF 
Follow-up 
Potential Hy’s Law criteria not met 
If the patient does not meet PHL criteria the Investigator will: 
x 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
Potential Hy’s Law criteria met 
If the patient does meet PHL criteria the Investigator will: 
x 
Notify the AstraZeneca representative who will then inform the central Study Team  
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 
x 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated  
x 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician.   
x 
Complete the 3 Liver CRF forms as information becomes available  
x 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
x 
Assess if the patient meets study-specific withdrawal criteria (Section 3.9). 


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Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IP.  
The AstraZeneca Medical Science Director and Global Safety Physician will also be involved 
in this review together with other patient matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below. 
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
x 
If the alternative explanation is an AE/SAE, record the AE /SAE in the eCRF 
accordingly and follow the AZ standard processes 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP: 
x 
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes.  
 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
x 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above. 
x 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review. 


Clinical Study Protocol Appendix D 
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References 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf  


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Appendix D 
Breathlessness, Cough Sputum Scale 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
102 (107) 
Appendix E 
Taste questionnaire 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
103 (107) 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
104 (107) 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
105 (107) 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
106 (107) 
 
 


Clinical Study Protocol Appendix E 
Drug Substance AZD8871  
Study Code D6640C00004 
Version 3.0 
Date 16 December 2016 
107 (107) 
 
 
 

SAP_001.pdf: 
Statistical Analysis Plan 
Drug Substance AZD8871
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 1 of 50
Statistical Analysis Plan
Drug Substance
AZD8871
Study Code
D6640C00004
Date
26 June 2017
A phase IIa, randomised, multi-centre, double-blind, placebo-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


Redacted


Redacted


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 4 of 50
TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
SIGNATURE OF STUDY STATISTICIAN...........................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ....................................................3
TABLE OF CONTENTS .........................................................................................................4
LIST OF ABBREVIATIONS ..................................................................................................7
1.
STUDY DETAILS...................................................................................................9
1.1
Study objectives.......................................................................................................9
1.1.1
Primary objective.....................................................................................................9
1.1.2
Safety objectives ....................................................................................................10
1.1.3
Exploratory objectives ...........................................................................................10
1.2
Study design...........................................................................................................10
1.3
Number of patients.................................................................................................14
2.
ANALYSIS SETS .................................................................................................14
2.1
Definition of analysis sets......................................................................................14
2.1.1
Screening analysis set ............................................................................................14
2.1.2
Full analysis set......................................................................................................14
2.1.3
Safety analysis set..................................................................................................14
2.1.4
PK analysis set .......................................................................................................15
2.1.5
Per Protocol Analysis Set.......................................................................................15
2.2
Violations and deviations.......................................................................................15
3.
PRIMARY AND SECONDARY VARIABLES...................................................19
3.1
General definitions.................................................................................................19
3.1.1
Handling of missing or partial dates ......................................................................19
3.1.1.1
Imputation for concomitant medication start and stop dates .................................20
3.1.1.2
Imputation for adverse event start dates ................................................................22
3.1.2
Repeated and unscheduled visits............................................................................23
3.1.2.1
Spirometry variables ..............................................................................................23
3.1.2.2
Safety variables......................................................................................................23
3.2
Assessment of study population.............................................................................23
3.2.1
Demographic and baseline characteristic variables ...............................................23
3.2.2
Surgical and medical history..................................................................................23
3.2.3
Prior and concomitant medications........................................................................23
3.2.4
Duration of exposure..............................................................................................24
3.2.5
Treatment compliance............................................................................................24


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 5 of 50
3.3
Efficacy variables...................................................................................................25
3.3.1
Pulmonary function variables ................................................................................25
3.3.1.1
Primary outcome variable......................................................................................26
3.3.1.2
Secondary FEV1 -related variables ........................................................................26
3.3.1.3
Other FEV1 -related variables................................................................................26
3.3.2
Other efficacy variables .........................................................................................26
3.3.2.1
Total Score BCSS and cough, breathlessness and sputum individual 
domain scores.........................................................................................................26
3.3.2.2
Rescue medication use (Salbutamol).....................................................................27
3.3.2.3
Taste.......................................................................................................................27
3.4
Pharmacokinetic variables .....................................................................................27
3.5
Safety variables......................................................................................................29
3.5.1
Adverse events.......................................................................................................29
3.5.2
Serious adverse events ...........................................................................................29
3.5.3
Laboratory variables ..............................................................................................30
3.5.4
ECG........................................................................................................................31
3.5.5
Vital signs ..............................................................................................................32
4.
ANALYSIS METHODS .......................................................................................32
4.1
General principles ..................................................................................................32
4.1.1
Statistical testing....................................................................................................32
4.1.2
Presentation of results............................................................................................33
4.2
Analysis methods...................................................................................................33
4.2.1
Analyses of study population.................................................................................33
4.2.1.1
Patient disposition..................................................................................................33
4.2.1.2
Demographic and baseline characteristics ............................................................34
4.2.1.3
Exposure ................................................................................................................36
4.2.1.4
Treatment compliance............................................................................................36
4.2.2
Analysis of the primary variable: change from baseline in trough FEV1 at 
Day 15....................................................................................................................36
4.2.3
Analysis of the FEV1 -related secondary variables................................................37
4.2.4
Analysis of the other FEV1 -related variables........................................................37
4.2.5
Analysis of the other efficacy variables.................................................................38
4.2.6
Exploratory outcome variables ..............................................................................38
4.2.6.1
Taste Assessment...................................................................................................38
4.3
Analysis of pharmarcokinetic variables.................................................................38
4.3.1.1
Descriptive statistics ..............................................................................................38
4.3.1.2
Analysis of AUC(0-24) , Cmax at Day 1 and Day 14 and accumulation 
between Day 1 and Day 14 ....................................................................................40
4.4
Safety .....................................................................................................................40
4.4.1.1
Adverse events.......................................................................................................41
4.4.1.2
Laboratory data ......................................................................................................42
4.4.1.3
ECG........................................................................................................................46


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 6 of 50
4.4.1.4
Vital signs ..............................................................................................................49
5.
INTERIM ANALYSES (NOT APPLICABLE)....................................................50
6.
CHANGES OF ANALYSIS FROM PROTOCOL ...............................................50
7.
REFERENCES (NOT APPLICABLE) .................................................................50
8.
APPENDIX (NOT APPLICABLE).......................................................................50
LIST OF TABLES
Table 1
Important protocol deviations and population classification....................16
Table 2
  Laboratory safety variables ....................................................................31
Table 4
Expanded normal ranges and notable abnormalities for laboratory 
parameters.................................................................................................45
Table 4
  PCS ECG criteria: QTcF exceeding ICH boundaries.............................48
Table 5
  PCS ECG criteria: Heart Rate and QRS interval....................................48
Table 6
  PCS vital sign criteria.............................................................................49
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................13


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 7 of 50
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 curve
AUC0-x
Area under curve from time 0 to x hours
AUC0-x/xh
Area under curve from time 0 to x hours normalized by x hours
AUClast
Area under the curve from time 0 to last quantifiable measurement
BCSS
Breathlessness, Cough, Sputum Score
BDR
Blind data review
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CI
Confidence interval
COPD
Chronic obstructive pulmonary disease
ECG
Electrocardiogram
eCRF
electronic case report form
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
GOLD
Global Initiative for Chronic Obstructive Lung Disease
ICF
Informed consent form
IP
Investigational product
ITT
Intention-to-treat
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
PCS
Potentially clinically significant


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 8 of 50
Abbreviation or 
special term
Explanation
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
RR interval
Duration in milliseconds between two R peaks of two consecutive  
QRS complexes
SAE
Serious adverse event
SAP
Statistical analysis plan
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
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal
WHO
World Health Organization
WO
Wash out


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 9 of 50
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
Primary objective:
Endpoints:
To evaluate the efficacy of inhaled 
AZD8871 in patients with moderate to 
severe COPD
Primary
•
Change from baseline in Trough FEV1 on 
Day 15
Secondary
•
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 8 to Day 15)
•
Change from baseline in Peak FEV1 over 
treatment duration (Day 8 to Day 14)
•
Change from baseline in FEV1 AUC0-4/4h at 
Day 1, Day 8, and Day 14
•
Change from baseline in FEV1 AUC0-8/8h at 
Day 1, and Day 14
•
Change from baseline in FEV1 AUC0-24/24h
at Day 1, and Day 14 
•
Change from baseline in Trough FVC on 
Day 2,  Day 8, and Day 15
•
Change from baseline in Peak FVC on 
Day 1, Day 8 and Day 14
•
Change from baseline in Total Score of 
Breathlessness, Cough Sputum Scale 
(BCSS) questionnaire and cough, 
breathlessness and sputum individual 
domain scores on Day 8 and Day 14 of 
treatment
•
Change from baseline in average daily 
rescue medication use assessed on Day 8
and Day 14 of treatment 
Secondary objective:
Endpoints:


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 10 of 50
To investigate the PK of AZD8871 and 
its metabolites 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 metabolites LAS191861 and LAS34850 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))]
1.1.2
Safety objectives
Safety objectives:
Endpoints:
To evaluate the safety and tolerability of 
inhaled AZD8871 in patients with 
moderate to severe COPD
•
AEs/Serious Adverse Events (SAEs)
•
Vital signs
•
ECG
•
Clinical laboratory assessments
1.1.3
Exploratory objectives
Exploratory objectives:
Endpoints:
To evaluate the taste of inhaled AZD8871 in 
patients with moderate to severe COPD
!
Taste assessment
1.2
Study design
This is 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 and placebo, administered using a DPI device once 
daily, for 2 weeks, in patients with moderate to severe COPD.
This multi-centre study will be conducted at 2 sites in Europe (Germany and United Kingdom 
[UK]).  It is planned that approximately 42 men and women of non-childbearing potential 
aged 40 to 80 years (both inclusive) with moderate to severe COPD will be randomised to the 


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 11 of 50
study.  A subset of 20 patients, who will have specifically consented, will also undergo PK 
assessments.  The entire study period is scheduled to take from a minimum of 4.5 months 
(140 days) to a maximum of 5.6 months (175 days) for each individual patient.  The study is 
anticipated to run for approximately 8 months and should not exceed 10 months.
Patients will be provided with salbutamol as rescue medication to be used as needed 
throughout the study and with ipratropium to be used according to the approved dosage and 
regimen during the run-in and wash-out periods.
The study will consist of a Screening period, 3 treatment periods (each separated by a 
wash-out period), and a Follow-up Visit. 
Screening period: This will last up to 28 days and consists of a Screening Visit (Visit 1), 
Visit 2, and a run-in period.  
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 (confirm inclusion criteria #6 and 
#7): These must be performed at Visit 2.
Only patients who fulfil the reversibility criterion (improvement of FEV1 ≥12% and 200 mL 
after administration of salbutamol) and fulfil FEV1 predicted values (FEV1 ≥40% and <80% 
from predicted normal value and FEV1/forced vital capacity (FVC)
ratio <70%) 
post-salbutamol at Visit 2, will be started on the run-in period to assess clinical stability.
If the reversibility criteria or FEV1 predicted values are not met, the tests may be repeated at 
the latest, up to Day-14.  If any of these 2 criteria are not achieved at the repeat attempt, the 
patient will not be randomised.
The duration of run-in period will be between a minimum of 14 and a maximum of 28 days. 
During the run-in period, all patients will receive ipratropium following the approved dosage 
and regimen (must be discontinued 8 hours before any pulmonary function test).
During the randomised treatment period of the study, each patient 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. 
Patient will receive one of the 3 following possible 
treatments in any given period, in a randomised manner:
!
AZD8871 100 μg once daily


Statistical Analysis Plan 
Drug Substance 
Study Code D6640C00004
Version 1.3
Date 26 June 2017
Page 12 of 50
!
AZD8871 600 μg once daily
!
Placebo
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 
28 up to 35 days, during which patients will receive ipratropium following the approved 
dosage and regimen (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 pre-best test review ., 
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). 
If the FEV1 stability criterion is not met, an additional 
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, 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 28 up to 35 days after last 
administration of the IP.


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 at the doses of 100


Page 14 of 50
1.3
Number of patients
The study was powered to demonstrate superiority of AZD8871 100 μg and 600 μg versus 
placebo for the primary efficacy endpoint.  With a total of 30 patients, there is 80% power to 
detect a difference between actives and placebo for the change from baseline to trough FEV1
at Day 15 equal to 100 mL, assuming a within-patient SD of 135 mL, 2-sided 5% significance 
level and a normal distribution.  Assuming an approximate 25% dropout, the total sample size 
as approximately 42 (multiple of 6 sequences).  
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.  
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Screening analysis set
The screening analysis set will consist of all patients screened.
The screening analysis set will be used for reporting disposition and screening failures.
2.1.2
Full analysis set
The Full Analysis Set (FAS) population is defined as all patients randomised and receiving at 
least one dose of 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.
2.1.3
Safety analysis set
The safety analysis set consists of all randomised patients who receive at least one dose of IP.  
For summaries based on the safety set, 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 safety analysis set 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 
major 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 non-randomised 
treatments.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 15 of 50
2.1.4
PK analysis set
The PK analysis set (PKS) will consist of all patients in the safety analysis set who received at
least 1 dose of AZD8871 (100 μg or 600 μg ) and have at least 1 of the parameters Cmax, 
AUC 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 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
2.1.5
Per Protocol Analysis Set
The Per Protocol (PP) analysis set (PPS) will consist of all patients who receive at least 1 dose
of AZD8871 (100 μg or 600 μg ) or placebo,  who have at least 1 pre-dose and 1 post-dose 
measurement for forced expiratory volume in one second (FEV1) and who have no important 
protocol deviations thought to impact the analysis of the lung function data.
The available lung function data for any patients excluded from the PP analysis set for a given 
study period will be listed only. Only patients in the PP analysis set will be included in the 
descriptive statistics and statistical analyses.
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 PPS 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 PP set, PK set, safety 
set, or FAS set. During the blind data review (BDR) the final list of the important protocol 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 16 of 50
deviations affecting efficacy will be finalyzed and documented prior to unblinding of the 
study data..
Table 1
Important protocol deviations and population classification
Excluded from analysis set
Item
#
Event description
PPS 
SAF
PKS
FAS
1
Provision of informed consent not performed before any study specific procedures.
No
No
No
No
2
ICF source document not available at site, or any issue with the ICF document.
No
No
No
No
3
Female Patient is pregnant, lactating or is of childbearing potential
No
No
No
No
4
Patient has a current diagnosis of asthma
Yes
No
No
No
6
Patient has alpha-1 antitrypsin deficiency as the cause of COPD.
Yes
No
No
No
7
Patient is less than 40 or more than 80 years of age
No
No
No
No
8
Patient has no established clinical history of 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.
Yes
No
No
No
10
Patient has post-bronchodilator FEV1/FVC ratio >=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 does not fulfil reversibility criteria to salbutamol at Visit 2. Reversibility is 
defined as ≥12% and ≥200 mL increase in FEV1 after inhalation of 4 puffs of 
salbutamol (400 μg).  If the criterion is not met, the test can be repeated at the latest, up 
to Day -14.
Yes
No
No
No
13
Patient with body mass index (BMI) >=40 kg/m2 at the time of Screening
Yes
No
No
No
14
Patient is not free from any clinically active 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
15
Patient has other active pulmonary disease such as active tuberculosis, lung cancer, 
bronchiectasis, sarcoidosis, idiopathic interstitial pulmonary fibrosis, primary 
pulmonary hypertension, or uncontrolled sleep apnoea.  
Yes
No
No
No
16
Patient has undergone lung volume reduction surgery, lobectomy, or bronchoscopic 
lung volume reduction
Yes
No
No
No
17
Patient is using nocturnal positive pressure
Yes
No
No
No
18
Patient has been hospitalised due to poorly controlled COPD within 3 months of 
Screening.
Yes
No
No
No
19
Patient has acute worsening of COPD or lower respiratory tract infections that required 
antibiotics or corticosteroids in the 6-week interval prior to Screening (Visit 1), or 
during the Screening Period (between Visits 1 and 3).
Yes
No
No
No
20
Patient has changed their smoking status (ie, start 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 (see protocol section 3.2, criteria 15).
No
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).
No
No
No
No
23
Patient with heart rate <50 bpm.
No
No
No
No
24
Patient has clinically significant uncontrolled hypertension
No
No
No
No


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 17 of 50
Excluded from analysis set
Item
#
Event description
PPS 
SAF
PKS
FAS
26
Patient with seizures or history of seizures requiring anticonvulsants within 12 months 
prior to Screening.
No
No
No
No
27
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.
No
No
No
No
28
Patient with symptomatic bladder neck obstruction, acute urinary retention or 
symptomatic non-stable prostate hypertrophy.
No
No
No
No
29
Patient has a serum potassium value <3.5 mmol/L at Screening and on repeat testing.  
Note: however potassium replacement and rescreening is allowed if serum potassium 
concentration was <3.5 mmol/L at Screening. 
No
No
No
No
30
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.
No
No
No
No
31
Patient has known narrow-angle glaucoma.
No
No
No
No
32
Patient has a history of hypersensitivity to β2-agonists, muscarinic anticholinergics or 
lactose/milk protein.  
No
No
No
No
33
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.
No
No
No
No
34
Patient received a live attenuated vaccination within 30 days prior to Screening.
No
No
No
No
35
Patient donated or lost >500 mL of blood and plasma within the previous 3 months 
prior to Screening
No
No
No
No
34
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.
No
No
No
No
35
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
No
No
No
No
36
Patient previously enrolled in the present study
Yes
Yes
Yes
Yes
37
Participation in another clinical study with an IP within the last 30 days or 5 half-lives 
(whichever is longer) prior to Screening.
Yes+++
No
Yes+++
No
38
Patient with known human immunodeficiency virus (HIV) infection or chronic hepatitis 
B or C infection.
No
No
No
No
39
Patient did not fulfill fasting requirements on day 1, 8, and 14 before IP administration 
and following dose administration and prior to safety laboratory testing (protocol 
section 3.8, criteria 2 and 4)
No
No
No
No
40
Salbutamol not withheld at least 6 hours prior to each spirometry visit and ipratropium 
not withheld at least 8 hours before visits 3, 6, and 9.
Yes
No
No
No
41
Patient could not abstain from list in protocol section 3.8, criteria 7
No
No
No
No
42
Patient who had 2 or more exacerbations of COPD (moderate or severe in intensity) 
within the last year prior to Screening
Yes
No
No
No
43
Patient who took any concomitant medication not permitted by this protocol as 
described in Table 5 section 7.7 of the protocol and from the following class:
Anticholinergics, B2-adrenergic agonists, combinations(inhaled), corticosteroids, 
Methyl-xanthines, Mast-cell stabilizers, Leukotriene modifiers, Selective and non-
selective β-blocking agents (oral or topical including eye drops), Phosphodiesterase IV 
inhibitors
Yes++
No
Yes ++
No


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 18 of 50
Excluded from analysis set
Item
#
Event description
PPS 
SAF
PKS
FAS
44
The patient did not satisfy the FEV1 stability criterion at Visit 6 or 9: the mean of the 
pre-dose FEV1 should be within 20% or 200mL of the pre-best test review. (see secton 
5.1.1 for details)
Yes
No
No
No
45
Incorrect study medication received.
Yes++
No
Yes++
No
46
Patient did not take any IP
Yes++
Yes
Yes++
Yes++
47
Overall treatment compliance < 70 % per treatment according to drug accountability
Yes++
No
Yes++
No
48
Subject was dispensed/administered the wrong kit of medication
Yes++
No
Yes++
No
49
Rescue medication (Salbutamol inhaler, 100 μg) used within 6 hours hours prior, 
and/or 36 hours post IP dosing in each period or ipatroprium used within 8 hours prior 
to first day within each period and during the treatment period
Yes++
No
Yes++
No
50
Procedure not performed (missing PK samples to prevent calculation of PK 
parameters).
No
No
Yes++
No
51
Missing baseline data for the spirometry (FEV1 main variable)
Yes++
No
No
No
52
Patient was not fasted for 8 hours prior to laboratory sampling 
No
No
No
No
53
Patient was not fasted for 4 hours prior to iSTAT sampling per protocol specification
No
No
No
No
54
FEV1 and FVC measurements performed outside tolerance window
No
No
No
No
55
Fulfilling withdrawal criteria during the study but not withdrawn.
No
No
No
No
56
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
57
Other protocol deviations
Yes+++
No
Yes+++
No
++Excluded from the specific timepoint or period only. +++ To be confirmed at the DRM; timepoint specific, global PPS/PKS exclusion or 
no exclusion.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 19 of 50
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General definitions
Baseline will be calculated for each patient and each treatment period except for total score 
BCSS and for rescue medication which will have baseline calculated for each patient over the 
run-in period.
For spirometry variables, the baseline value for each treatment period is defined as the average 
of the two pre-dose values recorded on Day 1 of each period. If one of the values is missing,
the available value will be used as baseline. If a patient’s first period baseline value is missing, 
then the value at pre-bronchodilator at screening will be used.  If the baseline value is missing 
for a subsequent treatment period (ie, the second, third treatment periods), then the average of 
the available baseline values for the other treatment periods for the patient will be used to 
impute the missing one.  For example, if the third period baseline is missing, the average of 
the first, and second period baseline values will be imputed as the third period baseline value. 
Note that within a treatment period, for all FEV1 endpoints, the same baseline FEV1 value will 
be used; similarly for the FVC endpoints, the same baseline FVC value will be used.
Baseline for daily rescue medication use will be the daily average of puffs recorded in the e-
Diary during the run-in period, prior to the first dose of double-blind investigational product;
this baseline will be used as baseline for all treatments in each period. Baseline values will be 
computed only for those patients recording at least 4 diary entries during this period.
The average of the Total Score BCSS and cough, breathlessness and sputum individual 
domain scores obtained during the run-in period, prior to the first dose of double-blind 
investigational product, will be used as baseline for all treatments in each period. Baseline 
values will be computed only for those patients recording at least 4 diary entries during this 
period.
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.
Change from baseline for all spirometry variables, vital signs, laboratory variables including  
i-STAT, and ECG variables will be calculated as the value at the respective time point minus 
the value at baseline in the specific period.
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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 20 of 50
!
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.
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):


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 21 of 50
!
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. 
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. 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 22 of 50
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 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. 
!
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. 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 23 of 50
For 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.
3.1.2
Repeated and unscheduled visits
In general, if a visit is repeated, at screening or at Day 1 visit, prior to first dose of IP in each 
Period, then all data collected at the repeated visit will be used in all analyses at Screening or 
Day 1.
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 non-missing 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.
3.1.2.2
Safety variables
For repeated laboratory tests, vital signs and ECG measurements that are taken on the same 
day and time as a pre-dose scheduled visit and time point (i.e. pre-dose at Day 1 of each 
Period), the latest non-missing result will be used for that visit and time point.  For 
measurements that are taken on the same day and time as a post-dose scheduled visit and time 
point, the first non-missing result will be used for that visit and time point.
3.2
Assessment of study population
3.2.1
Demographic and baseline characteristic variables
!
Demographic characteristics (including 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, 20.0 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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 24 of 50
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 parient.
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 24 h 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 considerd to be taken during wash-out periods if it is taken after 24 h 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 study overall 
will not be considered concomitant.
For the purpose of inclusion in prior or concomitant mediation summaries, incomplete 
medication start and stop dates will be imputed as detailed in Section 3.1.1.
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 (%) = 
  !" #""$ %&'( ) *(+ % &%(% # *!)
  !" #""$ ,#-%) ) *(+ % &%(% # *!) × 100.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 25 of 50
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 
the hour preceding the scheduled morning study drug administration, allowing 
approximately 45 min between them.
!
The Day 1 and Day 14 FEV1 trough value 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). The Day 8 FEV1 trough 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. 
!
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 30 minutes, 1 hour, 2 hours or 4 hours post-
dose).
!
Definition above also apply for 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 
post-dose.
!
8 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, and 8 hours post-dose.
!
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, 23 hours, and 23.45 hours post-dose.
AUC is defined as the area under the curve, normalised for time.  
For t= 4, 8, 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, non-missing FEV1
values at the following time points are required in order to calculate the normalised AUC0-8/8h: 
pre-dose; at least one value between 0 and 4 hours and the value at 8 hours post-dose.  For 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 26 of 50
AUC0-24/24h , non-missing FEV1 values at the following time points are required in order to 
calculate the normalised AUC0-24/24h: pre-dose; 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.
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 or 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 8 to Day 15)
!
Change from baseline in Peak FEV1 over treatment duration (Day 8 to Day 14)
3.3.1.3
Other FEV1 -related variables
!
Change from baseline in FEV1 AUC0-4/4h on Day 1, Day 8, and Day 14
!
Change from baseline in FEV1 AUC0-8/8h on Day 1, and Day 14
!
Change from baseline in FEV1 AUC0-24/24h on Day 1, and Day 14
!
Change from baseline in Trough FVC on Day 2, Day 8 and Day 14
!
Change from baseline in Peak FVC on Day 1, Day 8, and Day 14
!
Change from baseline in FEV1 on Day 1, Day 8, and Day 14 at each timepoint
3.3.2
Other efficacy variables
3.3.2.1
Total Score BCSS and cough, breathlessness and sputum individual domain scores
The average of the Total Score BCSS and cough, breathlessness and sputum individual 
domain scores obtained the run-in period baseline will be used as baseline for all treatments in 
each period.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 27 of 50
The daily change from baseline obtained after treatment in Total Score BCSS 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 
3.3.2.2
Rescue medication use (Salbutamol)
The baseline for daily rescue medication use will be the daily average of puffs recorded in the 
e-Diary during the run-in period, prior to the first dose of double-blind investigational product;
this baseline will be used as baseline for all treatments in each period.
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 
3.3.2.3
Taste 
For each evaluated item (Sweet, Salty, Sour, Bitter, Metallic, Hot/Spicy, Overall Rating,Smell, 
Would take again), the score (from 0 to 10) will be summarized by treatment.  The answer 
(Y/N) to the question “Do you think this medicine smells?” and the duration of the taste of the 
medicine stays in the mouth will also be summarized by treatment. 
3.4
Pharmacokinetic variables
The PK analyses of the plasma concentration data for AZD8871 and its metabolites 
(LAS191861 and LAS34850), will be performed at Covance, UK, on behalf of AstraZeneca.
The actual sampling times will be used in the plasma PK parameter calculations. 
PK parameters will be derived using non-compartmental methods with Phoenix® 
WinNonlin® Version 6.3, or higher. Pharmacokinetic analyses will be conducted according to 
AstraZeneca SOPs for PK analyses, if not otherwise indicated. 
Plasma concentrations below the lower limit of quantification (BLQ) from the time of pre-
dose sampling (t=0) up to the time of the first quantifiable concentration will be set to a value 
of 0. After this point, BLQ plasma concentrations will be set to missing for all concentration 
profiles. 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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 28 of 50
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 the AUC parameter to be summarised.
When possible, the following PK parameters will be assessed for AZD8871 and its 
metabolites, LAS191861 and LAS34850 on plasma concentrations:
Day 1:
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
AUClast - Area under the plasma concentration-curve from time zero to the time of last 
quantifiable concentration
AUC(0-24) - Area under the plasma concentration-curve from time zero to 24 hours post-dose
Cmax/D - Observed maximum concentration divided by dose 
AUC(0-24) /D - Area under the concentration-time curve zero to 24 h divided by the dose 
For metabolites LAS191861 and LAS34850 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
Day 14:
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 
AUClast - Area under the plasma concentration-curve from time zero to the time of last 
quantifiable concentration
AUC(0-24) - Area under the plasma concentration-curve from time zero to 24 hours post-dose


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 29 of 50
Cmax/D - Observed maximum concentration divided by dose 
AUC(0-24) /D - Area under the concentration-time curve zero to 24 h divided by the 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)
For metabolites LAS191861 and LAS34850 only:
MRCmax - Metabolite to parent ratio for Cmax
MRAUC0-24 - Metabolite to parent ratio for AUC0-24
3.5
Safety variables
3.5.1
Adverse events
AEs: The number and percentage of patients who experienced 1 or more TEAEs, 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. 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.  
A TEAE that occurs during a wash-out period will be associated to the last treatment taken.  
An AE that occurs more than 30 days after the last IP administration will not be counted as a 
TEAE.  
3.5.2
Serious adverse events
An 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


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 30 of 50
!
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 30 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
Laboratory variables 
Laboratory parameters will be recorded at Visit 1, pre-dose at visits 3, 6, 9, and 24h postdose 
at visits 5, 8, 11, and at follow-up.
The laboratory variables detailed in 
Table 2
Laboratory safety variables


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 31 of 50
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
Coagulation parameters (INR, PTT and aPTT)a
S/P-Calcium, total
S/P-Chloride
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
U-Ketones
U-Nitrites
ALP=Alkaline phosphatase; ALT=Alanine transaminase; aPTT=Activated 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; PTT=Partial 
thromboplastin time.
a. Coagulation parameters will be assessed at Screening and Follow-up Visits only. 
will be recorded. In addition, serum 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.  


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 32 of 50
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.
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
Coagulation parameters (INR, PTT and aPTT)a
S/P-Calcium, total
S/P-Chloride
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
U-Ketones
U-Nitrites
ALP=Alkaline phosphatase; ALT=Alanine transaminase; aPTT=Activated 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; PTT=Partial 
thromboplastin time.
a. Coagulation parameters will be assessed at Screening and Follow-up Visits only. 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 33 of 50
3.5.4
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.  
Number of ECG abnormalities in each category of conduction defects, rhythsm, MI signs and 
others will be reported at each timepoint from each day within each treatment.
The following ECG parameters will be analyzed:
!
Heart rate
!
RR interval: Duration in milliseconds between two R peaks of two consecutive
!
QRS complexes
!
PR interval: Duration in milliseconds from the beginning of wave P to onset of 
ventricular 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:
∀
QTcB interval: QT interval corrected using Bazett formula 
(QT[msec]/RR[sec]1/2)
∀
QTcF interval: QT interval corrected using Fridericia’s formula 
(QT[msec]/RR[sec]1/3)
For HR, and QTcF parameters, between-group differences will be presented at each timepoint 
(day, timepoint (hours) within day). 
3.5.5
Vital signs
Systolic and diastolic blood pressure (BP) will be recorded at screening, pre-dose and 1, 2, 4, 
and 24 hours 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, and follow-up.  


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 34 of 50
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 Placebo and 
!
AZD8871 100 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. As such, no formal hypothesis 
testing will be performed for this study and results from statistical analyses cannot be 
interpreted in terms of statistical significance.  
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 100 μg, AZD8871 600 
μg, 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, 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.
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 be presented, 
but these cannot be interpreted in terms of statistical significance.  The presentation of 
p-values will be to three decimal places unless a p-value is less than 0.001, in which case 
“<0.001” will be displayed.
A month is operationally defined to be 30.4 days


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 35 of 50
4.2
Analysis methods
4.2.1
Analyses of study population
4.2.1.1
Patient disposition
The number and percentage of patients who are screen failures (i.e., patients screened but not 
randomised), will be summarised overall for the screening analysis set. The reson for screen 
failure will be listed.
The number and percentage of patients screened, 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 the 
screening analysis set. 
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 analysis set.  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 Safety 
population.
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): 
012345
4123456
!
Time from diagnosis of COPD to randomisation (years), calculated as:
date of randomisation −date of diagnosis of COPD
365.25
!
Time from most recent exacerbation to randomisation (months), calculated as:
date of most recent exacerbation −date of diagnosis of COPD
30.4
!
Number of exacerbations in previous 12 months
!
Pre-bronchodilator FEV1 at screening (L)
!
Pre-bronchodilator FEV1 % predicted at screening


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 36 of 50
!
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 (%)
!
FEV1 absolute reversibility at screening (mL)
!
Bronchial reversibility at screening (%)
!
Baseline FEV1 (L)
!
Baseline FVC (L)
!
Baseline FEV1 % predicted
!
Baseline FVC % predicted
The total counts and percentages of patients will be presented for the categorical variables of:
!
Sex
!
Race
!
Ethnicity
!
Smoking status (Current smoker, Former smoker)
!
Smoking history (number of pack-years)
!
Severity of airflow limitation at screening, defined as:
o
Stage II (moderate): post-bronchodilator FEV1/FVC < 70% and 
post-bronchodilator FEV1 % predicted ≥ 50% and < 80%
o
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 bronchial 
reversibility ≥ 12% and FEV1 absolute reversibility ≥ 200 mL. 
Medical history will be listed and the number and percentage of patients with any medical 
history will be summarised for the safety analysis set 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 for the safety analysis set. Those medications continuing 
after ICF will be reported as well and classified in both prior and concomitant 
medication groups.
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), 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 37 of 50
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 safety analysis set, using 
descriptive statistics. 
4.2.1.4
Treatment compliance
Treatment compliance (%) will be summarised by treatment for the safety analysis set, using 
continuous type descriptive statistics. 
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 analysis set. 
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 100 μg versus Placebo 
! AZD8871 600 μg versus Placebo
Treatment comparison among active treatments will be also explored.
A sensitivity analysis will be conducted for internal validity purposes, whereby patients with 
important deviations from protocol deemed to affect efficacy will be excluded from the 
analysis (see Section 2.2).  To confirm the achievement of the main objectives of this study, 
the above summary and analysis of change from baseline in trough FEV1 at Day 15 will be 


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 38 of 50
repeated for the PP analysis set, with those patients with any important protocol deviation 
affecting efficacy being excluded from the FAS set for the respective treatments. 
An additional sensitivity analysis will be performed using for 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.
For all mixed models, the estimation method used will be Restricted Maximum Likelihood 
(REML). The Kenward and Roger version of the F-test 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 analysis set and will be 
based on the same model as described in 4.2.2.
!
Change from baseline in Trough FEV1 over treatment duration (Day 8 to Day 15)
!
Change from baseline in Peak FEV1 over treatment duration (Day 8 to Day 14)
The analyses of the 2 above endpoints will be performed using the FAS analysis set. 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 8 and Day 15)
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 version of the F-test will be used. 
4.2.4
Analysis of the other FEV1 -related variables
All analyses below will be based on the FAS analysis set and will be based on the same model 
as described in 4.2.2.
!
Change from baseline in FEV1 AUC0-4/4h at Day 1, Day 8, and Day 14
!
Change from baseline in FEV1 AUC0-8/8h at Day 1, and Day 14


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 39 of 50
!
Change from baseline in FEV1 AUC0-24/24h at Day 1, and Day 14
!
Change from baseline in Trough FVC on Day 2, Day 8, and Day 15
!
Change from baseline in Peak FVC on Day 1, Day 8, 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 
analysis set 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. 
4.2.5
Analysis of the other efficacy variables
The change from baseline in Total Score BCSS 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.  
The change from baseline in use of rescue medication at Day 8, and at Day 14 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.
4.2.6
Exploratory outcome variables
4.2.6.1
Taste Assessment
For each evaluated item (Sweet, Salty, Sour, Bitter, Metallic, Hot/Spicy, Overall Rating,Smell, 
Would take again), the score (from 0 to 10) will be summarized by treatment.  
4.3
Analysis of pharmarcokinetic variables 
4.3.1.1
Descriptive statistics
A listing of PK blood sample collection times as well as derived sampling time deviations will 
be provided.  AZD8871, LAS191861 and LAS34850 plasma concentrations will be listed by 
subject and time-point.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 40 of 50
Plasma concentrations for AZD8871 and its metabolites will be summarised by dose level of 
AZD8871 using descriptive statistics (n, geometric mean, geometric coefficient of variation 
[CV%], arithmetic mean, arithmetic SD, minimum, median and maximum) based on the PK 
analysis set.
For descriptive statistics for plasma concentrations that are below the LLOQ will be handled 
as follows:
•
Where there is NR, these will be set to missing.
•
At a time point where less than or equal to 50% of the values are BLQ, all BLQ values 
will be set to the LLOQ, and all descriptive statistics will be calculated accordingly.
•
At a time point where more than half (but not all) of the values are BLQ, the arithmetic 
mean, arithmetic SD, geometric mean and CV% will be set to Not Determined (ND).  The 
maximum value will be reported from the individual data, and the minimum and median will 
be set to BLQ.
•
If all values are BLQ at a time point, no descriptive statistics will be calculated for that 
time point.  Not applicable (NA) will be written in the field for arithmetic SD and geometric 
CV% and BLQ will be written in fields for arithmetic mean, geometric mean, minimum, 
median, and maximum.
•
The number of BLQ values (n above LLOQ) will be reported for each time point.
For display in figures:
• For mean plots: BLQ values will be handled as described for the descriptive statistics. If this 
handling results in a geometric mean of "NA", "ND" or "BLQ", then the value plotted at that 
time-point will not be plotted (made missing)
• For individual plots and combined individual plots: BLQ values will be set to zero on Day1, 
pre-dose; at all other time-points, BLQ values will be set to missing
All plasma PK parameters for AZD8871 and metabolites will also be listed and summarised 
using using the same descriptive statistics as for the plasma concentrations, based on the PKS.  
Summaries will be presented by dose level of AZD8871, Day and parameter. For tmax only n, 
median, minimum and maximum will be reported.
The statistics for geometric mean, geometric mean+/-geometric SD and geometric CV% will 
be calculated as follows: 
Geometric mean: Calculated as exp[ML]
Geometric mean +/- geometric SD: Calculated as exp[ML +/- SDL]
Geometric CV% : Calculated as 100 x sqrt[exp(SL
2) – 1]


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 41 of 50
For the geometric mean, geometric mean +/- geometric SD and geometric CV%, the following 
holds:
• SDL is the arithmetic standard deviation of the natural log-transformed variable
• ML is the arithmetic mean of the natural log-transformed variable
• exp denotes the power function based on the natural base e
• The variable will not be calculated if one more of the raw values (prior to log-transform) is 
zero
Data from patients excluded from the PK analysis set will be included in the data listings, but 
not in the summaries or in the inferential statistics or in mean figures or combined individual 
figures
Individual plasma concentrations versus actual time will be plotted in linear and semi 
logarithmic scale, with separate plots for each subject and concentrations for Day 1 and Day 
14 (where applicable).  Combined individual plasma concentration per dose level of AZD8871 
will also be presented in linear and semi logarithmic scale with separate plots for each dose 
level and day (Day 1 and Day 14).
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, with each 
Day (Day 1 and Day 16) overlaid on the same plot..  
All plots will be repeated for AZD8871 and its metabolites. All mean and combined 
individual plots will be based on the PK analysis set. All individual plots will be based on the 
safety analysis set.
Additional graphical presentations of PK data may be added at the discretion of the PK 
Scientist.
4.3.1.2
Analysis of AUC(0-24) , Cmax at Day 1 and Day 14 and accumulation between Day 1 
and Day 14
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, 
dose, day and dose by day interaction 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.  Product 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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 42 of 50
4.4
Safety
All safety summaries will be based on the safety analysis set. 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 severity, outcome, action taken with IMP , and 
relationship to study drug.  
Any AE occurring before the first dose of IP, or more than 30 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
!
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
If severity is missing for a TEAE, then a severity of severe will be assigned.  The imputed 
values for severity will be used for the summary of TEAEs by severity; the actual values will 
be presented in the data listings.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 43 of 50
If the relationship to treatment is missing for a TEAE, a relationship of related will be 
assigned.  The imputed values for relationship to treatment will be used for the summary of 
TEAEs by relationship to treatment; the actual values will be presented in data listings.
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 causally related to treatment 
!
All TEAE with outcome = death
!
All TEAE with outcome = death, causally related to treatment 
!
All TESAE (including events with outcome = death)
!
All TESAE (including events with outcome = death), causally related to treatment 
!
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, HLT, and PT (this table will also include the number and percentage of TEAEs 
episodes).
!
SOC, PT, and intensity
!
SOC, PT, and causality with the IMP
!
SOC, PT and seriousness
!
SOC, PT and action taken     
!
SOC, PT and outcome
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.
Key patient information (age/sex/race) for patients experiencing SAEs and discontinuation of 
study drug due to AEs will be presented in a listing.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 44 of 50
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 extended 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 postdose 
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 (±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 (low, normal or high as above) at baseline to a 
postbaseline 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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 45 of 50
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 4 and 
the ratio of endpoint value to baseline value is also greater than the corresponding coefficient 
(multiplying factor) specified in Table 4, 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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 46 of 50
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
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


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 47 of 50
Table 3
Expanded normal ranges and notable abnormalities for laboratory 
parameters
Laboratory Parameter
Expanded Normal Ranges
Notable Abnormalities
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
4.4.1.3
ECG
All ECG data collected will be listed.
Mean absolute values and mean change from baseline for ECG parameters will be 
summarised by treatment, day (Day 1, 8, and 14) and timepoint within day, 95% confidence 
intervals for the change from baseline will be provided in addition to the usual descriptive 
statistics parameters.
Graphical presentation of mean change from baseline (±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 Error! Reference source not found.. 
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).  


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 48 of 50
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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 49 of 50
Table 4
PCS ECG criteria: QTcF exceeding ICH boundaries
Category 1: QTcF value above the following cut-off at any time during 
treatment
Criterions:
     >450 (ms)
     >480 (ms)
     >500 (ms)
Category 2: QTcF increase by more than following cut-off at any time during 
treatment
Criterions:
     >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 < 120 
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 
≥ 250 msec if 
baseline is 
< 250 msec


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 50 of 50
baseline value
bpm = beats per minute.
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 ± 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 < 200
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.


Statistical Analysis Plan 
Study Code D6571C00002
Edition Number 
Date 26 June 2017
Page 51 of 51
5.
INTERIM ANALYSES (NOT APPLICABLE)
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Additional exploratory endpoints for efficacy were added 
!
Change from baseline in FEV1 AUC0-4/4h at Day 1, Day 8, and Day 14
!
Change from baseline in FEV1 AUC0-8/8h at Day 1, and Day 14
!
Change from baseline in FEV1 AUC0-24/24h at Day 1, and Day 14 
!
Change from baseline in Trough FVC on Day 2,  Day 8, and Day 15
!
Change from baseline in Peak FVC on Day 1, Day 8 and Day 14
!
Additional exploratory endpoints were added 
Change in definition of TEAE: 
An AE will be considered a TEAE if it was not present prior to the date of the first dose of IP. 
As opposed to what is presently written in the protocol, AE  present prior to the date of the 
first dose of IP and that  increased in severity after IP administration will not be considered 
TEAE.  
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 parameter will be performed.
7.
REFERENCES (NOT APPLICABLE)
8.
APPENDIX (NOT APPLICABLE)