Conditions: Asthma
Keywords: inhaled TLR9 agonist withdrawal design loss of control
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 81
Healthy volunteers: no

Brief summary:
Ph2a study planned to be run at approximately 16-18 sites in 4 EU countries (Denmark, Hungary, Poland and Sweden) enrolling approximately 170 patients to ensure 70 randomized patients with eosinophilic, moderate to severe asthma. The patients will receive 13 once weekly inhaled doses of the study drug. Treatment is initiated on top of their ICS/LABA controller medication, which is then tapered down and withdrawn during a period of 3 weeks and during the last 3 weeks of treatment the study drug is given as monotherapy. SABA is used as reliever medication during the whole study period. Primary endpoint is Loss of asthma control. When the endpoint is met, patients will resume their ICS/LABA, will be followed for an additional 4 weeks and will thereafter discontinue the study.

Detailed description:
Ph2a study planned to be run in approximately 16-18 sites in 4 EU countries (Denmark, Hungary, Poland and Sweden) enrolling approximately 170 patients to ensure 70 randomized patients with eosinophilic, moderate to severe asthma.

The study has a withdrawal design.The patients will receive 13 once weekly inhaled doses of the study drug (AZD1419 or placebo). Treatment is initiated with 6 doses of the study drug on top of their ICS/LABA controller medication. Prior to the 7th dose of the study drug the LABA is withdrawn. The following 3 doses are given when ICS is tapered down. Dose 7 is given on top of 100% of their ICS, dose 8 is given on top of 50% of the ICS dose, which is then tapered down to 25% the following week and withdrawn completely prior to dose 10 of the study drug. During the last 3 weeks of treatment (ie last 4 doses), the study drug is given as monotherapy. SABA is used as reliever medication during the whole study period. Primary endpoint is Loss of asthma control, defined as any of the following criteria: a) An increase of ACQ-5 to 1.5 or more b) A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline on 2 consecutive days c) At least six additional reliever inhalations of SABA in a 24-hour period relative to baseline on 2 consecutive days and d) An exacerbation requiring systemic corticosteroids

When the endpoint is met, patients will resume their regular ICS/LABA controller medication and will be followed for an additional 4 weeks, when they do an Early Discontinuation (ED) Visit and will thereafter leave the study. For patients not loosing their asthma control, the full Observational period is up to week 52, when they will do an End of Treatment Visit (EOT). Study procedures are the same on ED and EOT Visits.

Arms:
arm 1: Dose adaption of AZD1419, 4 mg or 8 mg or 1 mg based on occurence of AE's arm 2: Matching placebo

Interventions: intervention 1: AZD1419 intervention 2: Placebo
Intervention descriptions: intervention 1: Inhaled AZD1419 administered at the clinic as once weekly inhalations with the I-neb® device. Start dose is 4 mg and dose adaptation is applied (downtitration to 1mg or uptitration to 8 mg or remain on 4 mg) based on appearance of flu like adverse events intervention 2: Inhaled Placebo administered at the clinic as once weekly inhalations with the I-neb® device. Start dose is Placebo 4 mg and dose adaptation is applied (downtitration to 1mg or uptitration to 8 mg or remain on 4 mg) based on appearance of flu like adverse events

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol 
Drug Substance
AZD1419
Study Code
D2500C00003
Version
3
Date
17 October 2016
A Phase 2 Placebo-Controlled, Randomized, Double Blind, Adaptive Dose 
Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With 
Eosinophilic, Moderate to Severe Asthma
Sponsor: AstraZeneca AB, S-151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
2(86)
VERSION HISTORY
Version 2.0, Initial creation
Updates done in Sect. 1.2 (2 typos corrected), Sect 1.3 (paragraph added), Figure 1 (Visit 
windows), Sect 3.1 (Incl crit 3), Sect 3.2 (typo corrected and Excl crit 2 & 9), Sect 3.8 
(restriction added), Table 1 (typo corrected and clarification of FEV1), Sect 4.2.2 
(clarification re vaccination), Sect 5.1.5 (clarification of FEV1) and Table 3 (typo
corrected).
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.


PROTOCOL SYNOPSIS
A Phase 2 Placebo-Controlled, Randomized, Double Blind, Adaptive Dose 
Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With 
Eosinophilic, Moderate to Severe Asthma
International Co-ordinating Investigator:
Professor Vibeke Backer
Bispebjerg Hospital
Bispebjerg Bakke 23
2400 Copenhagen NV
Denmark
Study site(s) and number of patients planned
This study will be a multi-centre study conducted at approximately 20 centres in 4-5 countries. 
Approximately 170 patients will be enrolled to achieve 70 randomised patients.
Study period
Phase of development
Estimated date of first patient enrolled
Q4 2016
II
Estimated date of last patient completed
Q4 2018
II
Study design
This phase 2a study is a randomized, double-blind, placebo-controlled trial designed to assess 
the efficacy and safety of 13 once weekly doses of inhaled AZD1419 administered to patients 
with eosinophilic asthma controlled on a maintenance treatment of inhaled corticosteroids 
(ICS) and a long-acting β2 agonist (LABA), but no other controller medication.
Prior to randomization patients will undergo an approximately 2-4 week screening period. 
Eligible patients will be prescribed their usual controller medication (i.e. ICS + LABA in 
separate inhalers, in addition to a rescue medication inhaler (short-acting β2 agonist [SABA]), 
and issued electronic diaries, peak flow and FeNO meters to record asthma symptoms and 
lung function during each morning and evening at home. Asthma control will be assessed 
using the 5-item asthma control questionnaire (ACQ-5) and when patients have shown to be 
controlled (ACQ-5 ≤0.75) they are randomized to receive AZD1419 or placebo administered 
as an inhalation at the clinic once per week.
A withdrawal design will be used where the first 6 doses of IMP will be administered as add-
on to the patient’s regular ICS + LABA. The controller treatment will then be tapered down 
during the next 3 doses of AZD1419/placebo and the last 4 doses will be administered during 
a period of complete withdrawal of maintenance treatment. SABA will be allowed and used as 


Clinical Study Protocol Synopsis
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Study Code D2500C00003
Version 3
Date 17 October 2016
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reliever medication during the whole study. The first 4 doses of IMP will be given as 4mg per 
week after which the dose is potentially adjusted to 1 mg or 8 mg per week based on 
frequency and severity of flu-like adverse events (arthralgia, chills, pyrexia, myalgia)
occurring within 24h of inhalation in the individual patient.
The patients will be monitored closely with regards to asthma symptoms, reliever use and lung 
function and upon loss of control of their asthma they will resume their ICS + LABA 
controller medication and are considered to have met the primary endpoint. The patients are 
then followed for an additional 4 weeks.
Objectives
Primary Objective:
Outcome Measure:
To assess the efficacy of inhaled AZD1419 in 
eosinophilic asthma patients after withdrawal of
controller treatment of ICS + LABA
Time to loss of asthma control
For the purpose of the study loss of asthma control is defined as any of the following:
(a)
An increase of ACQ-5 to 1.5 or more 
(b)
A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline 
on 2 consecutive days
(c)
At least six additional reliever inhalations of SABA in a 24-hour period relative to 
baseline on 2 consecutive days
(d)
An exacerbation requiring systemic corticosteroids
Secondary Objective:
Outcome Measure:
To further assess the efficacy of inhaled 
AZD1419 in eosinophilic asthma patients after 
withdrawal of controller treatment of ICS + 
LABA
Proportion of patients who experience loss of asthma 
control
Changes over the course of the study in ACQ-5
Changes over the course of the study in asthma daily 
diary score
Changes over the course of the study in number of 
moderate and severe exacerbations 
Changes over the course of the study in the use of 
reliever bronchodilator (short-acting beta-agonist 
SABA) 
Changes over the course of the study in pre- and 
post-bronchodilator FEV1 
Changes over the course of the study in PEF
Changes over the course of the study in fractional 
exhaled nitric oxide (FeNO) 


Clinical Study Protocol Synopsis
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
inhaled AZD1419 in eosinophilic asthma 
patients after withdrawal of controller treatment 
of ICS + LABA
Adverse events, vital signs, ECG and laboratory 
parameters 
Weekly peak expiratory flow rate (PEFR)
Lung diffusion capacity (DLco)
Exploratory objective:
Outcome Measure:
! To assess the responses of selected systemic 
peripheral blood and sputum biomarkers to 
inhaled AZD1419 in eosinophilic asthma 
patients after withdrawal of controller 
treatment of ICS + LABA
! Peripheral blood and sputum biomarkers (to be 
specified)
! To assess the composite endpoint for 
exacerbations, CompEx 
! Time to first CompEx event
! Changes over the course of the study in CompEx
! To investigate the genes and genetic variation 
that may influence response to AZD1419
! DNA from whole blood
! To assess the expression of selected genes in 
cells from whole blood and sputum
! RNA from whole blood and sputum
! To assess the effects on DNA 
methylation
! DNA from whole blood
! To assess the immune function of PBMC
! PBMCs
Target patient population
The study population will comprise adult eosinophilic asthma patients on a background 
treatment of ICS + LABA.
Duration of treatment
The total duration of patient participation will be up to 56 weeks. This includes an 
approximately 2-4 week screening period prior to the first trial treatment, a 12 week dosing 
period with AZD1419 or placebo and an up to 40-week observation/follow up period 
following the last trial treatment. 
Investigational product, dosage and mode of administration
The investigational product, AZD1419 or matching placebo, will be administered once weekly 
using the commercially available and CE marked I-neb® Adaptive Aerosol Delivery [ADD] 
System from Philips Respironics. 
AZD1419/placebo is supplied as a solution at a concentration of 2 mg/mL, 8 mg/mL and 16 
mg/mL in phosphate-buffered saline.
Three inhaled dose levels of AZD1419/placebo, 1 mg, 4 mg and 8 mg may be investigated in 
a 12 week regimen consisting of 4 once weekly inhaled doses of 4 mg followed by 8 weeks of


Clinical Study Protocol Synopsis
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Study Code D2500C00003
Version 3
Date 17 October 2016
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inhaled doses of 1 mg, 4 mg, or 8 mg. The maximum possible dose that any patient will 
receive during the study is 8 mg.
The placebo for this trial is phosphate-buffered saline, pH 7.2.
Statistical methods and sample size
The primary efficacy variable is the time to loss of asthma control, and the primary analysis is 
to compare the time to loss of asthma control for AZD1419 with placebo. The time to loss of 
control in the AZD1419 group will be compared to that of the placebo group using a log rank 
test (with accompanying Kaplan-Meier plot).  The hypothesis test will be one-sided, with 
alpha=0.05.
The secondary outcome variables listed above will be analysed longitudinally using all 
measurements taken over the course of the study.  Continuous variables will be modelled 
using mixed effects models; categorical outcomes will be modelled using generalized 
estimating equations.  Additionally, all outcomes will be summarized by treatment group at 
each measurement time point.
This trial has about 90% power to yield a statistically significant (alpha = 0.05, 2-sided) 
difference between the pooled active and placebo groups in time to loss of asthma control 
given that the cumulative number of controlled subjects at week 52 is 20% and 60% for 
control versus active respectively. Assuming a drop-out of about 10-15%, this will require 
about 70 patients in total (32 events).


Clinical Study Protocol
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Study Code D2500C00003
Version 3
Date 17 October 2016
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TABLE OF CONTENTS
PAGE
TITLE PAGE............................................................................................................................1
VERSION HISTORY ..............................................................................................................2
PROTOCOL SYNOPSIS .........................................................................................................3
TABLE OF CONTENTS .........................................................................................................7
1.
INTRODUCTION .................................................................................................15
1.1
Background and rationale for conducting this study .............................................15
1.2
Rationale for study design, doses and control groups............................................16
1.3
Benefit/risk and ethical assessment........................................................................17
1.4
Study Design..........................................................................................................19
2.
STUDY OBJECTIVES..........................................................................................21
2.1
Primary objective...................................................................................................21
2.1.1
Definition of Loss of asthma control .....................................................................21
2.2
Secondary objectives .............................................................................................21
2.3
Safety objectives ....................................................................................................22
2.4
Exploratory objectives ...........................................................................................22
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................22
3.1
Inclusion criteria ....................................................................................................22
3.1.1
Acceptable birth control methods ..........................................................................24
3.2
Exclusion criteria ...................................................................................................25
3.3
Enrolment and randomization................................................................................26
3.4
Procedures for handling incorrectly enrolled or randomized patients...................27
3.5
Methods for assigning treatment groups................................................................27
3.6
Methods for ensuring blinding...............................................................................27
3.7
Methods for unblinding..........................................................................................28
3.8
Restrictions ............................................................................................................28
3.9
Discontinuation of investigational product............................................................29
3.10
Criteria for withdrawal...........................................................................................29
3.10.1
Screen failures........................................................................................................29
3.10.2
Rescreening............................................................................................................29
3.10.3
Withdrawal of the informed consent......................................................................29


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3.11
Discontinuation of the study..................................................................................30
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................31
4.1
Enrolment/screening period...................................................................................34
4.2
Treatment period....................................................................................................34
4.2.1
Sentinel Dosing Procedure.....................................................................................35
4.2.2
Dose Adaptation Procedure ...................................................................................35
4.3
Follow-up period/Observation period....................................................................36
5.
STUDY ASSESSMENTS .....................................................................................37
5.1
Efficacy assessments..............................................................................................37
5.1.1
Asthma Control Questionnaire ..............................................................................37
5.1.2
The Asthma Daily Diary........................................................................................38
5.1.3
Composite endpoint for exacerbations (CompEx).................................................39
5.1.3.1
Evaluation of Loss of asthma control ....................................................................39
5.1.4
Fractional Exhaled Nitric Oxide (FeNO)...............................................................40
5.1.5
Spirometry..............................................................................................................40
5.2
Safety assessments.................................................................................................40
5.2.1
Laboratory safety assessments...............................................................................40
5.2.1.1
Volume of Blood....................................................................................................41
5.2.2
Physical examination .............................................................................................42
5.2.3
ECG........................................................................................................................42
5.2.3.1
Resting 12-lead ECG .............................................................................................42
5.2.4
Vital signs ..............................................................................................................43
5.2.4.1
Pulse, pulse oximetry and blood pressure..............................................................43
5.2.5
Diffusing Capacity of the Lung for Carbon Monoxide (DLco).............................43
5.2.6
Chest X-ray of the Lung ........................................................................................43
5.3
Other assessments ..................................................................................................43
5.3.1
Patient reported outcomes......................................................................................43
5.3.2
Sputum induction...................................................................................................44
5.4
Pharmacokinetics ...................................................................................................44
5.5
Pharmacodynamics ................................................................................................44
5.5.1
Collection of samples.............................................................................................44
5.5.2
Storage, re-use and destruction of pharmacodynamic samples .............................45
5.6
Pharmacogenetics ..................................................................................................45
5.6.1
Collection of pharmacogenetic samples ................................................................45
5.6.2
Storage, re-use and destruction of pharmacogenetic samples ...............................45
5.7
Biomarker analysis.................................................................................................46
5.7.1
Storage, re-use and destruction of biological samples...........................................46
5.7.2
Labelling and shipment of biological samples.......................................................46
5.7.3
Chain of custody of biological samples.................................................................46
5.7.4
Withdrawal of Informed Consent for donated biological samples ........................47


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Study Code D2500C00003
Version 3
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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................47
6.1
Definition of adverse events ..................................................................................48
6.1.1
Definition of Flu-like Symptoms...........................................................................48
6.2
Definitions of serious adverse event......................................................................48
6.3
Recording of adverse events ..................................................................................49
6.3.1
Time period for collection of adverse events.........................................................49
6.3.2
Follow-up of unresolved adverse events................................................................49
6.3.3
Variables ................................................................................................................49
6.3.4
Causality collection................................................................................................50
6.3.5
Adverse events based on signs and symptoms.......................................................50
6.3.6
Adverse events based on examinations and tests...................................................51
6.3.7
Hy’s Law................................................................................................................51
6.4
Reporting of serious adverse events.......................................................................52
6.5
Overdose ................................................................................................................52
6.6
Pregnancy...............................................................................................................53
6.6.1
Maternal exposure..................................................................................................53
6.6.2
Paternal exposure...................................................................................................53
6.7
Management of IMP related toxicities/Dose Reductions ......................................54
6.8
Study governance and oversight ............................................................................54
6.8.1
Data Safety Monitoring Board...............................................................................54
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................54
7.1
Identity of investigational product(s).....................................................................54
7.2
Dose and treatment regimens.................................................................................55
7.2.1
Study Treatments ...................................................................................................55
7.3
Labelling ................................................................................................................55
7.4
Storage ...................................................................................................................55
7.5
Compliance ............................................................................................................55
7.6
Accountability........................................................................................................55
7.7
Concomitant and other treatments .........................................................................56
7.7.1
Other concomitant treatment..................................................................................56
7.8
Post Study Access to Study Treatment (Not applicable).......................................56
8.
STATISTICAL ANALYSES BY ASTRAZENECA OR DELEGATE................56
8.1
Statistical considerations........................................................................................56
8.2
Sample size estimate..............................................................................................57
8.3
Definitions of analysis sets ....................................................................................57
8.3.1
Efficacy analysis set...............................................................................................57


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8.3.2
Safety analysis set..................................................................................................57
8.4
Outcome measures for analyses.............................................................................57
8.4.1
General Definitions................................................................................................57
8.4.1.1
Definition of baseline.............................................................................................57
8.4.1.2
Visit and period windows ......................................................................................58
8.4.2
Calculation or derivation of efficacy variables......................................................58
8.4.2.1
Time to loss of asthma control...............................................................................58
8.4.3
Calculation or derivation of PRO variables...........................................................58
8.4.3.1
Asthma Control Questionnaire (ACQ-5)...............................................................58
8.5
Methods for statistical analyses .............................................................................59
8.5.1
Patient disposition, demography data and patients characteristics ........................59
8.5.2
Exposure ................................................................................................................59
8.5.3
Violations and deviations.......................................................................................59
8.5.4
Analysis of the primary variable (s).......................................................................60
8.5.4.1
Analysis of loss of asthma control as group proportions.......................................60
8.5.5
Analysis of the secondary variable(s)....................................................................60
8.5.5.1
Time to first moderate or severe exacerbation.......................................................60
8.5.5.2
Proportion of patients with ≥1 moderate or severe asthma exacerbation ..............60
8.5.5.3
Forced expiratory volume in 1 second (FEV1) ......................................................61
8.5.5.4
Peak expiratory flow (PEF) ...................................................................................61
8.5.5.5
Analysis of ACQ-5 ................................................................................................61
8.5.5.6
Analysis of fractional exhaled nitric oxide (FeNO)...............................................61
8.5.5.7
Other airways measurements .................................................................................61
8.5.5.8
Reliever medication ...............................................................................................62
8.5.6
Interim analyses .....................................................................................................62
8.4.7 
Sensitivity analysis (if applicable).........................................................................62
8.4.8
Exploratory efficacy analysis.................................................................................62
8.5.9
Safety analysis .......................................................................................................63
8.5.9.1
Adverse events.......................................................................................................63
8.5.9.2
Vital signs ..............................................................................................................63
8.5.9.3
Diffusing Capacity of the Lung for Carbon Monoxide (DLco).............................63
8.5.9.4
Physical examination and ECG .............................................................................63
8.5.9.5
Haematology, clinical chemistry and urinalysis ....................................................63
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................64
9.1
Training of study site personnel.............................................................................64
9.2
Monitoring of the study .........................................................................................64
9.2.1
Source data.............................................................................................................64
9.2.2
Study agreements...................................................................................................64
9.2.3
Archiving of study documents...............................................................................65
9.3
Study timetable and end of study...........................................................................65
9.4
Data management by AstraZeneca or delegate......................................................65
10.
ETHICAL AND REGULATORY REQUIREMENTS.........................................66


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10.1
Ethical conduct of the study...................................................................................66
10.2
Patient data protection............................................................................................66
10.3
Ethics and regulatory review..................................................................................66
10.4
Informed consent ...................................................................................................67
10.5
Changes to the protocol and informed consent form.............................................68
10.6
Audits and inspections ...........................................................................................68
11.
LIST OF REFERENCES.......................................................................................68
LIST OF TABLES
Table 1
Schedule of events ..........................................................................................31
Table 2
Exacerbation categories ..................................................................................39
Table 3
Laboratory Safety Variables ...........................................................................41
Table 4
Volume of blood to be drawn from each patient ............................................42
LIST OF FIGURES
Figure 1
Phase 2a Study Design....................................................................................20
Figure 2
Dosing.............................................................................................................36
LIST OF APPENDICES
Appendix A
Additional Safety Information........................................................................71
Appendix B
International Airline Transportation Association (IATA) 6.2 Guidance 
Document........................................................................................................73
Appendix C
Pharmacogenetics Research............................................................................74
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law..................................................................................77
Appendix E
ACQ-5.............................................................................................................81
Appendix F
Asthma Daily Diary........................................................................................85


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Study Code D2500C00003
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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
AAD
Adaptive Aerosol Delivery
AE
Adverse event
ANA
Antinuclear antibody
AZ
AstraZeneca
CBC
Complete blood count
CO
Carbon monoxide
CpG
Cytidine-phospho-guanosine
CRF
Case Report Form (electronic/paper)
CRP
C-reactive protein
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CXCL-10 
C-X-C motif chemokine 10
(Formerly known as IP-10 - Interferon inducible protein 10)
DAE
Discontinuation of Investigational Product due to Adverse Event
DBP
Diastolic blood pressure
DLco
Diffusing capacity of the lung for carbon monoxide
DNA
Deoxyribonucleic acid 
dsDNA
Double-stranded DNA
DSMB
Data and safety monitoring board
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
FAS
Full analysis set
FEV1
Forced expiratory volume in 1 second
FEF25-75
Forced expiratory flow 25% to 75%
FeNO
Fractional exhaled nitric oxide
GCP
Good Clinical Practice
GINA
Global Initiative for Asthma
HCV
hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate
HV
Healthy volunteer
IC
Inspiratory capacity


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Abbreviation or 
special term
Explanation
ICF
Informed consent form
ICH
International Conference on Harmonisation
ICS
Inhaled corticosteroids
ICI
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally. 
IFN-α
Interferon alpha
Ig, IgE, IgG
Immunoglobulin, Immunoglobulin E, Immunoglobulin G
IL
Interleukin
IP/IMP
Investigational (Medicinal) Product 
IP-10
Interferon inducible protein 10 (see CXCL-10)
IXRS
IVRS or IWRS Interactive Voice or Web Response System
ISS
Immunostimulatory sequence
LABA
Long-acting beta agonist(s)
LDH
Lactate dehydrogenase
LSLV
Last Subject Last Visit
MTD
Maximum tolerated dose
NICE
National Institute for Health and Care Excellence
OAE
Other Significant Adverse Event
OCS
Oral corticosteroids
ODN
Oligodeoxynucleotide
PBMC
Peripheral blood mononuclear cell
PC20
Provocative concentration of methacholine or histamine causing a 20% fall in 
FEV1
PD
Pharmacodynamics
PD15
Provocative Dose of mannitol causing a 15% fall in FEV1
PEF
Peak expiratory flow 
PGx
Pharmacogenetic research
PS ODN
Phosphorothioate oligodeoxynucleotide
RNA
Ribonucleic acid
SABA
Short-acting beta agonists
SAD
Single ascending dose
SADR
Serious adverse drug reaction
SAE
Serious adverse event 
SAP
Statistical analysis plan
SBP
Systolic blood pressure


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Abbreviation or 
special term
Explanation
SUSAR
Suspected Unexpected Serious Adverse Reaction
Th1, Th2
T helper 1, T helper 2
TLR
Toll-like receptor
VC
Vital capacity
WBDC
Web Based Data Capture
WOCBP
Women of childbearing potential


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a common, chronic respiratory disease affecting up to 18% of the population in 
different countries, and with a global prevalence of approximately 300 million patients
(GINA 2015). Asthma is characterized by wheeze, shortness of breath, chest tightness and/or
cough, and by expiratory airflow limitation. Both symptoms and airflow limitation 
characteristically vary over time and in intensity. Worsening is often triggered by factors such 
as exercise, allergen or irritant exposure, change in weather, or viral respiratory infections. 
In many patients the underlying immunological basis for asthma is a preponderant T-helper 
cell Type 2 (Th2) differentiation of T cells specific for environmental allergens 
(Holgate 2012) and an immune response polarized towards Th2 responses. This results in the 
production of cytokines such as IL-4, IL-5, and IL-13, leading to eosinophilic pulmonary 
inflammation and bronchial hyperresponsiveness. The current approach to anti-inflammatory 
controller therapy in asthma is based on a step-wise intensification of maintenance treatment
primarily centered on daily inhaled corticosteroids (ICS) with the addition of long-acting β2 
agonists (LABA).
Human Toll-like receptors (TLRs) are a key family of pattern-recognition receptors expressed 
in cells of the innate immune system. Recognition of invading pathogens by a TLR triggers 
innate immune responses that promote adaptive immune response and enhance development 
of long term acquired immunity (O’Neill et al 2009). Stimulation of specific TLRs can also 
elicit patterns of cytokine and chemokine production that orients the adaptive response 
towards a particular helper T cell subset. In humans, the TLR family is composed of 10 
different receptors. One sub-family of TLRs, comprising TLR3, TLR7, TLR8 and TLR9, is 
located on the endosomal membrane of cells of the innate immune system and detects nucleic 
acids from invading pathogens. TLR9, the target of AZD1419, recognizes unmethylated CpG 
motifs in bacterial, viral, and fungal DNA. 
Activation of TLR9 by CpG-containing DNA from an invading pathogen leads to maturation 
of plasmacytoid dendritic cells (pDCs) and subsequent production of T-helper type-1 (Th1) 
cytokines, including IFN-α, and chemokines such as CXCL-10. Stimulation of the innate 
immune response through TLR9 has the potential to alter T cell responses to environmental 
antigens from a Th2-dominant allergic response toward a more balanced Th2/Th1 response. 
This immune modification may have the effect of reducing the asthmatic response to e.g. 
allergic triggers, potentially inducing a sustained clinical improvement in airway function and 
asthma symptoms after a relatively short course of treatment.
Stimulation of the innate immune response in asthma via TLR9 has been investigated with the 
compound CYT003-QbG10 (Cytos Biotechnology AG), a virus-like particle containing the 
oligonucleotide TLR9 agonist G10, delivered as a subcutaneous injection. In a phase 2 trial
this was shown to reduce asthma symptoms and allowed patients to maintain both lung 
function (forced expiratory volume in 1 second [FEV1]) and asthma control as measured by 


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the Asthma Control Questionnaire, also after removing the patients’ controller medication
(Beeh et al 2013).
AZD1419 is planned to be developed as a potential disease-modifying therapy for asthma. 
AstraZeneca considers that a course of inhaled AZD1419 administered once weekly for a 
limited period may confer disease remission for a period of time after the course, and 
potentially remove the need for asthma controller medication. The proposed clinical trial of 
AZD1419 in patients with moderate to severe asthma is designed to further characterize the 
safety and efficacy of AZD1419 treatment, and to determine whether AZD1419 provides 
sustained asthma control in patients when removing their controller ICS + LABA medication.
1.2
Rationale for study design, doses and control groups
This study is designed as a withdrawal trial, i.e. the asthma controller (maintenance) 
medication will be reduced and discontinued during the treatment period and the patients are 
followed for up to one year with regards to loss of asthma control (as defined in 2.1.1). 
In addition to the study by Beeh et al 2013, described above, similar withdrawal designs have 
been shown to be valuable in asthma trials evaluating the monoclonal IL-4 receptor antibody 
dupilumab (Wenzel et al 2013) and House Dust Mite Sublingual Allergen Immunotherapy 
(Virchow JC et al 2016), respectively. Controller medication was withdrawn from patients 
with not fully controlled asthma (ACQ-5 between 1.5-3 and 1 to 1.5, respectively, at 
randomization) and followed until need to resume the maintenance medication. A withdrawal 
design is considered appropriate for evaluating the potential for AZD1419 to re-balance the 
immune system with a subsequent disease remission allowing the patients to retain asthma 
control despite having their controller medication reduced and discontinued. There is currently 
no marketed TLR9 agonist, and placebo will be used as comparator to AZD1419. Use of 
SABA is allowed as reliever medication throughout the study.
Asthma patients with Th2 polarized airway inflammation is the target population for 
AZD1419 in this study. Peters et al (Peters et al 2013) have suggested that peripheral blood 
eosinophil counts of 230 cells/mL or above, a value that had similar sensitivity and specificity 
as sputum eosinophilia, is indicative of airway Th2-high driven asthma. For the present study 
we have chosen to allow historical data for blood eosinophils - up to 2 years old - setting the 
cut-off at 250 cells/μL, and >150 cells/μL at screening.
A combined single ascending dose (SAD), multiple ascending dose (MAD) trial in healthy 
adult volunteers (men and women) has been performed with AZD1419 administered once 
weekly for 4 weeks in doses up to 23.1 mg. The dose levels and the weekly dosing regimen 
used in the SAD/MAD was based on results from pharmacodynamics studies and nonclinical 
efficacy (in the ragweed and ovalbumin [OVA] mouse models of allergic pulmonary 
inflammation) and pre-clinical safety studies. Data from the SAD/MAD study suggested 
target engagement at all dose levels. Flu-like symptoms emerged at the 2 highest doses (15.4 
and 23.1 mg), with the 15.4 mg dose regarded as the maximum tolerated dose. Dose levels of 
0.8, 2.3, and 7.7 mg were considered well tolerated. In the proposed study the highest dose 
given will be 8.0 mg/week. However, the dose of IMP (AZD1419 or placebo) will be adapted 


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during the study based on the occurrence and severity of flu-like symptoms in the individual 
patient, to maintain safety and tolerability while testing efficacy in controlling asthma 
symptoms. Patients will start with 4 weeks of 4.0 mg/week inhaled AZD1419, then dosing 
will be adapted for each patient individually, see Section 4.2.2. Pre-clinical data have 
suggested that 12 weekly treatments with the TLR9 agonist ISS 1018 induce suppression of 
allergic airway inflammation lasting for 15 weeks post treatment when the last evaluation was 
performed (Campbell et al 2014 ).  In the present study 13 doses will be administered once 
weekly. This will allow for dosing of IMP on top of controller medication and then allow time 
for safe withdrawal of ICS+LABA as well as dosing in the absence of controller medication.
1.3
Benefit/risk and ethical assessment
Asthma is a chronic inflammatory disorder of the airways associated with substantial 
morbidity. There are currently no available treatments shown to provide remission in asthma, 
but based on data gathered to date AstraZeneca considers AZD1419 to have the potential to 
induce long-term remission and disease control in asthmatics, removing the need for controller 
(maintenance) medication.
TLR9 agonists delivered as subcutaneous, intramuscular or intratumoral injection have been 
widely investigated in clinical studies, mainly for treatment of malignancies and as vaccine 
adjuvants, but also evaluated for treatment of asthma and allergic rhinitis. The most 
commonly reported adverse events are injection site reactions, flu-like symptoms (including 
headache, chills, fatigue, headache, myalgia and pyrexia) and in some cases hematological 
effects such as transient lymphopenia (Scheiermann J and Klinman DM 2014, Qin M et al 
2014).
AZD1419 was not detected in any plasma sample from patients in the highest dose cohort 
(23.1 mg) in the previous trial and the systemic exposure in the proposed study, where the 
maximum given dose will be 8 mg, is expected to be low. The aim is to keep the sensitive 
parameter flu-like AEs at a low or absent level. Patients will start at 4 mg/week and based on 
occurrence of the flu-like symptoms in the individual patient, the dose will be maintained or 
adapted up or down. Should symptoms occur, they should be treated per standard medical 
practice (e.g. paracetamol) based on the judgment of the investigator. 
TLR9 agonists could potentially, by inducing type 1 interferon production, aggravate or 
contribute to the development of autoimmune disease. To mitigate the potential risk for 
subsequent autoimmune reactions patients with a history of autoimmune disease will be 
excluded from taking part in the study. Transient increases in antinuclear antibodies (ANA) 
and anti-doublestranded DNA (anti-dsDNA) without clinical relevance have been seen upon 
CpG oligodeoxynucleotide (CpG ODN) (TLR9 agonist) and Interferon α (IFN-α) exposure. 
To increase our knowledge for the future clinical program patients will donate blood samples 
during the study for later analysis of selected auto-antibodies.
The nonclinical data support the administration of AZD1419 in human repeat-dose inhalation 
studies of up to 13 weeks duration with the proposed doses. Toxicology safety studies 
performed in monkey indicate that AZD1419 induces a dose dependent and transient 


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activation and recruitment of immune cells in the lungs that persists for at least 2 weeks after 
cessation of dosing, but fully resolves after 8 to 12 weeks after the last dose. The data from the 
previous clinical trial with AZD1419 does not indicate risk for local adverse effects in the 
lungs when administered to healthy volunteers. However, patients with asthma or other lung 
diseases may react differently. In the proposed study, patients with lung disease other than 
asthma or clinically relevant chest x-ray changes will be excluded. All doses of study drug 
will be administered at the clinic and the patients will be observed at the clinic for at least 6 
hours after the first dose and for at least 2 hours after the remainder of doses. Patients will be 
followed from start of treatment with standard Adverse Event (AE) monitoring and daily lung 
function tests using home spirometry (peak expiratory flow [PEF]), and in addition spirometry 
performed at the clinic during scheduled visits. Patients will be encouraged to contact the 
study site if they have any concerns about their lung function during the study.
A sentinel dosing period will precede open enrollment into the trial. Four patients will be 
randomly assigned 1:1 either to placebo or AZD1419 at 4 mg/week and observed at the clinic 
for 24 hours after the first 2 doses for significant safety concerns, including bronchospasm and 
allergic reactions. These patients will then continue in the study in accordance with the study 
protocol. After the last of the 4 sentinel patients has received 4 doses, a Data Safety 
Monitoring Board (DSMB) will review safety data and approve enrollment of additional 
patients in the study.
During the dosing period the patients’ controller medication (ICS + LABA) will be gradually 
reduced and discontinued. There is a risk of asthma worsening during the study due to this 
withdrawal design. SABA will be allowed and should be used as needed during the whole 
study. Patients are required to be well controlled in their asthma (ACQ-5 <0.75) at time of 
randomization and are closely monitored on a daily basis with regards to asthma symptoms, 
reliever use and lung function (PEF), captured in an ePRO device, during and after the 
withdrawal period. An automatic asthma action plan will be embedded in the ePRO device 
and upon worsening of asthma control, i.e. not being adequately controlled as indicated by 
ACQ-5 >1.5, or reduction in PEF and/or increase in rescue medication beyond the set limits 
the patient will be prompted to resume his/her regular ICS+ LABA controller medication and 
an alert will be sent to the site (see Section 5.3). With these precautions a gradual worsening 
of asthma will be detected and the endpoint criteria for reduced asthma control are set so that 
ICS+LABA can be resumed without undue delay and without risk for patients. 
No reproductive toxicology data are available for AZD1419. However, in multiple dose 
toxicity studies no effects on reproductive organs were observed in either mice or cynomolgus 
monkeys. Women of childbearing potential will be allowed in the present study provided that 
contraceptive methods are used as described in this Clinical Study Protocol. 
Although the systemic exposure of AZD1419 is expected to be low, systemic Type 1 
cytokines (e.g. IFN-α) produced as a result of target engagement may be harmful for an 
unborn child or lead to spontaneous abortion and the Investigator needs to stress the 
importance of complying with the contraceptive requirements to Women of Child Bearing 
Potential.


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Women who are breastfeeding, pregnant (verified by urine dipstick pregnancy test) or intends 
to become pregnant during the study are not allowed to be included. 
Pregnancy tests and check of contraceptive compliance will be performed during the 
treatment. Use of CYP3A4 inducing drugs that may reduce effect of hormonal contraceptives 
are not allowed.
Patients with asthma may have a potential benefit from treatment as described in the 
introductions section. With the mitigations and monitoring implemented in the study the 
overall benefit/risk for the trial patients is judged acceptable.
A detailed assessment of the overall risk/benefit of AZD1419 is given in Section 6 of the 
Investigator’s Brochure.
1.4
Study Design 
This phase 2a study is a randomized, double-blind, placebo-controlled trial designed to assess 
the efficacy and safety of 13 once weekly doses of inhaled AZD1419 administered to patients 
with eosinophilic asthma controlled on a maintenance treatment of ICS plus a LABA but no 
other controller medication.
A withdrawal design will be used where the first 6 doses of IMP will be administered as add-
on to the patient’s regular ICS + LABA medication. The controller medication will then be 
tapered down and discontinued during the next 3 doses of IMP, and the last 4 doses will be 
administered during a period of complete ICS and LABA withdrawal (see Figure 1). In 
addition the study drug dose level will be adjusted using an adaptive dosing scheme (defined 
in Section 4.2.2) based on appearance of flu-like symptoms. The primary endpoint is loss of 
asthma control, defined in Section 2.1.1. When a patient meets the primary endpoint the 
patient will resume ICS + LABA and will be followed for an additional 4 weeks before 
discontinuing the study. 
The total duration of patient participation will be up to 56 weeks. This includes a screening 
period of approximately 2-4 weeks, a 12 week dosing period and an up to 40-week 
observation period following the last dose, further outlined in Section 4. The schedule of trial 
procedures is presented in Table 1.   
The study will start with a sentinel dosing period to be conducted at 1 or 2 selected study 
centers, during which 4 patients will be randomly assigned 1:1 either to placebo or AZD1419 
at 4 mg, dosed once weekly. Sentinel patients will be observed at the clinic for 24 hours after 
each of the first two doses, for details see Section 4.2.1. A Data Safety Monitoring Board 
(DSMB) will review safety data from these patients and approve enrollment of additional 
patients in the study (details in Section 6.8.1).


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Figure 1
Phase 2a Study Design


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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of inhaled AZD1419 in 
eosinophilic asthma patients after withdrawal of 
controller treatment of ICS + LABA
Time to loss of asthma control.
2.1.1
Definition of Loss of asthma control
For the purpose of the study Loss of asthma control is defined as any of the following:
a)
An increase of ACQ-5 to 1.5 or more 
b)
A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline on 2 
consecutive days
c)
At least six additional reliever inhalations of SABA in a 24-hour period relative to 
baseline on 2 consecutive days
d)
An exacerbation requiring systemic corticosteroids
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To further assess the efficacy of inhaled 
AZD1419 in eosinophilic asthma patients after 
withdrawal of controller treatment of ICS + 
LABA
Proportion of patients who experience loss of asthma 
control
Changes over the course of the study in ACQ-5
Changes over the course of the study in asthma daily 
diary score
Changes over the course of the study in number of 
moderate and severe exacerbations 
Changes over the course of the study in the use of 
reliever bronchodilator (short-acting beta-agonist 
SABA) 
Changes over the course of the study in pre- and 
post-bronchodilator FEV1 
Changes over the course of the study in PEF
Changes over the course of the study in fractional 
exhaled nitric oxide (FeNO) 


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2.3
Safety objectives
Safety Objective:
Outcome Measure :
To evaluate the safety and tolerability of 
AZD1419 in eosinophilic asthma patients after 
withdrawal of controller treatment of ICS + 
LABA
Adverse events, vital signs, ECG and laboratory 
parameters 
Weekly peak expiratory flow rate (PEFR)
Lung diffusion capacity (DLco)
2.4
Exploratory objectives
Exploratory objective:
Outcome Measure:
! To assess the responses of selected systemic 
peripheral blood and sputum biomarkers to 
inhaled AZD1419 in eosinophilic asthma 
patients after withdrawal of controller 
treatment of ICS + LABA
! Peripheral blood and sputum biomarkers (to be 
specified)
! To assess the composite endpoint for 
exacerbations, CompEx 
! Time to first CompEx event
! Changes over the course of the study in number of 
CompEx events
! To investigate the genes and genetic variation 
that may influence response to AZD1419
! DNA
! To assess the expression of selected genes in 
cells from whole blood and sputum
! RNA from whole blood and sputum
! To assess the effects on DNA methylation
! DNA from whole blood
! To assess the immune function of PBMC
! PBMCs
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.
Provision of informed consent prior to any study specific procedures 
2.
Male and female patients 18 years and above
3.
Physician-diagnosed asthma requiring treatment with ICS and a long-acting beta 
agonist (LABA), but no other controller medication. The ICS plus LABA can be 


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any combination inhaler or 2 separate inhalers. Patients must have taken ICS plus 
LABA controller medication for at least 3 months prior to screening
4.
Pre-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% predicted
5.
Female patients must be 1 year post-menopausal, surgically sterile, or using an 
acceptable method of contraception, refer to Section 3.1.1.
6.
Negative pregnancy test (urine) and a date of last menstruation consistent with non-
pregnancy for female patients of childbearing potential.
7.
Male patients must be surgically sterile or using an acceptable method of 
contraception (defined as barrier methods in conjunction with spermicides) from the 
first dose of the IMP and until 1 month after the last dose of the IMP to prevent 
pregnancy in a partner.
8.
Blood eosinophil levels ≥ 250 cells/μL at screening OR a history of blood 
eosinophil levels ≥ 250 cells/μL at any time in the preceding 2 years AND blood 
eosinophil levels ≥ 150 cells /μL at screening. The eosinophilia must be believed to 
be due to asthma and not have other known causes, e.g. helminth infection
9.
ACQ-5 score ≤1.5 at screening
10.
ACQ-5 score ≤0.75 at randomization
11.
Documentation of any of the following within 5 years prior to Visit 1:
!
Proof of post-bronchodilator reversibility in FEV1 of ≥12% and ≥200 mL 
(Pellegrino et al 2005) 
!
Proof of a positive response to a methacholine or histamine challenge (a 
decrease in FEV1 by 20% [PC20] at ≤8 mg/mL) performed according to 
ATS/ERS guidelines (American Thoracic Society 2000)
!
Proof of positive response to mannitol challenge (a decrease in FEV1 by 15% 
[PD15] at ≤635 mg or a >10% decrease in FEV1 between consecutive doses) 
(Anderson et al 2009)
!
Proof of diurnal variability in PEF >20% over the course of 24 hours in at least 
4 out of 7 consecutive days
If historical documentation is not available, proof of reversibility or a positive 
response to a methacholine, histamine or mannitol challenge or diurnal variation 
must be demonstrated according to above and documented during Visit 1
12.
In the judgment of the investigator: able to adhere to study procedures including 
correct twice-daily use of the electronic symptom diary, home monitoring of peak 
flow, ability to perform spirometry and FeNO measurements
13.
Patients should be willing to switch to fixed dose morning and evening ICS+LABA 
in separate inhalers, together with SABA as rescue medication.


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14.
Patients who are blood donors should not donate blood during the study and for 
3 months following their last dose of the IMP
In addition to the above, the following additional inclusion criterion will be applied to the 
Sputum Subset (approximately 20% of patients in selected sites)
15.
Able to produce an adequate sputum sample at screening following induction with 
inhaled hypertonic saline
For inclusion in the genetic research, patients must fulfil all of the inclusion criteria above 
and:
16.
Provide informed consent for the genetic sampling and analyses.
3.1.1
Acceptable birth control methods
Acceptable birth control methods are tubal occlusion, intrauterine device (provided coils are 
copper-banded), levonorgestrel intrauterine system (eg, Mirena™), medroxyprogesterone 
injections (eg, Depo-Provera™), etonogestrel implants (eg, Implanon™, Norplan™), normal 
and low dose combined oral pills, norelgestromin / ethinylestradiol transdermal system, 
intravaginal device (eg, ethinylestradiol and etonogestrel ), desogestrel (eg, Cerazette™), total 
sexual abstinence and vasectomised sexual partner. 
Women should have been stable on their chosen method of birth control for a minimum of 3 
months before entering the trial and should continue with birth control for 1 month after the 
last dose of inhaled IMP. In addition to the acceptable birth control method (except for the 
practice of total sexual abstinence), condom should be used by male partner for sexual 
intercourse from randomization (Visit 2) and for 1 month after the last dose of inhaled 
AZD1419/matching placebo to prevent pregnancy.
The birth control method will be verified in the medical records prior to study start 
(contraceptive history) and women of childbearing potential will be asked to verify 
compliance at each visit up to 1 months after the last investigational product administration. 
Patients should be made aware of the availability of emergency “post-coital” contraception if 
there is an indication for it (eg, missing IUD threads or a late injection). Acceptable 
emergency methods of contraception to be used should only include those approved by a 
regulatory agency in the patient’s region.
Women not of childbearing potential are defined as women who are either permanently 
sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Women will be considered postmenopausal if they have been amenorrheic 
for 12 months prior to the planned date of randomization without an alternative medical cause. 
The following age specific requirements apply:


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Women <50 years old would be considered postmenopausal if they have been amenorrheic for 
12 months or more following cessation of exogenous hormonal treatment and follicle 
stimulating hormone (FSH) levels in the postmenopausal range.
Women ≥50 years old would be considered postmenopausal if they have been amenorrheic for 
12 months or more following cessation of all exogenous hormonal treatment
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Clinically significant lung disease other than asthma (eg, chronic obstructive 
pulmonary disease, cystic fibrosis, allergic bronchopulmonary aspergillosis, active 
tuberculosis). Patients with CT or chest X-ray findings indicating bronchiectasis 
which in the opinion of the Investigator are not clinically significant may be 
enrolled at the discretion of the Investigator
2.
Current tobacco smoking (smoking must have stopped for ≥6 months prior to 
enrolment) or a history of tobacco smoking for ≥10 pack-years (one pack year 
= 20 cigarettes smoked per day for 1 year)
3.
Receipt of any marketed or investigational biologic within 4 months or 5 half-lives 
prior to enrolment (whichever is longer) or receipt of any investigational non-
biologic agent within 30 days or 5 half-lives prior to enrolment (whichever is 
longer)
4.
Known history of allergy or reaction to any component of the IMP formulation
5.
Use of immunosuppressive medication (including but not limited to: methotrexate, 
troleandomycin, cyclosporine, azathioprine, systemic corticosteroids including 
regular treatment with OCS or intramuscular long-acting depot corticosteroids, or 
any experimental anti-inflammatory therapy) within 3 months prior to enrolment 
(Visit 1)
6.
Receipt of immunoglobulin or blood products within 30 days prior to enrolment
(Visit 1)
7.
Positive HIV, hepatitis B surface antigen or hepatitis C virus antibody serology. 
Patients with a history of hepatitis B vaccination without a history of hepatitis B are 
allowed to be enrolled
8.
History of autoimmune disease including but not limited to Wegener’s 
granulomatosis, system lupus erythematosus, rheumatoid arthritis, Sjögren’s 
syndrome, multiple sclerosis, autoimmune thrombocytopenia, primary biliary 
cirrhosis or any other autoimmune disease considered clinically relevant by the 
investigator
9.
Ongoing allergen immunotherapy or plans to begin such therapy during the study 
period. The last dose of immunotherapy must have been taken at least 6 months 
prior to inclusion


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10.
History of chronic alcohol or drug abuse within 12 months of the enrolment visit
11.
Perturbation of usual sleep pattern except due to asthma symptoms (eg, night shift 
workers)
12.
Breast feeding, pregnancy or intention to become pregnant during the course of the 
study
13.
DLco ≤60% of the lower limit of normal 
14.
Changes in chest X-ray suggesting clinically significant parenchymal disease other 
than asthma (further on X-ray in Section 5.2.6)
15.
Any clinically significant abnormal findings in physical examination, vital signs, 
dECG, haematology, clinical chemistry, or urinalysis, which in the opinion of the 
Investigator, may put the patient at risk because of his/her participation in the study,
or may influence the results of the study, or the patient’s ability to complete entire 
duration of the study
16.
Receipt of live attenuated vaccines within 30 days prior to the date of 
randomization and during the study including the follow-up period (Receipt of 
inactive/killed vaccinations (e.g., inactive influenza) is allowed)
17.
Major surgery within 8 weeks prior to the enrolment visit, or planned in-patient
surgery or hospitalization during the study period
18.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
19.
Previous randomisation in the present study
In addition, any of the following is regarded as criteria for exclusion from the 
genetic research:
20.
Previous bone marrow transplant
21.
Whole blood transfusion within 120 days of the date of genetic sample collection
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Enrolment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
2.
Assign potential patient a unique enrolment number, beginning with ‘E#’.
3.
Determine patient eligibility. See Section 3.4.
4.
Assign eligible patient unique randomisation code (obtained via the IxRS)


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If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Patients can only be randomized into the study once.
Randomisation codes will be assigned strictly sequentially as patients become eligible for 
randomisation.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
The randomization scheme for this study will be generated by the biostatistics group at 
AstraZeneca or designee. This will be done using AZRand system. Randomization will be 
performed through a centralized interactive voice and web response system (IxRS). Patients 
will be block randomized 1:1 to either placebo or AZD1419, with no stratification.  
3.6
Methods for ensuring blinding
The study is double-blind; patients, study site personnel and AZ personnel involved in the 
evaluation of the data must be kept blinded.
Packaging and labelling of study drug will be performed in a way that ensures blinding.
The following personnel will have access to the randomisation list:
!
AstraZeneca Supply Chain
!
IxRS vendor
!
CRO for drug distribution (Fisher)
Randomization will occur after eligibility has been confirmed based on all study inclusion and 
exclusion criteria.


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If all eligibility criteria are met, blinded personnel will contact the centralized interactive 
voice and web response system (IxRS) to receive a randomization number and treatment 
assignment. 
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 from the IxRS. Routines for this 
will be described in the IxRS user manual that will be provided to each centre.
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 investigational product 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
The following restrictions are applied during the trial or as indicated below:
!
Patients should abstain from donating blood and plasma during the study
!
Anti-IgE therapy
!
Allergen immunotherapy
!
Male patients should refrain from fathering a child or donating sperm 
during the treatment and until 3 weeks following the last dose
!
WOCBP using hormonal contraceptives should abstain from use of any 
medication with CYP3A4 enzyme inducing properties, (eg, fenytoin, 
fenobarbital, primidon, karbamazepin, oxkarbazepin, rifampicin, 
rifabutin, ritonavir, topiramat, felbamat and herbal medicines such as St 
John’s Wort) from Visit 1 until 1 months after last dose of IMP.
!
ICS, LABA and SABA are the only asthma medications allowed in the 
study


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Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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3.9
Discontinuation of investigational product
Patients may be discontinued from investigational product (IMP) in the following situations:
!
Patient decision. The patient is at any time free to discontinue treatment, 
without prejudice to further treatment
!
Adverse Event
!
Severe non-compliance with the study protocol 
!
Risk to the patient as judged by the Investigator and/or AstraZeneca.
!
Eligibility criteria not fulfilled (see Section 3.1)
!
Patient lost to follow-up
!
Pregnancy 
!
Other (reason to be specified by the Investigator in the electronic Case 
Report Form)
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are patients who do not fulfil the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded 
as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion criteria).
This reason for study withdrawal is only valid for screen failures (not randomized patients).
3.10.2
Rescreening
Patients who fail screening because of negative reversibility or challenge tests, or patients that 
are not controlled (i.e. ACQ-5 >0.75) at time for randomization, may be re-screened once. 
Patients who fail screening because of clinically significant vital signs and/or lab 
abnormalities without identified reversible etiology may not re-screen. Patients that screen fail 
for other reasons may potentially re-screen on a case-by-case basis after discussion with 
AstraZeneca study team physician. Any re-screened patients will keep their original enrolment 
number but will re-sign their Informed Consent Form (ICF). Re-screening is only allowed 
once for any patients.
3.10.3
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (investigational product 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 adverse events (AE). Provided the patient consents to do a follow-up visit, it is 
recommended that such a visit is scheduled after two weeks. Otherwise the Investigator will 
follow up AEs outside of the clinical study. 


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Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn patients will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
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 CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
However, the sponsor reserves the right to terminate the study at any time. Reasons for 
terminating the study may include, but are not limited to, the following:
!
Inability to enroll sufficient patients into study
!
Good Clinical Practice (GCP) compliance issues that compromise the 
validity of the study
!
Determination by the DSMB that patient safety is at risk
Guidelines for termination and withdrawal of individual patients are described in Section 3.10.


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Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Schedule of events
Trial Period Screening
Dosing period
Observation
period
EOT/EDb UNS
Procedure
Week
-4
0
1
2
3
4
5
6
7
8
9
10
11
12
13
16 20 28
36 48
52
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17 18
19 20
21
Informed consent
X
Inclusion/Exclusion criteria
X
Demographics/Medical & Surgical 
history/Prior medications
X
Height and weight 
X
Urine drug screenc
X
12-Lead ECG
X
X
Chest X-rayd
X
Serum chemistrye
X
Xg
Xg
X
X
Hematologye
X
Xg
Xg
X
X
Urinalysise
X
LH/FSH
X
Pregnancy testingf
X
X
X
X
X
X
X
X
X
Serology (HIV, hepatitis B and C tests)
X
Contraceptive history and compliance 
(WoCBP only)
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
Serum for Ig, IgG and IgE
X
Serum for e.g. ANA, anti-ds DNA, anti-
thyroid antibodies
X
X
X
X
Randomization
X
Inhalation/iNeb technique training
X
AZD1419/placebo treatment
X
X
X
X X
X
X
X
X
X
X
X
X
LABA therapy
X
→→→→→→
ICS therapy
X
→→→→→→→→
→


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Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
32(86)
Table 1
Schedule of events
Trial Period Screening
Dosing period
Observation
period
EOT/EDb UNS
Procedure
Week
-4
0
1
2
3
4
5
6
7
8
9
10
11
12
13
16 20 28
36 48
52
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17 18
19 20
21
SABA rescue therapy (as needed)
X
→→→→→→→→
→
→
→
→
→
→
→→→
→→
→
Whole blood for gene expression
Xg
Xg
X
X
Xg
X
X
X
X
X
X
X
Whole blood for DNA methylation
X
X
X
Induced sputum (PD)h
X
Xn
Xn
Xn
X
Exploratory biomarkers (including CXCL-10 
(plasma)i
Xg
Xg
X
X
Xg
X
X
X
X
X
X
X
Single urine samples for exploratory 
biomarkers
Xg
Xg
X
X
Xg
X
X
X
X
X
X
X
Frozen PBMC sampleh
Xg
Xg
X
X
Xg
X
X
X
X
X
X
X
Pharmacogenomic samplej
X
Concomitant medications
X
→→→→→→→→
→
→
→
→
→
→
→→→
→→
→
Adverse event assessment
X
→→→→→→→
→
→
→
→
→
→
→→→
→→
→
Serious adverse event assessment 
X
→→→→→→→→
→
→
→
→
→
→
→→→
→→
→
eDiary and PEF meter distribution, training,
and collection
Xl
X
eDiary and PEF recordingk
Xl
X
→→→→→→→
→
→
→
→
→
→
→→→
→→
X
Compliance check (by site staff) of the 
patients’ eDiary, PEF and FeNO recording
X →→→→→→
→
→
→
→
→
→
→→→
→→
X
Asthma symptom score and reliever use 
(eDiary)
X
→→→→→→→
→
→
→
→
→
→
→→→
→→
X
Asthma control questionnaire (ACQ-5)m
X
→→→→→→→
→
→
→
→
→
→
→→→
→→
X
Spirometry (Pre- & post bronchodilator 
FEV1 at the clinic)
X
X
X
X
X
X
X
X
X
X
X
Lung diffusion capacity testing (DLco)
X
X
X
X
X
X
X
Full physical examination 
X
X
X
X
X
Vital signs
X
X
X
X
X
X
Fractional excretion of nitric oxide (FeNO) 
measurement at the clinic
X
X
X
X
X
X
X
X
X
X
X
Niox Vero FeNO@Home (measurements 
X
→→→→→→→
→
→
→
→
→
→
→→→
→→
X


Clinical Study Protocol
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
33(86)
Table 1
Schedule of events
Trial Period Screening
Dosing period
Observation
period
EOT/EDb UNS
Procedure
Week
-4
0
1
2
3
4
5
6
7
8
9
10
11
12
13
16 20 28
36 48
52
Dose
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16 17 18
19 20
21
done by the patient every other day)
EOT = end of trial; UNS = unscheduled visit. For any efficacy/safety or exploratory assessments as indicated.
a.
Can be done on several/different days within the up to 4 weeks screening period
b.
Patients who discontinue trial participation prior to completion of all scheduled visits will be required to complete an Early Discontinuation (ED) visit.
c.
According to local practice. 
d.
At screening and on other visits if indicated, see Section 5.2.6
e.
For details see Table 3.
f.
Urine pregnancy testing will be conducted in WOCBP. The test must be negative prior to trial treatment. Dipstick may be used.
g.
Prior to and 24 h after dose.
h.
At selected sites. 
i.
To be stored frozen for future testing.
j.
DNA for pharmacogenomic analysis will only be collected from those patients who consent.
k.
Morning and evening recording.
l.
Training and distribution of the eDiary and PEF devices will be done on a V1b scheduled approximately one week prior to randomization to ensure 
sufficient number of baseline recordings (at least 5 days, twice daily).
m.
Recorded weekly in the eDiary.
n.
Only taken at 24h after dose


Clinical Study Protocol
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Study Code D2500C00003
Version 3
Date 17 October 2016
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4.1
Enrolment/screening period
At screening, Visit 1, consenting patients are assessed to ensure that they meet eligibility 
criteria. The screening period will be approximately 2-4 weeks. The screening procedures will 
be performed according to the Schedule of Events, Table 1, and can be performed over several 
days if needed.
All eligible patients will be taking ICS and LABA during the screening period, with SABA 
rescue therapy as needed. Patients will be prescribed their usual controller medication (i.e. ICS 
+ LABA) in separate inhalers, in addition to a rescue medication inhaler (SABA). To facilitate 
the tapering down during the treatment period, the ICS will be prescribed in a dose that will 
allow stepwise reduction using the same inhaler.
If the patient does not have historical positive post-bronchodilator reversibility or challenge test 
(methacholine, histamine or mannitol) information fulfilling that inclusion criterion, a 
reversibility or challenge test can be performed at Visit 1. In case the patient does not meet the 
eligibility criterion at this occasion, e.g. suspected to be due to bronchodilator treatment taken 
prior to the visit, a second re-test may be performed (not earlier than the next calendar day) as 
part of Visit 1. To increase the chances for a positive reversibility or challenge test at the re-test, 
patients should withhold their usual bronchodilator medications on the morning of the test, e.g.
SABA for at least 6 hours and LABA for at least 12 hours before the test.
4.2
Treatment period
When patients are comfortable using the prescribed inhalers and have gone through the 
inclusion/screening assessments the patients may be randomized. An ACQ-5 score of <0.75 is 
required for randomization. A total of 70 patients are planned to receive 13 weekly doses of 
IMP (1:1) during the conduct of the study. Study drug will be administered as a nebulized 
inhalation (using the I-neb® device (Philips Respironics)) at the clinic. The patients will be 
observed at the clinic for at least 6 hours after the first dose and for at least 2 hours after the 
remainder of doses.
Patients will receive placebo or AZD1419 at 4 mg/week for 4 weeks, after which each patient’s 
dose will be maintained or adjusted up or down based on the individual patient’s frequency and 
severity of flu-like AEs (defined in Section 6.1.1) appearing within 24 hours after dosing, see 
Figure 2. All decisions are subject to investigator judgment. If an investigator believes that a 
patient is not tolerating a dose for any reason, the next dose can be reduced independent of the 
rules described. Further instructions on Dose Adaptation are included in Section 4.2.2.
During the dosing period, patients will have ICS + LABA controller medications tapered down
and discontinued. LABA will be stopped on the evening prior to receiving dose 7 (Visit 8), and 
ICS will then be gradually tapered down and discontinued during the next 3 weeks. The first 
week after LABA discontinuation, the patients will receive their usual full dose of ICS. The 
week thereafter the total daily ICS dose will be reduced by 50% and the week thereafter the 
total daily dose will be reduced to 25% of the patient’s usual full dose of ICS. ICS is 
discontinued in the evening prior to receiving IMP dose 10 (Visit 11). The regimen for tapering 
down the ICS according to the above guidelines will be decided by the Investigator for the 
individual patient, i.e. as appropriate the Investigator will adjust the ICS dose down and 


Clinical Study Protocol
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Study Code D2500C00003
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potentially change dosing regimen from BID to QD to achieve half and then a quarter of the 
daily dose of ICS. Patients will be able to use SABA reliever therapy as needed at all times 
during the study. Reliever use will be monitored on a daily basis in the ePRO device, as a 
component of asthma control throughout the trial.
For details of all assessments done during the treatment period refer to Section 5 and for timing 
of the procedures refer to Table 1.
4.2.1
Sentinel Dosing Procedure
The first 4 patients randomized in the study at one or two selected sites constitute the sentinel 
group and will be evaluated by a DSMB for safety before enrolment of additional patients can 
commence. The sentinel patients will be randomly assigned (1:1) to receive AZD1419 or 
placebo (4mg) once weekly. After the first 2 doses (i.e. Visits 2 and 3) the 4 sentinel patients 
will be observed for 24 hours at the clinic for safety (including allergic reactions or 
bronchospasm). In addition to the assessments outlined in Table 1, assessment of AEs, vital 
signs and FEV1 measurements will be carried out at the following time points after dose: 0.5, 1, 
2, 6, 12, 24 hours, and in addition as needed as judged by the investigator. These patients will 
then continue in the study in accordance with the study protocol.
When the last of the 4 sentinel patients has received 4 doses, the DSMB will review safety data 
and approve enrolment of additional patients into the study. The DSMB may recommend 
further measures to ensure patient safety when administering first doses of IMP to additional 
patients.
4.2.2
Dose Adaptation Procedure 
Given the well-known potential for flu-like symptoms from TLR9 agonism, dosing for each 
patient will be adapted based on the individual’s flu-like AEs. The flu-like symptoms usually 
respond well to paracetamol (and otherwise resolve spontaneously within 24-48 hours following 
dosing), and the dose adaptation should be based on the assessment of flu-like symptoms after 
intake of paracetamol.
After the first 4 doses an assessment of the individual patient will be performed according to 
experiences of flu-like AEs (arthralgia, chills, pyrexia, myalgia) within 24h of inhalation, with 
adaptation of AZD1419 accordingly:
If no or only mild flu-like AEs occur after the first 4 doses, then the subsequent doses will be 
stepped up to 8 mg.
If any severe flu-like AEs occur after any of the first 4 doses, then the subsequent doses will be 
stepped down to 1 mg.
Otherwise, the subsequent doses will be maintained at 4 mg.
All patients will continue dosing with placebo or AZD1419 at the adjusted levels until they 
have received a total of 13 inhaled weekly doses. 


Clinical Study Protocol
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Study Code D2500C00003
Version 3
Date 17 October 2016
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All dosing decisions are subject to investigator judgment. If an investigator believes that a 
patient is not tolerating a dose for any reason, the next dose can be reduced independent of the 
rules described above.
Dosing will be stopped in patients who do not tolerate a 1mg dose and they will be followed for 
an additional 4 weeks for safety before they discontinue the study.
Since e.g. side effects from influenza vaccination could potentially impact the interpretation of 
the flu-like symptoms after the dosing of study drug, it is suggested that such vaccination 
should be performed e.g. 2 days after a dose of IMP.
For definition of severity of AE (including flu-like symptoms), see Section 6.3.3.
Figure 2
Dosing
9 x 8 mg doses
9 x 4 mg doses
4 x 4 mg doses.
If any severe flu-like AEs <24 h 
of inhalation
Step down to 1 mg
9 x 1 mg doses
If any severe flu-like AEs
If no or mild flu-like AEs
ADAPTATION
Stepped up to 8 mg
OR
Maintained at 4 mg
OR
Stepped down to 1 mg
else
4.3
Follow-up period/Observation period
After the treatment period patients are followed until they experience loss of asthma control or 
for the whole period of up to 52 weeks (Visit 21). For details of the study assessments during 
the observation period refer to the Schedule of events, Table 1.
Patients will be monitored with regards to safety, tolerability and efficacy aspects during the 
whole study period. In addition to assessments performed at the clinical visits, an ePRO device 
coupled with a home spirometer will on a daily basis capture asthma symptoms, reliever use 
and lung function (PEF) and a FeNO meter measurements will be performed every second day.


Clinical Study Protocol
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Study Code D2500C00003
Version 3
Date 17 October 2016
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At any time during the tapering period or after, when patients experience loss of asthma control
as defined below, they will resume their usual ICS+LABA asthma controller therapy and will 
be considered to have reached the primary endpoint. They will then stop IMP administration 
and will be followed for an additional 4 weeks in the study.
For the purpose of the study Loss of asthma control is defined as any of the following:
a)
An increase of ACQ-5 to 1.5 or more 
b)
A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline on 
2 consecutive days
c)
At least six additional reliever inhalations of SABA in a 24-hour period relative to 
baseline on 2 consecutive days
d)
An exacerbation requiring systemic corticosteroids
Upon a), b) or c) being fulfilled, an automatic asthma action plan will be triggered in the ePRO 
device prompting the patient to resume their usual ICS + LABA medication. In addition an alert 
will be sent to the site/Investigator. Upon receiving such an alert the Investigator should contact 
the patient and arrange a visit to the clinic for evaluation, see Section 5.1.3.1. Blood sampling 
for biomarkers should be part of this evaluation.
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and query 
handling. The investigator will ensure that data are recorded in 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. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived at 
the study site.
5.1
Efficacy assessments
5.1.1
Asthma Control Questionnaire
The ACQ was developed by Professor Elizabeth Juniper (Juniper et al 1999a). The ACQ 
includes 7 items covering all the criteria deemed necessary by international guidelines 
committees for determining the adequacy of asthma control (symptoms, FEV1, and SABA used 
as reliever medication). The ACQ has undergone rigorous validation and has been shown to 
have strong evaluative and discriminative measurement properties (Juniper et al 1999a). In this 
study, the 5-item version, the ACQ-5, will be used, in which the FEV1 and SABA question is 
excluded since it will be collected outside the questionnaire. It has been shown that exclusion of 
these questions does not alter the validity and the measurement properties of the questionnaire 
(Juniper et al 2001). Linguistically validated translations of the ACQ-5 into the local languages 
will be used. The original North American English version is included in Appendix E.


Clinical Study Protocol
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Study Code D2500C00003
Version 3
Date 17 October 2016
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The ACQ-5 will be self-administered within the ePRO once weekly during the study. The 
questions take approximately 2 to 3 minutes to complete.
5.1.2
The Asthma Daily Diary
The Asthma Daily Diary will be completed in the ePRO device each morning and evening and 
will include the following daily recordings: morning and evening home peak expiratory flow 
data (obtained from the home peak flow meter), asthma symptoms, inhalations of reliever 
medication, nights with awakenings due to asthma symptoms, asthma maintenance medication 
compliance, see Appendix F.
Home peak expiratory flow measurement
An electronic, hand-held home spirometer connected to an ePRO device will be dispensed to 
the patient prior to randomization to monitor their PEF at home. The PEF should be monitored 
morning and evening every day, and the measurements should be performed by the patient 
before intake of asthma maintenance treatment upon rising in the morning, and at bedtime in the 
evening. Patients should perform 3 successive peak flow manoeuvres while sitting or standing, 
but in the same position at every testing; the highest of the 3 values will be captured for the 
morning and for the evening manoeuvres. Note that FeNO measurements should be performed 
before the PEF measurements, see Section 5.1.4. Investigator/authorized delegate will check 
patient’s adherence to correct use of the hand-held spirometer at each visit.
Asthma symptoms
Asthma symptoms during night time and daytime will be recorded by the patient twice daily in 
the Asthma Daily Diary, according to the following scoring system:
0 = no asthma symptoms
1 = you are aware of your asthma symptoms but you can easily tolerate the symptoms
2 = your asthma is causing you enough discomfort to cause problems with normal activities
(or with sleep)
3 = you are unable to do your normal activities (or to sleep) because of your asthma
Daytime is defined as the time period between the morning lung function assessment (upon 
rising in the morning) and the evening lung function assessment. Night time is defined as the 
time period between the evening lung function assessment (at bedtime) and the morning lung 
function assessment.
Reliever medication
The number of reliever medication inhalations taken will be recorded by the patient in the 
Asthma Daily Diary twice daily. The number taken between the morning and evening lung 
function assessments will be recorded in the evening. The number of inhalations taken between 
the evening and morning lung function assessments will be recorded in the morning. Reliever 
medication usage is captured in the daily diary as the number of inhaler puffs.
Night-time awakenings
Night-time awakenings due to asthma symptoms will be recorded by the patient in the Asthma 
Daily Diary each morning by answering the question whether he/she woke up during the night 
due to asthma symptoms by a “yes” or “no” response.


Clinical Study Protocol
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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Asthma maintenance medication
Asthma maintenance medication administration will be recorded in the Asthma Daily Diary in 
the morning and evening as “yes” or “no” response.
5.1.3
Composite endpoint for exacerbations (CompEx)
CompEx will be assessed as an exploratory variable. It consists of a mixture of severe asthma 
exacerbation and diary driven events. Several different definitions based on selection of ingoing 
variables exists, thus several variants of CompEx will be explored. The main outcome will be 
based on a definition including morning and evening PEF and day-time and night-time reliever 
medication. The Statistical Analysis Plan (SAP) will contain the details concerning this 
surrogate composite endpoint.
Exacerbations are defined as follows in this study:
Table 2
Exacerbation categories
Severe exacerbation 
A worsening in asthma symptoms and:
-  Use of systemic corticosteroids for at least three days 
and/or
-   An unscheduled visit or emergency room visit due to
    asthma symptoms that requires at least one dose of 
    systemic corticosteroids and/or
-   An in-patient hospitalization due to asthma requiring at 
     least one dose of systemic corticosteroids
Moderate exacerbation
A temporary increase in maintenance therapy in order to 
prevent a severe event supported by a sustained (≥2d) 
worsening in at least one key control metric ie asthma 
score, reliever medication use, night time awakening or 
morning PEF
Duration of a severe exacerbation
The start of an exacerbation is defined as the start date of 
systemic corticosteroids or emergency room visit or 
hospital admission, whichever occurs first, and the end 
date is defined as the last day of systemic corticosteroids or 
hospital discharge, whichever occurs last. 
Duration of a moderate exacerbation
For moderate exacerbations the start date is defined as the 
first day of increase in temporary maintenance therapy and 
the end date is defined as the last day of this treatment.
5.1.3.1
Evaluation of Loss of asthma control
Upon Loss of asthma control (as previously defined) the patient should be assessed by the 
Investigator and data recorded in the exacerbation module in the eCRF. Information regarding 
the circumstances for the loss of control, e.g. if there were any specific triggers, should be 
noted. Sampling for biomarkers should also be performed using the Loss of control Lab kit.
Worsening of asthma symptoms leading to treatment with systemic corticosteroids, 
hospitalisation, or emergency room visits from Visit 1 until the End of Treatment Visit should 


Clinical Study Protocol
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
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also be recorded in the exacerbation module in the eCRF. A copy of the medical record should 
be obtained for exacerbation evaluated and treated at non-study sites (e.g. by the primary care 
health care provider or at an ER/hospital) and details entered into the exacerbation eCRF 
module in a timely fashion. Changes in concomitant medication due to exacerbation must be 
recorded in the appropriate module of the eCRF.
5.1.4
Fractional Exhaled Nitric Oxide (FeNO)
The American Thoracic Society and NICE recommend the use of FeNO in the diagnosis of 
eosinophilic airway inflammation (Dweik et al 2011). Specific devices used for measuring the 
amount of FeNO in the breath of a patient will be provided by the sponsor. This sample is 
collected by having the patient breathe into the mouthpiece of the device that performs the 
measurement. At the clinic FeNO must be performed prior to spirometry assessment.
FeNO measurements will be done both at the clinic (for time points see Table 1) and by the 
patients at home using the NIOX Vero® device every second day. The home based FeNO 
measurement should be performed in the morning before morning PEF measurement and before 
morning maintenance treatment inhalation. Detailed instructions for use will be provided to the 
patients at Visit 2.
5.1.5
Spirometry
Spirometry, pre- and post bronchodilator, will be performed at the site at timepoints indicated in 
the Schedule of Events (Table 1) according to the joint ATS-ERS Task Force 2005 guidelines 
(Miller et al 2005). Results will be entered in the eCRF.
Spirometry will be performed to monitor different compartments of the lung and identify post-
treatment trends in airway function. Vital Capacity (VC), FEV1, Forced Expiratory Flow 25% 
to 75% (FEF25-75), and Inspiratory Capacity (IC) will be used as composite measures of 
airways and parenchyma. Changes in airway function with increased hyperreactivity are 
expected to give a signal in the FEV and IC while changes in lung volume mainly will be 
detected in the VC. 
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 Table 1.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will be 
recorded on the appropriate eCRF.
Additional details for specific tests are provided in the Laboratory Manual.


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The following laboratory variables will be measured:
Table 3
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatise (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
S/P-Alanine transaminase (ALT)
S/P-Albumin
S/P-Potassium
S/P-Calcium, total
S/P-Sodium
S/P-Creatine kinase (CK)
S/P-CRP
S/P-TSH
Viral Serology
Urinalysis (dipstick)
Hepatitis B surface antigen (HbsAg)
U-Hb/Erythrocytes/Blooda
Hepatitis C virus antibody
U-Protein/Albumin
HIV I and II
U-Glucose
Urine pregnancy test
Endocrinology (female patients only)
Follicle-stimulating hormone (FSH) a
Luteinising hormone (LH)a
a.
FSH and LH for women under the age of 50 considered to be post-menopausal to determine that the hormones 
are in the post-menopausal range and that the women thereby not need any contraceptives
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.
NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer to 
Appendix X ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin - Hy’s Law’, for further instructions.
5.2.1.1
Volume of Blood.
The total volume of blood that will be drawn from each patient in this study is specified in 
Table 4.


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Table 4
Volume of blood to be drawn from each patient
Assessment
No of 
samplesb
Sample volume 
(mL)
Total volume (mL)b
Safety – Clinical Chemistry
8
5
40
Safety – Haematology
8
2
16
Serology (HIV, Hepatitis B & C)
Serum for Ig, IgG and IgE 
Serum for e.g. ANA, anti-ds DNA, anti-thyroid 
antibodies
1
1
4
4
3.5
10
4
3.5
40
Endocrinology (LH, FSH)a
1
2.5
2.5
Exploratory Biomarkers including e g CXCL-
10 biomarker (plasma)
15
10
150
Whole blood for gene expression
Whole blood for DNA methylation
Frozen PBMC sample
15
4
15
2.5
8.5
10
37.5
34
150
Pharmacogenetics 
1
10
10
Total
73
487.5
a
only females
b
The number of samples may be changed due to additional sampling at unscheduled visits and the blood 
volume required may be altered to fit the assay requirements. The total volume of blood drawn from each 
patient will however not exceed 450 mL during a 3 month period.
5.2.2
Physical examination
A complete physical examination will be performed as indicated in Table 1, and include an 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen skin, 
head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, abdomen, musculo-
skeletal (including spine and extremities) and neurological systems.
The outcome of the examination is to be recorded as normal/abnormal in the eCRF, with any 
abnormalities specified. Any new or aggravated clinically relevant abnormal medical finding at 
a physical examination as compared with the baseline measurement will be reported as an AE 
(see Section 6.1)
Height and weight are collected only at screening.
5.2.3
ECG
5.2.3.1
Resting 12-lead ECG
12-lead pECG recordings will be collected at screening and at the safety follow-up visit at the 
end of the trial. The investigator will make an overall evaluation of the pECG as normal or 
abnormal. If abnormal, it will be decided whether or not the abnormality is clinically significant or 
not clinically significant and the reason for the abnormality will be recorded on the eCRF.


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Abnormal values shall not be recorded as AEs unless deemed clinically significant. The printout 
of the ECG is to be signed, dated and filed in the ISF along with a signed and dated copy (if the 
printouts are not on archive-quality paper).
5.2.4
Vital signs
Vital signs will include pulse, pulse oximetry, and systolic and diastolic blood pressure. Vital 
signs will be obtained at timepoints indicated in Table 1 (and ad-hoc as medically indicated).
5.2.4.1
Pulse, pulse oximetry and blood pressure
Pulse (beats/minute, radial artery, during 30 seconds) and pulse oximetry will be measured 
before blood pressure and in a lying position after 10 minutes of rest. Thereafter, systolic and 
diastolic blood pressure (mmHg, the cuff method on the arm opposite to the one used for blood 
sampling) will be measured using the same cuff, appropriate for arm circumference, and in the 
same position, throughout the study. During the treatment period it should be done 15 minutes 
post-dose. Patients should be in the same position for the vital signs measurements throughout 
the study.
5.2.5
Diffusing Capacity of the Lung for Carbon Monoxide (DLco). 
DLco will be determined at visits as indicated in Table 1. DLco, with other measures of 
spirometry, will be used to assess the alveolar compartment, and is expected to be a sensitive 
technique for detection of alveolar inflammation. Measurement of DLco will be performed by 
single-breath carbon monoxide (CO) uptake according to the joint ATS-ERS Task Force 2005 
guidelines (Macintyre et al 2005). 
5.2.6
Chest X-ray of the Lung
Chest X-ray will be performed at screening. It needs not be repeated for patients that have 
performed a chest X-ray during the last 12 months and as long as it is released for use in the 
CRF. Chest X-ray can be repeated, if indicated, during the study e.g. upon clinically relevant 
adverse events.
5.3
Other assessments
5.3.1
Patient reported outcomes
Patients will be supplied with an ePRO device combined with a hand-held home spirometer, 
and a separate FeNO measurement device during the screening period prior to or at 
Visit 2. 
All patients will be carefully instructed and trained in how to complete and how to handle the
devices. Patients should be informed that the recordings made electronically cannot be 
retrospectively or prospectively entered and must be completed within a defined time window. 
The patients must understand and be willing to use the devices and be instructed in how and 
where to request help if problems occur.
At home, patients will complete the eDiary each day and the FeNO every other day from the 
morning after Visit 2 throughout the study, as described in Sections 5.1.1 to 5.1.4.


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5.3.2
Sputum induction
Sputum induction should be performed in a subgroup of patients (approximately20% of the 
patients) at selected sites according to local procedures. An FEV1 measurement will be
performed after the each sputum induction cycle for safety reasons.
The method for processing of induced sputum will be described in the Laboratory Manual. The 
sputum collection is also summarized in Section 5.5.1.
5.4
Pharmacokinetics
AZD1419 was not detected in any plasma sample from patients in the highest dose cohort (23.1 
mg) in the previous trial and is therefore expected to be below the limit of quantification in the 
present trial where the highest dose given will be 8 mg. Pharmacokinetics sampling will not be 
performed.
5.5
Pharmacodynamics
5.5.1
Collection of samples
The pharmacodynamics (PD) of inhaled AZD1419 will be assessed by effects on TLR9-
mediated interferon (IFN), Th2, and airway-remodelling associated genes and gene products. 
Additionally, changes in peripheral blood mononuclear cells will also be assessed.
These assessments will be performed in serum, whole blood, induced sputum, urine and 
peripheral blood mononuclear cells:
!
Serum collections should be taken at study time points indicated in the 
Schedule of Events, Table 1 and will be assayed for CXCL-10, and 
multiplex other biomarkers.
!
Peripheral whole blood will be collected by standard venipuncture into 
appropriate collection tubes for subsequent RNA isolation gene expression 
profiling and DNA methylation analysis. 
!
Sputum will be induced by inhalation of nebulized hypertonic saline 
according to local procedures. On dosing days, at visits indicated in Table 
1, samples will be collected 24 hours after dosing. Sputum will be analyzed 
for cytology, RNA, and protein. Sputum cytology preparation will be 
performed according to local laboratory procedures. 
Notes: Sputum will be analyzed only in patients able to produce a specimen. 
Salbutamol may be used to prevent bronchospasm, which may ensue because of 
sputum collection.
!
Urine will be collected and stored for future exploratory research.
!
PBMCs will be collected (at selected sites) and assessed for immune 
function.
Additional details regarding specimen preparation, handling, and analysis will be provided in 
the Laboratory Manual.


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5.5.2
Storage, re-use and destruction of pharmacodynamic samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last Visit, 
after which they will be destroyed. The results of any investigation will be reported either in the 
Clinical Study Report itself or as an addendum, or separately in a scientific report or 
publication.
5.6
Pharmacogenetics
5.6.1
Collection of pharmacogenetic samples
The patient’s participation in the pharmacogenetic (PGx) research components of the study is 
optional. The DNA sample will only be collected from those patients who consent.
The blood sample for genetic research will be obtained from the patients after randomisation.
Although genotype is a stable parameter, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an adverse event (AE), 
such patients would be important to include in any genetic analysis. If for any reason the sample 
is not drawn at Visit 2 it may be taken at any visit until the last study visit. Only one sample 
should be collected per patient for genetics during the study.
Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
Peripheral whole blood will be collected by standard venipuncture for investigating the genes 
and genetic variation that may influence response to AZD1419. 
Additional details regarding sample preparation, handling, and analysis will be provided in the 
Laboratory Manual.
5.6.2
Storage, re-use and destruction of pharmacogenetic samples
The processes adopted for the coding and storage of samples for genetic analysis are important 
to maintain patient confidentiality. Samples will be stored for a maximum of 15 years from the 
date of the Last Patient’s Last Visit, after which they will be destroyed. DNA is a finite resource 
that may be used up during analyses. The results of any further analyses will be reported either 
in the Clinical Study Report itself or as an addendum, or separately in a scientific report or 
publication.
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample. The DNA sample will be assigned a unique number replacing the information on 
the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA number 
only. The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory. No personal details 
identifying the individual will be available to any person (AstraZeneca employee or contract 
laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded. The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access within the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca. The link will be used to 


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identify the relevant DNA samples for analysis, facilitate correlation of genotypic results with 
clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent when the patient has requested disposal/destruction of collected samples 
not yet analysed. 
5.7
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory.
Biological samples will be collected and may be analysed for exploratory biomarkers to assess 
correlations with disease activity, effects of study drug, clinical outcomes and toxicity.
Pharmacodynamics (PD) data will use descriptive statistics to assess and compare the up and 
downregulation of TLR9-mediated interferon (IFN), Th2, and airway-remodeling gene and 
gene products or changes in PBMC functional assessments. PD parameters will be analyzed 
using the PD population.
5.7.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last Visit, 
after which they will be destroyed. The results of this biomarker research will be reported either 
in the Clinical Study Report itself or as an addendum, or separately in a scientific report or 
publication. The results of this biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca biobank during the entire life 
cycle.


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5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Principal Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study site, 
are immediately identified, disposed of /destroyed, and the action 
documented
!
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site
!
Ensures that the patient and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
Patient safety will be the primary responsibility of the investigator. The investigator, in 
consultation with the sponsor’s Medical Monitor, may withdraw further study treatment for 
safety reasons in an individual patient who experiences any of the following:
!
Pregnancy (described in Section 6.6)
!
Development of an exclusionary medical condition (described in Section 
3.2)
!
An AE or SAE that, in the judgment of the investigator, requires treatment 
withdrawal due to its nature, severity, or required treatment, regardless of 
the causal relationship to treatment


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!
A clinically significant change in laboratory results, vital signs, or general 
condition that, in the judgment of the investigator, requires treatment 
withdrawal
!
Worsening of asthma signs or symptoms that, in the judgment of the 
investigator, place the patient at increased risk, such as:
−Decrease in FEV1 of more than 20 percent compared to baseline FEV1 
that is persisting, not effectively treatable with SABA, and clinically 
significant as judged by the investigator.
−Decrease in oxygen saturation to less than 85 percent (on room air) that is 
persisting and requires treatment with supplemental oxygen 
−Emergency room treatment, hospitalization, or intubation for asthma 
Treatment withdrawal may also occur due to voluntary withdrawal of consent by a patient. 
The investigator or designee must notify the sponsor of all treatment withdrawals in a timely 
manner, before the patient’s next scheduled dose. The reason for any treatment withdrawal will 
be recorded in the appropriate case report form (CRF).
Patients, who undergo treatment withdrawal for any reason, including withdrawal of consent, 
will be encouraged to complete safety follow-up assessments (ref EOT/ED visit in Table 1).
6.1
Definition of adverse events
An adverse event is the development of an undesirable medical condition or the deterioration of 
a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product. An undesirable medical condition can 
be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram). In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
6.1.1
Definition of Flu-like Symptoms
For the dose adaptation in the present study flu-like symptoms are defined as events of 
arthralgia, chills, pyrexia (fever), or myalgia, any of which occur within 24 hours after 
treatment with IP. The severity of these flu-like symptoms are defined as mild, moderate and 
severe in accordance with the general AE definitions described below (Section 6.3.3), and 
should for the purpose of dose adaptation be graded with regards to severity after intake of e.g. 
paracetamol. The individual symptoms should be reported, i.e. not reported as the preferred 
term "Influenza-like illness".
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
follow-up), that fulfils one or more of the following criteria:
!
Results in death


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!
Is immediately life-threatening
!
Requires in-patient hospitalisation or prolongation of existing 
hospitalisation 
!
Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the patient or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from randomization, throughout the treatment period and 
including the follow-up period.
SAEs will be recorded from the time of informed consent.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
6.3.3
Variables 
The following variables will be collect for each AE;
!
AE (verbatim)
!
The date and time when the AE started and stopped
!
Maximum intensity of the adverse event 
Intensity rating scale:
1 mild (awareness of sign or symptom, but easily tolerated)
2 moderate (discomfort sufficient to cause interference with normal activities)
3 severe (incapacitating, with inability to perform normal activities)
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)
!
Action taken with regard to investigational product
!
Outcome.


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In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date Investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Description of AE. It is important to distinguish between serious and 
severe AEs. Severity is a measure of intensity whereas seriousness is 
defined by the criteria in Section 6.2. An AE of severe intensity need not 
necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it 
meets the criteria shown in Section 6.2. On the other hand, a stroke that 
results in only a limited degree of disability may be considered a mild 
stroke but would be a SAE when it satisfies the criteria shown in Section 
6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A
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 were last 
asked?’, or revealed by observation will be collected and recorded in the CRF. 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.
Adverse events will be reviewed with the patient before dosing at each visit. 


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!
Adverse Events (AEs)
Adverse events, as defined in Section 6.1, will be evaluated from Visit 1 through the duration of 
trial participation. 
Flu-like symptoms (defined in Section 6.1.1) are important in dose adaptation for each patient, 
and therefore will be tracked but not solicited by investigators and site staff.
Exacerbations of asthma symptoms, including need for SABA medication, and worsening of 
asthma control requiring the need for controlling medications (ICS/LABA) are important for the 
primary endpoint of the trial and should be closely monitored.
!
Serious Adverse Events
Serious Adverse Events (SAEs), as defined in Section 6.2, will be evaluated from the time the 
consent is signed through the duration of trial participation. Any SAE occurring from the time 
the consent is signed through completion, whether or not related to the investigational medicinal 
product, must be reported to AstraZeneca or its designee within 24 hours of the knowledge of 
the event.
The investigator will assess all SAEs occurring after consent and prior to enrolment for their 
potential effect on patients’ continued eligibility to enrol.
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 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator uses 
the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE.
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 D for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.


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6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site personnel reports 
a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site personnel how to 
proceed. 
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
study drug and the EU Summary of Product Characteristics (SPC) for the maintenance 
treatment products.
6.5
Overdose
The IMP in this study is administered at the study site under oversight by the site staff. Hence 
the risk for an overdose is considered low. There is no experience of overdose and no antidote 
to AZD1419. In cases of known or suspected overdose, symptomatic treatment and monitoring 
of vital functions and e.g. haematology parameters should be performed according to routine 
clinical practice based on the judgment of the investigator. In addition, should an overdose 
occur the following procedures should be followed:
!
An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.
!
An overdose without associated symptoms is only reported on the 
Overdose CRF module.


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If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous miscarriages 
should be reported and handled as SAEs. Elective abortions without complications should not 
be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective 
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed up 
and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.6.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the treatment and 
until 1 month following the last dose of IMP.
Pregnancy of the patient’s partners is not considered to be an adverse event. However, the
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy,
normal birth or congenital abnormality) should if possible be followed up and documented. To 
capture information about a pregnancy from the partner of a male patient, the male patient’s 
partner consent must be obtained to collect information related to the pregnancy and outcome; 


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the male patient should not be asked to provide this information. A consent form specific to this 
situation must be used.
6.7
Management of IMP related toxicities/Dose Reductions
For information on the Dose adaptation scheme, please see Section 4.2.2.
6.8
Study governance and oversight
The safety of the patients in this clinical trial is closely monitored on an on-going basis by 
AstraZeneca representatives including the study physician. Issues identified will be addressed; 
for instance this could involve amendments to the study protocol and letters to Investigators.
In addition there is also a Data Safety Monitoring Board (DSMB), see below.
6.8.1
Data Safety Monitoring Board
An internal AstraZeneca Data Safety Monitoring Board (DSMB) that is independent of the 
study team will be appointed for the study. The DSMB will consist of at minimum a physician 
as clinical representative and a representative from Patient Safety. The DSMB will be 
responsible for review of safety of the sentinel patients and approval of enrollment of additional 
patients into the study. The DSMB will also have general responsibility for oversight of patient 
safety in this trial. At its discretion, the DSMB may review any available blinded safety data at 
any time. The DSMB may also request and review unblinded safety data on any patient(s) or
group. The DSMB will also have the authority to pause enrollment and/or request safety-related 
changes to the study protocol. Details of the DSMB membership and planned reviews of safety 
will be defined in a separate document (DSMB Charter) which will be finalized before the first 
subject is randomized in the study.
Further details on the DSMB composition and function will be provided in the DSMB Charter.
The charter will include information about procedures for unblinding of safety information.
In addition a separate data monitoring committee will evaluate data for a potential Interim 
Analysis, see Section 8.5.6
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
AZD1419 drug substance is an oligodeoxynucleotide (ODN) comprising 22 deoxyribo-
nucleotides linked through a phosphorothioate backbone. AZD1419 is a TLR9 agonist with 
3 CpG motifs. AZD1419 drug substance is produced as a freeze-dried solid. The molecule is 
produced as the sodium salt. AZD1419 drug substance is produced by solid phase synthesis and 
is not a biological medicinal product.
AZD1419 drug product is intended for inhalation via nebulization and is supplied as 2 mg/mL, 
8 mg/mL and 16 mg/mL solution of AZD1419 in phosphate-buffered saline and will be 


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administered once weekly using the commercially available and CE marked I-neb® Adaptive 
Aerosol Delivery [ADD] System from Philips Respironics. 
Investigational product
Dosage form and strength
Manufacturer
AZD1419
Nebuliser solution 2 mg/mL, 8 mg/ml and 
16 mg/mL
AstraZeneca
Placebo 
Placebo for AZD1419 nebuliser solution AstraZeneca
The investigational products will be manufacturing in accordance with Good Manufacturing 
Practice (GMP) supplied by AstraZeneca.
7.2
Dose and treatment regimens
7.2.1
Study Treatments
A total of 70 eligible patients will be randomly assigned 1:1 to receive 13 inhaled once weekly 
doses of either placebo or AZD1419 during the conduct of the study. Study drug will be 
administered at the clinic. All eligible patients will be taking ICS and LABA during the 
screening period, with SABA as rescue therapy during the study. 
All patients randomized to AZD1419 will have 4 mg/week of AZD1419 or placebo for 4 doses. 
After the 4th dose, the 5th dose will be adapted based on tolerability for the final 9 doses. Refer 
to Section 4.2.2 for details of the dose adaptation procedure.
Instructions for the I-neb will be provided by AstraZeneca.
7.3
Labelling
Label will be prepared in accordance with Good Manufacturing Practice (GMP) and local
regulatory guidelines. The label will fulfil GMP Annex 13 and Medical Device Directive 
requirements for labelling. The label text will be translated into local language.
7.4
Storage
All study drugs and placebo should be kept in a secure place under appropriate storage 
conditions. The investigational product labels specify the appropriate storage. The IP storage 
area must be temperature monitored and the site will maintain documentation of the temperature 
monitoring. Handling instruction will be provided separately by AstraZeneca.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded in 
the appropriate sections of the Case Report Form.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Study Protocol. The 
study personal will account for all study drugs dispensed to and returned from the patient. The 
study personal will account for all study products (I-nebs) received at the site, unused study 


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drug at site and study drug returned by the patients and for appropriate destruction. Destruction 
should not take place until approved by responsible person at AstraZeneca. Certificates of 
delivery, destruction should be signed.
The I-nebs used in the study should be returned to AstraZeneca after study closure.
7.7
Concomitant and other treatments 
The ICS, LABA and SABA treatment should be prescribed by the Investigator and provided 
locally.
7.7.1
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.
7.8
Post Study Access to Study Treatment (Not applicable)
8.
STATISTICAL ANALYSES BY ASTRAZENECA OR DELEGATE
Analyses will be performed by AstraZeneca or its representatives.  
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first patient
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. 
All personnel involved with the analysis of the study will remain blinded until the database is 
locked and all protocol violations are identified.
8.1
Statistical considerations
The primary outcome measure is loss of asthma control, as defined in Section 2.1.1. A number 
of secondary outcomes will also be considered (detailed below).
For the primary analysis of time to loss of asthma control, loss of control is considered to be 
permanent, given that patients are withdrawn from the study in such an event. Patients who 
withdraw from treatment and/or the study will have time to event censored at the first missed 
visit.
The primary hypothesis will be tested one-sided, with alpha=0.05.  All other hypothesis tests 
will be two-sided, with alpha=0.05. Confidence intervals will be two-sided, at the 95% level
There will be no adjustments for multiplicity.
All efficacy analyses will be based on the Full Analysis Set, but with no imputation of missing 
values. For the summary statistics and analyses of secondary parameters, all data available at 
each time point will be used.


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Safety analyses will include all patients who receive at least one dose of IMP (safety 
population) and all safety parameters will be described using the Safety population, using 
summary statistics presented by treatment group
8.2
Sample size estimate
This trial has about 90% power to yield a statistically significant (alpha = 0.05, 2-sided) 
difference between the pooled active and placebo groups in time to loss of asthma control given 
that the cumulative number of controlled subjects at week 52 is 20% and 60% for control versus 
active respectively. Assuming a drop-out of about 10-15%, this will require about 70 patients in 
total (32 events).
8.3
Definitions of analysis sets
All efficacy analyses will be performed using an ITT approach based on the full analysis set. 
For consistency, demographic and baseline characteristics will be presented using the full 
analysis set. Safety objectives will be analysed based on the Safety population. 
All patients analysis set (All patients): This analysis set comprises all patients screened for the 
study and will be used for the reporting of disposition and screening failures.
8.3.1
Efficacy analysis set
Full analysis set: All patients randomized and receiving any IP will be included in the full 
analysis set, irrespective of their protocol adherence and continued participation in the study. 
Patients will be analyzed according to their randomized treatment, irrespective of whether or 
not they did not take IP or inadvertently received the wrong IMP, and irrespective of whether 
they prematurely discontinued the study. For patients who withdraw consent to participate in 
the study all data will be included up to the date of their study termination.
8.3.2
Safety analysis set
Safety analysis set (Safety): All patients who received any IMP will be included in the safety 
analysis set. Patients will be classified according to the treatment they actually received. A 
patient who has on one, or several occasions, received active treatment will be classified as 
active. All safety summaries will be based on this analysis set.
8.4
Outcome measures for analyses
8.4.1
General Definitions
8.4.1.1
Definition of baseline
In general, the last measurement on or prior to the date of randomization will serve as the 
baseline measurement for efficacy endpoints, while the last measurement prior to first dose of 
study treatment will serve as the baseline measurement for safety endpoints.
Change from baseline is computed as (post-randomization value - baseline value), with negative 
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Percentage change from baseline is computed as ((change from baseline) / baseline value) 
× 100%. 
If either the post-randomization value or the baseline value is missing, then the change or 
percentage change from baseline value will also be set to missing. 
Percentage change from baseline will not be calculated or presented for variables that may 
take 0 as a value.
8.4.1.2
Visit and period windows
A more detailed definition of visit and period windows will be provided in the statistical 
analysis plan (before unblinding the study). For analyses of time to event, actual date (if known) 
will be used in preference to the date of the visit on which the event was recorded.
8.4.2
Calculation or derivation of efficacy variables
8.4.2.1
Time to loss of asthma control
The primary outcome variable, loss of asthma control, is defined in Section 2.1.1. 
Time to loss of asthma control will be censored at 52 weeks for patients who do not experience 
loss of asthma control during the 52-week study period.
For patients who withdraw from the study without reporting loss of asthma control, time will be 
censored at the date of withdrawal, if known, else at the patient’s last clinical visit plus one day.
8.4.3
Calculation or derivation of PRO variables
8.4.3.1
Asthma Control Questionnaire (ACQ-5)
In the ACQ-5 questionnaire the patients are asked to recall the status of their asthma during the 
previous week with regards to symptoms, Appendix E. The questionnaire include questions on
a)
Awoken at night by asthma symptoms
b)
Severity of asthma symptoms in the morning
c)
Limitation of daily activities due to asthma
d)
Shortness of breath
e)
Wheeze
The questions of the ACQ-5 are measured on a 7-point scale scored from 0 (totally controlled) 
to 6 (severely uncontrolled). The ACQ-5 score is computed as the un-weighted mean of the 
responses.
If ACQ-5 reaches a value of 1.5 or more, the patient is reported as having loss of asthma control 
(this being one of the 4 criteria that define that outcome).


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8.5
Methods for statistical analyses
Summary data will be presented in tabular format by treatment. Categorical data will be 
summarized by the number and percentage of patients in each category. Continuous variables 
for parametric data will be summarized by descriptive statistics including N, mean, SD, median, 
and range. 
All data will be listed. Data listings will be sorted by treatment and patient number. 
8.5.1
Patient disposition, demography data and patients characteristics
Patient disposition will be summarized using the All patients analysis set. 
The number of enrolled patients will be summarized. The number and percentage of patients 
within each treatment group will be presented by the following categories; randomized, not 
randomized (and reason), received study treatment, did not receive study treatment (and 
reason), completed treatment, discontinued treatment (and reason), completed study, and 
discontinued study (including reason).
Demographic data such as age, gender, and race will be summarized by treatment group for the 
full analysis set.
Baseline characteristics will also be summarized by treatment for the full analysis set. These 
include medical, surgical and respiratory disease histories, weight, height and BMI, smoking 
status, history of allergy, FEV1 (pre and post-BD) at baseline, asthma duration, age at onset of 
asthma, asthma medications, the number of asthma exacerbations in the previous 12 months, 
and the number of asthma exacerbations requiring hospitalizations in the previous 12 months.
Medical and surgical histories will be summarized by MedDRA Preferred Term (PT) within the 
System Organ Class (SOC) level of MedDRA.
The number and percentage of patients who take concomitant medications, and those who take 
disallowed concomitant medications during the study, will be presented by treatment group. 
Concomitant medications will be classified according to the AstraZeneca Drug Dictionary. The 
summary tables will present data by generic term using Anatomical Therapeutic Chemical 
(ATC) classification system codes.
8.5.2
Exposure
Exposure to IP will be summarized by treatment group, for the safety analysis set.
8.5.3
Violations and deviations
Only important protocol deviations will be listed and tabulated in the CSR. 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, safety, or well-being include:
!
Patients who do not meet the inclusion criteria
!
Patients who do not meet the randomization criteria


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!
Patients who meet any of the exclusion criteria
!
Patients who use one or more disallowed medication (for any reason, 
unless otherwise specified) during the randomized treatment period 
!
Patients who received the incorrect study treatment or study dose at any 
time during the 52-week double-blind treatment period
!
Patients who developed withdrawal criteria during the study but were not 
withdrawn
8.5.4
Analysis of the primary variable (s)
The primary efficacy variable is the time to loss of asthma control, and the primary analysis is 
to compare the time to loss of asthma control for AZD1419 with placebo. The Time to loss of 
control in the AZD1419 group will be compared to that of the placebo group using a log rank 
test (with accompanying Kaplan-Meier plot)
The hypothesis test will be one-sided, with alpha=0.05.
8.5.4.1
Analysis of loss of asthma control as group proportions
The proportion of patients within each treatment group with loss of asthma control, at each 
clinical visit, will be modelled longitudinally using a generalized estimating equation (GEE) 
approach, with loss of control as a binary outcome variable.
Summary statistics will also be presented for each treatment group at each visit.
8.5.5
Analysis of the secondary variable(s)
8.5.5.1
Time to first moderate or severe exacerbation
Moderate and severe asthma exacerbation is defined in Section 5.1.3. Only exacerbations that 
are classified as moderate or severe will be analysed.
The null hypothesis, that the time to first moderate or severe exacerbation is not different 
between AZD1419 and placebo groups, will be tested using the log rank test (with 
accompanying Kaplan-Meier plot).
Time to first moderate or severe exacerbation will be censored at 52 weeks for patients who do 
not experience loss of asthma control during the 52-week study period.
For patients who withdraw from the study without reporting moderate or severe exacerbation, 
time will be censored at the date of withdrawal, if known, else at the patient’s last clinical visit 
plus one day.
8.5.5.2
Proportion of patients with ≥1 moderate or severe asthma exacerbation 
The proportion of patients with ≥1 asthma exacerbation will be compared between the two 
treatment groups at each clinical visit, using a generalized estimating equation (GEE) approach, 
with occurrence of any exacerbation since the start of treatment as a binary outcome variable.


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Summary statistics will also be presented for each treatment group at each visit.
8.5.5.3
Forced expiratory volume in 1 second (FEV1)
FEV1 is measured at each clinical visit.
FEV1 will be analysed at each visit longitudinally, using a mixed effects model with treatment, 
visit, treatment-by-visit interaction and baseline FEV1 as fixed effects and patient as random 
effect. At each visit, all available values will be used in this analysis.
Summary statistics will also be presented for each treatment group at each visit.
8.5.5.4
Peak expiratory flow (PEF)
PEF is measured daily using the ePRO device. For the purposes of summary and analysis, a 
weekly average PEF will be computed.
Weekly average PEF will be analysed longitudinally, using a mixed effects model with 
treatment, week and baseline PEF as fixed effects and patient as random effect. At each week, 
all observed values will be used in this analysis.
Summary statistics will also be presented for each treatment group at each week.
8.5.5.5
Analysis of ACQ-5
ACQ-5 is measured weekly using the ePRO recording device.
Weekly average ACQ-5 will be analysed longitudinally, using a mixed effects model with 
treatment, week and baseline ACQ-5 as fixed effects and patient as random effect. At each 
week, all observed values will be used in this analysis.
Summary statistics will also be presented for each treatment group at each week.
8.5.5.6
Analysis of fractional exhaled nitric oxide (FeNO)
FeNO is measured using the NIOX Vero® device every other day as well as at clinical visits. 
For the purposes of summary and analysis, a weekly average FeNO will be computed.
Weekly FeNO will be analysed longitudinally, using a mixed effects model with treatment, 
period and baseline FeNO as fixed effects and patient as random effect. At each period, all 
observed values will be used in this analysis.
Summary statistics will also be presented for each treatment group at each week.
8.5.5.7
Other airways measurements
The following collected variables will be compared between treatment groups using summary 
statistics only: Vital Capacity (VC), Forced Expiratory Flow 25% to 75% (FEF25-75),  
Inspiratory Capacity (IC) and asthma symptom score and its components, for example night 
time awakenings and maintenance medication.


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8.5.5.8
Reliever medication
Reliever medication is recorded as taken using the ePRO device.
Summary statistics will be presented for each treatment group, grouped by study visit.
8.5.6
Interim analyses
Two types of interim analyses may be performed for this study as defined below. None of them 
will have an impact on the type I error, hence no adjustment for the type I error is needed. A 
detailed description will be included in the statistical analysis plan, which will be finalised 
before first subject in (FSI, first subject receiving first dose).
Blinded monitoring
Blinded interim monitoring of the event rate during the trial will be performed. The monitoring 
and analysis will be performed by AstraZeneca or its representatives. 
Administrative Interim analysis
The study team may decide to do an administrative un-blinded analysis of the study with the 
intent to trigger internal (AstraZeneca) investment decisions. This interim analysis will not 
change the conduct of the trial.
To ensure the blinding of each patient’s treatment assignment throughout the study, the interim 
analysis will be performed by a limited number of personnel who are not involved in the 
conduct of the study. Study site personnel, AstraZeneca or its representatives, directly 
associated with the conduct of this study and the patients will remain blinded to the treatment 
assignment for individual patients until the completion of the study. The decision to perform 
this interim analysis will be done before FSI.
8.4.7 
Sensitivity analysis (if applicable)
An analysis will be conducted on the primary outcome variable, loss of asthma control, using 
the same log rank test as for the primary analysis, but making the assumption that all patients 
who withdraw from the study without recorded loss of control are classed as loss of control 
(instead of being censored), in order to test the sensitivity of the results to the use of 
censoring/lack of information regarding loss of control in patients who withdraw.
8.4.8
Exploratory efficacy analysis 
There will be an exploratory analysis of the composite endpoint for exacerbations, CompEx, 
including an analysis of time to first CompEx event, and the proportion of patients with 
CompEx events. The CompEx measure is still under development, therefore details of this 
analysis are deferred to the Statistical Analysis Plan.
The exploratory biomarkers collected during the study (urine, blood and sputum samples) will 
be analysed if indicated or at the end of the study.


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Exploratory biomarker data will be listed by treatment group, as will all data collected in the 
clinical database, but summaries and analyses will not form part of the clinical study report, 
being presented instead in a separate bioanalytical report.
8.5.9
Safety analysis 
All safety variables will be summarized by treatment group and evaluated descriptively utilizing 
the safety analysis set. No formal hypothesis testing of safety data is planned.
8.5.9.1
Adverse events
All AEs recorded in the eCRF will be coded according to the terminology of the latest version
of MedDRA. 
All AEs will be summarized by treatment group for the safety analysis set. Treatment-emergent 
AEs will be tabulated (number and percentage of patients) by system organ class, preferred term 
(PT), intensity, and relation to study medication according to the treatment actually received.
In addition, common AEs, AEs with outcome of death, SAEs, DAEs, and OAEs will be
summarized separately.
Adverse events will be summarized separately for the periods during which patients are taking
ICS+LABA (up until Week 6), during the period of ICS being tapered down (from week 6 to 
week 9), and during the subsequent remainder of the study.
8.5.9.2
Vital signs
Diastolic and systolic blood pressure, pulse oximetry and pulse at each visit for which they are 
recorded will be summarized by treatment group with descriptive statistics. Changes from 
baseline for each of these variables to each visit will also be summarized using descriptive 
statistics.
8.5.9.3
Diffusing Capacity of the Lung for Carbon Monoxide (DLco)
DLco at each visit for which it is recorded will be summarized by treatment group with 
descriptive statistics. Changes from baseline to each visit will also be summarized using 
descriptive statistics.
8.5.9.4
Physical examination and ECG
Physical examination and ECG readings will be summarized by treatment group at each visit 
for which they are recorded.
8.5.9.5
Haematology, clinical chemistry and urinalysis
Safety laboratory parameters at each visit will be summarized by treatment group with 
descriptive statistics. Changes from baseline for each of these variables to each visit will also be 
summarized using descriptive statistics.


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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 Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable
!
Confirm that the investigational team is adhering to the protocol, that data 
are being accurately and timely recorded in the CRFs, that biological 
samples are handled in accordance with the Laboratory Manual and that 
study drug accountability checks are being performed
!
Perform source data verification (a comparison of the data in the CRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent of 
participating patients. This will require direct access to all original records 
for each patient (e.g., clinic charts)
!
Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 


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inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the terms 
of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA).
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study is expected to start in Q4 2016 and to end by Q4 2018
The investigator(s) will be notified by the Sponsor when study recruitment is complete. The 
study may be terminated at individual centres if the study procedures are not being performed 
according to GCP, or if recruitment is slow. AstraZeneca may also terminate the entire study 
prematurely if concerns for safety arise within this study or in any other study with TLR9 
agonists.
If AstraZeneca decides to prematurely terminate or suspend the study, the Principal 
Investigator/Investigator, the head of the study site, and regulatory authorities should receive 
written notification of the reasons for the premature termination or suspension.
Completion of the study
Upon terminating the study, the Principal Investigator/Investigator will report in writing the 
completion of the study as well as the summary of the results to the head of the study site in 
accordance with the study site’s rules. The head of the study site, who is informed of the 
termination by the Investigator, will provide a written notification of the results to the IRB and 
AstraZeneca. 
9.4
Data management by AstraZeneca or delegate
Data management will be performed by AstraZeneca/Cognizant Data Management Centre staff
according to the Data Management Plan. 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 AstraZeneca 
Drug Dictionary. Classification coding will be performed by the Medical Coding Team at the 
AstraZeneca/Cognizant Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.


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The data will be validated as defined in the Data Management Plan. Quality control procedures 
will be applied to each stage of data handling to ensure that all data are reliable and have been 
processed correctly. The Data Management Plan will also clarify the roles and responsibilities 
of the various functions and personnel involved in the data management process
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports are produced and reconciled with the Patient Safety database and/or 
the investigational site. 
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless required 
to do so by law.
Precautions are taken to preserve confidentiality and prevent genetic data being linked to the 
identity of the patient. In exceptional circumstances, however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may require 
access to the relevant files, though the patient’s medical information and the genetic files would 
remain physically separate.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final study protocol, including the final version of the 
Informed Consent Form and any other written information and/or materials to be provided to 


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the patients. The Investigator will ensure the distribution of these documents to the applicable 
Ethics Committee, and to the study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should submit 
the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
10.4
Informed consent
The Principal Investigator(s) at each centre will:
!
Ensure each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study
!
Ensure each patient is notified that they are free to discontinue from the 
study at any time
!
Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided
!
Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study
!
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File
!
Ensure a copy of the signed Informed Consent Form is given to the patient
!
Ensure that any incentives for patients who participate in the study as well 
as any provisions for patients harmed as a consequence of study 
participation are described in the informed consent form that is approved 
by an Ethics Committee.


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10.5
Changes to the protocol and informed consent form
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before the 
revised form is used. 
If local regulations require, any administrative change will be communicated to or approved by 
each Ethics Committee.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee may 
perform audits or inspections at the centre, including source data verification. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities 
and documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements. The Investigator will contact AstraZeneca immediately if contacted by 
a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
American Thoracic Society 2000
American Thoracic Society. Guidelines for Methacholine and Exercise Challenge Testing 1999. 
Am J Respir Crit Care Med 2000;161:309-329.
Anderson et al 2009
Anderson SD, Charlton B, Weiler JM et al. Comparison of mannitol and methacholine to 
predict exercise-induced bronchoconstriction and a clinical diagnosis of asthma. Respir Res 
2009 Jan 23;10:4. doi: 10.1186/1465-9921-10-4.
Beeh et al 2013
Beeh KM, Kanniess F, Wagner F, Schilder C, Naudts I, Hammann-Haenni A et al. The novel 
TLR-9 agonist QbG10 shows clinical efficacy in persistent allergic asthma. 
J Allergy Clin Immunol 2013;131(3): 866-74.


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Campbell et al 2014
Cambell C.R., Salomon H., Lloyd, C.M. Coffman, R.L. A limited CpG-containing 
oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway 
inflammation in mice. Thorax 2014:69, 565-573.
Dweik et al 2011
Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO et al. An official ATS 
clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical 
applications. Am J Respir Crit Care Med 2011;184(5):602-15.
Holgate 2012
Holgate ST. Innate and adaptive immune responses in asthma. Nat Med 2012;18(5):673-83.
Juniper et al 1999
Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the 
Asthma Quality of Life Questionnaire. Chest 1999;115:1265-70.
Juniper et al 1999a
Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Resp J 1999;14:902-7.
Juniper et al 2001
Juniper EF, O’Byrne PM, Roberts JN. Measuring asthma control in group studies: do we need 
airway calibre and rescue β2-agonist use? Respir Med 2001;95:319-23.
Macintyre et al 2005
Macintyre N, Crapo Ro, Viegi G, Johnson DC, van der Grinten CP, Brusasco et al. 
Standardisation of the single-breath determination of carbon monoxide uptake in the lung. 
Eur Respir J 2005;26(4):720-35.
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.
O’Neill et al 2009
O'Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors for infectious 
and inflammatory diseases and cancer. Pharmacol Rev 2009;61(2):177-97.
Pellegrino et al 2005
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R et al. Interpretative 
strategies for lung function tests. Eur Respir J 2005;26:948-68.


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Peters et al 2013
Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of 
asthma. Michael C. Peters, Zesemayat K. Mekonnen, Shaopeng Yuan, Nirav R. Bhakta, 
Prescott G. Woodruff and John V. Fahy. J Allergy Clin Immunol 2014;133:388-94.
Qin M et al 2014
Qin M, Yong Li, Xu Yang and HongQuan Wu. Safety of Toll-like receptor 9 agonists: a 
systematic review and meta-analysis. Immunopharmacol Immunotoxicol, 2014; 36(4): 251–
260.
Scheiermann J and Klinman DM 2014
Scheiermann J and Klinman DM. Clinical evaluation of CpG oligonucleotides as adjuvants for 
vaccines targeting infectious diseases and cancer. Vaccine. 2014 November 12; 32(48): 6377–
6389.
Virchow JC et al 2016
Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, Ljørring C, Riis B, de Blay 
F. Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With 
Allergic Asthma: A Randomized Clinical Trial. JAMA. 2016 Apr 26;315(16):1715-25
Wenzel et al 2013
Sally Wenzel, Linda Ford, David Pearlman, Sheldon Spector, Lawrence Sher, Franck 
Skobieranda, Lin Wang, Stephane Kirkesseli et al. Dupilumab in Persistent Asthma with 
Elevated Eosinophil Levels. The New England Journal of Medicine. June 27, 2013 vol. 368 
no. 26, 2455-2466.


Clinical Study Protocol Appendix A
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Study Code D2500C00003
Version 3
Date 17 October 2016
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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 jeopardize the patient or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv 
hydrocortisone treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose 
requiring treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic 
bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, 
etc) or convulsions that do not result in hospitalisation
Development of drug dependency or drug abuse


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


Clinical Study Protocol Appendix B
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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:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:
!
UN 3373 - Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA 
regulations
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
!
Biological samples transported in dry ice require additional dangerous 
goods specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for 
packing and transportation and packing should be done by an IATA 
certified person, as applicable
!
Samples routinely transported by road or rail are patient to local 
regulations which require that they are also packed and transported in a 
safe and appropriate way to contain any risk of infection or 
contamination by using approved couriers and packaging / containment 
materials at all times. The IATA 650 biological sample containment 
standards are encouraged wherever possible when road or rail transport is 
used.


Clinical Study Protocol Appendix C
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Appendix C
Pharmacogenetics Research
Background and Rationale
AstraZeneca intends to perform genetic research in the AZD1419 clinical development 
programme to explore how genetic variations may affect the clinical parameters associated 
with AZD1419 and/or agents used in combination or as comparators. Collection of DNA 
samples from populations with well described clinical characteristics may lead to 
improvements in the design and interpretation of clinical trials and, possibly, to genetically 
guided treatment strategies.
It is emphasised that AstraZeneca will only look for markers within genes relevant to the 
mode of action of and response to AZD1419 and asthma. No other research will be performed 
on the samples.
Genetic Research Objectives
The objective of this research is to collect and store DNA for future exploratory research into 
genes/genetic variation that may influence response (ie, distribution, safety, tolerability and 
efficacy) to AZD1419 and/or susceptibility to asthma.
Genetic Research Plan and Procedures
Selection of genetic research population
Study selection record
All randomized patients will be asked to participate in this genetic research. Participation is 
voluntary and if a patient declines to participate there will be no penalty or loss of benefit. The 
patient will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and:
!
Provide informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous allogeneic bone marrow transplant
!
Non-leukocyte depleted whole blood transfusion in 120 days of genetic 
sample collection


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Discontinuation of patients from this genetic research
Specific reasons for discontinuing a patient from this genetic research are:
Withdrawal of consent for genetic research: Patients may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 3.10 of the main Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at Visit 2 or at any 
other Visit after randomisation. Although genotype is a stable parameter, early sample 
collection is preferred to avoid introducing bias through excluding patients who may withdraw 
due to an adverse event (AE), such patients would be important to include in any genetic 
analysis. If for any reason the sample is not drawn at Visit 2, it may be taken at any visit until 
the last study visit. Only one sample should be collected per patient for genetics during the 
study. Samples will be collected, labelled, stored and shipped as detailed in the Laboratory 
Manual.
For blood volume, see Table 4 of the Clinical Study Protocol.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 25
years, from the date of last patient last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
For all samples irrespective of the type of coding used the DNA will be extracted from the 
blood sample. The DNA sample will be assigned a unique number replacing the information 
on the sample tube. Thereafter, the DNA sample will be identifiable by the unique DNA 
number only. The DNA number is used to identify the sample and corresponding data at the 
AstraZeneca genetics laboratories, or at the designated contract laboratory. No personal details 
identifying the individual will be available to any person (AstraZeneca employee or contract 
laboratory staff working with the DNA.)
The samples and data for genetic analysis in this study will be single coded. The link between 
the patient enrolment/randomisation code and the DNA number will be maintained and stored 
in a secure environment, with restricted access WITHIN the Clinical Genotyping Group 
Laboratory Information Management System (LIMS) at AstraZeneca. The link will be used to 
identify the relevant DNA samples for analysis, facilitate correlation of genotypic results with 
clinical data, allow regulatory audit and to trace samples for destruction in the case of 
withdrawal of consent.


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Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 8 of the main Clinical Study Protocol.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre. The 
principal investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely discontinue from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or third party contracted 
to work with AstraZeneca to analyze the samples.
The results from this genetic research may be reported in the CSR for the main study, or in a 
separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of patients that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A statistical 
analysis plan will be prepared where appropriate.


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


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!
AST ≥3xULN
!
TBL ≥2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with 
the original local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Definitions within 
this Appendix for definition) by reviewing laboratory reports from all 
previous visits (including both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Definitions within 
this Appendix for definition) by reviewing laboratory reports from all 
previous visits
Follow-up
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Perform follow-up on subsequent laboratory results according to the 
guidance provided in the Clinical Study Protocol.
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central 
Study Team 


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


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∀
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:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious 
criteria and causality assessment as per above
!
Continue follow-up and review according to agreed plan. Once the 
necessary supplementary information is obtained, repeat the review and 
assessment to determine whether HL criteria are met. Update the SAE 
report according to the outcome of the review.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf


Clinical Study Protocol Appendix D
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Appendix E
ACQ-5
ASTHMA CONTROL 
QUESTIONNAIRE (ACQ-
5)
(SYMPTOMS ONLY)
© 1997
QOL TECHNOLOGIES LTD.
For further information:
Elizabeth Juniper, MCSP, MSc Professor
20 Marcuse Fields Bosham, 
West Sussex PO18 8NA, England
Telephone: +44 1243 572124
Fax: +44 1243 573680
E-mail: juniper@qoltech.co.uk
Web: http://www.qoltech.co.uk
©
The Asthma Control Questionnaire (ACQ) is copyrighted and all rights are 
reserved. No part of this questionnaire may be sold, modified or 
reproduced in any form without the express permission of Elizabeth 
Juniper on behalf of QOL Technologies Limited
DECEMBER 2002


Clinical Study Protocol Appendix D
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Study Code D2500C00003
Version 3
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SYMPTOMS ONLY MODIFIED JUNE 2014
NORTH AMERICAN ENGLISH


Clinical Study Protocol Appendix E
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Date 17 October 2016
83(86)
ASTHMA CONTROL QUESTIONNAIRE©
Page 1 of 1
Please answer questions 1 - 5.
Circle the number of the response that best describes how you have been during the past 
week.
1.
On average, during the past week,
how often were you woken by your 
asthma during the night?
0
Never
1
Hardly ever
2
A few times
3
Several times
4
Many times
5
A great many times
6
Unable to sleep because of asthma
2.
On average, during the past week,
how bad were your asthma symptoms 
when you woke up in the morning?
0
No symptoms
1
Very mild symptoms
2
Mild symptoms
3
Moderate symptoms
4
Quite severe symptoms
5
Severe symptoms
6
Very severe symptoms
3.
In general, during the past week, how
limited were you in your activities 
because of your asthma?
0
Not limited at all
1
Very slightly limited
2
Slightly limited
3
Moderately limited
4
Very limited
5
Extremely limited
6
Totally limited


Clinical Study Protocol Appendix E
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
84(86)
4.
In general, during the past week, how
much shortness of breath did you 
experience because of your asthma?
0
None
1
A very little
2
A little
3
A moderate amount
4
Quite a lot
5
A great deal
6
A very great deal
5.
In general, during the past week, how
much of the time did you wheeze?
0
Not at all
1
Hardly any of the time
2
A little of the time
3
A moderate amount of the time
4
A lot of the time
5
Most of the time
6
All the time
SYMPTOMS ONLY MODIFIED JUNE 2014
NORTH AMERICAN
ENGLISH


Clinical Study Protocol Appendix E
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
85(86)
Appendix F
Asthma Daily Diary
Asthma Diary as used in AZ studies (from NIMBUS, slight variations exists, eg asking 
about reliever instead of rescue medication)
Endpoint/Variable
Item/question
Response
Morning diary
Asthma 
symptoms
Please describe your 
asthma symptoms 
during the night 
0 = no asthma symptoms
1 = you are aware of your asthma symptoms but 
you can easily tolerate the symptoms
2 = your asthma is causing you enough 
discomfort to cause problems with normal 
activities (or with sleep)
3 = you are unable to do your normal activities 
(or to sleep) because of your asthma
Night-time 
awakenings
Did your asthma cause 
you to wake up last 
night?
Yes
No
Rescue 
medication
Since bedtime, did 
you use rescue 
medication during the 
night to relieve your 
asthma symptoms?
Yes
No
(if “yes”)
Since bedtime, how 
many puffs of rescue 
medication did you 
take to relieve your 
asthma symptoms?
Lung function
PEF/FEV1
Evening diary


Clinical Study Protocol Appendix E
Drug Substance AZD1419
Study Code D2500C00003
Version 3
Date 17 October 2016
86(86)
Asthma 
symptoms
Please describe your 
asthma symptoms 
since this morning 
0 = no asthma symptoms
1 = you are aware of your asthma symptoms but 
you can easily tolerate the symptoms
2 = your asthma is causing you enough 
discomfort to cause problems with normal 
activities (or with sleep)
3 = you are unable to do your normal activities 
(or to sleep) because of your asthma
Rescue 
medication
Since this morning, 
did you use rescue 
medication during the 
day to relieve your 
asthma symptoms?
Yes
No
(if “yes”)
Since morning, how 
many puffs of rescue 
medication did you 
take to relieve your 
asthma symptoms?
Lung function
PEF/FEV1


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SAP_001.pdf: 
Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
Statistical Analysis Plan
Study Code
D2500C00003
Edition Number
2.0
Date
19Oct2018
A Phase 2 Placebo-Controlled, Randomised, Double Blind, Adaptive Dose 
Trial of the Safety and Efficacy of Inhaled AZD1419 in Adults With 
Eosinophilic, Moderate to Severe Asthma








Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
5(56)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................3
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................4
TABLE OF CONTENTS.....................................................................................5
LIST OF ABBREVIATIONS ..............................................................................8
AMENDMENT HISTORY................................................................................10
1.
STUDY DETAILS............................................................................................. 14
1.1
Study objectives................................................................................................. 14
1.1.1
Primary objective............................................................................................... 14
1.1.2
Secondary Objectives......................................................................................... 15
1.1.3
Safety objective..................................................................................................15
1.1.4
Exploratory objectives .......................................................................................16
1.2
Study design ...................................................................................................... 16
1.3
Number of patients............................................................................................. 17
2.
ANALYSIS SETS ............................................................................................. 19
2.1
Definition of analysis sets .................................................................................. 19
2.1.1
All patients analysis set (All Patients) ................................................................ 20
2.1.2
Full analysis set (FAS)....................................................................................... 20
2.1.3
Safety analysis set..............................................................................................20
2.2
Violations and deviations ................................................................................... 20
3.
PRIMARY AND SECONDARY VARIABLES................................................. 21
3.1
General Principles.............................................................................................. 21
3.1.1
Baseline definitions............................................................................................21
3.1.2
Study day........................................................................................................... 22
3.1.3
Absolute and percent change from baseline........................................................ 22
3.1.4
Visit windows....................................................................................................23
3.1.5
Handling of missing data....................................................................................23
3.2
Primary efficacy outcome measure..................................................................... 24
3.3
Secondary endpoints .......................................................................................... 26
3.3.1
Proportion of patients who experience loss of asthma control............................. 26
3.3.2
Asthma Control Questionnaire (ACQ-5) ............................................................26


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
6(56)
3.3.3
Asthma daily diary score.................................................................................... 26
3.3.4
Time to moderate or severe exacerbation ........................................................... 27
3.3.5
Proportion of subjects with 1 moderate or severe exacerbation during 52-
weeks of treatment ............................................................................................. 28
3.3.6
Reliever medication use ..................................................................................... 29
3.3.7
FEV1 pre/post BD ..............................................................................................29
3.3.8
Peak Expiratory Flow (PEF) ..............................................................................30
3.3.9
Fractional Exhaled Nitric Oxide (FeNO)............................................................30
3.3.10
Vital Capacity and Forced Expiratory Flow at 25-75%....................................... 30
3.3.11
Night time awakenings....................................................................................... 30
3.4
Calculation or derivation of safety variable(s) .................................................... 31
3.4.1
Adverse events...................................................................................................31
3.4.2
Laboratory ......................................................................................................... 32
3.4.3
Vital signs.......................................................................................................... 33
3.4.4
Electrocardiograms (ECG)................................................................................. 33
3.4.6
Diffusing Capacity of the Lung for Carbon Monoxide........................................ 34
3.5
Calculation or derivation of exploratory endpoints ............................................. 34
3.5.1
Composite endpoint for exacerbations (CompEx)...............................................34
3.5.2
Biomarker analysis.............................................................................................37
3.5.3
Pharmacogenetics research (PGx) ...................................................................... 38
3.5.4
Pharmacodynamics research (PD)...................................................................... 38
3.5.5
Sputum Induction............................................................................................... 38
4.
ANALYSIS METHODS....................................................................................38
4.1
General principles.............................................................................................. 38
4.2
Analysis methods............................................................................................... 39
4.2.1
Patient disposition, demography data and patients characteristics....................... 39
4.2.2
Prior and Concomitant Medications ................................................................... 40
4.2.3
Exposure and Compliance.................................................................................. 41
4.2.3.1
Exposure............................................................................................................ 41
4.2.3.2
Compliance........................................................................................................ 41
4.2.4
Analysis of the primary variable......................................................................... 43
4.2.4.1
Loss of asthma control as group proportions ...................................................... 43
4.2.4.2
Analysis of ACQ-5 ............................................................................................ 44
4.2.4.3
Asthma daily diary score....................................................................................45
4.2.4.4
Reliever Bronchodilator (Use of SABA) ............................................................ 45
4.2.4.5
Forced expiratory volume in 1 second (FEV1).................................................... 45
4.2.4.6
Peak expiratory flow (PEF)................................................................................46
4.2.4.7
Analysis of fractional exhaled nitric oxide (FeNO)............................................. 46
4.2.4.8
Time to moderate or severe exacerbation ........................................................... 47
4.2.4.9
Proportion of patients with a moderate or severe asthma exacerbation............... 47
4.2.4.10
FVC and FEF25-75............................................................................................ 47
4.2.4.11
Night time awakenings....................................................................................... 47
4.2.4.12
Data collected at Sentinel Dosing procedures..................................................... 48


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
7(56)
4.2.5
Safety analysis ...................................................................................................48
4.2.5.1
Adverse events...................................................................................................48
4.2.5.2
Laboratory data.................................................................................................. 49
4.2.5.3
Vital signs.......................................................................................................... 50
4.2.5.4
Diffusing Capacity of the Lung for Carbon Monoxide (DLco) ........................... 50
4.2.5.5
ECG................................................................................................................... 50
4.2.5.6
Physical examination ......................................................................................... 51
4.2.5.7
Composite endpoint for exacerbations (CompEx)...............................................51
5.
INTERIM ANALYSES ..................................................................................... 51
5.1
Sensitivity analysis............................................................................................. 51
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 52
7.
REFERENCES ..................................................................................................53
8.
APPENDIX ....................................................................................................... 54
8.1
Appendix A Analysis windows .......................................................................... 54
LIST OF TABLES
Table 1
Summary of Outcome Variables and Analysis Populations....................19
Table 2
Vital signs reference ranges...................................................................33
Table 3
Definition of diary events evaluated as possible building blocks 
for CompEx ..........................................................................................37
Table 4
ECG reference ranges............................................................................51
Table 5
Analysis windows for weekly summaries..............................................54
Table 6
Analysis windows for scheduled visits ..................................................56
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................18


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
8(56)
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
ACQ-5
Asthma Control Questionnaire-5
AE
Adverse Event 
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AZDD
Astra Zeneca Drug Dictionary
BD
Bronchodilator 
BMI
Body Mass Index
CI
Confidence Interval
CompEx
Composite Endpoint for Exacerbations
CRF
Case Report Form (electronic/paper)
CSR
Clinical Study Report
CSP
Clinical Study Protocol
CV
Coefficient of Variation 
DAE
Discontinuation of Investigational Product due to Adverse Event
DLco
Diffusing Capacity of the Lung for Carbon Monoxide
DSMB
Data Safety Monitoring Board
ECG
ePRO
Electrocardiogram
Electronic Patient Reported Outcome 
FAS
Full Analysis Set
FEF 25-75
FENO
FEV1
FVC
Forced Expiratory Flow at 25-75% of the forced vital capacity
Fractional Exhaled Nitric Oxide
Forced Expiratory Volume in 1 second
Forced Vital Capacity
IC
Inspiratory Capacity
ICS
Inhaled Corticosteroids
ICU
Intensive Care Unit
IFN-α
Interferon
Ig, IgE, IgG
Immunoglobulin, Immunoglobulin E, Immunoglobulin G


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
9(56)
Abbreviation or 
special term
Explanation
IP
Investigational Product
ITT
Intention To Treat
LABA
LOCF
Long-acting Beta Agonist(s)
Last observation carried forward
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed-effect Model Repeated Measures
PBMC
Peripheral Blood Mononuclear Cell
PA
CompEX diary event: Peak Expiratory Flow, Awakenings
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PEFR
Peak Expiratory Flow Rate
PGx
Pharmacogenetic
PR
CompEX diary event: Peak Expiratory Flow, Reliever use
PR(PQ)
ECG interval measured from the onset of the P wave to the onset of the 
QRS complex
PRS
CompEX diary event: Peak Expiratory Flow, Reliever use, Symptoms
PRSA
CompEX diary event: Peak Expiratory Flow, Reliever use, Symptoms, 
Awakenings
PS
CompEX diary event: Peak Expiratory Flow, Symptoms
PT
Preferred Term
QRS
ECG interval measured from the onset of the QRS complex to the J point
REML
Restricted Maximum Likelihood
RR
The time between corresponding points on 2 consecutive R waves on ECG
SABA
Short-Acting Beta Agonists
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SD
Standard Deviation
SI
Système International
SOC
System Organ Class
TBL
Total Bilirubin
VC
Vital Capacity
ULN
Upper Limit of Normal


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
10(56)
AMENDMENT HISTORY
Date
Brief description of change
01May2018
Section 3.1.5: Added more detail regarding handling of missing data when 
calculating weekly means for eDiary data.
Section 3.3.3: Added sentence to refer to Section 3.1.5 when calculating weekly 
means.
Section 3.3.7: Deleted text stating that only spirometry tracings determined to be 
acceptable or borderline will be used. Added a sentence regarding the value of 
Percent predicted normal for FEV1.
Section 3.3.8: Added sentence to refer to Section 3.1.5 when calculating weekly 
means.
Section 3.3.9: Added sentence to refer to Section 3.1.5 when calculating weekly 
means.
Section 3.3.10: Clarified that these measurements were made pre- and post-
Bronchodilator.
Section 3.4.1: Added sentence regarding Flu-like Adverse Events. 
Section 3.4.1.1: Other Significant Adverse events section is removed.
Section 3.4.3: Pulse Oximetry is replaced by Peripheral Oxygen Saturation in 
Table 2.
Section 3.4.4: Added a sentence to refer to Table 4 for ECG reference ranges.
Section 4.2.1: Identification of the five covariates to be used in Blinded 
Deliverable review analyses.
Section 4.2.3.2: Added that compliance for FeNO will be calculated using the 
recordings from the NIOX Vero device at home. Changed eDiary compliance 
definition - replaced ‘dosing occasions’ with ‘recordings’.
Section 4.2.4.2: Added k=patient subscript to mixed effect model for repeated 
measures analysis model definition.
Section 4.2.4.3: Added k=patient subscript to mixed effect model for repeated 
measures analysis model definition.
Section 4.2.4.4: Clarified summary statistics table. Added a sensitivity analysis 
summary table. 
Section 4.2.4.5: Added k=patient subscript to mixed effect model for repeated 
measures analysis model definition.
Section 4.2.4.6: Added k=patient subscript to mixed effect model for repeated 
measures analysis model definition. Added two summary tables for PEF 
summary statistics (morning weekly average and evening weekly average). 
Section 4.2.4.12: Removed ‘Vital Capacity’ as duplicated with ‘Forced Vital 
Capacity’. 
Section 4.2.5.1: Removed Other Significant Adverse events from section as this 
is redundant. Added definition of Flu-like Adverse events.


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
11(56)
Date
Brief description of change
01May2018
14Aug2018
Section 4.2.5.5: Defined ECG reference ranges in a table.
Section 5.1: Described the sensitivity analysis summary table for Reliever 
Medication.
Section 6: Updated the section to describe further changes of analysis from 
protocol.
Section 8.1: Updated the analysis windows of weekly summaries table. Updated 
the analysis windows for scheduled visits table.
Section 1.3 replaced Figure 1 with the version with correct visit schedule from 
v3 of protocol.
Section 3.1.1 Clarification of baseline definition calculations.
Section 3.1.5 Removed (>50%) and no imputations of missing values. Noted to 
treat patients that have discontinued as a separate scenario. Included age at 
asthma diagnosis and years since most recent exacerbation variables in partial 
dates section.
Section 3.4.2 Urinalysis shift-table removed.
Section 3.3.1 Removed at least one and >1.
Section 3.3.6 Replaced ‘between the morning and evening’ with ‘day-time and 
night-time’.
Section 3.3.8 Added explanation which measurements will be treated as daytime 
assessments and night-time assessments
Section 3.3.9 Removed repeated FeNO baseline definition.
Section 3.3.11 Removed (>50%).
Section 3.5.1 Updated slope diary events, and added in change from baseline. 
Updated baseline calculation definition.
Section 4.1 Removed section for log-transformed as no longer applicable.
Section 4.2.1 For the final analysis, only age and gender will be included as 
covariates for the statistical models.
Section 4.2.3 Removed ‘by dose’.
Section 4.2.3.2 Updated the categories for treatment compliance levels. Added 
clarification for treatment compliance calculation. Added clarification in FeNO, 
eDiary and ACQ-5 sections.
Section 4.2.4.1Removed ‘at least one episode’ and ‘since start of treatment’.
Section 4.2.4.12 Replaced this section to cover how efficacy data collected 
during sentinel vists will be processed. 
Section 4.2.5.1 Updated to increase number of Flu-like AE tables.
Section 4.2.5.2 Removed section ‘for urinalysis’ as not required.
Section 4.2.5.3  Added text regarding data collected at Sentinel visits.
Section 4.2.5.5 Shift table changed to be summary of change from baseline to 
the end of study.
Section 4.2.5.7 Updated hypothesis test to be 2 sided as it is not primary. 
Section 5.1 Added LOCF as another imputation method required for Reliever 
Medication summary statistics. Included sensitivity analysis for asthma 


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
12(56)
Date
Brief description of change
6Sep2018
04Oct2018
19Oct2018
symptom scores.
Appendix A Table 5 and 6, updated visit windows.
Section 3.1.1 Definition of baseline added for ACQ-5.
Section 3.1.4 Clarifications made regarding handing of unscheduled visits.
Section 3.3.4 Removed paragraph describing new exacerbations as not 
applicable.
Section 3.3.5 Removed ‘≥’ as we will only capture one moderate or severe 
exacerbation per patient in the study.
Study 3.4.1 Modified AE period categorisation definitions.
Section 4.2.2 Deleted requirement for disallowed concomitant medication table
Section 4.2.4.8 Removed ‘first’as we will only only capture one moderate or 
severe exacerbation per patient in the study.
Section 4.2.4.9 Removed ‘≥’ as we will only capture one moderate or severe 
exacerbation per patient in the study.
Section 6 Updated the section to describe further changes of analysis from 
protocol.
Section 3.1.1 Added definition for mean baseline reliever medication.
calculation. Added text regarding how to program if ‘number of puffs of rescue 
inhaler’ is missing.
Section 3.3.3 Renamed ‘Daily Asthma symptom scores‘ to ‘Asthma Daily 
Diary’. Added worked example for Asthma Daily Diary (weekly total).
Section 3.3.4 Removed ‘first’ as we will only capture one moderate or sever 
exacerbation per patient in the study.
Section 3.3.6 Added clarification for how the weekly total mean reliever 
medication is calculated.
Section 3.3.8 Added calculation for weekly PEF mean.
Section 4.2.4.4 Removed the baseline term from the model.
Section 4.2.4.5 Clarified which baseline covariate is used depending on whether 
pre-dose/pre-BD or pre-dose/post-BD.
Appendix A Table 5. First column removed.
Section 2.1.2 Updated FAS definition.
Section 3.1.1 Added a definition for PEF baseline variables.
Section 3.1.5 Clarified approach for dealing with inconsistencies in Reliever 
Medication responses. Added missing rule text for Asthma Daily Diary and 
Reliever Medication.
Section 3.2 Made explicit that ePRO provider sets ACQ-5 to missing if 
responses to any questions are missing.
Section 3.3 Removed ‘≥1’ as we will only capture one moderate or severe 
exacerbation per patient in the study.
Section 3.3.2 Made explicit that ePRO provider sets ACQ-5 to missing if 
responses to any questions are missing.
Section 3.3.3 Clarified worked example for Asthma Daily Diary weekly 


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
13(56)
Date
Brief description of change
averages.
Section 3.3.4 Removed ‘first’ as we will only capture one moderate or sever 
exacerbation per patient in the study.
Section 3.3.8 Clarified defintions for weekly PEF calculations.
Section 3.3.11 Removed rule for setting weekly mean to missing if >4 missing 
daily values.
Section 3.4.1 Clarification. Replaced ‘occurring’ with ‘starting’.
Section 3.4.2. Defined ‘on-treatment’.
Section 3.5.1 Clarified Slope Diary event calculation.
Section 3.5.2 Clarified Biomarkers will not be part of CSR.
Section 4.2.1 Clarification regarding Medical history and Surgical history.
Section 4.2.2 Clarification on Prior and Concomitant medication definitions.
Section 4.2.3.1 Specified that the dosing frequency was 7 days.
Section 4.2.3.2 Clarified how to calculate the expected number of 
dosings/recordings.
Section 4.2.4 Clarified hypothesis text and text describing model.
Section 4.2.4.1 Clarified that Proc GLIMMIX will be used.
Section 4.2.4.2 Results to be presented by overall and each timepoint.
Section 4.2.4.3 Results to be presented by overall and each timepoint.
Section 4.2.4.4 Removed covariate ‘number of asthma exacerbations in the year 
prior to the study’ from model.
Section 4.2.4.5 Results to be presented by overall and each timepoint.
Section 4.2.4.6 Results to be presented by overall and each timepoint.
Section 4.2.4.7 Expanded MMRM section.
Section 4.2.4.9 Clarified text describing model.
Section 4.2.5.2 Defined ‘on-treatment’.
Section 5.1 Clarified that Proc GLIMMIX will be used.
Section 6 Described update to FAS definition.


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
14(56)
1.
STUDY DETAILS
This is the statistical analysis plan (SAP) for study D2500C00003. The SAP describes the 
statistical analyses specified in the clinical study protocol (CSP) in more detail; any changes 
with regards to what is already specified in the CSP will be described in Section 6.
This statistical analysis plan (SAP) is based on version 3.0 of the clinical study protocol 
(CSP – 17 October 2016) for the study D2500C00003.
1.1
Study objectives
1.1.1
Primary objective
Primary Objective:
Outcome Measure:
To assess the efficacy of inhaled AZD1419 in 
eosinophilic asthma patients after withdrawal of 
controller treatment Inhaled Corticosteroids 
(ICS) + Long-acting Beta Agonist(s) (LABA)
Time to loss of asthma control.
Loss of asthma control is defined by any of the 
following:
!
An increase of Asthma Control Questionnaire 
(ACQ-5) to 1.5 or more
!
A reduction of 30% or more in morning peak 
expiratory flow (PEF) from baseline on 2 
consecutive days
!
At least six additional relieve inhalations of 
Short-Acting Beta Agonists (SABA) in a 24-
hour period relative to baseline on 2 
consecutive days
!
An exacerbation requiring systemic 
corticosteroids


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
15(56)
1.1.2
Secondary Objectives
Secondary Objective:
Outcome Measure:
To further assess the efficacy of inhaled 
AZD1419 in eosinophilic asthma patients after 
withdrawal of controller treatment of ICS + 
LABA
!
Proportion of patients who experience loss of 
asthma control. 
!
Changes over the course of the study in 
ACQ-5. 
!
Changes over the course of the study in 
asthma daily diary score. 
!
Changes over the course of the study in 
number of moderate and severe 
exacerbations. 
!
Changes over the course of the study in the 
use of reliever bronchodilator (short-acting 
beta-agonist SABA).
!
Changes over the course of the study in pre-
and post-bronchodilator Forced Expiratory 
Volume in 1 second (FEV1).
!
Changes over the course of the study in Peak 
Expiratory Flow (PEF). 
!
Changes over the course of the study in
Fractional exhaled nitric oxide (FeNO)
1.1.3
Safety objective
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
AZD1419 in eosinophilic asthma patients after 
withdrawal of controller treatment of ICS + 
LABA
!
Adverse events, vital signs, electrocardiogram
(ECG), and laboratory parameters
!
Weekly peak expiratory flow rate (PEFR)
!
Lung diffusion capacity (DLco)


Statistical Analysis Plan 
Study Code D2500C00003
Edition Number 2.0
Date 19Oct2018
16(56)
1.1.4
Exploratory objectives
Exploratory Objective:
Outcome Measure:
!
To assess the responses of selected 
systemic peripheral blood and sputum 
biomarkers to inhaled AZD1419 in 
eosinophilic asthma patients after 
withdrawal of controller treatment of ICS 
+ LABA
!
Peripheral blood and sputum biomarkers 
!
Other biomarkers may be considered
!
To assess the composite endpoint for 
exacerbations, CompEx
!
Time to first CompEx event
!
Changes over the course of the study in number 
of CompEx events
!
To investigate the genes and genetic 
variation that may influence response to 
AZD1419
!
DNA from whole blood
!
To assess the expression of selected genes 
in cells from the whole blood and sputum
!
RNA from whole blood and sputum
!
To assess the effects on DNA methylation
!
DNA from whole blood
!
To assess the immune function of PBMC
!
PBMCs
Results from the exploratory analyses, if performed, may be reported separately from the 
Clinical Study Report (CSR).
The analysis of all exploratory variables other than CompEx will be outside the scope of this 
SAP.
1.2
Study design
This is a randomised, double blind, placebo-controlled Phase 2a study designed to assess the 
efficacy and safety of 13 once weekly doses of inhaled AZD1419 administered to patients 
with eosinophilic asthma controlled on a maintenance treatment of Inhaled Corticosteroids 
(ICS) plus a Long-acting Beta Agonist(s) LABA but no other controller medication.
This study is a multi-centre study conducted at 16 centres in 4 countries.
Prior to randomisation patients will undergo an approximately 2-4 weeks screening period. 
Eligible patients will be prescribed their usual controller medication (i.e. ICS + LABA in 
separate inhalers, in addition to a rescue medication inhaler (short-acting B2 agonist [SABA]), 
and issued electronic diaries, peak flow and FeNO meters to record asthma symptoms and 
lung function during each morning and evening at home. Asthma control will be assessed 
using the 5-item asthma control (ACQ-5) and when patients have shown to be controlled 
(ACQ-5<= 0.75) they are randomised to receive AZD1419 or placebo administered as an 
inhalation at the clinic once per week. 
A withdrawal design will be used where the first 6 doses of investigational product (IP) will 
be administered as add-on to the patient’s regular ICS + LABA medication. The controller 


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medication will then be tapered down and discontinued during the next 3 doses of IP, and the 
last 4 doses will be administered during a period of complete ICS and LABA withdrawal (see 
Figure 1). In addition the study drug dose level will be adjusted using an adaptive dosing 
scheme (defined in Section 4.2.2 of the protocol) based on appearance of flu-like symptoms. 
The primary endpoint is loss of asthma control, defined in Section 1.1.1. When a patient meets 
the primary endpoint, the patient will resume ICS + LABA and will be followed for an 
additional 4 weeks before discontinuing the study.
The total duration of patient participation will be up to 56 weeks. Prior to randomisation
patients will undergo an approximately 2-4 week screening period, which is then followed by 
a 12 week dosing period and an up to 40 week observation period following the last dose. The 
study design is presented in Figure 1. The schedule of trial procedures is presented in Table 1 
of the CSP.
The study will start with a sentinel dosing period to be conducted at 1 or 2 selected study 
centres during which 4 patients will be randomly assigned 1:1 either to placebo or AZD1419 
at 4 mg, dosed once weekly. Sentinel patients will be observed at the clinic for 24 hours after 
each of the first two doses, for details see Section 4.2.1 of the protocol. A Data Safety 
Monitoring Board (DSMB) will review safety data from these patients and approve enrolment 
of additional patients into the study. 
Patients will be monitored with regards to safety, tolerability and efficacy aspects during the 
whole study period. In addition to assessments performed at the clinical visits, an electronic 
patient reported outcome (ePRO) device coupled with a home spirometer will on a daily basis 
capture asthma symptoms, relieve use, lung function peak expiratory flow (PEF) and a 
fractional exhaled nitric oxide (FeNO) meter measurements will be performed every second 
day.  
1.3
Number of patients
This trial has about 90% power to yield a statistically significant (alpha = 0.05, 2-sided) 
difference between the pooled active and placebo groups in time to loss of asthma control 
given that the cumulative number of controlled patients at week 52 is 20% and 60% for 
control versus active respectively. Assuming a drop-out of about 10-15%, this will require 
about 70 patients in total (32 events).
Approximately 135 patients have been enrolled to achieve 81 randomised patients.


Statistical Analysis Plan 
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Figure 1
Study flow 
chart


Statistical Analysis Plan 
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2.
ANALYSIS SETS
2.1
Definition of analysis sets
All efficacy analyses will be performed using an intention-to-treat (ITT) approach based on 
the full analysis set. For consistency, demographic and baseline characteristics will be 
presented using the full analysis set. Safety objectives will be analysed based on the Safety 
population.
Table 1
Summary of Outcome Variables and Analysis Populations
Objective
Outcome Variable
Population
Efficacy
Time to Loss of Asthma Control
FAS
Proportion of patients experience loss of asthma 
control
ACQ-5
Asthma daily diary score
Moderate or severe exacerbations
Proportion of subjects with ≥ 1 moderate or 
severe exacerbation during 52 weeks of treatment
Reliever medication use
FEV1
PEF
FeNO
FVC and FEF 25-75%
Night-time awakenings
Safety
AEs
SA
Vital Signs
ECG
Laboratory parameters
DLco
Exploratory 
CompEx
FAS


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2.1.1
All patients analysis set (All Patients)
This analysis set will comprise all patients screened for the study and will be used for 
reporting of disposition and screening failures.
2.1.2
Full analysis set (FAS)
All patients with a signed ICF who were randomised and receiving any IP will be included in 
the full analysis set, irrespective of their protocol adherence and continued participation in the 
study. Patients will be analysed according to their randomised treatment, irrespective of 
whether or not they  received the wrong IP, and irrespective of whether they prematurely 
discontinued the study. For patients who withdraw consent to participate in the study all data 
will be included up to the date of their study termination.
2.1.3
Safety analysis set
All patients who received any IP will be included in the safety analysis set. Patients will be 
classified according to the treatment they actually received. A patient who has one, or several 
occasions, received active treatment will be classified as active. Patients will be classified 
according to the following: 
!
If a patient receives at least one dose of AZD1419 they will be included in the active 
treatment group. 
!
If a patient receives placebo only, they will be included in the placebo treatment group.
All safety summaries will be based on this analysis set. Any deviations from the randomised 
treatment assignment will be listed and considered when interpreting the safety data.
2.2
Violations and deviations
Only important protocol deviations will be listed and tabulated in the CSR. 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, safety, or well-being include:
!
 Patients who do not meet the inclusion criteria
!
 Patients who do not meet the randomisation criteria
!
 Patients who meet any of the exclusion criteria
!
 Patients who use one or more disallowed medication (for any reason, unless otherwise 
specified) during the randomised treatment period. A list of concomitant medications 
for all subjects will be provided for physician review before each data review meeting, 
for the identification of disallowed medication.


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!
 Patients who received the incorrect study treatment or study dose at any time during 
the 12-week double blind treatment period
!
Patients who developed withdrawal criteria during the study but were not withdrawn
!
Patients who do not take ICS + LABA regime as per the study schedule
All-important protocol deviations will be identified and documented prior to unblinding of the 
data.
Important deviations will be programmatically derived. In addition, an IMPACT report will be 
provided by the AZ Study lead in an Excel file. The IMPACT report will be reviewed together 
by the study team in order to make decisions regarding patient evaluability. The protocol 
deviation classification process and data flow will be clarified in a separate document.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
General Principles
3.1.1
Baseline definitions 
In general, the last measurement on or prior to the date of randomisation will serve as the 
baseline measurement for efficacy endpoints, while the last measurement prior to first dose of 
IP will serve as the baseline measurement for safety endpoints. 
For the following parameters, only measurements recorded at the baseline visit (Visit 2 (Week 
0)) taken pre-bronchodilator are considered for the baseline: Inspiratory Capacity (IC), 
FEV1/FVC ratio, FEV1 reversibility, FEV1 reversibility (%), Diffusing Capacity of the Lung 
Carbon Monoxide (DLco), FeNO, average FeNO.
If Visit 2 (Week 0) measurement is missing, the last non-missing value before Visit 2 will be 
used as baseline instead. 
For the following parameters, baseline is calculated at each timepoint (pre-bronchodilator and 
post-bronchodilator): FEV1, Forced Vital Capacity (FVC), Forced Expiratory Flow 25%,
Forced Expiratory Flow 75%, Forced Expiratory Flow 25% to 75% (FEF25-75%) and PEF
(collected at the clinic). For post-bronchodilator (BD) measurements, where it is possible to 
have multiple spirometry records per time point, the first measurement will be used (i.e. the 
measurement after the first BD administration).
The baseline for Electronic Patient Reported Outcome (ePRO) will be derived from what is 
captured on the ePRO device 5 days prior to Visit 2 (Week 0) for PEF, Asthma Daily Diary
scores and Reliever medication use. The 5 days do not have to be strictly consecutive.


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For night-time baseline diary scores, the calculations should comprise 5 mornings including 
the morning of randomisation. For daytime baseline diary scores, the calculations should 
comprise 5 evenings prior to randomisation.
For PEF evening baseline mean, the calculations should comprise of the mean of last 5 
evening values prior to randomisation. For PEF morning baseline mean, the calculations 
should comprise of the mean of last 5 morning values prior to and including day of
randomisation. For PEF baseline mean, this is calculated as the average of the morning 
baseline mean and the evening baseline mean. 
The mean baseline usage of reliever medication will be calculated as the sum of puffs of 
reliever medication (last 5 morning usages + last 5 evening usages prior to visit 2 
(randomisation))/5. The morning session at visit 2 is included in the calculation. If in the 
reliever medication diary data ASMDMQ2=0 (i.e. Use of rescue medication is response to 
symptoms=No) and ASMDMQ2A=missing (Number of puffs of rescue inhaler=missing), 
then EXDOSE will be set to zero in the SDTM datasets.
The baseline for ACQ-5 will be captured at the baseline visit (Visit 2 (Week 0)). If more than 
one result is captured prior to the date of randomisation, then the result from the closest prior
visit will be used.
The baseline at clinic FeNO measurements will be captured at clinic at the baseline visit (Visit 
2 (Week 0)). As the first FeNO measurement taken at home on the Niox Vero FeNO device 
will be captured at Visit 2+2d (Week 0 +2d), i.e. 2 days post first administration of IP, the 
clinic FeNO measurement taken at baseline visit will be the baseline for this endpoint.
For demography, laboratory data, vital signs, physical examination and ECG, baseline will be 
defined as the latest non-missing assessment prior to first dose at the baseline visit (Visit 2
(Week 0)). If no time is recorded for an assessment, and the assessment takes place at Visit 2
(Week 0), this will be assumed to be a pre-dose assessment.
3.1.2
Study day
Whenever data is summarised over time, study day will be calculated based on the actual 
assessment date. Efficacy data assessments will be summarised in relation to date of 
randomisation. Safety data will be summarised in relation to date of first dose. 
If actual assessment date is prior to randomisation / first dose then study day will be: 
Study day = Actual assessment date – Randomisation / first dose date. 
If actual assessment date is on or after randomisation / first dose then study day will be: 
Study day = Actual assessment date – Randomisation / first dose date + 1.
3.1.3
Absolute and percent change from baseline 
Absolute change from baseline outcome variables is computed as 


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(post-randomisation value – baseline value). 
Percent change from baseline is computed as 
((post-randomisation value – baseline value) / baseline value) × 100%.
If either the post-randomisation value or the baseline value is missing, then the absolute or 
percent change from baseline value will also be set to missing.
Percentage change from baseline will not be calculated or presented for variables that may 
take 0 as a value.
3.1.4
Visit windows
For the exacerbation-related analyses no windows will be applied. 
Daily eDiary and ePRO data (PEF, ACQ-5, FeNO) will primarily be summarised and 
analysed as weekly averages e.g. over days 2 - 8, 9 - 15 and 16 - 22 etc, separately.
The assessment period of visit windows will be defined in Appendix A, Table 5.
Summaries and analyses of non-eDiary or non-ePRO data will be based on CRF visit 
designation, defined in Appendix A, Table 6. 
Any data collected at unscheduled visits will be listed, included within baseline data in shift 
plots, and will be included in the definition of maximum/minimum within-period value.
The Unscheduled visits will be included when applying the visit windows to ensure that all 
available data are used in the analysis. For weekly summaries, the mean of all non-missing 
observations within an assigned window is calculated. For visit data, if there are duplicate 
observations assigned to the same visit window, the following data handling conventions will 
be adopted:
1. If there are two or more observations within the same visit window, the non-missing 
observation closest to the scheduled visit will be used in the analysis. 
2. If two observations are collected on the same day, the non-missing observation with 
the later collection time will be included in the analysis. 
3.1.5
Handling of missing data 
All efficacy analyses will be based on the Full Analysis Set. Missing data rules for efficacy 
endpoints can be found in Sections 3.2 and 3.3. For eDiary endpoints (derived datasets ADQS, 
ADRE, ADEXSUM), when weekly means are calculated for summary statistics this will be 
calculated as the average of the non-missing values over a period of 7 sequential days e.g. if 
non-missing values are only recorded for 3 days then the denominator for the mean is 3. For 


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rescue medication weekly mean calculation where a patient discontinues treatment part-way 
through a week, the mean would be calculated as the average of what is recorded regardless of 
how many days were recorded in that part-week. For the eDiary endpoint rescue medication, 
in the event that a patient has recorded that they have taken rescue medication 
(ASMDMQ2=1) but the associated number of puffs collected is missing or recorded as zero
(ASMDMQ2A=missing or 0), this missing or zero value will be changed to EXDOSE=1 in 
the SDTM datasets,
As the daily total for Asthma Daily Diary scores and Reliever medication are defined as the 
sum of the daytime and night-time scores on a specific day (e.g. sum of day 1 evening plus 
day 2 morning), if either daytime or night-time scores is missing, the daily total is set to 
missing.
Missing safety data will not be imputed. 
Laboratory values of the form “<x” (i.e. below the lower limit of quantification) or “>x” (i.e. 
above the upper limit of quantification) will be imputed as “x” in the calculation of summary 
statistics but displayed as “<x” or “>x” in the listings. 
For the diagnosis of Allergic Rhinitis, age at asthma diagnosis, years since most recent 
exacerbation and similar variables based on date calculations, if only partial dates are 
recorded, these will be imputed as the earliest possible date e.g. if day is missing but month 
and year are present then the 1st of the month will be imputed in order to derive the time since 
diagnosis variable. If the day and month are missing but the year is present, then the 1st
January of that year will be imputed in order to derive the time since diagnosis variable. 
Partial dates will be flagged in listings and the analysis.
3.2
Primary efficacy outcome measure
The primary outcome measure is time to loss of asthma control. The EXACA module of the 
eCRF will be used to derive the Loss of asthma control variable. For the purpose of the study,
loss of asthma control is defined as any of the following:
a) An increase of ACQ-5 to 1.5 or more 
In the ACQ-5 questionnaire the patients are asked to recall the status of their asthma during 
the previous week with regards to symptoms. The questionnaire include questions on
1. Awoken at night by symptoms
2. Limitation of normal daily activities
3. Waking in the morning with symptoms
4. Dyspnoea
5. Wheeze


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The questions of the ACQ-5 will be measured on a 7-point scale scored from 0 (totally 
controlled) to 6 (severely uncontrolled). The ACQ-5 score is computed as the un-weighted 
mean of the responses. If response to any of the questions is missing, the ACQ-5 score is 
set to missing by the ePRO provider. If ACQ-5 reaches a value of 1.5 or more, the patient 
is reported as having loss of asthma control.
b) A reduction of 30% or more in morning peak expiratory flow (PEF) from baseline on 2 
consecutive days
PEF is measured daily using the ePRO device. Patients should perform 3 successive peak 
flow manoeuvres while sitting or standing, but in the same position at every testing; the 
highest of the 3 values will be captured for the morning and for the evening manoeuvres.
c) At least six additional reliever inhalations of SABA in a 24-hour period relative to baseline 
on 2 consecutive days
The number of reliever medication inhalations taken will be recorded by the patient in the 
Asthma Daily Diary twice daily. The number taken between the morning and evening lung 
function assessments will be recorded in the evening. The number of inhalations taken 
between the evening and morning lung function assessments will be recorded in the 
morning. Reliever medication usage is captured in the daily diary as the number of inhaler 
puffs.  
d) An exacerbation requiring systemic corticosteroids
Upon a), b) or c) being fulfilled, an automated asthma action plan will be triggered in the 
ePRO device prompting the patient to resume their usual ICS + LABA medication and to 
contact the PI.
The primary endpoint Time to loss of asthma control will be calculated as follows:
Start Date of first loss of asthma control – Date of Randomisation + 1. 
The start date of the first loss of asthma control will be the earliest of:
1. Date of the first increase in ACQ-5 of 1.5 or more
2. Date of the first of two consecutive days with a reduction of 30% or more in PEF
3. Date of the first of two consecutive days with six additional SABA inhalations relative 
to baseline
4. Date of the earliest use of systemic corticosteroids to treat an asthma exacerbation 
Time to loss of asthma control will be censored at 52 weeks for patients who do not 
experience loss of asthma control during the 52-week study period or at the time point after 
which an loss of asthma control experience could not be assessed (for lost-to-follow-up 
patients). For patients who withdraw from the study without reporting loss of asthma control, 
time will be censored at the date of withdrawal, if known, else at the patient’s last clinical visit 
plus one day.


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3.3
Secondary endpoints
Secondary efficacy variables include proportion of patients with loss of asthma control, ACQ-
5, eDiary variables, proportion of patients with a moderate or severe exacerbation, PEF, FEV1
and FeNO. These are described in more detail below.
3.3.1
Proportion of patients who experience loss of asthma control 
The proportion of patients who experience loss of asthma control during the 52-weeks of 
treatment will be a supportive measurement to the primary objective. The outcome variable 
will categorize each patient as having loss of asthma control symptom being met or not 
(yes=1/no=0).
The proportion of such patients will be calculated for each treatment group as:
Number of patients with loss of asthma control indication during the 52-week treatment 
period/ number of patients in treatment group
3.3.2
Asthma Control Questionnaire (ACQ-5)
In the ACQ-5 questionnaire the patients are asked to recall the status of their asthma during 
the previous week with regards to symptoms, see Section 3.2 for specific questions. 
The ACQ-5 questions will be measured on a 7-point scale scored from 0 (totally controlled) to 
6 (severely uncontrolled). The ACQ-5 score is computed as the un-weighted mean of the 
responses. If response to any of the questions is missing, the ACQ-5 score will be set to 
missing by the ePRO provider. If ACQ-5 reaches a value of 1.5 or more, the patient is
reported as having loss of asthma control.
As mentioned above, the ACQ is based on 5-item version. The ACQ-5 will be self-
administered within the ePRO once weekly during the study. 
The outcome variable for ACQ-5 is a weekly average.
3.3.3
Asthma daily diary score
Asthma symptoms during night-time and daytime will be recorded by the patient each
morning and evening in the Asthma Daily Diary. Symptoms will be recorded using a scale 0-
3, where 0 indicates no asthma symptoms. The outcome variables, asthma symptom daytime 
score (recorded in the evening), night-time score (recorded in the morning), and total score 
will be calculated and presented separately. 
The outcome variable Asthma Daily Diary total score will be calculated by taking the sum of 
the night-time and daytime asthma symptom scores recorded each day. The outcome variable 
Asthma Daily Diary total weekly mean for a specific week will be calculated as the sum of 
non-missing daily total is divided by the number of non-missing days of that week. If a patient
is missing a value for either night-time or daytime asthma symptom score on a given day, then 
the total score for that day will be set to missing.


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Example for Asthma Daily Diary total weekly mean calculation:
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Morning
Prior 
randomisation
night-time 
scores 
(D1_M)
Day 1 
night-
time 
scores 
(D2_M)
Day 2 
night-
time 
scores 
(D3_M)
Day 3 
night-
time 
scores 
(D4_M)
Day 4 
night-
time 
scores 
(D5_M)
Day 5 
night-
time 
scores 
(D6_M)
Day 6 
night-
time 
scores 
(D7_M)
Day 7 
night-
time 
scores 
(D8_M)
Evening
Daytime 
scores on Day 
1 (D1_E)
Day 2 
daytime 
scores 
(D2_E)
Day 3 
daytime 
scores 
(D3_E)
Day 4 
daytime 
scores 
(D4_E)
Day 5 
daytime 
scores 
(D5_E)
Day 6 
daytime 
scores 
(D6_E)
Day 7 
daytime 
scores 
(D7_E)
Day 8 
daytime 
scores 
(D8_E)
Total daily scores for each day is defined as: D(n)_E+D(n+1)_M, where n = 1, 2, ..7
Week 1 morning mean, W1_M,: (D2_M+..+D8_M)/7. “/7” is for illustration in this example, 
the number of non-missing days will be used in the analysis.
Week 1 evening mean, W1_E, is defined as: (D1_E+…+D7_E)/7. “/7” is for illustration in 
this example, the number of non-missing days will be used in the analysis.
Total daily scores on a weekly basis should be [D(n)_E+D(n+1)_M]/7 where n=1,…7. “/7” is 
for illustration in this example. The number of non-missing number of days will be used in the 
analysis.
The number of asthma symptom-free days will be calculated for each patient as the total 
number of days in the 52 week treatment period where the total asthma symptom score is 0. 
The outcome variable proportion of asthma symptom-free days will be calculated using the 
total number of days with completed asthma symptom score diary during the 52-week 
treatment period as the denominator.
Summary statistics will be presented by treatment and week for the number of asthma 
symptom-free days and the proportion of asthma symptom-free days. The handling of missing 
data in the calculation of weekly average daytime asthma daily diary score, weekly average 
night-time asthma daily diary score and weekly average total asthma daily diary score is 
described in Section 3.1.5.
3.3.4
Time to moderate or severe exacerbation 
Severe exacerbation is defined as a worsening in asthma symptoms and 
!
Use of systemic corticosteroids for at least three days and/or 
!
An unscheduled visit or emergency room visit due to asthma symptoms that 
requires at least one dose of systemic corticosteroids and/or 


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!
An in-patient hospitalization due to asthma requiring at least one dose of systemic 
corticosteroids.
Moderate exacerbation is defined as a temporary increase in maintenance therapy in order to 
prevent a severe event supported by a sustained (≥ 2 day) worsening in at least one key control 
metric i.e. asthma score, reliever medication use, night time awakening or morning PEF.
The start and stop dates of severe exacerbations experienced by a patient during the treatment 
period will be derived from the following rule.
!
The start date of a severe exacerbation is defined as the start date of systemic 
corticosteroids or increased use of systemic corticosteroids or of emergency room visit 
or hospital admission, whichever occurs first. 
!
The stop date is defined as the last day of systemic corticosteroids/increased use of 
systemic corticosteroids or hospital discharge, whichever occurs last.
The start and stop dates of moderate exacerbations experienced by a patient during the 
treatment period will be derived from the following rule.
!
The start date of a moderate exacerbation is defined as the first day of increase in 
temporary maintenance therapy. 
!
The stop date is defined as the last day of this treatment.
The EXACA module of the eCRF will be used to derive the severe exacerbation variable. The 
MED1 module of the eCRF will be used to derive the moderate exacerbation variable.
Time to a moderate or severe exacerbation will be censored at 52-weeks for patients who do 
not experience a moderate or severe exacerbation during the 52-week study period or at the 
time point after which a moderate or severe exacerbation experience could not be assessed 
(for lost-to-follow-up patients). For patients who withdraw from the study without reporting a 
moderate or severe exacerbation, time will be censored at the date of withdrawal, if known, 
else at the patient’s last clinical visit plus one day.
As defined for the primary analysis, exacerbations that occur after a subject has discontinued 
IP but before maximum follow-up time will still be accounted when deriving the total number 
of exacerbations. Likewise, the follow-up time will reflect the follow-up time regardless of 
whether or not the subject is still on IP.
3.3.5
Proportion of subjects with 1 moderate or severe exacerbation during 52-
weeks of treatment
The proportion of patients who experience 1 moderate or severe exacerbation during the 52-
weeks of treatment will be a supportive measurement to the primary objective. The outcome 
variable will categorize each patient as having one moderate or severe exacerbation 
experience being met or not (yes=1/no=0).


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The proportion of such patients will be calculated for each treatment group as:
Number of patients with 1 moderate or severe exacerbation during the 52-week treatment 
period/ number of patients in treatment group
3.3.6
Reliever medication use
The number of rescue medication inhalations taken will be recorded by the patient in the 
Asthma Daily Diary twice daily. The number taken at daytime lung function assessments will 
be recorded in the evening. The number of inhalations taken at night-time lung function 
assessments will be recorded in the morning. Reliever medication usage is captured in the 
daily diary as the number of inhaler puffs. 
The number of inhalations (puffs) per day will be calculated as follows:
Number of night inhaler puffs + number of day inhaler puffs
The outcome variable total weekly mean reliever medication use for a specific week will be 
calculated the same way as total weekly Asthma Daily Diary scores in Section 3.3.3, i.e. Day 
1 should be D1_E+D2_M,  and the weekly mean is (D1 total +D2 total+..+D7 total)/ non-
missing number of days.
3.3.7
FEV1 pre/post BD 
The pre/post BD FEV1 will be determined by the spirometry tests at the clinic at each visit as 
scheduled. To ensure quality control all spirometry measurements are reviewed to ensure that 
they meet ATS/ERS (American Thoracic Society 2000) criteria for acceptability. Section
5.1.2 of the CSP contains further details of the spirometry recordings.
The endpoints are:
1) absolute change from baseline in pre-BD FEV1 (L)
2) percentage change from baseline in pre-BD FEV1  
3) absolute change from baseline in post-BD FEV1 (L)
4) percentage change from baseline in post-BD FEV1
The absolute changes from baseline are the main FEV1 endpoints. The percentage changes 
from baseline are supportive endpoints. 
A reversibility test will be performed at Visit 1 (Week -4), with spirometry assessment 30±10
minutes before and after administration of short-acting β2 agonist.
The percent reversibility is calculated as follows:
Reversibility (%) = (FEV1 post – FEV1 pre) / FEV1 pre x 100


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The value of Percent predicted normal for FEV1 used as part of the eligibility process will not 
be checked programmatically. 
3.3.8
Peak Expiratory Flow (PEF) 
Morning and evening PEF measurements will be taken at home on the ePRO device by the 
patient on a daily basis and then averaged over the week. The outcome variable is weekly 
average total PEF. The weekly morning PEF average for Week 1 is calculated as 
(D2_M+..+D8_M)/non-missing days) and weekly evening PEF average is calculated as 
(D1_E+…+D7_E)/non-missing days). Weekly average total PEF is calculated as the average 
of the weekly morning mean and the weekly evening mean. The handling of missing data is 
described in Section 3.1.5. 
3.3.9
Fractional Exhaled Nitric Oxide (FeNO)
FeNO measurements will be taken at home by patients every second day. FeNO 
measurements will also be taken at designated time points at the study centre. 
The home FeNO outcome variable is a weekly average FeNO based on the average of 
measurements taken at home for a specific week. The handling of missing data in the 
calculation of weekly average FeNO is described in Section 3.1.5.
The home FeNO outcome variable will be separate to the clinic FeNO outcome variable.
3.3.10
Vital Capacity and Forced Expiratory Flow at 25-75%
FVC and FEF25-75 are spirometry measurements taken pre- and post- BD at clinic visits 1
(Week -4), 2 (Week 0), 6 (Week 4), 9 (Week 7), 14 (Week 12), 15 (Week 13), 16 (Week 16), 
17 (Week 20), 18 (Week 28), 19 (Week 36) and 21 (Week 52). 
Summary statistics will also be presented for each treatment group at the specified visits.
3.3.11
Night time awakenings 
Night-time awakenings due to asthma symptoms will be recorded by the patient in the Asthma 
Daily Diary each morning by answering the question whether he/she woke up during the night 
due to asthma symptoms by a “yes” or “no” response.
Summary statistics will also be presented for each treatment group at each week. 
The outcome variable is a weekly mean calculated as the number of times the subject 
answered ‘yes’ over a period of 7 sequential days. The first weekly mean (the treatment 
weekly mean) will be based on the morning recording on Day 2 up to and including the 
morning recording on Day 8. The second weekly mean (the follow-up weekly mean) will be 
based on the morning recording on Day 9 up to and including the morning recording on Day 
15 and so on.


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3.4
Calculation or derivation of safety variable(s)
The following safety data will be collected: vital signs, physical examination (include 
assessment of the following: general appearance, respiratory, cardiovascular, abdomen, skin, 
head and neck(including ears, eyes, nose and throat) lymph nodes, thyroid, musculoskeletal 
(including spine and extremities) and neurological systems, 12-lead ECG, haematology, 
clinical chemistry, urinalysis, DLco, PEFR and reported adverse events (AEs).
Change from baseline (Visit 2) to each post-baseline time point where scheduled assessments 
were made will be calculated for relevant measurements.
3.4.1
Adverse events
The definitions of adverse events (AEs) and serious adverse events (SAEs) are given in 
Sections 6.1 and 6.2 of the CSP.
All AEs recorded in the eCRF will be coded according to the terminology of the latest version 
of the Medical Dictionary for Regulatory Activities (MedDRA).
All adverse events will be listed for each patient and summarised by treatment actually 
received. Treatment-emergent AEs will be tabulated (number and percentage of patients) by 
system organ class (SOC), preferred term (PT), intensity and relation to study medication. 
Any AE occurring before the start of study treatment will be included in the data listings but 
will not be included in the summary tables of AEs and excluded from safety analysis set. 
If an AE has a missing onset date then unless the stop date of the AE indicates otherwise, this 
will be considered ‘on-treatment’. Similarly, if an AE has a partial onset date, then unless the 
partial onset date or the stop date indicates otherwise, this will be considered ‘on-treatment’.
AE data will be categorized according to their onset date into the following periods: 
!
AEs starting during pre-treatment (onset date ≥Visit 1 (Week -4) and before the first 
dose of IP)
!
AEs starting during study (onset date ≥the first day of IP and ≤Visit 21 (Week 52))
!
AEs starting during ICS + LABA treatment period (onset date ≥the first day of IP and 
< Visit8 (Week 6))
!
AEs starting during ICS taper down period (onset date ≥Visit 8 (Week 6) and < Visit 
11 (Week 9))
!
AEs starting during remainder of study (onset date ≥Visit 11 (Week 9) ≤Visit 21 
(Week 52))
The timing of AEs will be assigned to the period in which they first started. The same during 
treatment definition will be used for laboratory and physical examination data, where 
applicable. Note, not all Exacerbations will be recorded as AEs.


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Common AEs, AEs with outcome of death, SAE, DAEs and Flu-like AEs will be summarized 
separately. Flu-like AEs are defined in Section 4.2.5.1. 
3.4.2
Laboratory 
Blood and urine samples will be used for determination of clinical chemistry, haematology 
and urinalysis parameters taken at scheduled time points as specified in Table 1, Section 4 of 
the CSP. The laboratory parameters to be measured are given in Table 3, Section 5.2.1 of the 
CSP. Laboratory data will be reported using Système International (SI) units.
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent scheduled assessment will be calculated. 
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The central laboratory or 
local laboratory (for assessments measured at a local laboratory) reference ranges will be used 
for laboratory variables. All values (absolute and change) falling outside the reference ranges 
will be flagged.
Urinalysis data will be categorised as negative (0), trace, or positive (+) at each time-point and 
will be listed only. 
For the purposes of haematology and clinical chemistry shift tables, baseline will be defined 
as the latest non-missing assessment prior to first dose, and during-study is as defined in 
Section 3.4.1. Shift-tables will not be presented for the specific periods separately, i.e.
ICS+LABA treatment period, ICS taper-down period or during the remainder of study. On 
treatment is defined as from date of first dose and including visit 14 (week 12).
For the liver function tests: Aspartate Aminotransferase (AST), Alanine Aminotransferase 
(ALT), Alkaline phosphatase (ALP) and total bilirubin (TBL), the multiple of the central or 
local laboratory upper limit of the normal (ULN) range will be calculated for each data point.
Multiple = Value / ULN
i.e. if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2.
Patients who meet any of the following criteria at any point during the study will be flagged:
!
AST ≥ 3xULN
!
ALT ≥ 3xULN
!
TBL ≥ 2xUL


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3.4.3
Vital signs
Vital sign assessments (pulse, systolic blood pressure, diastolic blood pressure and pulse 
oximetry), will be performed as in accordance with the schedule provided in Table 2, Section
4 in the CSP. Height and weight will be assessed at screening only.
Change from baseline in vital signs will be calculated for each post-randomisation visit.
Absolute values for vital signs will be compared to the relevant reference ranges and classified 
as low (below range), normal (within range or on limits of range) and high (above range). All 
values (absolute and change) falling outside the reference ranges will be flagged.
Body mass index will be calculated from the height (in meters) and weight (in kilograms) as 
follows: 
BMI = kg/m2
Table 2
Vital signs reference ranges
Parameter
Standard Units
Lower Limit
Upper Limit
Change Criteria
Diastolic Blood Pressure* 
mmHg
<60
>100
∀15
Systolic Blood Pressure*
mmHg
<90
>160
∀30
Pulse*
Beats/min
<50
>100
∀20
Peripheral Oxygen Saturation
%
<90
=100
N/A
* Will be taken lying down
3.4.4
Electrocardiograms (ECG)
Twelve-lead ECG measurements will be recorded in accordance with the protocol at screening 
and at the safety follow-up visit at the end of the trial. 
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant.
Abnormal values shall not be recorded as AEs unless deemed clinically significant. The 
printout of the ECG is to be signed, dated and filed in the Investigator study file along with a 
signed and dated copy (if the printouts are not on archive-quality paper).
The reference ranges for the ECG tests are presented in Table 4.
3.4.5
Physical examination (not stated in the safety outcome measures)
Complete physical examinations will be performed at Visits 1 (Week -4), 6 (Week 4), 9
(Week 7), 15 (Week 13) and 21 (Week 52). Any new or aggravated existing finding(s) judged 
as clinically significant by the Investigator, at any post baseline physical examination during 
the study, compared to the screening (i.e. Visit 1) assessment will be reported as an AE.


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3.4.6
Diffusing Capacity of the Lung for Carbon Monoxide 
Measurement of the diffusing capacity of the lung for carbon monoxide (DLco) will be 
performed at Visits 1 (Week -4), 2 (Week 0), 6 (Week 4), 9 (Week 7), 15 (Week 13) and 17
(Week 20). 
3.5
Calculation or derivation of exploratory endpoints
3.5.1
Composite endpoint for exacerbations (CompEx)
CompEx (Anne L Fuhlbrigge et al. 2017) will be assessed in two ways: (i) as time to first 
CompEx event during the 52-weeks following randomisation and (ii) as proportion of patients 
with a CompEx event during the 52-weeks following randomisation. 
A CompEx event is defined as the first occurrence of either a diary event or a severe 
exacerbation.  
For the development of CompEx, the following diary variables are particular of interests: peak 
expiratory flow (P), reliever medication use (R), asthma symptoms (S) and night-time 
awakening (A).  Diary events for the purpose of this study, which must include peak 
expiratory flow (P), are defined as either at least two variables fulfilling threshold criteria, or 
at least one variable fulfilling a threshold criterion and the slopes for all variables fulfilling the 
slope criteria.
Deterioration criteria for the individual diary event are defined as either changes from 
baseline, larger than a pre-specified threshold for at least 2 consecutive days, or as a 
worsening greater than a certain magnitude (slope) over at least 5 days.
The baseline levels of deterioration should be calculated for each individual as the mean over 
the 5 days ending just before the day of randomisation for each of the diary variables (they do 
not have to be 5 consecutive days). If <5 days data are available, then take the mean for the 
number of days where data is collected, and if missing, the first 3 days after randomisation
should be used. No imputation of missing diary data after randomisation should be performed.
Five variants of CompEx (based on diary records Peak expiratory flow and Reliever 
medication use (PR); Peak expiratory flow and Symptoms (PS); Peak expiratory flow and 
Awakenings (PA); Peak expiratory flow, Reliever medication use and Symptoms (PRS) and 
Peak expiratory flow, Reliever mediation use, Symptoms and Awakenings (PRSA) 
respectively) will be explored and are defined in Table 3 along with criteria for events in term 
of thresholds and slopes. PRS is pre-specified to be the primary diary event endpoint of 
interest.
A diary event required the fulfilment of at least two worsening criteria defined as:
1. at least two variables fulfilling threshold criteria; or


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2. at least one variable fulfilling a threshold criterion and the slopes for all variables 
fulfilling the slope criteria.
The occurrence of a diary event within a subject is defined as the first occasion when either 
(1) or (2) above occurs. For example, in the case of the algorithm for the PRS diary event 
defined in Table 3: this diary event is based on PEF [morning (m) and evening (e)], reliever 
use [morning and evening] and symptoms [morning and evening], giving six different diary 
variables to consider. The diary event for case (1) is defined so that the threshold deterioration 
criterion needs to be fulfilled for one of the PEF variables at the same time as the criterion is 
fulfilled for either one of the reliever or symptom variables. This gives in total eight variable 
combinations (Pm/Rm, Pm/Re, Pe/Rm, Pe/Re and Pm/Sm, Pm/Se, Pe/Sm, Pe/Se) where the 
deterioration needs to be fulfilled for both variables in at least one combination in order for a 
diary event to occur. The first of the two days where the threshold is reached for at least two 
variable is taken as the starting point of the event.
The diary event for (2) will occur when one of the six diary variables fulfils the threshold 
deterioration criterion at the same time as the slope criterion is fulfilled for all six variables.
The thresholds (as T1 in the reference paper) for the diary event endpoints are defined as 
follows:
!
PEF morning/evening: ≥ 15% decrease compared to baseline
!
Reliever medication (rescue) use morning/evening: increase ≥ 1.5 doses compared 
to baseline
!
Asthma symptoms morning/evening: increase of ≥ 1 score compared to baseline or 
absolute score of 4
!
Night-time awakening: awakening with increase in rescue use (> 0.5 doses) relative 
to baseline
The slopes (as S3 in the reference paper) for the diary event endpoints are defined as follows:
!
PEF morning/evening: decrease rate > 3% per day
!
Reliever medication (rescue) use morning/evening: increase rate > 0.3 doses per day
!
Asthma symptoms morning/evening: increase rate > 0.2 scores per day
!
Night-time awakening: increase rate > 0.1 doses per day
The following is an illustrative example for calculating the slope for PEF (evening):
!
Fit a univariate linear regression line y = k*x + m


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!
where y = PEF change from baseline (evening), x = day, k = slope and m =
intercept
Slopes are computed over 5-day intervals with the last day of the interval being the start day 
of the event. If there is less than 2 days with available data in an interval, slope is set to 
missing and the condition is not fulfilled. Thresholds are computed for 2-day intervals with 
the first day of the interval being the start day of the event.
Threshold diary events are defined as starting at the earliest on the start day of treatment (Day 
1), with event on Days 1-2, and at the latest ending on Day 364 (event on Days 364-365).
Slope diary events (start day of treatment = Day1) are defined as starting at the earliest on Day 
5 (with event on Days 1-5) and ending latest on Day 365 (with event on Days 361-365).
However, if slope diary events are calculated for those days where at least one variable fulfills 
a threshold criterion, the last possible day for a slope diary event will be Day 364.
For subjects prematurely discontinuing, the above definitions will be amended for actual end 
day of treatment and actual start day of post-treatment.
Events are searched for up to the last day with entry in the diary cards. Missing values indicate 
no event. Missing diary data will not be imputed. If diary card entries stop prematurely (before 
the last day in the study) or if the patient lacks data during the period, the patient is to be 
censored as having no event at the last day in the period. This will be either the last day with 
recordings in the diary or the last day the patient was assessed for severe asthma exacerbation.
The outcome variables for CompEx events will be as follows:
!
Time to first CompEx event during the 52-weeks following randomisation, for each 
of CompEx PR, PS, PA, PRS and PRSA
!
Proportion of patients with a CompEx event during the 52-weeks following 
randomisation, for each of CompEx PR, PS,PA, PRS and PRSA


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Table 3
Definition of diary events evaluated as possible building blocks for 
CompEx
Diary event 
Variables 
Definition 
PR 
P - PEF morning/evening 
R - Reliever morning/evening 
2/2 days above threshold on PEF (morning or 
evening) and reliever (morning or evening), 
or 2/2 days above threshold on 1/4 variables + 4/4 
slopes 
PS 
P - PEF morning/evening 
S - Symptoms morning/evening 
2/2 days above threshold on PEF (morning or 
evening) and symptoms (morning or evening), 
or 2/2 days above threshold on 1/4 variables + 4/4 
slopes 
PA 
P - PEF morning/evening 
A - Awakenings + Reliever 
morning 
2/2 days above threshold on PEF (morning or 
evening) and awakenings, 
or 2/2 days above threshold on 1/3 variables + 3/3 
slopes 
PRS 
P - PEF morning/evening 
R - Reliever morning/evening 
S - Symptoms morning/evening 
2/2 days above threshold on PEF (morning or 
evening) and [reliever (morning or evening), or 
symptoms (morning or evening)], 
or 2/2 days above threshold on 1/6 variables + 6/6 
slopes 
PRSA 
P - PEF morning/evening 
R - Reliever morning/evening 
S - Symptoms morning/evening 
A - Awakenings 
2/2 days above threshold on PEF (morning or 
evening) and [reliever (morning/evening), or 
symptoms (morning or evening), or awakenings 
(with reliever morning increased)], 
or 2/2 days above threshold on 1/7 variables + 7/7 
slopes 
Abbreviations: PEF: peak expiratory flow; R: reliever use (doses); A: awakenings + morning reliever use; S: 
symptoms
3.5.2
Biomarker analysis
Biomarkers will be taken at study time points in accordance with the protocol.
The exploratory biomarker data will not be included in the CSR, and the analysis is not 
described in this SAP.


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3.5.3
Pharmacogenetics research (PGx)
Data collected in the pharmacogenetics research will not be included in the CSR, and the 
analysis is not described in this SAP.
3.5.4
Pharmacodynamics research (PD)
Data collected in the pharmacodynamics research will not be included in the CSR, and the 
analysis is not described in this SAP.
3.5.5
Sputum Induction 
Data collected in the sputum induction research will not be included in the CSR, and the 
analysis is not described in this SAP.  
4.
ANALYSIS METHODS
4.1
General principles
The analysis of the study outcome variables will include all data captured during the 52-week
double blind treatment and follow-up period. This includes data regardless of whether IP was 
prematurely discontinued or delayed, and/or irrespective of protocol adherence, unless the 
patient withdraws consent or assent to study participation. 
A summary table which counts patients who have been incorrectly randomised and who 
received incorrect treatment will be presented. 
Summary data will be presented in tabular format by treatment. Categorical data will be 
summarized by the number and percentage of patients in each category. Continuous variables 
for parametric data will be summarized by descriptive statistics including N, mean, (standard 
deviation) SD, median, and range.
Minimum and maximum values will be reported to the same degree of precision as the raw 
data unless otherwise stated. Mean, median, SD, confidence intervals (CIs), geometric mean 
and CV will be reported to one further degree of precision. Percentage frequencies will be 
presented to one decimal place.
Given the number of endpoints in the secondary analyses, multiplicity procedures will not be
used to attempt to control ‘alpha’ across all secondary endpoints.
All data will be listed. Data listings will be sorted by treatment and subject number. 
Summaries by visit will include baseline but not visits intended for screening and 
randomisation.
All hypothesis testing will be reported using 2-sided tests except for the primary analysis 
which will be 1-sided and the p-value will be presented to 4 decimal places. Where confidence 


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intervals (CI) are presented for treatment comparisons these will be presented as 2-sided 95% 
CIs.
Plots of data by visit or visit window will cover the entire study period including follow-up.
4.2
Analysis methods
4.2.1
Patient disposition, demography data and patients characteristics
Patient disposition will be summarized using the All Patient analysis set.
The number of enrolled patients will be summarized. The number and percentage of patients 
within each treatment group will be presented by the following categories; randomised, not 
randomised (and reason), received study treatment, did not receive study treatment (and 
reason), completed treatment, discontinued treatment (and reason), completed study, and 
discontinued study (including reason).
The number and percentage of patients, who discontinued IP, but remained in the study will 
be presented by treatment group. Kaplan-Meier plots will be produced summarizing the time 
(in days) to discontinuation of IP and withdrawal from the study.
Demographic data such as age, gender, race and ethnicity will be summarized by treatment 
group for the FAS.
Various baseline characteristics will also be summarized by treatment for the FAS. These 
include weight, height, body mass index (BMI), medical, surgical and respiratory disease 
histories, history of allergic rhinitis, FEV1 (pre and post-BD) at baseline, age at onset of 
asthma, asthma duration, the number of asthma exacerbations in the previous 12 months, the 
number of asthma exacerbations requiring hospitalizations in the previous 12 months, number 
of exacerbations resulting in antibiotic treatment, type of recent exacerbations, the number of 
admissions to ICU (Intensive Care Unit) for asthma during the hospitalization, eosinophil 
count, smoking status, nicotine consumption, reversibility test.
The following covariates are deemed to be of interest for inclusion in the statistical models of 
the primary and secondary endpoints. Possible covariates include but are not limited to: age at 
first asthma allergy status, whether hospitalized within the last year, race, sex, baseline 
spirometry variable measurements, baseline PEF, baseline ACQ-5 and baseline asthma 
symptom scores. For Blinded Deliverable review analyses, the following five covariates have 
been selected: age, race, sex, age at first asthma allergy status and whether hospitalized within 
the last year. For the final analysis, only age and gender will be included as covariates in the 
statistical models.
Medical and surgical histories will be summarized by using the latest version of MedDRA
Preferred Term (PT) within the System Organ Class (SOC) level of MedDRA. For medical 
history, conditions are identified as current or past in the eCRF HISM page. Surgical history is 
specified in the HISS eCRF page.


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4.2.2
Prior and Concomitant Medications
The number and percentage of patients who had prior medications and take concomitant 
medications will be presented by treatment group for the FAS. Concomitant medications will 
be classified according to the AstraZeneca Drug Dictionary. The summary tables will present 
medications by generic term using Anatomical Therapeutic Chemical (ATC) classification 
system codes. 
Separate tables will be presented for all medications received during the following periods
!
Prior: Medications with a start and stop date before Visit 2 date (first day of IP). If the 
stop date is missing or partial and it cannot be determined whether the subject stopped 
the drug before the start of study medication, the medication will be considered as 
concomitant. 
!
Concomitant medications while on treatment: Medications with start date ≤ the last 
day of IP and stop date ≥ the first day of IP. If the start or stop date is missing or 
partial and cannot be determined, the medication will be considered as concomitant. If 
the medication started whilst on IP and was ongoing (no stop date) then this is also a 
concomitant medication.
!
Concomitant medications during follow-up: Medications categorised as ‘Concomitant’ 
that are still ongoing one day after the last day of IP, and also
#
Medications with start date > last day of IP and ≤ date of Visit 21; this is only 
applicable for subjects that are treated for the entire treatment period
#
Medications with start date > last day of IP and ≤ the last day of IP + 1 week; 
this is only applicable for subjects that prematurely discontinue IP
Previous disease-related treatments will also be tabulated. 
Tables for maintenance medications (started prior to and ongoing after the first day of IP) will 
be produced displaying the baseline total daily dose of ICS and LABA. The number of 
patients using other maintenance asthma medications at baseline will also be summarised. In 
addition, the total number of days of oral glucocorticosteroid treatment associated with asthma 
exacerbations per patient from the first day of IP up to Week 52 will also be summarised. 
Medications will be classified according to the AstraZeneca Drug Dictionary (AZDD). 
Percentages will be calculated relative to the number of patients in the FAS.
Data from patients who discontinued IP, where possible and relevant, be included in the 
appropriate medication summaries.


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4.2.3
Exposure and Compliance 
Extent of exposure to IP by compliance, total treatment duration by mean daily dose, and 
recordings on eDiary will be summarized by treatment group and using both the safety 
analysis set and full analysis set. 
The date and time of all IP administrations, and all missed doses will be listed using the safety 
analysis set.
4.2.3.1
Exposure 
Extent of exposure to IP is defined as the number of days between the start and the end dates 
of study therapy:
Extent of exposure (days) = (Last dosing date +7 days) - first dosing date + 1.
Dosing period of IP is up to and including week 12, i.e. there is a maximum of 13 weekly 
doses. The calculation for study treatment exposure is consistent across all patients including 
those who prematurely discontinued. Expected dosing administrations can be determined by 
number of weeks from first dose to discontinuation. 
Extent of therapy summaries will be provided for the safety and FAS analysis sets. The 
numbers and percentages of subjects falling into each category will be presented for each 
treatment group, presenting N, mean, SD, median and range.
4.2.3.2
Compliance
Compliance will be summarized for each treatment group, presenting mean, standard 
deviation, 1st quartile, median, 3rd quartile, and range. In addition, the following compliance 
categories will be derived: <80%, 80% -120%, >120%The numbers and percentages of 
subjects falling into each category will be presented for each treatment group. Missing 
responses will not be imputed. Data collected prior to Visit 2 (Week 0) will not be included in 
the compliance calculations.
In addition, the total number of dosing administrations will be calculated per patient. The 
maximum number of possible dosing administrations for IP is 13. If the patient withdraws 
from the study before the 12 week dosing period is completed, the total number of dosing 
administrations expected depends on the duration of the patient in the study.  Compliance is 
defined as:
Compliance (%) = (Number of dosing administrations made/number of dosing
administrations expected) x 100
Compliance for PEF
The PEF will be monitored morning and evening. Patients will perform 3 successive peak 
flow manoeuvres while sitting or standing, capturing the highest value for morning and 


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evening manoeuvres. Protocol states that Investigator will check patient’s adherence to correct 
use of the hand-held spirometer at each visit.
Compliance (%) = (Number of recordings made /number PEF recordings expected) x 100
If a patient completes the 52 weeks of the study, they would be expected to have a maximum 
of 2 recordings per day for 365 days i.e. 730 recordings.  If the patient withdraws from the 
study early, the total number PEF recordings expected is based on the duration of the patient 
in the study. 
Compliance for FeNO
Although FeNO is measured by patients using the NIOX Vero device once in the morning 
every second day as well as at the clinic at designated visits, compliance will be calculated 
using the recordings from the NIOX Vero device at home only. 
Compliance (%) = (Number of recordings made/number FeNO recording expected) x 100
If a patient completes the 52 weeks of the study, they would be expected to have a maximum 
of 1 recording every other day for 365 days i.e. 183 recordings.  If the patient withdraws from 
the study early, the total number FeNO home recordings expected is based on the duration of 
the patient in the study.
Compliance for eDiary 
The ePRO device is used by the patients to record various measurements twice a day, morning 
and evening as well as night-time awakenings once every day. 
Compliance (%) = (Number of recordings made /number recordings expected) x 100
If a patient completes the 52 weeks of the study, they would be expected to have a maximum 
of 2 recordings per day for 365 days i.e. 730 recordings.  If the patient withdraws from the 
study early, the total number eDiary recordings expected is based on the duration of the 
patient in the study.
Compliance for ACQ-5
ACQ-5 will be self-administered within the ePRO once weekly during the study. Compliance 
is based on the Overall ACQ-5 Score.
Compliance (%) = (Number of Overall ACQ-5 scores recorded/number of Overall ACQ-5 
scores expected) x 100
If a patient completes the 52 weeks of the study, they would be expected to have a maximum 
of 52 ACQ-5 scores.  If the patient withdraws from the study early, the total number ACQ-5 
scores expected is based on the duration of the patient in the study.


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4.2.4
Analysis of the primary variable
Under a proportional hazard assumption, we can define the hazard ratio as θ =HA(t)/HB(t) for 
all t ≤ τ, τ is the largest observation time. A represents the active treatment arm (AZD1419), B 
represents placebo and H(t) is the hazard function. To compare the effect of active treatment 
AZD1419 to placebo group, a log-rank (Mantel-Cox χ2) test will be carried out using the 
SAS® procedure PROC LIFETEST, where the null hypotheses will be:
H0: θ = 1
H1: θ < 1
The null hypothesis (H0) is that during the 52-week double-blind treatment period, the time to 
loss of asthma control in the AZD1419 arm is equal to the corresponding time to loss of 
asthma control in the placebo arm. The alternative hypothesis (H1) is that the time to loss of 
asthma control in the active arm (AZD1419) is longer than in the placebo arm. 
Time to loss of asthma control will be displayed graphically using a Kaplan-Meier plot (time 
axis, will be time from randomisation). 
A Cox proportional hazard model will be fitted to the data to compare the treatments using the 
SAS® procedure PROC PHREG. Results of the analysis will be summarized as hazard ratio, 
2-sided 95% confidence interval and p-value comparing AZD1419 with placebo. The 
hypothesis test will be 1-sided, with alpha=0.05. The covariates for inclusion in the statistical 
model are described in Section 4.2.1.
For patients who withdraw from the study without reporting loss of asthma control, time will 
be censored at the date of withdrawal, if known, else at the patient’s last clinical visit plus one 
day.
The assumptions underlying the statistical model will be explored. If the proportional hazards 
assumption does not hold then alternative methods will be explored which may include the 
following:1) Extend the model to include exposure-time interaction term or 2) if the variable 
for which there is evidence of non-proportional hazards is a confounder, rather than the main 
exposure of interest then regression may be stratified. 
Sensitivity analysis will be performed on the primary variable, see Section 5.1.
4.2.4.1
Loss of asthma control as group proportions
The proportion of patients with loss of asthma control will be compared between the two 
treatment groups at each clinical visit, using a generalized linear model based on a generalized 
estimating equations (GEE) approach, with occurrence of any loss of control as a binary 
outcome variable. Treatment group and visit will be included as factors in the model. The 
covariates for inclusion in the statistical model are described in Section 4.2.1. If a patient had 


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a ‘loss of asthma control’ event at one visit, the subsequent visits information should be 
removed. Each patient can only be counted once towards ‘loss of asthma control’.
This analysis will be carried out using a log-binomial regression model using PROC 
GLIMMIX in SAS with a random subject effect. The estimated treatment effect (i.e. the rate 
ratio of AZD1419 versus placebo), corresponding 95% confidence interval (CI), and two-
sided p-value for the rate ratio will be presented. 
In the case that If the GEE model fails to converge, due to the estimation method not being 
Restricted Maximum Likelihood (REML), then only the Mixed Model will be explored. The 
variance-covariance will be assumed to be unstructured. other options will be explored e.g. 
using the PROC GLIMMIX procedure in SAS. For PROC GLIMMIX, initially this will be 
fitted with a random statement fitting a random intercept and a Laplace approximation for 
maximum likelihood estimation. Again, to facilitate convergence, one or more of the
covariates could be removed leaving the basic model. In case this model also fails to 
converge, the random statement will be removed which will result in a conventional logistic 
regression model being fitted.
The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered.
Summary statistics will also be presented for each treatment group at each visit.
4.2.4.2
Analysis of ACQ-5 
Weekly average ACQ-5 score will be summarized by absolute score at each week by 
treatment group, together with the corresponding changes from baseline. Summaries will be 
descriptive statistics including N, mean, SD, median and range.
Weekly average ACQ-5 will be analysed longitudinally, using a mixed effects model for 
repeated measures (MMRM). Fixed categorical effects of treatment group and week will be 
included in the model with patient as a random effect. The baseline covariate will be the 
unweighted mean of the 5 questions at Visit 2 (Week 0). Further covariates for inclusion in the 
statistical model are described in Section 4.2.1. At each week, all observed values will be used 
in this analysis. The variance-covariance matrix will be assumed to be unstructured. If the 
procedure does not converge then a compound symmetric variance-covariance matrix will be 
used instead. The model is:
Weekly average in ACQijk = Treatment groupi +baseline ACQk + weekj + treatmenti*weekj + 
random patient effectk + covariatesk; (where i=treatment group, j=week and k=patient).
Results will be presented for each timepoint and overall in terms of LSMEANS, treatment 
differences in LSMEANS, 95% confidence intervals and p-values.


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The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered including transformation of the response variable 
or analysing the data using a non-parametric method.
4.2.4.3
Asthma daily diary score 
Weekly average Asthma daily diary score will be analysed using the same method, MMRM as 
described in Section 4.2.4.2.
Weekly average in Asthma daily diaryijk = Treatment groupi + baseline asthma daily diary 
scorek + weekj + treatmenti*weekj + random patient effectk + covariatesk; (where i=treatment 
group,j=week and k=patient).
Results will be presented for each timepoint and overall in terms of LSMEANS, treatment 
differences in LSMEANS, 95% CI and p-values.
The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered as described in Section 4.2.4.2.
Summary statistics for Asthma Daily Diary will be produced by treatment group over time for 
the weekly average and the change from baseline in weekly average. Daytime and night-time 
scores will be similarly summarized as well as total.
4.2.4.4
Reliever Bronchodilator (Use of SABA)  
Responder variable Reliever Bronchodilator (yes/no) will be analysed using a logistic 
regression model with responder at Week 52 as the response variable and covariates of 
treatment and week. Further covariates for inclusion in the statistical model are described in 
Section 4.2.4.2. The results of the analyses will be presented as odds ratios with associated 
95% CI and 2-sided p-value.
The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered.
Summary statistics will be produced for the Reliever medication for each treatment group over 
time for the weekly average and the change from baseline in weekly average. A sensitivity 
summary table is also described for this variable in Section 5.1.
4.2.4.5
Forced expiratory volume in 1 second (FEV1) 
FEV1 is measured at each clinical visit. FEV1 will be analysed at each visit longitudinally
separately for FEV1 pre-dose/pre-BD and FEV1 pre-dose/post-BD, using the same method, 
MMRM as described in Section 4.2.4.2.
FEVijk = Treatment groupi +baseline FEV1k + visitj + treatment j*visitj+ random patient 
effectk + covariatesk; (where i=treatment group, j=visit and k=patient.)


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The pre-dose/pre-BD baseline FEV1 covariate will be used in the pre-dose/pre-BD model.    
The pre-dose/post-BD baseline FEV1 covariate will be used in the pre-dose/post-BD model.   
Results will be presented for each timepoint and overall in terms of LSMEANS, treatment 
differences in LSMEANS, 95% confidence intervals and p-values. 
The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered as described in Section 4.2.4.2.
Summary statistics will be presented for each treatment group at each visit for pre-dose/pre-
BD FEV1 and pre-dose/post-BD FEV1. The absolute score at each planned visit by treatment 
group, together with the corresponding changes from baseline will be summarised. Summaries 
will be descriptive statistics including N, mean, SD, median and range.
4.2.4.6
Peak expiratory flow (PEF) 
PEF is measured daily using the ePRO device. For the purposes of summary and analysis, a 
weekly average PEF will be computed.
Weekly average PEF will be analysed longitudinally, using MMRM as described in Section
4.2.4.2.
Weekly average in PEFijk = Treatment groupi + baseline PEFk + weekj + treatmenti*weekj
+random patient effectk + covariatesk; (where i=treatment group, j=week and k=patient).
Results will be presented for each timepoint and overall in terms of LSMEANS, treatment 
differences in LSMEANS, 95% CI and p-values.
The assumptions underlying the statistical model will be explored. If assumptions do not hold, 
then alternative strategies will be considered as described in Section 4.2.4.2.
Summary statistics for PEF will be produced by treatment group over time for the weekly 
average and the change from baseline in weekly average, as well as morning weekly average 
and evenings weekly average. Summaries will be descriptive statistics including N, mean, SD, 
median and range.
4.2.4.7
Analysis of fractional exhaled nitric oxide (FeNO)  
FeNO is measured using the NIOX Vero® device every other day as well as at clinical visits. 
For the purposes of summary and analysis, a weekly average FeNO will be computed. 
Weekly FeNO will be analysed longitudinally, using MMRM as described in Section 4.2.4.2.
Weekly average in FeNOijk = Treatment groupi + baseline FeNOk + weekj + treatmenti*weekj  
+random patient effectk + covariatesk; (where i=treatment group, j=week and k=patient). 


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Results will be presented for each timepoint and overall in terms of LSMEANS, treatment 
differences in LSMEANS, 95% CI and p-values.
Summary statistics for FeNO will be produced by treatment group over time for the weekly 
average and the change from baseline in weekly average. Summaries will be descriptive 
statistics including N, mean, SD, median and range.
4.2.4.8
Time to moderate or severe exacerbation 
The null hypothesis, that the time to moderate or severe exacerbation is not different between 
AZD1419 and placebo groups, will be tested using the log rank test (with Kaplan Meier plot) 
as discussed in Section 4.2.4.
A Cox proportional hazard model will be fitted to the data using the SAS® procedure PROC 
PHREG, results of the analysis will be summarized as hazard ratio, 2-sided 95% CI and p-
values comparing AZD1419 with placebo. The hypothesis test will be 2-sided, with 
alpha=0.05.
Time to moderate or severe exacerbation will be censored at 52 weeks for patients who do not 
experience loss of asthma control during the 52-week study period.
For patients who withdrew from the study without reporting moderate or severe exacerbation, 
time will be censored at the date of withdrawal, if known, else at the patients last clinical visit
plus one day. 
The assumptions underlying the statistical model will be explored. If the proportional hazards 
assumption does not hold, then alternative strategies will be considered as described in 
Section 4.2.4.
4.2.4.9
Proportion of patients with a moderate or severe asthma exacerbation 
The proportion of patients with an asthma exacerbation will be compared between the two 
treatment groups at each clinical visit, using a generalized linear model based on a generalized
estimating equations (GEE) approach as described in Section 4.2.4.1, with occurrence of 
exacerbation since the start of treatment as a binary outcome variable.
4.2.4.10
FVC and FEF25-75
Summary statistics, including N, mean SD, median and range will also be presented for each 
treatment group at each visit. 
4.2.4.11
Night time awakenings
Weekly mean number (percentage) of nights with awakening due to asthma will be 
summarised by descriptive statistics including N, mean, SD, median, and range.


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4.2.4.12
Data collected at Sentinel Dosing procedures
Efficacy data collected during the sentinel dosing procedure (IC, FEV1/FVC ratio, PEF, DLco, 
FeNO, Forced Expiratory Flow 25%, Forced Expiratory Flow 75%, Forced Expiratory Flow 
25% to 75% (FEF25-75%), FEV1 and VC) at timepoints 0.5, 1,2, 6, 12 and 24 hours will not 
be included in descriptive summaries or any statistical analysis. This data will be listed only.
4.2.5
Safety analysis
All safety variables will be summarized by treatment received and evaluated descriptively 
utilizing the safety analysis set. No formal hypothesis testing of safety data is planned. 
4.2.5.1
Adverse events  
All AEs recorded in the eCRF will be coded according to the terminology of the latest version 
of MedDRA.  AEs may be based on signs and symptoms or may be based on examinations 
and tests as described in Sections 6.3.5 and 6.3.6 of the protocol respectively. 
An overall summary table will be produced showing the number and percentage of subjects 
with at least 1 AE in any of the following categories: AE, serious adverse events (SAEs), 
deaths due to AE and AEs causing discontinuation of IP (DAEs). The total number of AEs in 
the different AE categories in terms of AE counts will also be presented (i.e., accounting for 
multiple occurrences of the same event in a subject). 
AEs will be summarised by SOC and PT. For each PT, the number and percentage of subjects 
reporting at least one occurrence will be presented i.e. for a subject multiple occurrences of an 
AE will only be counted once. 
AEs (by PT) will be summarised by causality and maximum intensity. If a subject reports 
multiple occurrences of the same AE, the maximum intensity will be taken as the highest 
recorded maximum intensity (the order being mild, moderate and severe). A missing intensity 
will be considered as severe and a missing causal relationship to IP will be considered as 
related. 
The following will also be summarised by SOC and PT: SAEs; DAEs; most common AE’s 
(frequency of >5%) (by PT only); and AEs with outcome of deaths. 
Treatment-emergent AEs will be tabulated (number and percentage of patients) by system 
organ class, preferred term (PT), intensity, and relation to IP according to the treatment 
actually received.
Adverse events will be summarized separately for the following periods: AEs occurring 
during pre-treatment, AEs occurring during study, AEs occurring during ICS+LABA 
treatment period, AEs occurring during ICS taper down period and AEs occurring during 
remainder of study as defined in Section 3.4.1.
Summary tables will also be produced showing Flu-like Adverse Events by preferred term, 
relationship to treatment and severity. The number and percentage of subjects with at least 1 


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Flu-like AE will be displayed as well as the total number of AEs for each preferred term by 
maximum reported intensity.  Separate tables will be presented for each of the following 
periods: AEs occurring during study, AEs occurring during ICS+LABA treatment period,
AEs occurring during ICS taper down period and AEs occurring during remainder of study as 
defined in Section 3.4.1. A table will also be presented for the AEs occurring during IP only 
treatment period. This is defined as
!
AEs occurring during IP only treatment period (onset date ≥Visit 11 (Week 9) < Visit 
15 (Week 13))
Flu-like symptoms are defined as events of arthralgia, chills, pyrexia (fever), or myalgia (see 
section 6.1.1 of protocol).
4.2.5.2
Laboratory data
All continuous laboratory parameters will be summarized by absolute value at each visit by 
treatment group, together with the corresponding changes from baseline. The summary 
statistics presented will be the minimum, 1st quartile, median, 3rd quartile, maximum, mean 
and SD.  Mean changes from baseline over time will also be plotted by treatment group.
Central (or local) laboratory reference ranges will be used for the identification of individual 
clinically important abnormalities, and a shift table will be produced for each laboratory 
parameter to display low, normal, high, and missing values. The shift tables will present 
baseline and last on-treatment value for each parameter. On-treatment is defined from date of 
first dose and including visit 14 (week 12).
Shift plots showing each individual subject’s laboratory value at baseline and at the last on-
treatment value will be produced for each continuous laboratory variable. If any laboratory 
variables show any unusual features (high or low values or a general shift in the data points) at 
other time points, then shift plots of these data may be produced. A diagonal line indicating no
change, and horizontal and vertical reference lines indicating the limits of the central (or local) 
laboratory reference ranges will also be displayed on the shift plots.
Data for subjects who have treatment-emergent changes outside predefined criteria will be 
presented. This data presentation will include all visits for this subset of subjects. A change is 
treatment-emergent if it occurred during treatment, from the date of first dose of randomised 
treatment up to and including the follow-up period.
The frequency of treatment-emergent changes outside predefined criteria between baseline 
and each post-treatment time point will be tabulated
In order to identify potential Hy’s Law cases, maximum post baseline TBL will be plotted 
against maximum post baseline ALT, expressed as multiples of ULN. This plot will be 
repeated to show maximum post baseline TBL against maximum post baseline AST, 
expressed as multiples of ULN. These plots will be produced on a log scale and reference 
lines will be included at 2xULN for TBL and at 3xULN for ALT/AST. 


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For all subjects who meet the biochemical criteria for Hy’s law (potential Hy’s Law), a 
Subject Safety Narrative will be produced, and the relevant laboratory parameters will be 
tabulated showing all visits for these subjects. Subjects with elevated ALT or AST, and 
elevated TBL, at any time may be explored further graphically using individual subject profile 
plots.
Any data outside the laboratory reference ranges will be explicitly noted on the listings that 
are produced.
4.2.5.3
Vital signs  
All vital signs parameters will be summarized by absolute value at each visit by treatment 
group, together with the corresponding changes from baseline. The summary statistics
presented will be the minimum, 1st quartile, median, 3rd quartile, maximum mean and SD.
AstraZeneca defined reference ranges will be used for the identification of individual 
abnormalities, and a shift table will be produced for each vital signs parameter to display low, 
normal, high, and missing values. The shift tables will present baseline and 
maximum/minimum during treatment value, as applicable for each parameter.
Shift plots showing each individual subject’s vital signs value at baseline and at 
maximum/minimum will be produced for each continuous vital signs parameter.
Data for subjects who have treatment-emergent changes outside the predefined criteria will be 
presented, using AstraZeneca clinically important change criteria. This data presentation will 
include all visits for each parameter with treatment-emergent changes for this subset of 
subjects. A change is treatment-emergent if it occurred on study as defined in Section 3.4.1.
Data collected during the Sentinel visits will not be included as part of the summary statistics 
calculations or shift plots and will not be flagged,  However, all recorded vital signs data will 
be listed.
4.2.5.4
Diffusing Capacity of the Lung for Carbon Monoxide (DLco)  
DLco at each visit for which it is recorded will be summarized by treatment group with 
descriptive statistics.
4.2.5.5
ECG  
The Investigator’s assessment of the 12-lead ECG (normal or abnormal) will be listed for all 
subjects, along with detailing whether any abnormalities were clinically significant or not.
A shift table will be produced showing the change between baseline and the end of study 
assessment.
Absolute values and change from baseline for ECG parameters RR, PR, QRS and heart rate 
reported by the central ECG laboratory will be summarized by visit. The reference ranges are 
presented in Table 4.


Statistical Analysis Plan 
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Table 4
ECG reference ranges
Parameter
Standard Units
Lower Limit
Upper Limit
ECG Heart rate 
Beats/min
<60
>100
RR interval
ms
<60
>100
PR interval
ms
<120
>200
QRS duration
ms
<60
>120
4.2.5.6
Physical examination 
Shift tables (normal, abnormal (same as baseline, new or aggravated)) of baseline versus last 
on-treatment observation will be generated, presenting the assessment for each component of 
the complete physical examination separately. Listings of abnormal results will be produced.
4.2.5.7
Composite endpoint for exacerbations (CompEx) 
Time to (first) CompEx event, for each of the five variants of CompEx, will be compared 
between AZD1419 and Placebo using a Cox proportional hazard model adjusting for 
treatment group. The hypothesis test will be 2-sided, with alpha=0.05.
Data will be visualized using Kaplan-Meier plots. 
The proportion of subject’s with CompEx events will be compared between treatments using a 
log-binomial regression model. Treatment group will be included as a factor in the model. The 
back-transformed estimated treatment effect (i.e. the ratio of proportions, AZD1419 over 
placebo, will be presented with 2-sided 95% confidence interval and p-value (2-sided 
alternative). The model will be fitted using the SAS® procedure PROC GLIMMIX as 
described in Section 4.2.4.1.
5.
INTERIM ANALYSES
A purely Administrative Interim analysis (IA) will be conducted internally at AZ with no 
consequences for the trial. Therefore, the details of the IA are outside the scope of the SAP, as 
no interim outputs will be provided in the CSR.
5.1
Sensitivity analysis
An analysis will be conducted on the primary outcome variable, loss of asthma control, using 
the same log rank test as for the primary analysis, but making the assumption that all patients 
who withdraw from the study without recorded loss of control are classed as loss of control 
(instead of being censored), in order to test the sensitivity of the results to the use of 
censoring/lack of information regarding loss of control in patients who withdraw.


Statistical Analysis Plan 
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Summary statistics will be produced for the reliever medication for each treatment group over 
time for the weekly average and the change from baseline in weekly average by 1) imputing 
missing values to zero and 2) imputing using last observation carried forward (LOCF)
method. 
Summary statistics will be produced for Asthma Symptom scores (weekly total: mean total 
daily score, number of asthma symptom free days and proportion of asthma symptom free 
days endpoints) for each treatment group over time for the weekly average by 1) imputing 
missing values to zero and 2) imputing using last observation carried forward (LOCF) 
method. 
For LOCF, the missing values will be populated until the patient has their next non-missing 
value or until the patient either completes the study or withdraws from the study. For both 
imputation methods, the individual missing values should be imputed (not daily sums or 
weekly averages).
6.
CHANGES OF ANALYSIS FROM PROTOCOL
Updated detail to categorization of AE data.
Additional Cox proportional hazards model added for loss of asthma control for the primary 
endpoint
Additional Cox proportional hazards model added for time to first moderate or severe 
exacerbation as a secondary endpoint. 
Additional summary statistics for asthma daily diary score
Additional logistic regression analysis added to the analysis of reliever bronchodilator
Updated detail to the analysis of CompEx, using a Cox hazard model, and a log binomial 
regression model as well as Kaplan Meier plots. 
Updated statistical models for ACQ-5, Asthma Daily Diary score, PEF and FeNO to add a 
treatment*week interaction term.
Additional summary statistics for PEF.
Choice of covariates described for Blinded Deliverable review analyses and final analysis.
Summary statistics for time to loss of asthma control added.
Sensitivity summary statistics proposed for Reliever Medication and Asthma Symptom scores.


Statistical Analysis Plan 
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Changed a secondary endpoint definition from ‘proportion of patients who experience ≥1 
moderate or severe exacerbation during the 52-weeks of treatment’ to ‘proportion of patients 
who experience 1 moderate or severe exacerbation during the 52-weeks of treatment’.
Clarified the time to event analysis for ‘moderate or severe exacerbation’.
Clarified the FAS definition to remove ambiguity. Patients that ‘did not take IP’ will not be in 
the FAS.
7.
REFERENCES
Fuhlbrigge et al 2017
Fuhlbrigge, AL, Bengtsson T, Peterson S, Jauhiainen A, Eriksson G, Da Silva CA, Johnson A, 
Sethi T, Locantore N, Tal-Singer R, Fagerås M. A novel endpoint for exacerbations in asthma 
to accelerate clinical development: a post-hoc analysis of randomised controlled trials. Lancet 
Respir Med 2017;5:577–90


Statistical Analysis Plan 
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8.
APPENDIX
8.1
Appendix A
Analysis windows 
Table 5
Analysis windows for weekly summaries
Week
Adjusted windows for 
weekly measures using 
morning or daily 
assessments
Adjusted windows 
for weekly measures 
using evening 
assessments
1
2-8
1-7
2
9-15
8-14
3
16-22
15-21
4
23-29
22-28
5
30-36
29-35
6
37-43
36-42
7
44-50
43-49
8
51-57
50-56
9
58-64
57-63
10
65-71
64-70
11
72-78
71-77
12
79-85
78-84
13
86-92
85-91
14
93-99
92-98
15
100-106
99-105
16
107-113
106-112
17
114-120
113-119
18
121-127
120-126
19
128-134
127-133
20
135-141
134-140
21
142-148
141-147
22
149-155
148-154
23
156-162
155-161


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Week
Adjusted windows for 
weekly measures using 
morning or daily 
assessments
Adjusted windows 
for weekly measures 
using evening 
assessments
24
163-169
162-168
25
170-176
169-175
26
177-183
176-182
27
184-190
183-189
28
191-197
190-196
29
198-204
197-203
30
205-211
204-210
31
212-218
211-217
32
219-225
218-224
33
226-232
225-231
34
233-239
232-238
35
240-246
239-245
36
247-253
246-252
37
254-260
253-259
38
261-267
260-266
39
268-274
267-273
40
275-281
274-280
41
282-288
281-287
42
289-295
288-294
43
296-302
295-301
44
303-309
302-308
45
310-316
309-315
46
317-323
316-322
47
324-330
323-329
48
331-337
330-336
49
338-344
337-343
50
345-351
344-350
51
352-358
351-357
52
359-365
358-364


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Table 6
Analysis windows for scheduled visits
Visit
Target 
Day
Adjusted windows 
for scheduled visits
Visit 2 (Week 0)*
1
1 -  4
Visit 3 (Week 1)
8
5-11
Visit 4 (Week 2)
15
12-18
Visit 5 (Week 3)
22
19-25
Visit 6 (Week 4)
29
26-32
Visit 7 (Week 5)
36
33-39
Visit 8 (Week 6)
43
40-46
Visit 9 (Week 7)
50
47-53
Visit 10 (Week 8)
57
54-60
Visit 11 (Week 9)
64
61-67
Visit 12 (Week 10)
71
68-74
Visit 13 (Week 11)
78
75-81
Visit 14 (Week 12)
85
82-88
Visit 15 (Week 13)
99
89-109
Visit 16 (Week 16)
113
110-127
Visit 17 (Week 20)
141
128-169
Visit 18 (Week 28)
197
170-225
Visit 19 (Week 36)
253
226-295
Visit 20 (Week 48)
337
296-351
Visit 21 (Week 52)
365
352-375
*Prior to first dose/randomisation, visits will be assigned to the Nominal visit. The visit 
windows will be applied thereafter.