A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents With Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist
Phase: PHASE3
Conditions: Uncontrolled Asthma
Sponsor: AstraZeneca

Revised Clinical Study Protocol
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00008
Edition Number
4.0
Date
09 June 2017
A 52-Week, Multicentre, Randomized, Double-Blind, Parallel Group, 
Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of 
Tralokinumab in Adults and Adolescents with Asthma Inadequately 
Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist 
(STRATOS 2)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
International Co-ordinating Investigator: Professor Christopher Brightling
AstraZeneca Research and Development site 
representative
Study Leader
AstraZeneca Canada Inc.
1004 Middlegate Road
Mississauga, Ontario L4Y 1M4
Date 
This submission /document contains trade secrets and confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
The following Amendment(s) and Administrative Changes are included in this revised protocol: 
Amendment No.
Date of Amendment
Local Amendment No.
Date of local Amendment
1.0
17 November 2014
2.0
19 May 2015
3.0
08 October 2015
4.0
09 June 2017
Administrative 
change No.
Date of Administrative 
Change
Local Administrative 
change No.
Date of local 
Administrative Change

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
2(125)
PROTOCOL SYNOPSIS
A 52-Week, Multicentre, Randomized, Double-Blind, Parallel Group, 
Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of 
Tralokinumab in Adults and Adolescents with Asthma Inadequately 
Controlled on Inhaled Corticosteroid and Long-Acting β2-Agonist 
(STRATOS 2)
International Co-ordinating Investigator 
Professor Christopher Brightling
Institute for Lung Health
Leicester, United Kingdom
LE3 9QP
Study site(s) and number of subjects planned
Approximately 770 subjects will be randomized at approximately 225 study sites worldwide.
Study period
Phase of development
Estimated date of first subject enrolled
Q4 2014
3
Estimated date of last subject completed
Q3 2017
3
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the efficacy and safety of a fixed 300 mg dose of tralokinumab administered 
subcutaneously in subjects with uncontrolled asthma on inhaled corticosteroid plus long-
acting β2-agonist and having a history of asthma exacerbations.
Approximately 770 subjects will be randomized globally.  Subjects will be stratified at 
randomization by serum periostin level (<16.44 ng/mL or ≥ 16.44 ng/mL) sampled during 
run-in, geographical region, and age group (adults versus adolescents). 
Subjects will receive either tralokinumab 300 mg, or placebo every 2 weeks via subcutaneous 
injection at the study site, over a 52-week treatment period.
After the initial enrolment and confirmation of the entry criteria, subjects will proceed to a 
run-in period of 4 to 6 weeks to allow adequate time for all of the eligibility criteria to be 
evaluated. Subjects who meet the eligibility criteria will be randomized to a 52-week 
treatment period. Subjects will be maintained on their currently prescribed inhaled 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
3(125)
corticosteroid plus long-acting β2-agonist and any additional asthma controller medication,
without change, from enrolment throughout the run-in and treatment period.
Follow-up visits will be conducted at Weeks 56 and 72. The 20-week extended follow-up 
period is to ensure that adequate determination of immunogenicity can be determined.
Objectives
Primary Objective:
Outcome Measures:
To evaluate the effect of tralokinumab 300 
mg administered every two weeks 
compared with placebo on the annualised 
asthma exacerbation rate in two 
populations:
Biomarker positive population: Subjects 
in the all subject population meeting the 
baseline criteria for biomarker positive 
population specified in the statistical 
analysis plan (primary population)
All subjects: Adult and adolescent 
subjects with asthma that is inadequately 
controlled with inhaled corticosteroid plus 
long-acting β2-agonist (secondary 
population)
Primary outcome variable: The annualised 
asthma exacerbation rate up to Week 52  
  
Primary outcome measure: Asthma 
exacerbation rate reduction
An asthma exacerbation is defined by a 
worsening of asthma requiring:
!
Use of systemic corticosteroids for at least 3 
days; a single depo-injectable dose of 
corticosteroids will be considered equivalent 
to a 3-day course of systemic corticosteroids
!
An emergency room or urgent care visit 
(defined as evaluation and treatment for <24 
hours in an emergency room or urgent care 
center) due to asthma that required systemic 
corticosteroids (as per the above)
!
An inpatient hospitalization (defined as 
admission to an inpatient facility and/or 
evaluation and treatment in a healthcare 
facility for ≥24 hours) due to asthma

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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Key Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to lung function
Key outcome variable: Percent change from 
baseline in pre-dose/pre-bronchodilator forced 
expiratory volume in 1 second 
Key outcome measure: Percent difference vs. 
placebo at Week 52
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to asthma 
symptoms
Key outcome variable: Change from baseline in 
bi-weekly mean daily asthma symptom score 
(combined daytime and night-time score as 
captured in the Asthma Daily Diary) 
Key outcome measure: Mean difference vs. 
placebo at Week 52
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to asthma specific 
health-related quality of life
Key outcome variable: Change from baseline in 
Standardised Asthma Quality of Life 
Questionnaire for 12 Years and Older total score 
Key outcome measure: Mean difference vs. 
placebo at Week 52
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to Asthma 
Control Questionnaire-6 defined asthma 
control
Key outcome variable: Change from baseline in 
Asthma Control Questionnaire-6 
Key outcome measure: Mean difference vs. 
placebo at Week 52
Other Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to other endpoints 
associated with asthma exacerbations
!
Time to first asthma exacerbation and 
proportion of subjects with ≥1 asthma 
exacerbation

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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Other Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to emergency 
room visits, urgent care visits and 
hospitalizations due to asthma
!
Annual rate of asthma exacerbations that are 
associated with an emergency room, urgent 
care visit or a hospitalization
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to pre-dose and 
post bronchodilator forced expiratory 
volume in 1 second
!
Pre-dose/post-bronchodilator forced 
expiratory volume in 1 second 
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to health related 
quality of life.
!
European Quality of Life - 5 Dimensions 5 
Levels Questionnaire
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to health care 
resource utilization and productivity loss 
due to asthma
!
Work Productivity and Activity Impairment 
Questionnaire and Classroom Impairment 
Questionnaire
!
Asthma specific resource utilization (e.g., 
unscheduled physician visits, unscheduled 
phone calls to physicians, use of other asthma 
medications)
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to other 
measurements of asthma symptoms and 
asthma control
!
Rescue medication use 
!
Home peak expiratory flow (morning and 
evening) 
!
Night-time awakening due to asthma 
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
!
Pharmacokinetic parameters: Ctrough
!
Immunogenicity outcome variables:
incidence rate of positive anti-drug 
antibodies and characterization of their 
neutralizing potential

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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Safety Objectives:
Outcome Measures:
To evaluate the safety and tolerability of 
tralokinumab
!
Adverse Events/Serious Adverse Events
!
Vital signs
!
Digital electrocardiograms
!
Clinical chemistry/haematology/urinalysis
!
Physical examinations
Exploratory Objectives:
Outcome Measures:
To explore baseline periostin, dipeptidyl 
peptidase-4, and other biomarkers that may 
be associated with up-regulation of 
interleukin-13, as predictive biomarkers for 
treatment with tralokinumab
Key outcome variable:
!
The annualised asthma exacerbation rate 
up to Week 52 (key variable)
Other outcome variables:   
!
Percent change from baseline in pre-
dose/pre-bronchodilator forced expiratory 
volume in 1 second 
!
Change from baseline in bi-weekly mean 
daily asthma symptom score (combined 
daytime and night-time score as captured 
in the Asthma Daily Diary) 
!
Change from baseline in Standardised 
Asthma Quality of Life Questionnaire for 
12 Years and Older 
!
Change from baseline in Asthma Control
Questionnaire-6 
To explore change from baseline of   
biomarkers that may be associated with up-
regulation of interleukin-13, and possible 
correlation with clinical efficacy of 
tralokinumab
Biomarkers may include: 
!
Blood eosinophils
!
Dipeptidyl peptidase-4
!
Fractional exhaled nitric oxide
!
Periostin
!
Total serum Immunoglobulin E
Other biomarkers may be considered.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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Exploratory Objectives:
Outcome Measures:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Results from the exploratory analyses, if performed, may be reported separately from the 
Clinical Study Report.
Target subject population
Male and female adults and adolescents, 12-75 years of age inclusive, with asthma 
inadequately controlled by treatment with inhaled corticosteroid plus long-acting β2-agonist.
Duration of treatment
Following an initial enrolment at Week -4 to -6, subjects will enter a 4 to 6-week run-in period 
which will be followed by a 52-week treatment period.  The first dose of 
tralokinumab/placebo will be administered at Week 0. Subsequent doses will be administered 
every 2 weeks up until Week 50 (for a total of 26 doses) with an end of treatment visit 
occurring at Week 52. A minimum interval of 7 days is required between 2 dosing visits. Post-
treatment safety follow up visits will be performed at Weeks 56 and 72.
Investigational product, dosage and mode of administration
Tralokinumab 300 mg (150 mg/mL), or placebo, will be administered to subjects at the site 
via subcutaneous injection using 2 pre-filled syringes each containing 1 ml.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
8(125)
Statistical methods
The primary analysis of the efficacy endpoints will include all data captured during the double 
blind treatment period. The statistical analyses will compare tralokinumab to placebo in both 
populations. The biomarker positive population is not defined at the finalization of the clinical 
study protocol for this study, but will be defined based on results from study D2210C00007 
that is run in parallel before the unblinding of this study.
A hierarchical testing strategy will be applied for the confirmatory testing of primary and key 
secondary endpoints over the two populations to allow for control of type I error.
The primary efficacy objective will be evaluated through the null hypothesis test H0: rate ratio 
(tralokinumab/placebo) equals 1 vs. H1: rate ratio not equal to 1. The test will be based on a 
negative binomial model. Covariates and factors included in the model will include at least 
treatment and the stratifying variables. 
Key secondary outcome variables will be analyzed using a repeated measures analysis 
approach including at least treatment and stratifying variables as the explanatory variables. 
A total of 770 subjects are considered sufficient to show a reduction in annualised asthma 
exacerbation rate for tralokinumab compared to placebo in the overall study population.  
Sample size calculations in terms of number of subject years needed is based on an assumed 
annual exacerbation rate in the placebo group of 0.8, and shape parameter of 0.95 (over-
dispersion) in both the all-subject and biomarker positive population. The calculations are 
made for a 1% significance level for all subjects and a 4% significance level for the biomarker 
positive population. The methodology used is described in Keene et al 2007. Assuming a 
uniform loss to follow-up of 15% during the study, 770 randomized subjects are expected to 
provide approximately 710 subject years at risk. This is expected to provide at least 90% 
power for showing superiority with effects down to 37% asthma exacerbation reduction rate in 
the all-subject population. The proportion of subjects in the all-subject population falling 
within the biomarker positive subpopulation will depend on the biomarker positive criteria. 
Based on results from study D2210C00007, the testing strategy for this study has been revised 
to use a 5% significance level based on the biomarker positive population as the primary 
population, and it is estimated that approximately 20% to 35% of the studied subjects will 
fulfil the biomarker positive criteria. Using a 5% significance level for the biomarker positive 
population as the primary population, a true asthma exacerbation rate reduction of 50% would 
have a power between 70% and 90% to show superiority.
All safety parameters will be analyzed descriptively. The safety analyses will be based on the 
safety analysis data set, defined as all subjects who received at least 1 dose of investigational 
product.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
9(125)
TABLE OF CONTENTS
PAGE
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................16
1.
INTRODUCTION .................................................................................................20
1.1
Background and rationale for conducting this study .............................................20
1.2
Rationale for study design, doses and control groups............................................21
1.3
Benefit/risk and ethical assessment........................................................................22
1.4
Study Design..........................................................................................................23
2.
STUDY OBJECTIVES..........................................................................................26
2.1
Primary objective...................................................................................................26
2.2
Secondary objectives .............................................................................................26
2.3
Safety objectives ....................................................................................................28
2.4
Exploratory objectives ...........................................................................................29
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................30
3.1
Inclusion criteria ....................................................................................................30
3.2
Exclusion criteria ...................................................................................................34
3.3
Subject enrolment and randomization ...................................................................37
3.4
Procedures for handling incorrectly enrolled or randomized subjects...................38
3.5
Methods for assigning treatment groups................................................................38
3.6
Methods for ensuring blinding...............................................................................38
3.7
Methods for unblinding..........................................................................................39
3.8
Restrictions during and after the study ..................................................................40
3.9
Discontinuation of investigational product............................................................40
3.9.1
Procedures for discontinuation of a subject from investigational product ............40
3.10
Criteria for withdrawal...........................................................................................41
3.10.1
Screen failures........................................................................................................41
3.10.2
Withdrawal of the informed consent or assent.......................................................42
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................43
4.1
Enrolment/run-in period.........................................................................................50

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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4.1.1
Enrolment (Visit 1) ................................................................................................50
4.1.2
Run-in (Visit 2)......................................................................................................50
4.1.3
Randomization (Visit 3).........................................................................................51
4.1.4
Re-screening ..........................................................................................................51
4.2
Treatment period....................................................................................................52
4.3
Follow-up period....................................................................................................54
5.
STUDY ASSESSMENTS .....................................................................................54
5.1
Efficacy assessments..............................................................................................54
5.1.1
Assessment of asthma exacerbations.....................................................................54
5.1.2
Spirometry..............................................................................................................56
5.1.2.1
Reversibility test and post-BD FEV1 efficacy assessment ....................................58
5.1.3
Home PEF testing ..................................................................................................60
5.1.4
Periostin .................................................................................................................60
5.1.5
Level of fractional exhaled nitric oxide.................................................................61
5.1.6
Safety assessments.................................................................................................61
5.1.6.1
Laboratory safety assessments...............................................................................61
5.1.6.2
Pregnancy Test.......................................................................................................67
5.1.7
Physical examination .............................................................................................67
5.1.7.1
Complete physical examination.............................................................................67
5.1.7.2
Brief physical examination ....................................................................................67
5.1.8
dECG......................................................................................................................67
5.1.8.1
Resting 12-lead dECG ...........................................................................................68
5.1.9
Vital signs ..............................................................................................................68
5.1.9.1
Pulse, blood pressure and respiration rate..............................................................68
5.1.9.2
Body temperature...................................................................................................69
5.1.10
Other safety assessments........................................................................................69
5.1.10.1
Serology .................................................................................................................69
5.1.10.2
Infections................................................................................................................69
5.2
Other assessments ..................................................................................................69
5.2.1
Weight and height..................................................................................................69
5.2.2
Patient reported outcomes......................................................................................69
5.2.2.1
Asthma Daily Diary ...............................................................................................70
5.2.2.2
Asthma Control Questionnaire (ACQ-6)...............................................................71
5.2.2.3
Standardised Asthma Quality of Life Questionnaire for 12 Years and Older 
(AQLQ(S)+12).......................................................................................................71
5.2.2.4
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ).....................................................................72
5.2.2.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L) ................................72
5.2.2.6
Health care resource utilization..............................................................................73
5.2.2.7
Clinical – Global Impression of Change (CGIC) assessment................................73
5.3
Pharmacokinetics and Immunogenicity.................................................................73
5.3.1
Collection of samples.............................................................................................73

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Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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5.3.2
Determination of drug concentration.....................................................................74
5.3.3
Storage and destruction of pharmacokinetic samples............................................74
5.3.4
Immunogenicity.....................................................................................................74
5.3.5
Total IgE ................................................................................................................75
5.3.6
Phadiatop®..............................................................................................................75
5.4
Pharmacodynamics ................................................................................................75
5.4.1
Serum biomarkers ..................................................................................................75
5.5
Pharmacogenetics ..................................................................................................75
5.5.1
Collection of pharmacogenetic samples (optional)................................................75
5.5.2
Storage, re-use and destruction of pharmacogenetic samples ...............................76
5.6
Biomarker analysis.................................................................................................76
5.6.1
Storage, re-use and destruction of biological samples...........................................77
5.6.2
Labelling and shipment of biological samples.......................................................77
5.6.3
Chain of custody of biological samples.................................................................77
5.6.4
Withdrawal of Informed Consent or Assent for donated biological samples........77
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................78
6.1
Definition of adverse events ..................................................................................78
6.2
Definitions of serious adverse event......................................................................78
6.3
Recording of adverse events ..................................................................................79
6.3.1
Time period for collection of adverse events.........................................................79
6.3.2
Follow-up of unresolved adverse events................................................................79
6.3.3
Adverse event variables .........................................................................................79
6.3.4
Assessment of causality .........................................................................................80
6.3.5
Adverse events based on signs and symptoms.......................................................80
6.3.6
Adverse events based on examinations and tests...................................................81
6.3.7
Hy’s Law................................................................................................................81
6.3.8
Disease progression ...............................................................................................81
6.4
Reporting of serious adverse events.......................................................................82
6.5
Overdose ................................................................................................................82
6.6
Pregnancy...............................................................................................................83
6.6.1
Maternal exposure..................................................................................................83
6.6.2
Paternal exposure...................................................................................................83
6.7
Management of IP related toxicities ......................................................................83
6.8
Study governance and oversight ............................................................................84
6.8.1
Independent Adjudication Committee ...................................................................84
6.8.2
Data and safety monitoring board..........................................................................85
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................85
7.1
Identity of investigational product(s).....................................................................85
7.2
Dose and treatment regimens.................................................................................86

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Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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7.3
Labelling ................................................................................................................88
7.4
Storage ...................................................................................................................88
7.5
Compliance ............................................................................................................88
7.6
Accountability........................................................................................................89
7.7
Concomitant and other treatments .........................................................................89
7.7.1
Concomitant medications.......................................................................................89
7.7.2
Restrictions during and after the study ..................................................................90
7.7.2.1
Asthma medication restrictions..............................................................................90
7.7.2.2
Other medication restrictions.................................................................................92
7.7.2.3
Bronchial Thermoplasty.........................................................................................93
7.7.3
Other treatments.....................................................................................................93
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................93
8.1
Statistical considerations........................................................................................93
8.2
Sample size estimate..............................................................................................94
8.3
Definitions of analysis sets ....................................................................................94
8.3.1
Efficacy analysis set...............................................................................................95
8.3.2
Safety analysis set..................................................................................................95
8.3.3
PK analysis set .......................................................................................................95
8.3.4
PRO analysis set ....................................................................................................95
8.4
Outcome measures for analyses.............................................................................95
8.4.1
General Definitions................................................................................................95
8.4.1.1
Definition of baseline and subject baseline variables............................................95
8.4.1.2
Visit and period windows ......................................................................................96
8.4.2
Calculation or derivation of efficacy variables......................................................96
8.4.2.1
Exacerbation rate....................................................................................................96
8.4.2.2
Proportion of subjects with ≥ 1 asthma exacerbation during 52 weeks of 
treatment ................................................................................................................97
8.4.2.3
Time to first exacerbation ......................................................................................97
8.4.2.4
Forced expiratory volume in 1 second...................................................................97
8.4.2.5
Annualised asthma exacerbation rate associated with an ER or urgent care 
visit or a hospitalization.........................................................................................98
8.4.2.6
Forced Vital Capacity and Forced Expiratory Flow at 25-75% ............................98
8.4.3
Calculation or derivation of patient reported outcome variables...........................98
8.4.3.1
Asthma symptom score..........................................................................................98
8.4.3.2
Rescue medication use...........................................................................................99
8.4.3.3
Home peak expiratory flow (morning and evening)..............................................99
8.4.3.4
Asthma Control Questionnaire (ACQ-6)...............................................................99
8.4.3.5
Asthma quality of life questionnaire for 12 years and older (AQLQ(S) 
+12)......................................................................................................................100
8.4.3.6
European quality of life-5 dimensions-5 levels (EQ-5D-5L) ..............................100
8.4.3.7
Health care resource utilization............................................................................101

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Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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8.4.3.8
The Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions (WPAI+CIQ).................................................101
8.4.4
Calculation or derivation of safety variable(s).....................................................102
8.4.4.1
Adverse events.....................................................................................................102
8.4.4.2
Other significant adverse events ..........................................................................103
8.4.4.3
Laboratory variables ............................................................................................103
8.4.4.4
dECGs..................................................................................................................104
8.4.4.5
Physical examination ...........................................................................................104
8.4.4.6
Vital signs ............................................................................................................104
8.4.5
Calculations or derivation of Pharmacokinetic and Immunogenicity 
variables ...............................................................................................................105
8.5
Methods for statistical analyses ...........................................................................105
8.5.1
Testing strategy for primary and key secondary objectives.................................106
8.5.2
Sensitivity analyses..............................................................................................107
8.5.3
Subject disposition, demography data and subjects characteristics.....................108
8.5.4
Exposure ..............................................................................................................108
8.5.5
Violations and deviations.....................................................................................108
8.5.6
Analysis of the primary variable..........................................................................109
8.5.7
Analysis if secondary variable(s).........................................................................109
8.5.7.1
Lung Function......................................................................................................109
8.5.7.2
Asthma symptoms................................................................................................110
8.5.7.3
Asthma specific health-related quality of life......................................................110
8.5.7.4
ACQ-6 defined asthma control ............................................................................111
8.5.7.5
Other endpoints associated with asthma exacerbations.......................................111
8.5.7.6
Emergency room or urgent care visits and hospitalizations due to asthma .........112
8.5.7.7
Health care resource utilization and productivity loss due to asthma..................112
8.5.7.8
Asthma symptom, general health-related quality of life and asthma control ......112
8.5.8
Safety and tolerability..........................................................................................113
8.5.8.1
Adverse events.....................................................................................................113
8.5.8.2
Laboratory data ....................................................................................................113
8.5.8.3
dECGs..................................................................................................................114
8.5.8.4
Physical Examination...........................................................................................114
8.5.8.5
Vital Signs............................................................................................................115
8.5.8.6
Analysis of Immunogenicity variables ................................................................115
8.5.9
Analysis of pharmacokinetics..............................................................................115
8.5.10
Interim analysis....................................................................................................115
8.5.11
Exploratory analysis.............................................................................................116
8.5.11.1
Baseline periostin and DPP4 levels as predictive biomarkers.............................116
8.5.11.2
Deoxyribonucleic acid collected for future exploratory research........................116
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................116
9.1
Training of study site personnel...........................................................................116
9.2
Monitoring of the study .......................................................................................116
9.2.1
Source data...........................................................................................................117

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Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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9.2.2
Study agreements.................................................................................................117
9.2.3
Archiving of study documents.............................................................................117
9.3
Study timetable and end of study.........................................................................117
9.4
Data management by AstraZeneca ......................................................................118
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................119
10.1
Ethical conduct of the study.................................................................................119
10.2
Subject data protection.........................................................................................119
10.2.1
Pharmacogenomic data ........................................................................................119
10.3
Ethics and regulatory review................................................................................120
10.4
Informed consent and assent................................................................................120
10.5
Changes to the protocol and informed consent or assent forms ..........................121
10.6
Audits and inspections .........................................................................................121
11.
LIST OF REFERENCES.....................................................................................123
LIST OF TABLES
Table 1
Study Plan.................................................................................................43
Table 2
List of safety laboratory tests....................................................................62
Table 3
Clinical Chemistry (serum) Tests schedule..............................................62
Table 4
Haematology/Haemostasis (whole blood) schedule.................................64
Table 5
Urinalysis schedule...................................................................................65
Table 6
Volume of blood to be drawn from each subject......................................66
Table 7
Identity of investigational product............................................................86
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................25
Figure 2
Injection sites and rotation scheme...........................................................87

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LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 
Appendix C
IATA 6.2 Guidance document
Appendix D
Pharmacogenetics Research
Appendix E
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law
Appendix F
Maintenance Therapy Equivalence Table
Appendix G
Anaphylaxis: definition, signs and symptoms, management
Appendix H
Restricted and prohibited medications

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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
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-Drug Antibodies
AE
Adverse Event
AAER
Annual Asthma Exacerbation Rate
AERR
Asthma Exacerbation Reduction Rate
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APFS
Accessorized Prefilled Syringe
AQLQ(S)+12
Standardised Asthma Quality of Life Questionnaire for 12 Years and 
Older
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood Urea Nitrogen
CGIC
Clinical-Global Impression of Change
CO2
Carbon Dioxide
COPD
Chronic Obstructive Pulmonary Disease
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
dECG
Digital Electrocardiogram
DNA
Deoxyribonucleic Acid 
DPP4
Dipeptidyl Peptidase-4
DSMB
Data and Safety Monitoring Board

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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC)
eCRF
Electronic Case Report Form
ED
Emergency Department
ER
Emergency Room
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome device
EQ-5D-5L
European Quality of Life - 5 Dimensions - 5 Levels
FEF 25-75%
Forced Expiratory Flow at 25-75% of the forced vital capacity
FENO
Fractional Exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GLI
The Global Lung Function Initiative
GMP
Good Manufacturing Practice
HbA1c
Glycosylated haemoglobin
HIV
Human Immunodeficiency Virus
IATA
International Air Transport Association
ICH
International Conference on Harmonisation
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. 
ICS
Inhaled Corticosteroids
IgE
Immunoglobulin E
IL
Interleukin
IL-13
Interleukin-13 
IP
Investigational Product 
IPD
Investigational Product Discontinuation

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Abbreviation or 
special term
Explanation
IRB
Institutional Review Board
ISF
Investigator Study File
ITT
Intent-to-Treat
IUO
Investigational Use Only
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
LTRA
Leukotriene Receptor Antagonists
MAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
nAB
Neutralizing Antibodies
OCS
Oral Corticosteroids
PD
Pharmacodynamic(s)
PEF
Peak Expiratory Flow
PEO
Performance Evaluation Only
PK
Pharmacokinetic(s)
PNV
Predicted Normal Value
PRO
Patient Reported Outcome
PT
Preferred Term
Q2W
Every 2 Weeks
Q4W
Every 4 Weeks
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous
SOC
System Organ Class
Th2
T Helper 2 Cells
TLC
Total Lung Capacity
ULN
Upper Limit of Normal

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Abbreviation or 
special term
Explanation
UNS
Unscheduled
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential
WPAI+CIQ
Work Productivity and Activity Impairment Questionnaire and Classroom 
Impairment Questionnaire 

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction 
and airway hyper-responsiveness, with a global prevalence of approximately 300 million 
patients (GINA 2012). 
Approximately 5% to 10% of asthma patients have severe asthma, many of whom may be 
inadequately controlled by inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) 
in combination with additional controller therapies (Bateman et al 2010). These patients are at 
risk of asthma exacerbations, have a large medical need, and represent the greatest economic 
burden (Accordini et al 2006).
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012). There is 
considerable evidence that interleukin-13 (IL-13) is a key mediator in the pathogenesis of 
asthmatic disease. IL-13 is secreted predominantly by CD4+ T-helper 2 (Th2) cells and IL-13 
receptors are expressed on a number of cell types including those involved in the pathogenesis 
of asthma (Hershey 2003). There is evidence to support that IL-13 can increase development 
of airway hyper-responsiveness (Wardlaw et al 1988), potentiate bronchoconstriction 
(Grunstein et al 2002), increase the number of mucus-secreting cells and promote airway 
fibrosis in asthma (Wills-Karp et al 1998).
Tralokinumab is a human recombinant monoclonal antibody (MAb) of the immunoglobulin 
G4 subclass that specifically binds human IL-13, blocking interactions with the IL-13 
receptor. Tralokinumab is in development for the treatment of severe asthma. A phase 2a 
study (MI-CP199) provided evidence of improvement of lung function (forced expiratory 
volume in 1 second (FEV1)), following the addition of subcutaneous (SC) tralokinumab to 
standard asthma controller medications. Doses of 300 and 600 mg every 2 weeks of 
tralokinumab both resulted in comparable effects in FEV1 that were greater than that observed 
with a 150 mg dose (Piper et al 2013). Since low pre-bronchodilator (BD) FEV1 has been 
identified as a strong independent predictor of subsequent asthma exacerbations, it is plausible 
that the addition of tralokinumab will reduce the rate of asthma exacerbations in this 
population (Reddel et al 2009). 
In a phase 2b (CD-RI-CAT-354-1049) study with tralokinumab in adults with uncontrolled, 
severe asthma requiring high dose ICS and LABA, the efficacy and safety of the 2 regimens 
(300 mg every 2 weeks (Q2W) or, 300 mg Q2W for 12 weeks, followed by a 300 mg every 4 
weeks (Q4W) maintenance dosing [Q2/4W]) vs. placebo, was evaluated over a treatment 
period of 52 weeks. The primary endpoint for this study was the annualised asthma 
exacerbation rate (AAER) over 52 weeks, with secondary endpoints including pulmonary 
function, patient reported outcomes, including asthma symptoms. In the overall intent-to-treat 

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phase 2b population, an increase from baseline in pre-BD FEV1 to the end of treatment was 
seen with the Q2W dosing regime, but not with the Q2/4W dosing regime. 
In this phase 2b study, a subpopulation reversible on entry (FEV1 reversibility ≥ 12% and 
≥200ml in FEV1) an AAER reduction that was greater for the tralokinumab 300 mg Q2W 
cohort versus the Q2/4W cohort was seen. A further reduction of AAER was observed in a 
subgroup of reversible subjects with high (> median) serum periostin, a biomarker induced by 
IL-13.  This is the population to be studied in phase 3. The safety profile of all doses studied 
so far has been acceptable (for further details see the investigators brochure (IB)).
The purpose of this phase 3 study is to provide confirmatory evidence of the efficacy and 
safety of tralokinumab in the treatment of subjects with severe uncontrolled asthma despite 
treatment with ICS-LABA and any other additional controller medication. The study will 
evaluate the AAER and other aspects of lung function, asthma control, and safety to further 
characterize the benefit-risk profile of the drug and understand how best to position it in the 
treatment pathway. The study also aims at confirming effect in a biomarker (periostin or 
DPP4) positive target population, a population identified in a parallel phase 3 study 
(D2210C00007).
1.2
Rationale for study design, doses and control groups
This is a global study designed to investigate the safety and efficacy of the fixed dose 
tralokinumab (300mg) administered via SC injection every 2 weeks throughout a 52- week 
treatment period. Exacerbation-prone asthma subjects who remain uncontrolled on ICS-
LABA, and who demonstrate a reversibility, ≥12% and ≥200 mL in FEV1 at either visit 2 
(run-in) or Visit 3 (randomization), will be randomized into the study. Primary efficacy will 
be determined based on reduction in the rate of asthma exacerbations over 52 weeks for 
tralokinumab versus placebo. Subjects will be stratified at randomization by serum 
periostin level (<16.44 ng/mL or ≥ 16.44 ng/mL) sampled during the run-in, geographical 
region, and age group (adults versus adolescents). 
Previous efficacy studies of tralokinumab, including a phase 2b study with subjects on high 
dose ICS-LABA with or without additional asthma controller medications, have been 
conducted in adult subjects (18-75 years of age), and provide the basis for this pivotal phase 3 
study. Pharmacokinetic evaluations in adolescents with asthma confirm that the same dose as 
for adults is applicable and since it is expected that adolescent subjects (12-17 years of age) 
will respond similarly to adults, and are therefore to be included as part of the study 
population. Adolescents will therefore be recruited in the pivotal phase 3 studies.
Analysis of data from both phase 2 studies MI-CP199 and the phase 2b study, has 
demonstrated a clinically relevant effect on FEV1 from tralokinumab 300 mg Q2W.  In 
contrast, only limited, if any, improvement was observed with 150 mg Q2W (in study MI-
CP199) or 300 mg Q2/4W (in study CD-RI-CAT-354-1049).  Furthermore, an effect on 
AAER was observed with the 300 mg Q2W dosing regimen, but not with the Q2/4W dosing 
regimen in study CD-RI-CAT-354-1049. Since the safety profile in the CD-RI-CAT-354-1049 
study was acceptable in both treatment cohorts, and no clear safety related dose-response 

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pattern was identified, the dose of 300 mg Q2W has been selected for evaluation in this phase 
3 study. 
Pharmacokinetic/pharmacodynamic (PK/PD) modelling using all data obtained to date has 
also confirmed that a dose of 300 mg Q2W will result in near maximal increase in pre-BD 
FEV1 in the phase 3 subject population.
Subjects on placebo will receive maintenance therapy that includes their usual dose of ICS-
LABA (see section 7.7.2).
1.3
Benefit/risk and ethical assessment
There are few treatment options for subjects whose asthma remains uncontrolled on ICS-
LABA (GINA 2012). The evidence base for oral add-on therapies (i.e. oral corticosteroids 
(OCS), leukotriene inhibitors (LTRAs), and xanthenes) is limited. Anti-immunoglobulin E 
(IgE) therapy (i.e., omalizumab) improves control in a subset of subjects with severe asthma 
associated with IgE-mediated allergy to a perennial allergen. Hence, new therapies are needed 
for asthma management in subjects who remain uncontrolled on standard of care.
IL-13 is targeted as it plays a role in the allergic/Th2 type response which is a signature of 
asthma. An anti-IL-13 treatment may therefore be useful in treatment of asthma. Data from 
phase 2 studies support this notion. Thus, in a 24-week phase 2a study (MI-CP199) 
tralokinumab at a dose of 300 mg SC every 2 weeks (the dose proposed for the phase 3 
programme) provided improvement of lung function (FEV1), when added to standard asthma 
controller medications.  In addition the efficacy of tralokinumab has been studied in a 1 year 
long phase 2b study (CD-RI-CAT-354-1049) targeting adult subjects whose asthma was 
poorly controlled by high dose ICS-LABA. In this study, tralokinumab at a fixed dose of ≥ 
300 mg SC every other week produced improvements in multiple metrics of asthma control, 
including the annualised asthma exacerbation rate (AAER), lung function, ACQ-6 scores, and 
symptoms, in a subpopulation who demonstrated reversibility of FEV1 upon study entry.
Approximately 520 subjects with asthma have so far been exposed to tralokinumab at various 
doses and for different periods of time. The 1 year long phase 2b study has contributed 301 of 
these subjects with 140 of them receiving 300 mg every other week. In all studies conducted 
so far, tralokinumab has been well tolerated, and no safety concerns have been identified. 
However, because it is believed that the Th2 response may be of importance in the defense 
against helminthic parasitic infections, a theoretical risk for such infestations exists. IL-13 
may also play a role in regulating tumours (Hallett et al 2012), and although evidence for this 
is scarce and inconclusive, this theoretical risk needs to be considered. In conjunction with the 
performance of routine pharmacovigilance activities risk minimization measures therefore 
include exclusion of subjects with untreated parasitic infection and active or recent 
malignancy.
As with all biologics therapies, anti-drug antibodies (ADA), including neutralizing antibodies 
(nAb), may develop. Development of ADA to tralokinumab has been rare in the phase 1 and 2 

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studies conducted thus far (<1% overall). Theoretical risks due to development of ADA 
include decreased drug efficacy and hypersensitivity reactions (e.g., anaphylaxis or immune 
complex disease) and observation following administration of tralokinumab is therefore 
mandated.
Pharmacokinetic modelling suggests that exposure to tralokinumab is slightly higher in 
adolescents (12-17 years of age) than that in adults; however, considering the overall 
variability of tralokinumab PK, and the absence of safety findings at doses at or above 300 mg 
every other week in the phase 2 studies, dose adjustment is not considered to be required for 
subjects in this age group. 
In summary, the efficacy and safety data obtained to date support the continued clinical 
development of tralokinumab in adult and adolescent subjects with uncontrolled asthma.
A detailed assessment of the risk/benefit of tralokinumab in subjects with asthma is given in 
the IB.
1.4
Study Design 
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate efficacy and safety of a fixed 300 mg dose of tralokinumab administered SC in 
subjects with uncontrolled asthma receiving ICS (≥500μg fluticasone propionate dry powder 
formulation equivalents total daily dose) and a LABA, and having a history of asthma 
exacerbations.
Subjects will receive either tralokinumab 300 mg, or placebo every 2 weeks via subcutaneous 
injection at the study site, over a 52-week treatment period.
Approximately 770 subjects will be randomized at approximately 310 sites globally. Subjects 
will be stratified at randomization by serum periostin level (< 16.44 ng/mL or ≥ 16.44 ng/mL), 
sampled during run-in, geographical region, and age group (i.e. adults versus adolescents). 
After initial enrolment and confirmation of entry criteria, subjects will enter a run-in period of 
4 to 6 weeks to allow adequate time for all of the eligibility criteria to be evaluated. Subjects 
who meet eligibility criteria will be randomized to a 52-week treatment period. The first dose 
of tralokinumab/placebo will be administered at Week 0. Subsequent doses will be 
administered every 2 weeks up until Week 50 (for a total of 26 doses) with an end of 
treatment (EOT) visit occurring at Week 52.  Subjects will be maintained on their currently 
prescribed ICS-LABA and any additional maintenance asthma controller medications, without 
change, from enrolment throughout the run-in and treatment period. All subjects will have 
site visits every 2 weeks.  
Follow-up visits will be conducted at Weeks 56 and 72. The extended follow-up period is to 
ensure that adequate determination of immunogenicity can be determined.

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An Independent Adjudication Committee, blinded to subject treatment, will evaluate all ER 
or urgent care visits, hospitalizations, and deaths, to determine whether or not related to 
asthma. The adjudication committee will also review cardiovascular, cerebrovascular and 
malignant adverse events, occurring after randomization.  An Independent Data and Safety 
Monitoring Board (DSMB) will review all adolescent subject data for safety.

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Figure 1
Study flow chart
Visit 1 *                   Visit 2
Visits 30-31
FU
    Visit 3
                        Treatment period
Visits 3-28
    
        
Randomization 
1:1
End of 
treatment
End of 
treatment
Follow up
Enrolment/Run-in
Tralokinumab 300mg, SC every 2 weeks (n=385)
Placebo, SC every 2 weeks (n=385)
Week -6 to -4
Week -2
Week 0
Weeks 0-50
Week 52
Weeks 56-72
Follow up
EOT Visit 
29
*the run-in period can be 28 to 45 days in duration.  
Visit 1 should be completed within 45 to 28 days 
before V3.  V2 should occur within 17 to 14 days 
before V3, which includes a 3 day window.  V3 is 
considered day 0.

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the effect of tralokinumab 300 
mg administered every 2 weeks compared 
with placebo on the annualised asthma 
exacerbation rate in two populations:
Biomarker positive population: Subjects 
in the all subject population meeting the 
baseline criteria for biomarker positive 
population specified in the statistical 
analysis plan (primary population)
All subjects: Adult and adolescent 
subjects with asthma that is inadequately 
controlled with inhaled corticosteroid plus 
long-acting β2-agonist (secondary 
population)
Primary outcome variable: The annualised 
asthma exacerbation rate up to Week 52    
Primary outcome measure: Asthma 
exacerbation rate reduction
An asthma exacerbation is defined by a 
worsening of asthma requiring:
!
Use of systemic corticosteroids for at least 3 
days; a single depo-injectable dose of 
corticosteroids will be considered equivalent 
to a 3-day course of systemic corticosteroids
!
An emergency room (ER) or urgent care visit 
(defined as evaluation and treatment for <24 
hours in an emergency room or urgent care 
center) due to asthma that required systemic 
corticosteroids (as per the above)
!
An inpatient hospitalization (defined as 
admission to an inpatient facility and/or 
evaluation and treatment in a healthcare 
facility for ≥24 hours) due to asthma
2.2
Secondary objectives
Key Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to lung function
Key outcome variable: Percent change from 
baseline in pre-dose/pre-BD FEV1
Key outcome measure: Percent difference vs. 
placebo at Week 52

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Key Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to asthma 
symptoms
Key outcome variable: Change from baseline in 
bi-weekly mean daily asthma symptom score 
(combined daytime and night-time score as 
captured in the Asthma Daily Diary) 
Key outcome measure: Mean difference vs. 
placebo at Week 52
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to asthma specific 
health-related quality of life
Key outcome variable: Change from baseline in 
Standardised Asthma Quality of Life 
Questionnaire for 12 Years and Older (AQLQ 
(S) + 12) total score 
Key outcome measure: Mean difference vs. 
placebo at Week 52
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to Asthma 
Control Questionnaire-6 defined asthma 
control
Key outcome variable: Change from baseline in 
ACQ-6 
Key outcome measure: Mean difference vs. 
placebo at Week 52
Other Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to other endpoints 
associated with asthma exacerbations
!
Time to first asthma exacerbation and 
proportion of subjects with ≥1 asthma 
exacerbation
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to emergency 
room visits, urgent care visits and 
hospitalizations due to asthma
!
Annual rate of asthma exacerbations that are 
associated with an ER, urgent care visit or a 
hospitalization.
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards pre-dose and post 
BD FEV1
!
Pre-dose/post-BD FEV1

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Other Secondary Objectives:
Outcome Measures:
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to health related 
quality of life
!
European Quality of Life - 5 Dimensions - 5 
Levels  (EQ-5D-5L) Questionnaire
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to health care 
resource utilization and productivity loss 
due to asthma
!
Work Productivity and Activity Impairment 
Questionnaire and Classroom Impairment 
Questionnaire (WPAI+CIQ)
!
Asthma specific resource utilization (e.g., 
unscheduled physician visits, unscheduled 
phone calls to physicians, use of other asthma 
medications)
To assess the effect of tralokinumab 
compared with placebo in the two subject 
populations with regards to other 
measurements of asthma symptoms and 
asthma control
!
Rescue medication use 
!
Home peak expiratory flow (PEF) - morning 
and evening
!
Night-time awakening due to asthma 
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
!
Pharmacokinetic parameters: Ctrough
!
Immunogenicity outcome variables:
incidence rate of positive anti-drug antibodies 
and characterization of their neutralizing 
potential
2.3
Safety objectives
Safety Objectives:
Outcome Measures:
To evaluate the safety and tolerability of 
tralokinumab
!
Adverse Events/Serious Adverse Events 
(AEs/SAEs)
!
Vital signs
!
Digital electrocardiograms (dECGs)
!
Clinical chemistry/haematology/urinalysis
!
Physical examinations

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2.4
Exploratory objectives  
Exploratory Objectives:
Outcome Measures:
To explore baseline periostin, DPP4, and 
other biomarkers that may be associated 
with up-regulation of IL-13, as predictive 
biomarkers for treatment of tralokinumab
Key outcome variable:
!
The annualised asthma exacerbation rate 
up to Week 52 (key variable)
Other outcome variables:   
!
Percent change from baseline in pre-
dose/pre-BD FEV1
!
Change from baseline in bi-weekly mean 
daily asthma symptom score (combined 
daytime and night-time score as captured 
in the Asthma Daily Diary) 
!
Change from baseline in Standardised 
AQLQ (S) + 12 
!
Change from baseline in ACQ-6 
To explore change from baseline of   
biomarkers that may be associated with up-
regulation of IL-13, and possible 
correlation with clinical efficacy of 
tralokinumab
Biomarkers may include: 
!
Blood eosinophils
!
DPP4
!
FENO
!
Periostin
!
Total serum IgE
Other biomarkers may be considered.
 
 
 
 
 
 
 

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Exploratory Objectives:
Outcome Measures:
 
 
 
Results from the exploratory analyses, if performed, may be reported separately from the 
Clinical Study Report.
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each subject 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, subjects should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures for subjects 
who are at, or over the age of majority (as per local law). For subjects less than the 
age of majority, in addition to the subject providing informed assent, the subject’s 
legal guardian must also provide their informed consent.
2.
Female and male aged from 12 to 75 years, inclusively at time of enrolment (Visit 
1).  For those countries where local regulations permit enrolment of adults only, 
subject recruitment will be restricted to those who are ≥18 years.
3.
Women of childbearing potential (WOCBP) (after menarche) and all adolescent 
females must use a highly effective form of birth control (confirmed by the 
investigator). Highly effective forms of birth control includes: true sexual 
abstinence, a vasectomised sexual partner, Implanon, female sterilization by tubal 
occlusion, any effective intrauterine device/system (IUD/IUS), Depo-Provera™ 
injections, oral contraceptive, and Evra Patch ™ or Nuvaring™. WOCBP must 
agree to use highly effective method of birth control, as defined above, from 
enrolment, throughout the study duration and within 16 weeks after last dose of 
investigational product (IP), and have negative serum pregnancy test result at Visit 
1.
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 

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date of randomization without an alternative medical cause. The following age-
specific requirements apply:
! 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.
4.
Weight of ≥40 and <150 kg at enrolment (Visit 1).  
5.
Documented physician-diagnosed asthma for at least 12 months prior to enrolment 
with the subject having received an asthma controller regimen requiring treatment 
with medium-to-high dose ICS for at least 6 of the 12 months prior to enrolment 
(Visit 1). In addition, subjects must have used physician prescribed ICS (at a total 
daily dose ≥ 500μg fluticasone propionate via dry powder inhaler or equivalent 
delivered dose) that has been taken at a stable dose for at least 3 months prior to 
enrolment. 
6.
Documented treatment with ICS at a total daily dose corresponding to ≥500μg 
fluticasone propionate dry powder formulation equivalents and a LABA for at least 
3 months prior to Visit 1. The ICS and LABA can be parts of a combination 
product, or given by separate inhalers. For ICS-LABA combination preparations, 
the highest strength approved maintenance dose in the local country will meet this 
ICS criterion.
! In order to aid the assessment, ICS equivalents for high-dose and medium-
dose fluticasone propionate dry powder, as published by the Global 
Initiative for Asthma (GINA 2012) guidelines, are presented in Appendix F. 
The Investigator will assess the subject’s total daily ICS dose and determine 
that it corresponds to ≥500μg fluticasone propionate dry powder formulation 
equivalents. If the subject is on two or more different types of ICS, these can 
form parts of an addition, and the sum, however approximate, will be 
assessed.
The below defines the minimally acceptable documentation for subject inclusion:
1. Signed and dated notes from a referring physician, including name and dose 
of the ICS-LABA inhaler (or names and dosages, if used as separate 
inhalers).  
2. Evidence of prescriptions for ICS-LABA medications that demonstrate 
coverage for the duration specified in inclusion criteria 6 and 7.  

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3. Documented communication (e.g.: phone conversation) clarifying that the 
subject received treatment with ICS-LABA for asthma.  The name, dosage, 
and duration of use for each medication must be recorded.  This option 
should be used only if reasonable attempts to procure subject records have 
been unsuccessful.
7.
Additional maintenance asthma controller medications are allowed according to 
standard practice of care.  These medications must be stable for 3 months prior to 
enrolment (Visit 1).  Furthermore, after randomization, the subject's background 
maintenance medication for asthma shall remain unchanged throughout the study.
8.
At Visit 1 the subject must have a morning pre-BD FEV1 value <80% (<90% for 
subjects 12 to 17 years of age) of their predicted normal value (PNV). At Visit 2 the 
subject must have a morning pre-BD FEV1 value of ≥40 and <80% value (<90% for 
subjects 12 to 17 years of age) of their PNV.  If this is not met at Visit 2, it must be 
met at Visit 3. Prior to the lung function measurement, the subject should withhold 
their BD for the effect duration specific to the BD.
9.
A post-BD reversibility in FEV1 of ≥12% and ≥200 mL at Visit 2. If not met at Visit 
2, it must be met at Visit 3 (randomization). Before reversibility testing, the subject 
should withhold their BD for the effect duration specific to the BD.
10.
At least 2 documented asthma exacerbations in the 12 months prior to the date 
informed consent is obtained that required use of a systemic corticosteroid. In case 
of subjects who are re-screened within 30 days of their screen failure date; the 12 
months can be calculated from the date that the first informed consent was obtained.
The below defines what is acceptable to document exacerbations in this Program:
1. Discharge summaries from a hospital, emergency department, or an urgent care 
facility indicating that a subject was hospitalized/treated with systemic steroids 
for an asthma exacerbation.  
2. Signed and dated notes from a referring physician, including information 
regarding diagnosis and treatment of an exacerbation with systemic steroids.  
3. Subjects can provide evidence of prescriptions for systemic steroids used during 
an exacerbation.  
4. A documented conversation between the treating/referral physician or 
nurse/nurse practitioner certifying that a subject was treated for an exacerbation 
with steroids at their clinic or under their supervision.  The dates (month/year) 
of the exacerbations and verbal confirmation that appropriate prescriptions were 
provided is necessary.  This option should be used only if reasonable attempts to 
procure subject records have been unsuccessful.

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A combination of the above is acceptable to document the two required exacerbations. 
However, it is necessary for the Investigator to document how they obtained confirmation 
of the subject’s asthma exacerbations.  It is the Investigator’s responsibility to ensure 
subject eligibility into the clinical study.  In cases where the Investigator feels that 
alternative records to the above constitutes acceptable documentation, the Study 
Physician will be contacted for their assessment of eligibility prior to enrolment.  Every 
attempt should be made to obtain appropriate source documentation of medical records.  
11.
ACQ-6 score ≥1.5 at Visit 1 (Week - 6)
Prior to randomization at Visit 3, subjects should fulfil the following inclusion criteria:
12.
For WOCBP (including all adolescents) only: have a negative urine pregnancy test 
prior to administration of the IP.
13.
No requirement for additional asthma controller medication including an increase in 
ICS dose during run-in.
14.
Fulfilment of at least one of the following conditions over the 7 days prior to 
randomization:
! 2 days with a daytime or night-time symptoms score ≥1
! Reliever SABA use on > 2 days 
! ≥ 1 awakening due to asthma
15.
A morning pre-BD FEV1 of ≥40% and <80% (<90% for subjects 12 to 17 years of 
age) of the subject’s PNV at the day of the randomization visit, if not met at Visit 2.
16.
A post-BD reversibility in FEV1 of ≥12% and ≥200 mL must be met at either Visit 
2 or Visit 3, if not met at Visit 2.Theophylline and BD must be withheld prior to 
reversibility testing according to the period specified in Section 7.7.2 and Appendix 
H.  
17.
Ability to perform acceptable inhaler, peak flow meter, and spirometry techniques
18.
Show at least 70% compliance with both the usual asthma controller (i.e. ICS-
LABA and any other asthma controller medications) as evidenced by the subject 
having a minimum of 10 fully compliant dosing days in the 14 days prior to Visit 3 
(randomization) as reported by the subject in the eDiary.
19.
Compliance with the eDiary assessment schedule

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!
At least 10 of the 14 days prior to Visit 3 must have complete (morning and 
evening) eDiary assessments.  
For inclusion in the voluntary pharmacogenetic research, subjects should fulfil the 
following criterion:
20.
Provision of a signed and dated written informed consent for the pharmacogenetic 
sample and analysis. If a subject declines to participate in the pharmacogenetic 
research, there will be no consequence or loss of benefit to the subject. The subject 
will not be excluded from the other aspects of the study described in the CSP, as 
long as they consent to participate in the study.
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Clinically important pulmonary disease other than asthma (e.g., active lung 
infection, COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation 
syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and 
primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic 
disease, other than asthma, that are associated with elevated peripheral eosinophil 
counts (e.g., allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss 
syndrome, hypereosinophilic syndrome).
2.
Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, psychiatric, or major physical impairment that is not stable in the 
opinion of the Investigator and could:
!
Affect the safety of the subject throughout the study
!
Influence the findings of the studies or their interpretations
!
Impede the subject’s ability to complete the entire duration of study
3.
Known history of allergy or reaction to any component of the IP formulation.
4.
History of anaphylaxis following any biologic therapy.
5.
A helminth parasitic infection diagnosed within 6 months prior to enrolment (Visit 
1) that has not been treated with, or has failed to respond to, standard of care 
therapy.
6.
History of clinically significant infection, including acute upper or lower respiratory 
infections, requiring antibiotics or antiviral medication within 30 days prior 
enrolment (Visit 1) or during the run-in period. 

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7.
Tuberculosis requiring treatment within the 12 months prior to enrolment (Visit 1).
8.
Any clinically significant abnormal findings in physical examination, vital signs, 
dECG, haematology, clinical chemistry, or urinalysis during the run-in period, 
which in the opinion of the Investigator, may put the subject at risk because of 
his/her participation in the study, or may influence the results of the study, or the 
subject’s ability to complete entire duration of the study.
9.
History of chronic alcohol or drug abuse within 12 months of the enrolment visit, or 
a condition associated with poor compliance as judged by the Investigator.
10.
Positive hepatitis B surface antigen or hepatitis C virus antibody serology. Subjects 
with a history of hepatitis B vaccination without a history of hepatitis B are allowed 
to be enrolled. 
11.
History of any known primary immunodeficiency disorder including a positive 
human immunodeficiency virus (HIV) test at enrolment, or the subject taking 
antiretroviral medications as determined by medical history and/or subject’s verbal 
report.
12.
Current tobacco smoking (smoking must have stopped for ≥ 3 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).
13.
History of cancer:
! Subjects who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy was completed at least 
12 months prior to enrolment (Visit 1).
! Subjects who have had other malignancies are eligible provided that the 
subject is in remission and curative therapy was completed at least 5 years 
prior to enrolment (Visit 1).
14.
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).
15.
Clinically significant asthma exacerbation, in the opinion of the Investigator, 
including those requiring use of OCS 30 days prior to enrolment (Visit 1) or during 
the screening/run-in period.

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Edition Number 4.0
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16.
Receipt of immunoglobulin or blood products within 30 days prior to enrolment 
(Visit 1).
17.
Receipt of any marketed or investigational biologic agent within 4 months or 5 half-
lives prior to the enrolment visit, whichever is longer.
18.
Receipt of live attenuated vaccines 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) are allowed, 
provided they are not administered within 5 days before/after any dosing
visit.
19.
Receipt of any investigational non-biologic agent within 30 days or 5 half lives prior 
to enrolment (Visit 1), whichever is longer.
20.
Previous receipt of tralokinumab (CAT-354).
21.
Initiation of new allergen immunotherapy or change in existing immunotherapy is 
not allowed within 30 days prior to enrolment (Visit 1). However allergen 
immunotherapy initiated prior to this period may be continued provided there is a 
span of at least 5 days between the immunotherapy and IP administration.
22.
Current use of oral or ophthalmic non-selective β-adrenergic antagonist (e.g.,
propranolol). 
23.
Current use of five- lipoxygenase inhibitors (e.g., Zileuton) or roflumilast.
24.
Subjects that have undergone bronchial thermoplasty.
25.
Major surgery within 8 weeks prior to the enrolment visit, or planned in-subject 
surgery or hospitalization during the study period.
26.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 
times the upper limit of normal (ULN) at enrolment
27.
Pregnant, currently breast-feeding, or lactating women.
28.
Previous randomization in the present study.
29.
Concurrent enrolment in another clinical study where the subject is receiving an IP.
30.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).

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Edition Number 4.0
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31.
Employees of the clinical study site or any other individuals directly involved with 
the planning or conduct of the study, or immediate family members of such 
individuals.
32.
Individuals who are legally institutionalized.
For exclusion from the voluntary pharmacogenetic research:
33.
Previous allogeneic bone marrow transplant.
34.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
For procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomization
Investigator(s) should keep a record (i.e., a subject screening log) of subjects who entered pre-
study screening. The pre-screening/screening log will be evaluated periodically by 
AstraZeneca and/or its delegates during routine monitoring visits.
The Investigator(s) will:
1.
Obtain signed informed consent or assent from the potential subject, or their 
guardian/legal representative, before any study specific procedures are performed.
2.
Assign the potential subject a unique enrolment number (which begins with an ‘E’).
3.
Determine subject eligibility. See Section 3.
4.
Assign the eligible subject unique randomization code via the Interactive Web 
Response System/ Interactive Voice Response System (IWRS/IVRS).
5.
Subjects will be allocated to receive tralokinumab or placebo 1:1 ratio (i.e. 385 
subjects on active vs. 385 subjects on placebo).  Randomization numbers will be 
grouped in blocks.  Randomized subjects who discontinue will not be replaced. If a 
subject withdraws from participation in the study, then his/her enrolment/ 
randomization code cannot be reused.
Specific information concerning the use of the IWRS/IVRS will be provided in a separate 
instruction manual.

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3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication.  There can be no exceptions to this rule.  Subjects 
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 subject 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 subject from 
treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented.
3.5
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially in each stratum as subjects become 
eligible for randomization.
The randomization code will be assigned from a randomization list prepared by an internal 
AstraZeneca computerized system (Grand). The randomization will be stratified by baseline 
serum periostin level (< 16.44 ng/mL or ≥ 16.44 ng/mL) sampled during run-in, age 
(adult/adolescent) and geographical region (i.e. Asia Pacific, North America, South America, 
Central/Eastern Europe, and Western Europe/Rest of World).  Stratified randomization is used 
to allow for evaluation within sub-groups and/or to allow for heterogeneity in placebo 
exacerbations rates (regions). Randomization will be done in blocks.
3.6
Methods for ensuring blinding
This is a double-blind study in which tralokinumab and placebo are visually distinct from one 
another. Neither the subject nor any of the investigator or sponsor staff who are involved in 
the treatment or clinical evaluation and monitoring of the subjects will be aware of the 
treatment received. Since tralokinumab and placebo are visually distinct, IP will be handled by 
an unblinded IP manager at the site and will be administered by an unblinded investigational 
site study team member who will not be involved in the management of study subjects. (This 
could be the same person). 
Should an issue arise with the IP (e.g. damaged kit or syringe that has been assigned to a 
subject prior to administration, or any other unexpected event with the kit or syringe (e.g. a 
malfunction during IP administration) the unblinded IP manager at the site will contact a 
predetermined unblinded AstraZeneca site monitor (who is not otherwise involved in the 
project) to determine whether any specific actions are required.
A blinded AstraZeneca site monitor will perform IP accountability. In the event that the 
treatment allocation for a subject becomes known to the investigator or other study staff 

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Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
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involved in the management of study subjects, or needs to be known to treat an individual 
subject for an AE, the sponsor must be notified immediately by the investigator and if 
possible, before unblinding. 
All packaging and labelling of IP will be done in such way as to ensure blinding for all 
sponsor and investigational site staff (other than the unblinded IP manager who will directly 
handle the pre-filled syringes).
The following personnel will have access to the randomization list:
! those carrying out the packaging and labelling of IP
! those generating the randomization list
The information in the randomization list will be kept from other personnel involved in the 
conduct of the study, and in a secure location until the end of the study.
No member of the extended study team at AstraZeneca, or any CRO handling data, will have 
access to the randomization scheme during the conduct of the study, with the exception of the 
Supply Chain Study Management department and the Patient Safety department at 
AstraZeneca and personnel at the bioanalytical lab performing the PK sample analysis.
A DSMB will review safety data by assessing the safety of the interventions for adolescents 
only. The DSMB will have access to the individual treatment codes and will be able to merge 
these with the collected study data while the study is ongoing (see Section 0), if and as 
required. The personnel involved in the clinical study at AstraZeneca will remain blinded to 
these analyses and will have no knowledge of the results presented to the DSMB.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or pharmacists at the study sites from the 
IVRS/IWRS. Routines for this will be described in the IVRS/IWRS user manual that will be 
provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual subject have been made 
and documented.

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Edition Number 4.0
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3.8
Restrictions during and after the study
a)
Fertile and sexually active female subjects (including adolescent females) should use 
highly effective contraceptive methods throughout the study and at least for 16 weeks 
(5 half-lives) after last administration of the IP. 
b)
Subjects must abstain from donating blood, plasma from the time of informed 
consent or assent and for 16 weeks (5 half-lives) after last dose of IP.
3.9
Discontinuation of investigational product
At any time, subjects are free to discontinue IP or withdraw from the study (i.e., IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A subject that decides 
to discontinue the IP will always be asked about the reason(s) for their decision to withdraw 
and the presence of any AEs.  If possible, they will be seen and assessed by an Investigator(s).  
Adverse events will be followed up (as described in Section 6). The enrolment/randomization 
code of the withdrawn subject cannot be reused.
3.9.1
Procedures for discontinuation of a subject from investigational product 
Subjects will be discontinued from IP in the following situations:
1.
Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
2.
The subject experiences an AE that, in the opinion of the Investigator, contraindicates 
further dosing
3.
The development of any risk to the subject as judged by the Investigator or 
AstraZeneca 
4.
Severe non-compliance with the study protocol
5.
Pregnancy 
6.
Lost to follow-up1
7.
Development of any study specific criteria for discontinuation, including:
a.
An anaphylactic reaction to the IP requiring administration of epinephrine
b. A helminth parasitic infestation requiring hospitalization
                                                
1 A subject is considered lost to follow up when any of the following attempts of contact are failed: 3 attempts of 
either phone calls, faxes or emails; having sent 1 registered letter/certified mail; or one unsuccessful effort to 
check the status of the subject using publicly available sources, if allowed by local regulations.

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c.
An asthma-related event requiring intubation
d. Any malignancy
8.
Development of one or more of the following:
a.
Confirmed ALT or AST increase of ≥8 x ULN
b. Confirmed ALT or AST increase of ≥5 x ULN for more than 2 weeks
c.
Confirmed ALT or AST increase of ≥3 x ULN and total bilirubin of ≥2 x ULN 
d. ALT or AST of ≥3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥5%)
Subjects who discontinue IP or the study will always be asked about the reason(s) for 
discontinuation and the presence of any AEs. The Principal Investigator will perform the best 
possible observation(s), test(s) and evaluation(s) as well as give appropriate medication and all 
possible measures for the safety of the subject. They will also immediately inform 
AstraZeneca of the withdrawal. Adverse events will be followed up (see Section 6) and any 
questionnaires (e.g., for patient reported outcomes) are to be completed.
Discontinuation of IP does not necessarily mean discontinuation of follow-up or termination 
of study participation. Compliant subjects who are discontinued from the IP should be 
encouraged to continue to undergo all study related visits/procedures for the full 52-week 
study period in order to support the final efficacy and safety analysis for tralokinumab (see 
section 8). The reason for premature discontinuation of IP will be documented in the source 
documentation and recorded in the electronic case report form (eCRF).
It is essential to collect as much data as possible for all subjects throughout the study and 
especially all potential endpoint events. Complete withdrawal from the study (i.e., withdrawal 
of consent) has a direct negative impact on the potential validity of all study data and should 
be avoided wherever possible.
If the subject permanently discontinues IP prior to their completion of the study and wishes to 
continue with the study assessments, they may choose from 3 different follow-up options, as 
described in Section 4.2.
For subjects who wish to withdraw from the study completely refer to Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are subjects who do not fulfil the eligibility criteria for the study, and therefore 
must not be randomized.  These subjects should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., subject does not meet the required inclusion/exclusion 

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Edition Number 4.0
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criteria).  This reason for study withdrawal is only valid for screen failures, and not 
randomized subjects.
3.10.2
Withdrawal of the informed consent or assent
Subjects are free to withdraw from the study at any time (i.e., from receiving IP and/or having 
assessments performed), without prejudice to further treatment.
A subject who withdraws their consent or assent will always be asked about the reason(s) for 
their decision to withdrawal, and the presence of any AE.  The Investigator will follow up 
AEs outside of the clinical study. The subject must return the ePRO and ePEF devices.  
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced. 
If the subject only withdraws consent for the retention of blood samples for future exploratory 
use (e.g., DNA, study of markers of asthma, identifying potential new drug targets for asthma, 
or for assay development purposes), the subject will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF as well as in the Informed Consent Form (ICF) or assent form. The 
ICF or assent form must be re-signed and dated by both the subject and the investigator

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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
                                                
1 Visit 1 can be performed over a period of 3-working days, with the exception of documentation of informed consent and assent (if applicable) which can be 
completed up to 30 days prior to Visit 1.  Visit 1 can occur 2 to 4 weeks before visit 2.
2 The run-in period can be 28 to 45 days in duration.  Visit 1 should be completed within 45 to 28 days (days -45 to -28) prior to V3.  Visit 2 should occur 
within 17 to 14 days (days -17 to -14) prior to V3, which includes a -3 day window.  V3 is considered day 0.
3 All visits are to be scheduled based on the date of randomization and not from the date of the previous visit.

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Edition Number 4.0
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Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
Informed 
consent/ 
assent
X
Informed 
consent/
assent for 
DNA 
analysis (if 
applicable)
X
Inclusion/ 
Exclusion 
Criteria
X
X
X
Demographics
X
Medical and 
asthma 
history
X
Complete 
Physical 
examination
X
X
X
X
Brief 
Physical 
examination
X
X
X 
(V9 
only)
X
X 
(V13 
only)
X
X 
(V17 
only)
X
X 
(V21 
only)
X
X 
(V25 
only)
X 
(V27 
only)
X
X

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
45(125)
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
Height
X
X4
X4
Weight
X
X
X
X
X
Vital Signs
X
X
X5
X5
X5
X5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
dECG
X
X
X
Clinical 
Chemistry
X
X
X
X
X
X
X
X
X
Haematology
X
X
X
X
X
X 
(V9
only)
X
X 
(V13
only)
X
X 
(V17
only)
X
X 
(V21
only)
X
X 
(V25 
only)
X 
(V27
only)
X
X
X
X
X
Glycosylated
haemoglobin 
(HbA1c)
X
X
X
Urinalysis 
(dipstick)6
X
X
X
X
X
X
X
X
X
Urine 
pregnancy 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
                                                
4 Height assessed for adolescent subjects only.
5 Vital signs will be taken pre-dose prior to administration of IP. Subjects will be observed 2 hours post treatment for visits 3, 4, 5 and 6 with vital signs taken 
every 30 minutes.  For all other visits where IP is administered, subjects will be observed for a minimum of 1 hour, with vital signs taken every 30 minutes. 
6 Urine sample will only be sent to central lab for urinalysis if any dipstick parameters are assessed as abnormal.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
46(125)
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
test 
(dipstick)7
Total IgE
X
X
(V9 
only)
X
X
Phadiatop®
X
Serology 
(Hepatitis B, 
C;HIV-
1;HIV-2)
X
Serum β-
HCG
X
FSH8
X
Run-in 
Reversibility
X9
X9
ACQ-6 at 
the site10
X
X
X
X
                                                
7 For WOCBP and adolescent females, urine pregnancy test (dipstick) to be done at centre at each treatment visit prior to IP administration.
8 FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 months.
9 Run-in Reversibility on Visit 2 and Visit 3: For reversibility assessment the full procedure (section 5.1.2.1) should be followed until the subject either meets the FEV1 
reversibility requirement (≥12% and ≥200 mL) or completes all steps.  
10 ACQ-6 performed at the site unless completed at home the day prior.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
47(125)
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
ACQ-6 
adherence 
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AQLQ (S) 
+12 , 
WPAI+CIQ, 
EQ-5D-5L 
at the site11
X
X
X
AQLQ (S) 
+12, 
WPAI+CIQ, 
EQ-5D-5L 
adherence
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Health care 
resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
CGIC
X
X 
(V9 
only)
X
X
X
X
Asthma 
Daily Diary 
including 
home peak 
expiratory 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
                                                
11 AQLQ (S) +12 performed at the site unless completed at home the day prior.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
48(125)
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
flow 
assessment 
adherence
Spirometry, 
ePRO and 
ePEF device 
training
X
X
Pre-BD, 
Spirometry
X
X
X
X
X
X
X
X12
X
X
X
X
X
X
X
X
Post-BD, 
Spirometry
X
X
X13
X13
X13
X
PK
X
X
X
X
X
X
ADA/nAb
X
X
X
X
X
FENO
X
X
X
X
X
X
X
X
Assessment 
of asthma 
exacerbations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
                                                
12 Pre-BD Spirometry only at visit 9 and not at visit 10
13  Post-BD, Spirometry on Visit 7, Visit 29 (EOT) and IPD Visit: Only step 1 of the reversibility assessment (section 5.1.2.1) is required.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
49(125)
Assessment/ 
activity
Enroll-
ment
Run-
in
Random-
ization
Treatment
EOT
FU
FU
IPD
UNS15
V11
V22
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17 
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27 
V28
V29
V30
V31
w-6 to 
-4
w-2
w0
w2
w4
w6
w8
w10
w12 
w14
w16
w18
w20
w22
w24
w26
w28 
w30
w32
w34
w36
w38
w40
w42
w44
w46
w48 
w50
w52
w56
w72
Visit window (days)3
N/A
-3
N/A
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+7
+7
N/A
N/A
Administration 
of IP 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse 
events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood sample 
for periostin
X
X
X 
(V9 
only)
X
X
X
Blood sample 
DPP4 and 
other
biomarkers
X
X
X 
(V9 
only)
X
X
X
Blood 
sample for 
DNA 
(optional)
X14
ADA = anti-drug antibodies; AE=Adverse event; ACQ-6=Asthma Control Questionnaire 6; ADA=Anti-drug antibodies; AQLQ(S)+12=Standardised Asthma Quality of Life Questionnaire for 12 
Years and Older; β-HCG=Beta Human Chorionic Gonadotropin; BD=Bronchodilator; DNA=Deoxyribonucleic acid; DPP4=Dipeptidyl Peptidase-4; dECG=digital electrocardiogram; EOT =End 
of Treatment; ePRO=electronic Patient Reported Outcome device; FENO=Fractional Exhaled Nitric Oxide; FSH= Follicle-stimulating hormone; HIV=Human immunodeficiency virus; 
IgE=Immunoglobulin E; IPD= Investigational product discontinuation; nAb=Neutralizing antibodies; PK=Pharmacokinetic; PRO=Patient Reported Outcome
                                                
14 Blood sample for DNA may be collected at any visit after visit 1, only after the subject has signed a separate consent. 
15 UNS (Unscheduled Visit): At unscheduled visits for assessing an asthma exacerbation, the following assessments must be performed. For other unscheduled visits 
assessments may be performed per investigator’s judgement.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
50(125)
4.1
Enrolment/run-in period
4.1.1
Enrolment (Visit 1)
Each potential subject who is at, or over the age of majority (as per local law) will provide 
informed consent prior to the start of any study specific procedures and undergo assessments 
applicable for this visit (see Table 1).
For subjects less than the age of majority, in addition to the subject providing informed assent, 
the subject’s legal guardian must also provide their informed consent.
With the exception of documentation of informed consent and assent (if applicable), which 
can be completed up to 30 days prior to Visit 1, all other Visit 1 procedures should be 
completed within a 1 to 3-working day window.   The 3-day window is to enable subjects to 
return if necessary for the spirometry assessments on a morning when they have had their BD
medications withheld in accordance with the spirometry instructions (see section 5.1.2).The 
registration of the subject’s enrollment via IWRS/IVRS should occur on the day when the 
Visit 1 procedures are performed.
Visit 1 assessments are primarily concerned with assessing the subject’s eligibility 
(inclusion/exclusion) criteria, including their asthma disease state, the requisite level of 
severity based on maintenance medications, exacerbation history, and the current level of 
control based on an initial ACQ-6 score.
Spirometry will also be performed at Visit 1.  Subjects must have a pre-BD FEV1 value <80% 
of their PNV (<90% for subjects 12 to 17 years of age) in order to proceed in the study (as per 
Section 3.1, criterion 8).  If not, the subject will be screen failed.
Other study assessments and procedures to be performed at this visit include the recording of 
the subject’s demographics, a complete physical examination (including height and weight), 
vital signs, a dECG, recording the subject’s medical/surgical history and concomitant 
medications, collection of blood samples for haematology/clinical chemistry, serology and 
biomarkers, collection of a urine sample for urinalysis, and a pregnancy test for WOCBP.
A record of physician-diagnosed asthma, ICS-LABA use, use of other asthma controllers 
(Section 3.1, criteria  5, 6 and 7) and asthma exacerbations over the prior year (Section 3.1, 
criterion 10) is required for source documentation. A subject’s verbal history suggestive of 
asthma symptoms and/or prior asthma exacerbations, but without supporting documentation, 
is not sufficient to satisfy these inclusion criteria.
4.1.2
Run-in (Visit 2)
The run-in period (i.e., from Visit 1 to Visit 3) is 4 to 6 weeks (with a 3 day window) in 
duration. The subject should remain on their current asthma treatment with no changes 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
51(125)
throughout the entire run-in period. Assessments applicable for the run-in period are listed in
Table 1.
Visit 2 is primarily concerned with evaluating whether lung function meets the respective 
study eligibility criteria, to collect AE and concomitant medication information, as well as a 
blood sample for periostin (to be used for stratification at randomization).  
The protocol specified reversibility criterion (i.e. inclusion criterion 9) will be assessed at this 
visit.  Should this criterion not be met at Visit 2, subjects must fulfill it at Visit 3 in order to be 
randomised. 
The subject will be supplied with an electronic hand-held spirometer (peak flow meter) to 
measure the subject’s PEF at home, and an ePRO device to record asthma symptoms and 
complete relevant questionnaires (see section 5.2.2 for further details).
Visit 2 may be performed as a telephone visit (for collection of SAE information only) if the 
subject is confirmed as ineligible for the study (e.g., based on laboratory results from Visit 1, 
or medical history).
The subject’s eligibility should be evaluated at each visit during the run-in period with the 
relevant documentation entered in the source and eCRF.
4.1.3
Randomization (Visit 3)
Lung function with measurement of morning pre-dose, pre-BD and post-BD FEV1 will be 
performed on Visit 3 prior to randomization. Subjects should have a morning pre-BD FEV1 of 
≥40% and <80% (<90% for subjects 12 to 17 years of age) of the subject’s PNV, and fulfil the 
protocol-specified reversibility criterion (≥12% FEV1 and ≥200 mL), if either is not met at 
Visit 2. Other inclusion criteria at randomization will be confirmed at Visit 3. Before 
randomization the subject’s compliance with their usual asthma controller (ICS-LABA), and 
any other asthma controller medication, and ePRO completion must be confirmed (see section 
3.1, inclusion criteria 18 and 19). The subject should bring the ePRO device to this visit where
they will complete the ACQ-6, AQLQ(S)+12, EQ-5D-5L, and the WPAI + CIQ.
If the periostin value measured at Visit 2 is missing at randomization (Visit 3), the subject 
should not be randomized, nor should any Visit 3 assessments be performed. A new blood 
sample for periostin should be taken at this visit and a new Visit 3 visit should be re-scheduled 
to occur 2 weeks later, along with all other Visit 3 assessments.  
4.1.4
Re-screening
Subjects who experience an asthma exacerbation within 30 days prior to ICF date or during 
the screening/run-in phase should be screen failed.  They may be re-screened no sooner than 
30 days after their last dose of systemic steroids.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
52(125)
Subjects with respiratory infections requiring antibiotics or antiviral medication within 30 
days prior to the date informed consent is obtained or during the screening/run-in period may 
also be re-screened.
Re-screening for the above mentioned reasons is allowed only once for the subject. Subjects 
should be re-screened no later than 3 months failing initial enrolment.
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure and unforeseen personal events that mandate missed screening visits), 
subjects may potentially be re-screened. These cases should be discussed with the 
AstraZeneca Study Physician and documented approval for re-screening should be filed in the 
Investigator Study File (ISF).
Re-screening for subjects who have screen-failed due to an ACQ score <1.5 is not 
allowed.
Any re-screened subject will be re-enrolled and reassigned their originally assigned enrolment 
number after signing a new Informed Consent Form (ICF), or assent form, and after all run-in 
assessments have been performed as listed in Table 1 (with the exception of testing for HIV1 
an HIV2, hepatitis B and C, and FSH). Re-enrolment is only allowed once for any subject, 
regardless of whether this is due to an exacerbation or infection. The subject may not be re-
screened if any other eligibility criteria are failed.
4.2
Treatment period
Inclusion criteria at randomization will be confirmed at Visit 3. Before randomization the 
subject’s compliance with their usual asthma controller ICS-LABA and other asthma 
controller medication, and ePRO completion must be confirmed (see section 3.1, inclusion 
criteria 18 and 19).
Subjects confirmed as eligible will be randomized at Visit 3 (Week 0) in a 1:1 ratio (i.e. 385 
subjects on tralokinumab, and 385 subjects on placebo). Subjects will be administered 
tralokinumab 300mg or placebo via subcutaneous injection at the study site Q2W for a total of 
26 doses.
The first dose of the IP will be administered following randomization through IWRS/IVRS at 
Visit 3.
Following randomization the subject will receive 52 weeks of double-blind treatment, with the 
last dose of tralokinumab/placebo administered at Visit 28 (Week 50).
Subjects will have scheduled visits at 2-week intervals to complete protocol-specific 
assessments and IP administration, as listed in Table 1. Restrictions as set out in section 7.7.2
will continue to apply throughout the treatment period. In case of an asthma 
worsening/exacerbation (see section 5.1.1), subjects should be evaluated at the study site, 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
53(125)
when feasible, at an unscheduled visit, or ordinary visit if the worsening happens to fall within 
a scheduled visit window.
Subjects will continue to measure their PEF at home, as well as record asthma symptoms and 
responses to questionnaires in the Asthma Daily Diary throughout the 52-week treatment 
period (see section 5.2.2 for details).
Subjects will have brief physical exams performed at times listed in Table 1.  A complete 
physical exam will be performed at Visit 29 (Week 52). 
Additional blood samples will be obtained from the subjects at Visits 3, 9, 16 and 29 to 
further explore the relationship between the clinical response of tralokinumab and
biomarkers.
The subject’s adherence for completing all questionnaires in the ePRO will be assessed at all 
visits during the treatment period, with retraining provided as required.
At Week 52 subjects will come to the site for the End of Treatment (EOT) visit.  The subject 
should bring the ePRO device to the EOT visit and complete the ACQ-6, AQLQ(S)+12, EQ-
5D-5L, and the WPAI + CIQ, unless they have been completed at home prior to the visit.
The final follow up visits (i.e., 30 and 31) are to occur 4 weeks (+7 days) and 20 weeks (+7 
days) from the date of the EOT visit, respectively.
Subjects who prematurely discontinue IP (see section 3.9) should return to the study site and 
complete procedures described for the IP Discontinuation Visit (IPD visit), see Table 1. 
At the IP discontinuation visit, the subject will be given three options as to how they will be 
followed up:
1. Ideally, the subject should return for all regular clinic visits and perform all 
scheduled assessments until he/she completes a total of 52 weeks in the 
study, or,
2. The subject will be followed up on a monthly basis via telephone calls while 
continuing eDiary completion, until the subject completes 52 weeks in the 
study. No further procedures will be performed. Or,
3. The subject will be contacted at 52 weeks post randomization. No other 
study assessments will be performed prior to this contact.
For each option, an EOT visit will be conducted.
For option 1, all procedures will be done at each visit as indicated in Table 1.  For options 2 
and 3, AEs/SAEs, changes in concomitant medications and asthma exacerbation information 
are the minimum elements that must be collected at each contact. 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
54(125)
The subject’s decision needs to be documented in the eCRF and the specific section in the 
ICF/assent form addendum needs to be signed by the subject.
Should the subject choose option 2 or 3 above, they will complete the IP Discontinuation visit 
immediately and then a follow up telephone call at week 52.  If the subject chooses option 1, 
they will complete the IP Discontinuation visit immediately and then the EOT visit at week 
52.  The EOT visit/call will be completed immediately in the case of early withdrawal from 
option 1 or 2.
Subjects who initially chose options 1 or 2 and subsequently cannot or do not wish to comply 
with the requirements of the chosen option, can choose to continue with a less invasive option 
(i.e.: Subject initially choosing option 1 can continue with 2 or 3, subjects initially choosing 
option 2 can continue with 3).
Subjects who do not wish to have any follow up contacts at all, will be discontinued from the 
study. All discontinued subjects must return the ePRO and ePEF devices at the EOT visit.
Completion, or early termination of IP treatment, will be registered via the IWRS/IVRS for 
each subject.
4.3
Follow-up period
Subjects will have follow-up visits (30 and 31) at Weeks 56 and 72, respectively.
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 on eCRFs as specified in 
the study protocol and in accordance with the instructions provided.
The investigator will ensure 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 upon completion of the study.
5.1
Efficacy assessments
5.1.1
Assessment of asthma exacerbations
For the purpose of the protocol, an asthma exacerbation will be defined as a worsening of 
asthma that leads to any of the following:
!
Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
55(125)
!
An ER or urgent care visit (defined as evaluation and treatment for <24 hours in an 
ED or urgent care center) due to asthma that required systemic corticosteroids (as 
per above)
!
An inpatient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma 
The ePRO device will be programmed to alert both the subject and study site when certain 
pre-specified worsening thresholds are crossed as follows: 
!
Decrease in morning peak flow ≥30% on at least 2 of 3 successive days compared 
with baseline (last 10 days of run-in), and/or 
!
A ≥ 50% increase in rescue medication or one new or additional nebulized β2-
agonist on at least 2 of 3 successive days compared with the average use for the 
previous week, and/or 
!
Nocturnal awakening due to asthma requiring rescue medication use for at least 2 
of 3 successive nights, and/or; 
!
An increase in total asthma symptom score (the sum of day time [evening 
assessment] and night-time [morning assessment] of at least 2 units above the run-
in average (last 10 days of run-in), or the highest possible score (daily score of 6), 
on at least 2 of 3 successive days.
For the purpose of the protocol, worsening of asthma is defined as new or increased symptoms 
and/or signs (i.e., physical examination or lung function) that can be either concerning to the 
subject (subject-driven) or related to an Asthma Daily Diary alert (diary-driven).
If an exacerbation event is not associated with deterioration in at least one of the pre-specified 
subject-driven and/or diary-driven objective measurements, the Investigator will have to 
justify the decision for defining the event as an exacerbation. Events that are not supported by 
any objective assessment will be deemed not to be a protocol-defined exacerbation.
In order to calculate the number of exacerbations experienced by a subject during the 52-week 
treatment period, the following rule will be applied: 
!
The start of an exacerbation is defined as the start date of systemic corticosteroids, 
ER or urgent care visit requiring systemic corticosteroids, or hospital admission due 
to asthma, whichever occurs earlier, and the end date is defined as the last day of 
systemic corticosteroids or ER or urgent care visit or hospital discharge, whichever 
occurs later. 
Additional systemic corticosteroid treatments, ER or urgent care visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled. 
The subject may remain in the study after an exacerbation and continue to receive IP if the 
Investigator judges that it is medically appropriate for the subject to do so.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
56(125)
Reasonable attempts should be made by the Investigator to bring the subject into the study site 
for evaluation of a diary alert or subject initiated asthma worsening, particularly when it 
results in additional treatment being prescribed. Study site evaluations for asthma worsening 
may occur as an unscheduled visit or as part of an ordinary site visit if the worsening happens 
to be coincident with a scheduled visit window. 
A copy of the medical record should be obtained for exacerbations evaluated and treated at 
non-study sites (e.g., by the primary care HCP or at an ED/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.
Maximum follow-up time for a subject is approximately 52 weeks; defined as the time from 
randomization (Visit 3) to the date of Visit 29. For a subject lost to follow-up, this will be 
defined as the time from randomization to the time point after which an exacerbation could 
not be assessed (i.e., the last contact date). 
Exacerbations that occur after a subject has discontinued IP should still be accounted for when 
deriving the total number of exacerbations; and likewise, the follow-up time will reflect the 
follow-up time regardless of whether or not the subject is still on IP.
5.1.2
Spirometry
General requirements
Pulmonary function will be measured by spirometry at the study site using equipment 
provided by a central vendor. Spirometry will be performed by the Investigator or authorized 
delegate according to American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines (Miller et al 2005).
The vendor providing central spirometry services will be responsible for assuring that the 
spirometer used by each site meets ATS/ERS recommendations, and that the study site 
personnel who will be performing the testing are properly certified. Spirometry calibration 
will be detailed in a separate spirometry procedures manual.
Time of day for scheduled site visit spirometry
For adult subjects, spirometry testing must be initiated in the morning between 6:00 AM and 
11 AM according to the schedule provided in Table 1. For adolescent subjects, spirometry 
testing can be initiated during the whole day according to the schedule provided in Table 1. 
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomization spirometry was performed.
Subjects should be instructed not to use their maintenance twice daily LABA (or ICS-
LABA) within 12 hours of the scheduled site visit spirometry as this will affect the pre-BD 
FEV1 value; they may be taken subsequently at the site.  For theophylline and once daily BDs
a 48 hour washout period is required.  For the same reason, subjects should not use their 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
57(125)
SABA within 6 hours of scheduled spirometry/dECG assessments. This restriction is 
particularly critical for efficacy measures taken during the treatment period, but should also 
facilitate meeting the run-in FEV1 and reversibility eligibility criteria.
Options for handling subjects who have inadvertently taken their asthma medication within 
the restricted window are described in section 7.7.2.
Subjects that have a spirometry assessment at an unscheduled visit due to a worsening of 
asthma do not need to follow the washout instructions.
Spirometry technique
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Subjects should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the site. All spirometry manoeuvres (irrespective of whether to 
obtain values for FEV1, FVC, FEF 25-75%) should be performed with the subject seated in an 
upright position. If this is not comfortable for the subject, standing is permitted. The same 
position should be used by the subject for each forced expiratory manoeuvre from enrolment 
throughout the study. The head must not be tilted during manoeuvres and the thorax should be 
able to move freely; hence tight clothing should be loosened. A nose-clip should be used for 
the manoeuvre. Mouthpieces of the same dimension and shape should be used by the subject 
from enrolment throughout the study.
The spirometry manoeuvre consists of three phases; the first is maximal inspiration, the 
second is a “blast” of exhalation (to obtain the FEV1 value) and the last is a continuation to 
complete exhalation.  The subject should inhale rapidly and completely from functional 
residual capacity.  It is important that the preceding inspiration is fast and that any pause at 
full inspiration be minimal (i.e. only for 1-2 seconds).  The subject should be prompted to 
“blast”, not just “blow”, and they should be encouraged to fully exhale until the end of test 
criteria are met.  If the patient feels dizzy, the manoeuvre should be stopped, since syncope 
could follow due to prolonged interruption of venous return to the thorax.  Manoeuvres that do 
not meet the end of test criteria should not be used to satisfy the requirement of three 
acceptable manoeuvres.  However early termination, by itself, is not a reason to eliminate all 
the results from such a manoeuvre from further consideration.  
To allow recording of the FVC value, it is important that the whole manoeuvre lasts for at 
least 6 seconds. Ensure that none of the following has occurred: coughing during the first 
second, glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
spirometry session.  There should be at least 3 efforts that meet ATS/ERS acceptability 
criteria with the highest value and second highest value for FEV1 and FVC meeting the 
ATS/ERS reproducibility criteria.  The largest FVC and the largest FEV1 should be recorded 
after examining the data from all of the usable curves, even if they do not come from the same 
curve.  If the criteria for acceptability and reproducibility are not met with the first 3 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
58(125)
expiratory efforts, then additional attempts are required up to a maximum of 8.  If the 
reproducibility criteria is not fulfilled after the maximum number of manoeuvres has been 
performed, the highest of the FEV1 and FVC value that is deemed acceptable should be 
selected.   The absolute measurement (for FEV1), and the percentage of PNV (Quanjer et al 
2012) will be recorded. 
The mean forced expiratory flow between 25% and 75% of the FVC (FEF25–75%) is taken 
from the blow with the largest sum of FEV1 and FVC. The FEF25–75% must be measured 
with an accuracy of at least +5% of reading or +0.2 L whichever is greater. It is highly 
dependent on the validity of the FVC measurement and the level of expiratory effort.
Order of administration of usual asthma controller medication and IP relative to 
scheduled pre-and post-BD spirograms.
When spirometry is performed the subject´s usual asthma controller medication, BD and IP 
dose, should be withheld until after the final post-BD spirogram are complete. 
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at the study site for 
source data verification. The printout must be marked with the study code, subject enrolment 
code, date and time of measurement, and visit number.
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the subjects 
PNVs and are pre-programmed into the spirometer (Quanjer et al 2012). 
FEV1, expressed as percent of the PNV, will be calculated as follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100
5.1.2.1
Reversibility test and post-BD FEV1 efficacy assessment
The initial (pre-BD) FEV1 measurement (Section 5.1.2) must be completed before 
commencing the post-BD assessment.  
As before, ensure that the subject has withheld each of their theophylline and BD medications 
for the minimum period of time specified in Section 7.7.2 and Appendix H.  If the subject did 
not withhold their medications as specified, the reversibility assessment should be re-
scheduled within the next 7 days; other visit assessments may be completed as planned.  
Albuterol 90μg metered dose or Salbutamol 100μg metered dose will be used in the 
reversibility assessment.  Up to 8 doses may be administered at Visit 2 and Visit 3, and up to 4 
doses at the other visits (Visit 7, Visit 29 (EOT) and/or IP Discontinuation Visit). The dose 
should be adjusted if there is any concern about the effect on the subject’s heart rate, tremor or 
any other safety parameter during the assessment; the reason should be noted in the subject’s 
medical records.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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A spacer device should be used for administration of the SABA; nebulizers should not be 
used.  The same bronchodilator and type of device should be used at each visit where 
reversibility is assessed. 
Step 1: FEV1 measurement after 4 SABA inhalations  
For administration of albuterol/salbutamol, the subject will:
(i)
Perform a gentle, complete expiration 
(ii)
Inhale Dose 1 of the SABA to TLC and hold their breath for 5-10 seconds before the 
subject exhales.
(iii)
Rest for approximately 30 seconds before the next dose
(iv)
Repeat this for Dose 2, Dose 3 and Dose 4, resting for a further 15 – 20 minutes after 
Dose 4  
After resting for 15 – 20 minutes, proceed to measure FEV1 following the technique described 
in Section 5.1.2
Visit 2 and Visit 3:  if the inclusion criterion for reversibility is met (≥12% and ≥200 mL) this 
is the end of the reversibility assessment.  If it is not met the subject proceeds to Step 2.
Visit 7, Visit 29/EOT and/or IP Discontinuation Visit:  this is the end of the reversibility 
assessment.
Step 2: FEV1 measurement following a further 2 (total of 6) SABA inhalations (Only at 
Visit 2 and Visit 3, if assessed)
The subject will repeat the SABA inhalation procedures for Dose 5 and Dose 6.  (See Step 1 
above for instructions.)
After resting for 15 – 20 minutes FEV1 will be measured following the technique described in 
Section 5.1.2.  
This is the end of the reversibility assessment if either of the following occurs: 
•
the inclusion criterion for reversibility is met (≥12% and ≥200 mL) or 
•
the incremental change in FEV1 between Step 1 and 2 is ≤5% and the inclusion 
criterion is not met 
Subjects proceed to Step 3 if the incremental change in FEV1 between Step 1 and Step 2 is 
>5% and if the criterion for reversibility has not yet been met.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
60(125)
Step 3: FEV1 measurement following a further 2 (total of 8) SABA inhalations (Only at 
Visit 2, and Visit 3 if assessed)
The subject will repeat the inhalation procedures for Dose 7 and Dose 8, resting for 15 – 20 
minutes after Dose 8. (See Step 1 above for instructions).
After resting for 15 – 20 minutes, proceed to measure FEV1 following the technique described 
in Section 5.1.2. The reversibility assessment is now complete.
For subjects who need to perform step 2 and/or step 3 of the reversibility testing at visit 
3, the base-line value for the post-BD outcome variable in FEV1 will be derived from the 
value obtained after step 1.
5.1.3
Home PEF testing
An electronic, hand-held spirometer (peak flow meter) will be dispensed to the subject at Visit 
2. Home PEF testing will be performed by the subject in the morning upon awakening (and 
prior to taking their AM asthma controller) and in the evening at bedtime (and prior to taking 
their PM asthma controller). Recording of home PEF should start from the evening of Visit 2 
(Week -2) until the morning of Visit 29 (Week 52) using an ePEF meter device. When 
possible, ambulatory lung function measurements should be taken at least 6 hours after the last 
dose of SABA rescue medication.
Subjects 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.
The investigator/authorized delegate will check subject’s adherence to correct use of the peak 
flow meter at each visit as shown in Table 1 (or on EOT visit if prematurely discontinued 
from the study).
5.1.4
Periostin
An investigational use only (IUO)/performance evaluation only (PEO) assay is being 
specifically developed and validated as a companion diagnostic for tralokinumab to address 
the potential identification of a target population with an enhanced response rate based on the 
presence of high serum periostin as an indicator of IL-13 driven asthma. The performance 
characteristics of the periostin assay have not been established. No clinical decision or patient 
notification should be made based on the results obtained with this product.
A baseline periostin concentration level using the investigational assay will be determined for 
each subject enrolled in the trial.  Subject assessment with regards to periostin baseline level 
at Visit 2, will be used for stratification purposes.  Analysis will be performed by the central 
laboratory.  Blood samples will also be obtained at Visits 3, 9, 16, and 29. These samples may 
be used in existing and/or future clinical studies of in vitro diagnostic assays.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
61(125)
Instructions for sample collection, processing, storage, and shipment will be included in a 
separate laboratory manual provided to the sites.
5.1.5
Level of fractional exhaled nitric oxide 
Method of assessment
Fractional exhaled nitric oxide (FENO) measurements will be performed at Visits 1, 3, 5, 7, 16, 
23, and 29 (see Table 1). Subjects should not use their rescue SABA medication (e.g., 
albuterol/salbutamol) within 6 hours of the measurement. Inhaled BDs (including ICS-LABA) 
should be withheld for the effect duration specific to the BD.  If not, the visit must be 
rescheduled.
Measurements will not be performed until 2 weeks after a respiratory infection. Subjects will 
be asked whether they have had a respiratory infection in the 2 weeks prior to measurement, 
which will be recorded as “Yes or No” in the eCRF. Measurement of (FENO) will be 
performed prior to the spirometry measurements.
FENO will be measured using an electrochemical sensor. Information concerning the 
specifications and use of the analyzer will be provided in a separate instruction manual.
The standard single exhalation technique recommended by the ATS will be followed (Dweik 
et al 2011). 
Signed and dated printouts from the measurements will be kept in the ISF for Source Data 
Verification (SDV). Printouts will be marked with the study code, subject enrolment/ 
randomization code, date, time of measurement, visit number and subject initials. If a printout 
cannot be printed, the mean value of the measurements will be recorded in the subject’s 
medical records for SDV.
The vendor supplying the chemiluminescence analyzer to participating sites will be 
responsible for ensuring that the equipment and procedures for the measurement of FENO are 
validated prior to the start of the study. 
5.1.6
Safety assessments
5.1.6.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at visits in accordance with the schedule outlined in Table 1.  Haematology,
Clinical chemistry, and Urinalysis samples should be collected at unscheduled visits for 
assessing an asthma exacerbation, at a minimum. Other unscheduled visits may be initiated as 
needed, and assessments performed as per investigator’s judgement. For dosing visits, all 
samples will be taken prior to the administration of IP.
Detailed schedules of the chemistry, haematology, and urinalysis tests are presented in Table 
2, Table 3, Table 4, and Table 5, respectively.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
62(125)
Table 2
List of safety laboratory tests
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum)
B-Haemoglobin (Hb)
S-Alkaline phosphatase (ALP)
B-Leukocyte count
S-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen (BUN)
B-Mean corpuscular volume (MCV)
S-Calcium, total
B-Red blood cell (RBC) count
S-Carbon dioxide (CO2)
S-Chloride
S-Creatinine
S-Creatinine kinase
Urinalysis
S-CRP
U-Nitrite (dipstick)
S-Gamma-glutamyl transpeptidase (GGT)
U-Bilirubin (dipstick)
S-Glucose
U-Glucose (dipstick) 
S-Phosphorus
U-Blood (dipstick)
S-Potassium
U-Protein (dipstick
S-Sodium
U-Ketones (dipstick)
S-Total cholesterol
Urine microscopy and urine casts (as required)
Urine culture (as required)
S-Uric acid
Table 3
Clinical Chemistry (serum) Tests schedule
Visit
V1
V3
(Rand)
V5
V7
V16
V23
V29
IPD 
Visit
UNS 
Visit
Week
-6
0
4
8
26
40
52
(EOT)
N/A
N/A
ALP
X
X
X
X
X
X
X
X
X
ALT
X
X
X
X
X
X
X
X
X
AST
X
X
X
X
X
X
X
X
X
BUN
X
X
X
X
X
X
X
X
X
Calcium, total
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
63(125)
Visit
V1
V3
(Rand)
V5
V7
V16
V23
V29
IPD 
Visit
UNS 
Visit
Week
-6
0
4
8
26
40
52
(EOT)
N/A
N/A
Chloride
X
X
X
X
CO2
X
X
X
X
Creatinine
X
X
X
X
X
X
X
X
X
Creatinine 
kinase
X
CRP
X
GGT
X
X
X
X
X
X
X
X
X
Glucose 
X
X
X
X
Phosphorus
X
X
X
X
Potassium
X
X
X
X
Sodium
X
X
X
X
Total bilirubin
X
X
X
X
X
X
X
X
X
Total cholesterol
X
X
X
X
Uric acid
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
64(125)
Table 4
Haematology/Haemostasis (whole blood) schedule
VISIT
V1
V3
(Rand)
V4
V5
V7
V9
V11
V13
V15
V17
V19
V21
V23
V25
V27
V29
V30
V31
IPD 
Visit
UNS 
Visit
Week
-6
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52 
(EOT)
56 
(FU)
72
(FU)
N/A 
N/A
B-
Haemoglobin
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Leukocyte 
count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Leukocyte 
differential 
count 
(absolute 
count)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Platelet 
count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Hematocrit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Mean 
corpuscular 
volume
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Red blood 
cell count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
65(125)
Table 5
Urinalysis schedule
VISIT
V
1
V3
(Rand)
V
5
V7
V16
V23
V29
IPD 
Visit
UNS 
Visit
Week
-6
0
4
8
26
40
52 
(EOT)
N/A
N/A
U-Nitrite (dipstick)
X
X
X
X
X
X
X
X
X
U-Bilirubin (dipstick)
X
X
X
X
X
X
X
X
X
U-Glucose (dipstick)
X
X
X
X
X
X
X
X
X
U-Blood (dipstick)
X
X
X
X
X
X
X
X
X
U-Protein (dipstick)
X
X
X
X
X
X
X
X
X
U-Ketones (dipstick)
X
X
X
X
X
X
X
X
X
Urine microscopy and urine 
casts (as required)*
Urine culture (as required)*
* Urine samples will be analysed locally and sent for analysis at the central lab only when a positive dipstick 
result for any parameter is observed.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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The total volume of blood that will be collected from each subject during the study is 
presented in Table 6.
Table 6
Volume of blood to be drawn from each subject
Assessment
Sample volume 
(mL)
No. of samples
Total volume 3 
(mL)
Safety
Clinical chemistry
2.5
7
17.5
Haematology 
(including HbA1c)
2
18
36
FSH, β-HCG1
1
1
1
Serology
7.5
1
7.5
IgE
2.5
3
7.5
Phadiatop®
2.5
1
2.5
Periostin
6
5
30
DPP4 and other biomarkers
10
5
50
ADA/nAb
3.5
5
17.5
PK
3.5
6
21
Pharmacogenetics2
10
1
10
Total
200
1 Female subjects only
2 Optional
3 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 over 
the course of the study will not exceed 450 mL.
Urine will be tested locally and sent for analysis at the central lab only when a positive 
dipstick result for any parameter is observed.  Blood samples for determination of 
haematology/haemostasis and clinical chemistry will be performed at a central laboratory. For 
information on methods of collection, assessment, labelling, storage and shipment of samples 
please refer to the separate Laboratory Manual. 
A copy of the laboratory result report should be signed and dated by the Investigator and 
retained at the study site. 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities.  The laboratory results report should be signed and dated, and retained 
at site as source data for laboratory variables.  For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)  
Study Code D2210C00008
Edition Number 4.0
Date 09 June 2017
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NB. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix E, ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions.
5.1.6.2
Pregnancy Test
The following tests are applicable to female subjects only, and will be conducted in 
accordance with the schedule provided in Table 1
! Serum ß-human chorionic gonadotropin (ß-HCG) – the test done at 
enrolment (Visit 1) only, for WOCBP and adolescent females (analyzed at 
central laboratory)
! FSH – the test done at enrolment (Visit 1) only, for female subjects to 
confirm postmenopausal status in women <50 years who have been 
amenorrheic for >12 months
! Urine HCG – the test will be performed at the study site for WOCBP and 
adolescent females at each treatment visit before IP administration using a 
dipstick. Positive urine test result must be confirmed with serum β-HCG.
5.1.7
Physical examination
Physical examinations (complete and brief) will be performed in accordance with schedule 
provided in Table 1.
Baseline data will be collected at Visit 1. Any new finding(s) or aggravated existing 
finding(s), judged as clinically significant by the Investigator, will be reported as an AE as 
described in section 6.1.
5.1.7.1
Complete physical examination
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems.
5.1.7.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system. For the brief physical examination only, 
information on whether the assessment was performed or not will be recorded.
5.1.8
dECG
All ECG assessments must be performed using a digital electrocardiogram (dECG) device.  
dECGs will be performed in accordance with schedule provided in Table 1. dECG 

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assessments will be performed prior to blood drawing, spirometry, IP administration and BD 
administration.
For all subjects, the printouts of the dECG will be collected and signed, dated and stored at the 
study site along with a signed and dated photocopy of each printout (i.e., if the printout is not 
on archive-quality paper).
5.1.8.1
Resting 12-lead dECG
A 12-lead dECG will be taken in supine position, after the subject has been resting for at least 
5 minutes. The assessment should be performed before interventions with the subject (e.g.,
spirometry and administration of asthma-related medications and IP).
A standard dECG with a recommended paper speed of 50 mm/second covering at least 6 
sequential beats will be used. The Investigator or authorized delegate will be responsible for 
the overall interpretation and determination of clinical significance of any potential dECG 
findings. In case of discrepancy between the Investigator’s interpretation and that provided by 
the dECG machine (if applicable), the Investigator’s interpretation takes precedence and 
should be noted on the printout and recorded in the eCRF. Two identical copies of the dECG 
will be produced and quality checked and kept in case of further need for re-evaluation.
It is highly recommended that the same machine be used for all dECG assessments throughout 
the subject’s participation in the study.
dECG data and evaluation will be performed by the site Investigator and recorded in the 
eCRF.
5.1.9
Vital signs
Pre-dose vital signs (i.e., pulse, blood pressure, respiration rate and body temperature) will be 
obtained in accordance with schedule provided in Table 1.
Vital signs will be taken prior to blood drawing, IP administration, and, if possible, usual 
asthma controller medication. At Visits 3 through 6, subjects should be observed for a 
minimum of 2 hours after IP administration for the appearance of any acute drug reactions. 
For the remaining visits involving IP administration, subjects will be observed for a minimum 
of 1 hour after IP administration for any such reaction.
Vital signs should also be taken prior to per protocol BD administration, if applicable for that 
visit.
5.1.9.1
Pulse, blood pressure and respiration rate
Pulse rate and blood pressure should be measured after the subject has been resting for at least 
5 minutes. The measurement will be taken in sitting position. Pulse rate will be obtained 
before blood pressure.

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Respiration rate will be obtained after subject has been resting for at least 5 minutes, by 
counting number of breaths (i.e., how many times the chest rises) for one minute.
5.1.9.2
Body temperature
Body temperature will be measured in degrees Celsius prior to IP administration, in 
accordance with local standards.
5.1.10
Other safety assessments
5.1.10.1
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be 
assessed at enrolment (Visit 1) only.  All testing for these will be performed at a central 
laboratory.
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites.
5.1.10.2
Infections
Subjects experiencing a severe infection, defined as/resulting in:
! life-threatening
! requiring hospitalisation
! requiring treatment with antiviral medications, intravenous antibiotics or 
medications for helminth parasitic infections or,
! a permanent discontinuation of study drug.
All above events must be entered in the infection module in the eCRF.
5.2
Other assessments
5.2.1
Weight and height
Weight and height will be measured in accordance with the schedule provided in Table 1. 
The subject’s weight will be recorded in kilograms, and height will be recorded in 
centimetres. Weight and height measurements will be performed in light clothing and with 
shoes off.
5.2.2
Patient reported outcomes
Patient reported outcomes data will be captured using an ePRO. The device will be paired 
with a handheld spirometer (peak flow meter) for measuring at-home PEF testing (as outlined 

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in section 5.1.3). Subjects will be trained on basic ePRO operation will subsequently complete 
the ACQ-6 during Visit 1. After completing the Visit 1 ACQ-6, the device will remain at the 
site until Visit 2. At Visit 2, the site staff will set assessment reminder alarms on the device 
and train the subject on at-home use of the ePRO and handheld spirometer. Training will 
include explanation of device functionality and proper use of the spirometer. The subject will 
be asked to use both devices as part of the training and will be asked to verify completion of 
training on the ePRO device. Subjects will be provided with information on device use and 
issue resolution (e.g., helpdesk numbers) to conclude the training. 
At-home PRO assessment will start the evening of Visit 2. Subjects will be asked to bring the 
device back to the site for Visits 3 for the baseline assessments at the site. Following Visit 3 
all PRO data will be collected at home until Visit 29. Additional details concerning the 
assessments can be found in the subsequent sections (see sections 5.2.2.1 to 5.2.2.5).
5.2.2.1
Asthma Daily Diary
The Asthma Daily Diary will be completed each day from the evening of Visit 2 to the 
morning of Visit 29. The Asthma Daily Diary will include the following daily recordings: 
morning and evening home PEF data (obtained from the home peak flow meter), asthma 
symptoms, inhalations of rescue medication, nights with awakenings due to asthma 
symptoms, maintenance medication compliance. There will be triggers in the ePRO device to 
alert the subjects to signs of worsening of asthma and to contact their physician, please refer to 
section 5.1.1.
The subject should contact the study physician for evaluation after receiving a diary alert. The 
investigator/authorized delegate will check subject’s adherence to the Asthma Daily Diary at 
each visit as shown in Table 1.
Home PEF measurement
Details regarding home PEF measurement please refer to section 5.1.3.
Asthma symptoms
Asthma symptoms during night-time and daytime will be recorded by the subject each 
morning and evening in the Asthma Daily Diary, beginning the evening of Visit 2 until the 
morning of Visit 29.
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.
Rescue medication
The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be 
recorded by the subject in the Asthma Daily Diary twice daily (i.e., in the morning and in the 

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evening) beginning the evening of Visit 2 until the morning of Visit 29. The number of 
inhalations taken between the morning and evening lung function assessments will be 
recorded in the evening.  The number of inhalations taken between the evening and the 
morning will be recorded in the morning.
Nocturnal awakenings
Nocturnal awakenings due to asthma symptoms will be recorded by the subject in the Asthma 
Daily Diary each morning, beginning in the morning after Visit 2 until the morning of Visit 
29, by answering question whether he/she woke up during the night due to asthma symptoms 
by a “yes” or “no” response.
Maintenance medication
Maintenance medication administration will be recorded in the Asthma Daily Diary once daily 
in the morning, beginning in the morning after Visit 2 until the morning of Visit 29.
5.2.2.2
Asthma Control Questionnaire (ACQ-6)
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time 
waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and short-
acting β2-agonist use) omitting the FEV1 measurement from the original ACQ score.
Subjects will be asked to recall how their asthma has been during the previous week by 
responding to 1 question regarding their BD use, and 5 questions pertaining to their asthma 
symptoms.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 
indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled 
asthma, and a score >1.5 indicates uncontrolled asthma (Juniper et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful.
The questionnaire will be completed using the ePRO device.
Visit 1 ACQ-6 scores will determine eligibility for run-in and randomization (see section 3.1
inclusion criterion 11). An initial screening ACQ-6 will be taken at Visit 1 at study site. At 
Visit 3 subjects will complete ACQ-6. Once randomized, subjects will be asked to complete 
ACQ-6 once every 2 weeks (± 1 day) throughout the treatment period.
The Investigator/authorized delegate will check subject’s adherence to the ACQ-6 at each visit 
as shown in Table 1.
5.2.2.3
Standardised Asthma Quality of Life Questionnaire for 12 Years and Older 
(AQLQ(S)+12)
The AQLQ(S)+12 is a questionnaire that measures the health related quality of health-related 
quality of life assessment questionnaire developed for asthma subjects ages 12 and above.

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The questionnaire comprises 4 separate domains (i.e., asthma symptoms, activity limitations, 
emotional function, and environmental stimuli).
Subjects will be asked to recall their experiences during the previous 2 weeks and to score 
each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe 
impairment). The overall score will be calculated as the mean response to all questions. The 4 
individual domain scores (symptoms, activity limitations, emotional function, and 
environmental stimuli) are the means of the responses to the questions in each of the domains. 
Individual improvement in both the overall score and individual domain scores of 0.5 has been 
identified as a minimally important change. The questionnaire will be completed using the 
subject’s ePRO device.
The AQLQ(S)+12 will be first completed by the subject at the site at Visit 3 (Week 0), then 
every 4 weeks (±1 day) throughout the treatment period. At the EOT visit the AQLQ(S)+12 
will be completed during the visit unless completed the day prior.
The Investigator/authorized delegate will check the subject’s adherence to AQLQ(S)+12 at 
each visit as shown in Table 1.
5.2.2.4
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ)
The WPAI+CIQ consists of questions about how asthma and asthma related issues impact a 
subject’s ability to work, attend classes, and perform regular daily activities. The 
questionnaire relates to the subject’s experience over the previous 7 days. The WPAI+CIQ 
will be used to measure self-reported productivity loss. The questionnaire will be completed 
using the subject’s ePRO device.
The WPAI+CIQ will be first completed at Visit 3 (Week 0), then every 2 weeks (±1 day) at 
home throughout 52-week treatment period.
The Investigator/authorized delegate will check subject’s adherence to WPAI+CIQ at each 
visit as shown in Table 1.
5.2.2.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state

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The EQ-5D-5L will be completed weekly (+1 day) starting from Visit 3 (Week 0) throughout
Week 52 (Visit 29) using the ePRO device.
The investigator/authorized delegate will check subject’s adherence to EQ-5D-5L at each visit 
as shown in Table 1.
5.2.2.6
Health care resource utilization
Broad-based health care utilization asthma related event information will be collected by the
Investigator/authorized delegate at each visit (as shown in Table 1) and recorded in the 
appropriate eCRF module.
At Visit 1, Healthcare Resource Utilization (HRU) information will be collected with a ‘one 
year’ recall period. All the subsequent visits will collect HRU information with a recall period 
of ‘since the last scheduled visit’.
Note: cases of hospitalization must also be reported as an SAE (as described in sections 6.2
and 6.4). 
5.2.2.7
Clinical – Global Impression of Change (CGIC) assessment
The Clinical Global Impression of Change (CGIC) instrument is used to evaluate the overall 
response to treatment.  The investigator (clinician) will be asked to rate the degree to which 
the overall asthma status may have changed when compared to baseline (i.e. randomization 
visit/initiation of study drug).  The assessment uses a 7-point rating scale: 1 = Very Much 
Improved; 2 = Much Improved; 3 = Minimally Improved; 4 = No Change; 5 = Minimally 
Worse; 6 = Much Worse; and 7 = Very Much Worse.
The CGIC will be completed at the site visits as indicated in Table 1. It is recommended that 
the same clinician completes the CGIC at all applicable visits for an individual subject. Before 
making the assessment the clinician will need to access and review the results from all 
relevant assessments including lung function measurements (FEV1 and PEF) and patient 
reported outcomes (Asthma Daily Diary, ACQ-6 and AQLQ) performed before  the visit, 
Adherence to the patient reported outcomes should be closely monitored.
5.3
Pharmacokinetics and Immunogenicity
5.3.1
Collection of samples
Blood samples for determination of tralokinumab in serum will be collected pre-dose at the 
times presented in Table 1. It is important that date and time of each SC injection and sample 
collection be recorded for each subject.
Instructions for sample collection, labelling, processing, storage, and shipment will be 
provided in a separate laboratory manual provided to the sites.

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The volume of blood that will be collected from each subject for these assessments is 
presented in Table 6.
5.3.2
Determination of drug concentration
Samples for determination of tralokinumab concentration in serum will be analyzed by a 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method. Details of the 
analytical method used will be described in a bioanalytical report. The PK samples will be 
retained for future use at AstraZeneca, or designee, for a maximum of 15 years following the 
date of Last Subject Last Visit. 
A summary of PK analysis results will be reported in the CSR; details of the PK analysis will 
be reported separately in a bioanalytical report.
5.3.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled pharmacokinetic samples 
to further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to the AstraZeneca Biobank; see 
details in the Laboratory Manual).
5.3.4
Immunogenicity 
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment will be provided in a separate laboratory manual provided to the sites.
Samples used for immunogenicity analyses will be retained at AstraZeneca or designee for a
maximum of 15 years following the Last Subject’s Last Visit.  A summary of the analysis will 
be presented in the CSR. Details of the analytical method used will be described in a 
bioanalytical report.
Anti-tralokinumab antibodies
The pre-dose serum samples to measure presence of ADA will be collected according to the 
schedule of study procedures (see Table 1).
The presence or absence of ADA will be determined in the serum samples using a validated 
bioanalytical method. A tiered testing scheme will be employed, with the first step being 
screening. Samples found positive in the screening step will be tested in the confirmatory step. 

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Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titer 
determination and will be analyzed for the presence of nAb. 
Neutralizing antibodies
Neutralizing antibodies will be assessed at Visits 3, 16, 30, 31 and IPD according to the tiered 
testing scheme outlined above.
The presence or absence of nAb will be determined using a validated bioanalytical method. 
A summary of nAb incidence rate will be reported in the CSR and details of the nAb 
assessment will be reported separately in a bioanalytical report.
5.3.5
Total IgE 
Testing for total IgE will be performed at Visits 3, Visit 9 and Visit 29 (Weeks 0, 12 and 52, 
respectively).
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites.
5.3.6
Phadiatop®
Testing for phadiatop® will be performed at Visit 3 (Week 0).  The analysis for these will be 
performed by central laboratory. Instructions for sample collection, processing, storage, and 
shipment will be provided in a separate laboratory manual provided to the sites.
5.4
Pharmacodynamics
5.4.1
Serum biomarkers
Blood (serum) samples will be collected pre-dose according to the schedule in Table 1 to 
evaluate the pharmacology of tralokinumab, including but not limited to, periostin and DPP4.
The periostin level measured at Visit 2 will also be used for stratification at randomization.
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites. AstraZeneca or a designee will retain serum 
biomarker samples for investigation of the pharmacology of tralokinumab for a maximum of 
15 years following the last subject’s last visit. 
The results from the investigation of such samples may not be reported in the CSR but in 
separate reports and in scientific publications as appropriate.
5.5
Pharmacogenetics
5.5.1
 
 

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 i  
 
5.5.2
Storage, re-use and destruction of pharmacogenetic samples
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
5.6
Biomarker analysis 
The subject’s consent or assent to the use of donated biological samples for non-exploratory 
analysis purposes is mandatory.    
Biological samples (i.e., blood, plasma, serum) will be collected and may be analyzed for 
exploratory biomarkers to assess correlations with disease activity, effects of study drug, 
clinical outcomes and toxicity.

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5.6.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’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.
5.6.2
Labelling and shipment of biological samples
The Principal Investigator will ensure that samples are labelled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials will not be shipped and no further 
samples will be taken from the subject unless agreed with AstraZeneca, and appropriate 
labelling, shipment and containment provisions are approved.
5.6.3
Chain of custody of biological samples 
A full chain of custody will be maintained for all samples throughout their lifecycle.
The Principal Investigator, or delegate, at each site will keep full traceability of collected 
biological samples from the subjects while in storage at the site until shipment or disposal 
(where appropriate), along with documentation of receipt of arrival.
The sample receiver will keep full traceability of the samples while in storage and during use 
until used, or disposed of, or until further shipment along with documentation of receipt of 
arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, and auditing of external laboratory providers.
Samples retained for further use will be registered in Fisher Bioservices or designate during 
their entire life cycle.
5.6.4
Withdrawal of Informed Consent or Assent for donated biological samples 
If a subject withdraws consent or assent to the use of their donated biological samples that will 
be used for non-exploratory purposes, the samples will be disposed of/destroyed, and the 
action documented.  If samples are already analyzed, AstraZeneca is not obliged to destroy the 
results of this research. As collection of the biological samples that will be used for non-
exploratory purposes, is an integral part of the study, the subject will be withdrawn from 
further study participation.  Subjects who withdraw their consent/assent for the use of their 
samples to be used for exploratory/future use purposes, will be allowed to continue in the 
study.

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The Principal Investigator will be responsible for ensuring that:
! The subject’s withdrawal of informed consent or assent to the use of donated 
samples is notified immediately to AstraZeneca
! The biological samples from any subject who withdraws consent or assent to 
the use of these samples, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented
! The laboratory (ies) holding the samples is/are informed about the 
withdrawn consent or assent immediately, and that samples are disposed 
of/destroyed, the action documented, and the signed document returned to 
the study site
! The subject and AstraZeneca are informed about the sample disposal
AstraZeneca will ensure that the central laboratory (ies) holding the samples is/are informed 
about the withdrawn consent or assent immediately, the samples are disposed of/destroyed, 
and that the action is documented and provided 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.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
! Results in death
! Is immediately life-threatening

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! Requires in-subject hospitalization or prolongation of existing 
hospitalization 
! Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions
! Is a congenital abnormality or birth defect
! Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events, including SAEs will be collected from the time the subject signs the informed 
consent or assent form, throughout the treatment period and the follow-up periods (i.e., Visit 
30, (Week 56) and Visit 31, (Week 72)).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at any follow up visit in the study will be 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 subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Adverse event variables 
The following variables will be collected in the eCRF for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity* of the AE
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)
!
Action taken with regard to IP
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome
*Intensity rating scale:
1 mild (awareness of sign or symptom, but easily tolerated)
2 moderate (discomfort sufficient to cause interference with normal activities) 

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3 severe (incapacitating, with inability to perform normal activities)
In addition, the following variables (if applicable) will be collected in the eCRF for SAEs:
!
Date AE met criteria of serious
!
Date Investigator became aware of the SAE
!
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 the 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
Assessment of causality
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 provided in Appendix B to the 
Clinical Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you/your child 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 

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signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
CSR.  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 IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
will use 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).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
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 subject 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 E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.3.8
Disease progression
Symptoms of the disease under study
Asthma symptoms or signs, such as wheeze, cough, chest tightness, dyspnoea, breathlessness 
and phlegm, will be recorded as AEs when:
! the sign or symptom is serious according to definitions, see Section 6.2,
! the subject discontinues the study due to the sign or symptom, and/or
! the sign or symptom is new to the subject or not consistent with the subject’s 
pre-existing asthma history (defined as within 1 year of Visit 1 as judged by 
the investigator.
Asthma exacerbations should not be recorded as AEs after randomization, unless it fulfils any 
of the above criteria.  All asthma exacerbations should be recorded in the exacerbation eCRF 
as per section 5.1.1.

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If a subject discontinues IP due to a study specific discontinuation criterion, this should 
always be recorded as ’Development of study specific withdrawal’ on the termination form in 
the eCRF. In addition, the investigator must assess whether the asthma deterioration should 
also be reported as an AE leading to discontinuation of IP (DAE)/AE leading to withdrawal 
from study on the AE form.
6.4
Reporting of serious adverse events
All SAEs must be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the course of the study, Investigators or other site personnel must 
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 will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Subject Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel must inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 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 will be sent to the designated AstraZeneca representative(s).
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative(s) by telephone.
The AstraZeneca representative(s) will advise the Investigator/study site personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca IP.
6.5
Overdose
An overdose with associated AEs is to be recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF, as well as in the Overdose eCRF module.
An overdose without associated symptoms is only to be reported on the Overdose eCRF 
module.

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If an overdose with the AstraZeneca study drug occurs during the course of the study, the 
Investigator, or other site personnel, must inform appropriate AstraZeneca representative(s) 
immediately, and no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Subject 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 subject becomes pregnant during the course of the study IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the subject 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
will inform the appropriate AstraZeneca representatives within 1 day (i.e., immediately) but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Subject 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 pregnancy module in the eCRF will be used to report the pregnancy and the pregnancy 
outcome module will be used to report the outcome of the pregnancy.
6.6.2
Paternal exposure
There is no restriction on fathering children or donating sperm during the study.
6.7
Management of IP related toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions must be immediately available 

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when IP is being administered.  Study site personnel must be trained to recognize and treat 
anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are provided in 
Appendix G.
Anaphylaxis will be defined as serious reaction that is rapid in onset and may cause death
(Sampson et al 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios:
1. The acute onset of a reaction (minutes to hours) with involvement of the 
skin, mucosal tissue or both and at least one of the following: a) respiratory 
compromise; or b) reduced blood pressure or symptoms of end-organ 
dysfunction
2. Two or more of the following that occur rapidly after exposure: involvement 
of the skin/mucosal tissue, respiratory compromise, reduced blood pressure 
or associated symptoms and/or persistent gastrointestinal symptoms
3. Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration.  At Visits 3 through 6, subjects should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, subjects will be observed for a minimum of 1 hour after IP 
administration for any such reaction.
In order to help understand the potential drug-relatedness of any acute reaction, a blood 
sample should be drawn during the event for additional ADA testing (if not already scheduled 
as per table 1 for this visit). If an anaphylactic reaction occurs, a blood sample will be drawn 
from the subject as soon as possible after the event, at 60 minutes ± 30 minutes after the event, 
and at discharge for analysis of serum tryptase.  The serum tryptase sample will be tested at 
the local lab or central lab where applicable.
6.8
Study governance and oversight
6.8.1
Independent Adjudication Committee
Tralokinumab is being developed for the treatment of severe asthma. There is considerable 
variation in the severity of subjects who seek ER or urgent care, and in the clinical thresholds 
used to determine the need for hospitalization.
An Independent Adjudication Committee, blinded to subject treatment, will evaluate all ER or 
urgent care visits, hospitalizations and deaths, to determine whether or not related to asthma. 
The adjudication committee will also review cardiovascular, cerebrovascular and malignant 
adverse events occurring after randomization.  The committee will include specialists in 
pulmonology, cardiology, neurology and oncology and will operate in accordance with a 
dedicated Adjudication Committee Charter/Manual of Operations.

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6.8.2
Data and safety monitoring board
An external DSMB will monitor and protect the safety of adolescent subjects throughout the 
double blind treatment period of the study. The DSMB members will be selected for their 
expertise. The voting members of the DSMB will be comprised of external individuals 
including the DSMB chair. To minimize the potential introduction of bias, DSMB members 
will not have direct contact with the study site personnel or subjects. 
The DSMB will review safety data on a regular basis as set out in the DSMB charter. The data 
for review will be outlined in the DSMB charter. The DSMB will have access to individual 
treatment codes and will be able to merge these with the collected study data while the study 
is ongoing. For reference, the DSMB will also have access to study data from adults. Subject 
enrollment will continue during DSMB review of safety data.
The DSMB will operate in accordance with the dedicated DSMB Charter/Manual of 
Operations and will be agreed to in advance by the DSMB members.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
All investigational products will be manufactured in accordance with GMP.
Tralokinumab and placebo administered in the study will be a clear to opalescent, colourless 
to yellow solution free from, or practically free, from visible particles.
Subjects will be randomized at Visit 3 (Week 0) in a 1:1 ratio to receive tralokinumab 300 mg, 
or placebo, Q2W (26 doses).
Each subject will receive two SC injections of 150 mg tralokinumab at each dosing interval to 
receive a total dose of 300 mg, or placebo.  The identity details for the IP are found in Table 7.

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Table 7
Identity of investigational product
Investigational 
product
Concentration and 
Formulation 
Dosage form and 
strength
Manufacturer
Tralokinumab
Formulated at a 
nominal concentration 
of 150 mg/mL in 
50mM sodium 
acetate/acetic acid 
buffer, 85mM sodium 
chloride, 0.01% (w/v) 
PS-80 pH 5.5 solution.
150 mg/mL solution 
for injection in an 
accessorized pre-filled 
syringe, 1.0 mL fill 
volume.
MedImmune
Placebo
Placebo contains the 
same excipients, in the 
same concentration 
only lacking 
tralokinumab
Placebo solution for 
injection in an 
accessorized pre-filled 
syringe, 1.0 mL fill 
volume.
MedImmune
The accessorized prefilled syringe (APFS) is a single use, disposable system that is designed 
to administer the labelled dose of the system to the subcutaneous space during one injection 
and automatically provide a safety mechanism to reduce the occurrence of accidental needle 
sticks during disposal of the system. 
The APFS consists of a prefilled syringe sub-assembly (PFS-SA; 1 mL long prefilled syringe 
barrel with a 1/2 inch 27 gauge thin wall staked in needle, rigid needle shield, plunger stopper) 
and a safety device.
7.2
Dose and treatment regimens
The IP will be administered at the study site on treatment visits and within visit windows as
specified in Table 1. A minimum interval of 7 days is required between 2 dosing visits.
IP administration
IP will be administered by a qualified, unblinded healthcare professional. The two injections 
should be administered within the same body location, separated by at least 3 cm. The 
injection site must be recorded in the source documents at each treatment visit and recorded in 
the eCRF.

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IP must be equilibrated to room temperature for a minimum of 30 minutes prior to dose 
administration.
The person administering the dose will wipe the skin surface of the upper arm, anterior thigh 
or abdomen with alcohol, and allow to air dry. The skin will be pinched to isolate the SC 
tissue from the muscle. The needle will be inserted at a 90-degree angle approximately 
halfway into the SC tissue. The IP will be slowly injected (at least 5-second duration is 
recommended) into the SC tissue using gentle pressure. The area should not be massaged after 
injection.
It is advised that the site of injection of IP be rotated such that the subject receives IP at a 
different anatomical site at each treatment visit.  The suggested injection site rotation 
sequence is presented below in Figure 2. 
Figure 2
Injection sites and rotation scheme
In cases when rotation of the injection site is not favorable for the subject and/or Investigator, 
the injection site, along with the reason why the site was changed, should be recorded in the 
source documents and eCRF for each such occurrence.
Further details on IP administration are provided in the IP Handling Instructions. IP 
administration must be carried out according to these instructions.
Post IP Administration (Visits 3-6)
At each visit, the subject will be observed for the appearance of any acute drug reactions, for a 
minimum of 2 hours with vital signs taken every 30 minutes, until stable.
Post IP Administration (Visits 7- 28)
At each visit, the subject will be observed for the appearance of any acute drug reactions, for a 
minimum of 1 hour with vital signs taken every 30 minutes, until stable.

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Conditions requiring IP administration rescheduling
If any of the following should occur, the Investigator should reschedule the visit and
IP should not be administered until the rescheduled visit:
! The subject has an intercurrent illness, that in the opinion of the Investigator 
may compromise the safety of the subject in the study (e.g., viral illnesses)
! The subject, in the opinion of the Investigator, is experiencing an acute or 
emerging asthma exacerbation
! The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to 
IP administration
7.3
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with Annex 
13 and current Good Manufacturing Practice (GMP) and regulatory requirements of each 
country participating in the study.  The labels will be translated into local languages where 
applicable and required by local regulations.
7.4
Storage
Tralokinumab/placebo is to be stored at the study site in a secured facility with limited access 
and controlled temperature. The temperature should be monitored on daily basis and 
documented in the temperature monitoring log.
The IP must be kept in the original outer container and under conditions specified on the label.
In the following cases:
! Temperature excursion upon receipt or during storage at the study site
! Damaged kit upon receipt, or
! Damaged syringe/cartridge,
Site staff should not use the affected IP, and should immediately contact their AstraZeneca 
representative for further guidance. Damaged IP should be documented via IWRS/IVRS 
(please refer to the IWRS/IVRS manual for further details).
7.5
Compliance
The date and time of all IP administrations, as well as any missed doses, should be recorded in 
the appropriate section of the eCRF.

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7.6
Accountability
The study drugs provided for this study will be used only as directed in the protocol. 
It is the investigator’s responsibility to ensure that a procedure is established and maintained 
for the operation of the unblinded study drugs, this includes but is not limited to:
! The study drugs are administrated only by a qualified, unblinded health 
professional named in the delegation of responsibility log.
! An unblinded health professional will account for all study drugs dispensed 
to the subjects.
An unblinded health professional, if applicable, or the blinded AstraZeneca monitor will 
account for all study drugs received at the site, unused study drugs and for appropriate 
destruction. Certificates of delivery and destruction should be signed.
In case of malfunctioning APFS, the centre should contact the unblinded AstraZeneca monitor 
to initiate a product complaint process according to applicable guidelines.
7.7
Concomitant and other treatments 
7.7.1
Concomitant medications
Information about any treatment in the 3 months prior to the date of the subject’s informed 
consent or assent, and all the concomitant treatments given during the study, with reason for 
the treatment, will be collected by the Investigator/authorized delegate at each visit (as shown 
in Table 1) and recorded in the eCRF.
Note: to satisfy inclusion criterion 6, the history of continuous treatment with ICS 
corresponding to ≥500μg fluticasone propionate dry powder formulation equivalents plus a 
LABA for at least 3 months prior to Visit 1 should be documented in source and recorded in 
the eCRF (see section 4.1.1).
Maintenance of asthma controller medication 
All subjects are required to be treated with a stable dose of ICS corresponding to ≥500 μg 
fluticasone propionate dry powder formulation equivalents (as outlined in Appendix F) and 
LABA for at least 3 months prior to Visit 1 and during the treatment period. Subjects may also 
receive other physician prescribed asthma controller medications. 
The aim of this study is to establish the treatment effect of tralokinumab as an add-on 
treatment and therefore the maintenance asthma controller therapy should be maintained at a 
stable dose from Visit 1 until the end of the treatment period, in order to prevent any 
independent confounding of the anticipated treatment effect of tralokinumab. Changes to the 
subject’s maintenance asthma controller medication regimen are discouraged during the 
treatment period, unless judged medically necessary by the Investigator. Ideally, such 
changes should be discussed with the AstraZeneca Study Team Physician, prior to any change 

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being made. All changes in the subject’s maintenance medication should be documented in 
source along with rational for change and recorded in eCRF.
Maintenance medication is not regarded as an IP, but will be provided/reimbursed by 
AstraZeneca according to local regulations, in order to maintain appropriate oversight and 
access to this concomitant therapy.
Subjects on maintenance treatment with theophylline should have a documented blood 
concentration levels within therapeutic range. If this is not documented before signing the 
informed consent, it can be obtained after informed consent has been given or as part of the 
Visit 1 procedures. The sample can be analysed at the central or local lab as applicable.
Rescue medication
Salbutamol, albuterol or levalbuterol will be used as rescue medication during the study in the 
event of a worsening of asthma symptoms. As with the maintenance ICS-LABA, rescue 
medication is not regarded as an IP, but will be provided/reimbursed by AstraZeneca 
according to local regulations, in order to ensure access to essential rescue therapy.
7.7.2
Restrictions during and after the study
7.7.2.1
Asthma medication restrictions
Use of short-acting β2-agonists (SABA)
Regularly scheduled SABA use in the absence of any asthma symptoms is discouraged from 
enrollment and throughout the study duration.
Prophylactic use of SABA (e.g., prior to planned exercise) if deemed necessary by the subject 
and the Investigator, may be used, but should not be recorded in the Asthma Daily Diary. Any 
such use should be documented in medical notes and recorded in the eCRF.
SABA via a metered dose device is permitted as needed for worsening asthma symptoms (i.e., 
rescue use) and will be recorded in the Asthma Daily Diary as number of inhalations.
Rescue use of SABA administered via jet or ultrasonic nebulization is allowed.  Occasions 
where SABA was administered via nebulization will be recorded separately from metered 
dose inhaler inhalations in the Asthma Daily Diary.  
Use of short acting anticholinergics 
The use of short acting anticholinergics (e.g., ipratropium) as a rescue treatment for worsening 
asthma symptoms outside of managing an asthma exacerbation event is not allowed from 
enrollment and throughout the study duration.
Use of long-acting β2-agonists (LABA) as a reliever

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The use of LABA as a reliever (e.g., Symbicort maintenance and reliever treatment) is not 
allowed from enrollment and throughout the study duration.
Use of theophylline and once daily bronchodilators 
Use of theophylline and once daily BDs is allowed at the discretion of the Investigator.  
However use of these drugs should be stabilized at least 3 months prior to the subject entering 
the study.  Also, a 48 hour minimum wash-out period is required before spirometry if a 
subject is using theophylline or a once-daily BD. Should the subject be taking theophylline or 
the once daily BD in the evening, it is advised that the Investigator ask the subject to 
reschedule their theophylline or BD regimen to morning use, if there are no medical reasons to 
prevent this change.
Asthma medication restrictions on the days of scheduled site visit spirometry
Pre- and/or post-dose spirometry assessments will be performed at the study site at scheduled 
visits (see Table 1). Restriction to a subject’s maintenance medication is required prior to the 
spirometry as described below (also see section 5.1.2):
Visits 2 and 3
Subjects will be asked to withhold their twice daily BD therapy (including ICS-LABA) on the 
morning of the screening FEV1 measurement and reversibility test for 12–24 hours prior to 
the assessment for eligibility (see Section 3.1, inclusion criteria 8 and 9).  For once daily BDs 
the required washout is ≥48 hours. In case the subject does not meet the reversibility 
eligibility criteria, and a second re-test is done (not earlier than next calendar day and not later 
than 7 calendar days after the failed attempt), twice daily BDs may be withheld for 24 hours.  
Treatment Period (Visits 4-29)
It is important that a true pre-BD (i.e., trough) FEV1 reading obtained in order to maintain the 
integrity of planned efficacy analyses around lung function improvement. Therefore, 
subjects will be asked to withhold their usual BD and SABA as outlined in the section 
above for Visits 2 and 3.
The subject’s usual asthma controller medications may be administered, following completion 
of the pre-BD spirometry. The suggested order of administration of the subject’s usual asthma 
controller, per protocol SABA (on visits where post-BD spirometry is assessed), and IP 
administration relative to scheduled pre and post-BD spirometry is given in section 5.1.2.
If the subject has taken their usual ICS-LABA and/or any other BD without appropriate 
washout period (see Visits 2 and 3 above) before the site visit, the Investigator/authorized 
delegate should remind the subject of the importance of withholding their BD for an 
appropriate time and reschedule the visit for another day, within the allowed window. 

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If the subject has taken rescue SABA within 6 hours of the planned site visit spirometry they
should ideally 1) remain at the site until such time that the 6 hour window has been reached or
2) return on another day, within the visit window. If neither of these options is feasible for the
subject, spirometry may be performed with a notation indicating that the pre-BD spirometry
was conducted within 6 hours of SABA use.
Asthma medication restrictions prior to home PEF testing
Subjects should avoid taking their morning asthma controller medication prior to the morning 
home PEF testing, and should conduct the evening home lung function testing before taking 
evening asthma controller medication. When possible, home PEF testing, should be taken at 
least 6 hours after the last dose of SABA reliever medication
Asthma medication restrictions on unscheduled visits
Asthma medication restrictions on unscheduled visits may not be feasible, and may be applied 
at the discretion of the Investigator. Timing of recent controller and reliever SABA use 
relative to the unscheduled spirometry should be noted in the record.
Asthma medication restrictions at site visits with scheduled dECG assessment
Subjects should be instructed not to take their usual asthma controller medication prior to 
scheduled dECG assessment. Use of SABA should be avoided within 6 hours prior to the 
dECG assessment.
The medication restriction is waived for the enrolment dECG at Visit 1.
7.7.2.2
Other medication restrictions
! Use of oral or systemic immunosuppressive medication is not allowed.  
Topical administration of immunosuppressive medication may be allowed at 
the discretion of the Investigator.  Please see section 3.2, exclusion criteria 
14 and 17 for examples and further details.
! Receipt of live attenuated vaccines within 30 days prior to randomization 
and during the study, including the follow up period, is not allowed. 
Inactive/killed vaccines (e.g., inactive influenza vaccine) are allowed 
provided they are not administered within 5 days before/after any dosing 
visit.
! Subject should not receive allergen immunotherapy injection on the same 
day as the IP administration
! Subjects should not take any other excluded medications:
! Oral or ophthalmic non-selective β-adrenergic antagonist (e.g., 
propranolol)

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! five-lipoxygenase inhibitors (e.g. Zileuton) or roflumilast
A table with medication-related restrictions is presented in Appendix H.
7.7.2.3
Bronchial Thermoplasty
Subjects should not undergo bronchial thermoplasty during the entire study.
7.7.3
Other treatments
Other treatments which are considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the Investigator.  If any such treatments include medications other 
than those described above, these medications are to be recorded in the appropriate section of 
the eCRF.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
The main objectives of this study are to show efficacy of tralokinumab vs. placebo in two 
populations, the all-subjects and a biomarker positive population, with regards to asthma 
exacerbations (primary) and asthma control (key secondaries).
There are two pre-specified populations studied in this study; the all subject populations and 
the biomarker positive population. The all subject population is the same as that studied in 
another pivotal study (D2210C00007) run in parallel. The biomarker positive population is not 
defined at the finalization of the clinical study protocol for this study, but will be defined 
based on results from study D2210C00007.  The statistical analysis plan will be updated with 
this definition before the unblinding of the current study (D2210C00008). 
With regards to the key secondary objectives around asthma control; to show increased 
asthma control for tralokinumab vs. placebo the following is considered necessary:
1. With regards to the key secondary objectives around asthma control; to show increased 
asthma control for tralokinumab vs. placebo the following is considered necessary: an 
significant effect in percent change from baseline in pre-dose/pre-BD FEV1 at Week 
52 vs. placebo and
2. Either a significant effect in mean change from baseline in bi-weekly mean daily 
asthma symptom score (combined daytime and night-time score as captured in the 
Asthma Daily Diary) at Week 52 or A significant mean change from baseline in 
Standardised AQLQ(S) +12 Total score at Week 52.
Asthma control for a dosing regimen is only to be considered when a significant effect with 
regards to annualised asthma exacerbation rate up to Week 52 has been shown.

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Significant results in both the key secondary outcome variables for FEV1 and ACQ-6 could 
give additional support for increased asthma control.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. Analyses will be performed by AstraZeneca or its 
representatives.
All personnel involved with the analysis of the study will remain blinded until the database is 
locked and all protocol violations are identified.
8.2
Sample size estimate
The total study sample of 770 subject (385 subjects per group) are considered sufficient to 
show a reduction in annualised asthma exacerbation rate for tralokinumab, versus placebo in 
the overall study population. 
Sample size calculations in terms of number of subject years needed is based on an assumed 
annual exacerbation rate in the placebo group of 0.8, and shape parameter of 0.95 (over-
dispersion) in both the all-subject and biomarker positive population. The calculations are 
made for a 1% significance level for all subjects and a 4% significance level for the biomarker 
positive population. The methodology used described in Keene et al 2007. 
Assuming a uniform loss to follow-up of 15% during the study, 770 randomized subjects are 
expected to provide approximately 355 subject years at risk per treatment group. This is 
expected to provide at least 90% power for showing superiority with effects down to 37% 
asthma exacerbation rate reduction in the all-subject population. 
The proportion of subjects in the all-subject population falling within the biomarker positive 
subpopulation will depend on the biomarker positive criteria to be defined in the SAP before 
un-blinding of this study. Based on results from study D2210C00007, the testing strategy for 
this study has been revised to use a 5% significance level based on the biomarker positive 
population as the primary population, and it is estimated that approximately 20% to 35% of 
the studied subjects will fulfil the biomarker positive criteria. Using a 5% significance level 
for the biomarker positive population as the primary population, a true asthma exacerbation 
rate reduction of 50% would have a power between 70% and 90% to show superiority.
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 analyzed based on the Safety population.
All subjects analysis set (All subjects): This analysis set comprises all subjects screened for 
the study and will be used for the reporting of disposition and screening failures.

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Biomarker populations: The biomarker positive and negative populations will be defined in 
the SAP before un-blinding of this study. 
For the reporting of efficacy data, the biomarker positive and negative population will be a 
subset of the Full analysis set; the primary population for analysis is the biomarker positive 
population. For the reporting of safety data, the biomarker positive and negative population 
will be a subset of the Safety analysis set, and for the reporting of PK data, the biomarker 
positive and negative population will be a subset of the PK analysis set.
8.3.1
Efficacy analysis set
Full analysis set: All subjects randomized and receiving any IP will be included in the full 
analysis set, irrespective of their protocol adherence and continued participation in the study. 
Subjects will be analyzed according to their randomized treatment, irrespective of whether or 
not they have prematurely discontinued. For subjects who withdraw consent or assent 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 subjects who received any IP will be included in the safety 
analysis set. Subjects will be classified according to the treatment they actually received. A 
subject 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.
8.3.3
PK analysis set
Pharmacokinetic analysis set (PK): All subjects in the full analysis set who received 
Tralokinumab; including PK blood samples that are assumed not to be affected by factors 
such as protocol deviations (e.g., disallowed medication, or incorrect study medication 
received). All PK summaries will be based on this analysis set.
8.3.4
PRO analysis set
PRO outcome variables will be evaluated based on the full analysis set.
8.4
Outcome measures for analyses
8.4.1
General Definitions
8.4.1.1
Definition of baseline and subject baseline variables
For spirometry variables the measurement recorded at the baseline visit (Visit 3) will be used 
as baseline. If the Visit 3 measurement is missing, the last non-missing value before Visit 3 
will be used as baseline instead. For post-BD FEV1, the measurement after the first BD 
administration is the baseline.
The baseline for the ePRO variables (ACQ-6, AQLQ(s)+12, WPAI-CIQ, and EQ-5D-5L) will 
be captured on the ePRO device at Visit 3. Baseline for Asthma Daily Diary variables will be 
the bi-weekly mean for data collected between study day -14 and -1 (i.e. 14 to 1 day before 
Visit 3). 

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For laboratory data and physical examination, baseline will be defined as the latest non-
missing assessment prior to first dose. 
Absolute change from baseline outcome variables is computed as (post-randomization value –
baseline value). 
Percent change from baseline is computed as ((post-randomization value – baseline value) / 
baseline value) × 100%. If either the post-randomization value or the baseline value is 
missing, then the absolute or percent change from baseline value will also be set to missing.
8.4.1.2
Visit and period windows
For the exacerbation-related analyses no windows will be applied. 
For the patient reported questionnaires collected in the ePRO, the variables will be 
summarized based on the protocol scheduled Days with ± 3-day window. 
For the other questionnaires, the window is the same as the protocol-defined visit windows. 
For local laboratory data, and all vital signs, the visit recorded in the WBDC system will be 
used. 
For the central laboratory results and other endpoints that present visit-based data, the 
variables will be summarized based on the scheduled days with adjusted analysis-defined visit 
windows. 
A more detailed definition of visit and period windows will be provided in the statistical 
analysis plan.
8.4.2
Calculation or derivation of efficacy variables
8.4.2.1
Exacerbation rate
The primary endpoint is the annualised asthma exacerbation rate (AAER) up to Week 52.  
In the statistical analysis, the number of asthma exacerbations experienced by a subject during 
the 52-week double-blind treatment period will be used as response variable, and the 
logarithm of the subject’s corresponding follow-up time will be used as an offset in the 
analysis to adjust for subjects having different exposure times during which the events occur. 
Asthma exacerbation is defined in Section 5.1.1
In order to calculate the number of exacerbations experienced by a subject during the 52-week 
treatment period the following rule will be applied: 
!
The start of an exacerbation is defined as the start date of systemic corticosteroids, 
ER or urgent care visits requiring systemic corticosteroids, or hospital admissions 
due to asthma, whichever occurs earlier, and the end date is defined as the last day 
of systemic corticosteroids or ER or urgent care visit or hospital discharge, 
whichever occurs later. 

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Additional systemic corticosteroid treatments, ER or urgent care visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled.
Maximum follow-up time for a subject is approximately 52 weeks; defined as the time from 
randomization to the date of Visit 29. For a subject lost to follow-up, this will be defined as 
the time from randomization to the time point after which an exacerbation could not be 
assessed. 
For the production of summary statistics, the annual asthma exacerbation rate per subject is 
calculated, and standardized per a 52-week period according to the formula described below.
Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date – Visit 3 date + 
1).
8.4.2.2
Proportion of subjects with ≥ 1 asthma exacerbation during 52 weeks of 
treatment
The proportion of subjects with ≥ 1 asthma exacerbation during the 52 weeks of treatment will 
be a supportive variable to the primary objective. The variable will categorize each subject as 
having at least one asthma exacerbation or not (yes/no).
8.4.2.3
Time to first exacerbation
Time from randomization to the first asthma exacerbation will also be used as a supportive 
variable to the primary objective, and is calculated as follows:
Start Date of first asthma exacerbation − Date of Randomization + 1.
The time to first asthma exacerbation for subjects who do not experience an asthma 
exacerbation during the treatment period will be censored at the date of their last visit for the 
52-week double-blind treatment period, or at the time point after which an exacerbation could 
not be assessed.
8.4.2.4
Forced expiratory volume in 1 second
The key secondary variable is the pre-dose/pre BD FEV1
The percent change from baseline to each of the post-randomization visits (post Visit 3), up to 
and including the end of 52-week double-blind treatment visit (Visit 29), will be used as 
secondary efficacy outcome variable.
The absolute change from baseline to each of the post-randomization visits (post Visit 3) up to 
and including the end of 52-week double-blind treatment visit (Visit 29) will be used as a 
outcome variable.

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The same outcome variables will be derived for the secondary variable pre-dose/post- BD 
FEV1.
8.4.2.5
Annualised asthma exacerbation rate associated with an ER or urgent care 
visit or a hospitalization
The annual rate of asthma exacerbations that are associated with an ER or urgent care visit or 
a hospitalization will be a secondary efficacy variable.
The number of asthma exacerbations that are associated with an ER or urgent care visit or a 
hospitalization experienced by a subject during the 52-week treatment period will be derived 
using the same rule for start and end as described for the primary variable in section 8.4.2.1.
In the statistical analysis, the number of asthma exacerbations that are associated with an ER 
or urgent care visit or a hospitalization experienced by a subject during the 52-week double-
blind treatment period will be used as response variable, and the logarithm of the subject’s 
corresponding follow-up time will be used as an offset in the analysis to adjust for subjects 
having different exposure times during which the events occur.
Maximum follow-up time is approximately 52 weeks, and the follow-up time is derived a 
described in Section 8.4.2.1
Additionally, for the production of descriptive statistics, the annualised rate of asthma-related 
ER or urgent care visits and hospitalizations will be calculated using the same methodology as 
the annualised rate of exacerbations described in Section 8.4.2.1.
8.4.2.6
Forced Vital Capacity and Forced Expiratory Flow at 25-75%
The percent change from baseline to each of the post-randomization visits, up to and including 
the end of 52-week double-blind treatment visit (Visit 29/EOT) will be calculated for the 
exploratory variables FVC and FEF25-75%.
8.4.3
Calculation or derivation of patient reported outcome variables
Patient-reported outcomes data will be captured via an ePRO device. The definition of key 
secondary and secondary outcome variables are provided in the following sections.
8.4.3.1
Asthma symptom score
Asthma symptoms during night-time and daytime will be recorded by the subject each 
morning and evening in the Asthma Daily Diary. Symptoms will be recorded using a scale 0-
3, where 0 indicates no asthma symptoms. Asthma symptom daytime score, night-time score, 
and total score will be calculated separately. 
The total daily symptom score will be calculated by taking the sum of the daytime and night-
time asthma symptom scores for each day. If a subject is missing a value for either daytime or 
night-time asthma symptom score on a given day then the total score for that day will be set to 
missing.

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The key secondary outcome variable is the biweekly mean daily asthma symptom total score. 
The daily asthma symptom total score is defined as the sum of the daytime and night-time 
symptom scores as captured in the Asthma Daily Diary. The biweekly mean is calculated as 
the mean daily asthma symptom total over 14 sequential days.  If more than 7 daily scores 
(>50%) within that period is missing, then the daily asthma symptom mean score is set to 
‘missing’. 
8.4.3.2
Rescue medication use
The number of rescue medication inhalations and nebulizer treatments taken will be recorded 
by the subject in the Asthma Daily Diary twice daily.
The number of inhalations of rescue medication captured in the eDiary each day will be 
calculated per subject. If a subject is missing a value for either morning or evening rescue 
medication on a given day, then the total rescue medication use for that day will be set to 
missing.
Total rescue medication use, defined as the average number of inhalations (puffs) per day will
be calculated as the outcome variable.
8.4.3.3
Home peak expiratory flow (morning and evening)
Changes from baseline in morning and evening PEF up to Week 52 will be calculated.
8.4.3.4
Asthma Control Questionnaire (ACQ-6)
In the ACQ-6 questionnaire the subjects are asked to recall the status of their asthma during 
the previous week with regards to symptom, use of short acting β-agonists and BD. The 
questionnaire includes 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
6. Daily rescue medication
The questions of the ACQ-6 are measured on a 7-point scale scored from 0 (totally controlled) 
to 6 (severely uncontrolled). The ACQ-6 score is computed as the un-weighted mean of the 
responses.
Other variables based on ACQ-6 to report include:
!
ACQ-6-responder (Yes=1/No=0)
o
Responder: Change from baseline ACQ-6 score ∀-0.5
o
Non-responder :  Change from baseline ACQ-6 score > -0.5
!
ACQ-6-responder (improved/No Change / Deterioration)
o
Improvement: Change from baseline ACQ-6 score ∀-0.5

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o
No change: -0.5 < Change from baseline ACQ-6 score < 0.5
o
Deterioration:  Change from baseline ACQ-6 score ≥ 0.5
!
Subjects asthma control as measured by ACQ-6 score:
o
Well controlled : ACQ-6 score ∀0.75
o
Partly controlled : 0.75 < ACQ-6 score  <  1.5
o
Not well controlled : ACQ-6 score ≥ 1.5
8.4.3.5
Asthma quality of life questionnaire for 12 years and older (AQLQ(S) +12)
The AQLQ(S)+12) will be first completed at Visit 3 (Week 0), which will be used as the 
baseline assessment. Subjects are asked to recall their experiences during the previous 2 
weeks and to score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) 
to 1 (severe impairment).
The overall score is calculated as the mean response to all questions. The 4 individual domain 
scores (4 domains assessing 1) symptoms, 2) activity limitations, 3) emotional function, and 
4) environmental stimuli) are the means of the responses to the questions in each of the 
domains. 
The key outcome variable for the AQLQ(S)+12 will be the change in mean score from 
baseline to each of the post-randomization periods. The change from baseline will be derived 
as post-randomization score minus baseline score, there will be no imputation for missing 
values.
Other variables based on AQLQ(S) +12 to be reported include:
!
AQLQ(S) +12 -responder (Yes=1/No=0)
o
Responder: Change from baseline AQLQ(S) +12 score ≥  0.5
o
Non-responder :  Change from baseline AQLQ(S) +12 score < 0.5
!
AQLQ(S) +12 -responder (improved/No Change / Deterioration)
o
Improvement: Change from baseline AQLQ(S) +12 score ≥  0.5
o
No change: -0.5 < Change from baseline AQLQ(S) +12 score < 0.5
o
Deterioration:  Change from baseline AQLQ(S) +12 score  ≤ -0.5
8.4.3.6
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect increasing levels of 
difficulty.
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state.
The change from baseline in visual analogue scale will be calculated by visit.

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8.4.3.7
Health care resource utilization 
Broad-based health care utilization event information will be collected by the 
Investigator/authorized delegate at each visit as specified in the protocol and recorded in the 
appropriate eCRF module. Examples include aspects such as unscheduled physician visits or 
telephone calls or ambulance transport.
8.4.3.8
The Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions (WPAI+CIQ)
The Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment 
Questions (WPAI+CIQ) will be first completed at Visit 3 (Week 0), which will be used as the 
baseline assessment.
The WPAI+CIQ questionnaire is a 10-item questionnaire that assesses productivity and 
activity impairment over the previous week.
There are a maximum of 10 questions and a minimum of 3 questions that will be completed 
by subjects as follows:
1. Currently employed (yes/no)
2. Hours missed work due to health problems
3. Hours missed work due to other reasons
4. Hours actually worked
5. Degree health affected productivity while working (0-10 scale, with 0 meaning no 
effect)
6. Attends class in an academic setting (yes/no)
7. Hours missed class due to health problems
8. Hours actually attended class
9. Degree health affected productivity while attending class (0-10 scale, with 0 meaning 
no effect)
10. Degree health affected regular activities (other than work or class) (0-10 scale, with 0 
meaning no effect)
If the answer to question 1 is ‘No, not currently employed’, then the subject should skip to 
question 6. If the answer to question 6 is ‘No, not currently attending class’, then the subject 
should skip to question 10.
The WPAI+CIQ provide 4 scores: 
!
Absenteeism (work or class time missed),
!
Presenteeism (impairment at work or class/reduced on-the-job effectiveness), 
!
Work productivity loss (overall work or class impairment/absenteeism plus presenteeism) 

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!
Activity impairment. 
WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity.
For the work related questions, the following calculations should be used to create the 
outcomes of interest:
!
Absenteeism = Q2/(Q2+Q4)
!
Presenteeism = Q5/10
!
Work Productivity Loss = Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]
!
Activity Impairment = Q10/10
The class related questions will be used in a similar manner.
8.4.4
Calculation or derivation of safety variable(s)
The following safety data will be collected: vital signs, physical examination, 12-lead dECG, 
hematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline (Visit 3) to each post-baseline time point where scheduled assessments 
were made will be calculated for relevant measurements. 
8.4.4.1
Adverse events
Adverse events experienced by the subjects will be collected throughout the entire study and 
will be coded by the AstraZeneca designee using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA).
AE data will be categorized according to their onset date into the following study periods:
!
AEs occurring during run-in (onset date ≥ Visit 1 and before the first dose of study 
treatment)
!
AEs occurring during treatment (onset date ≥ the first day of study treatment and ≤ the 
last day of study treatment + 2 weeks) 
!
AEs occurring during follow-up, consisting of AE with
o
onset date > the last day of study treatment + 2 weeks and  ≤ date of week 72; 
this is only applicable for subjects that are treated for the entire treatment 
period
o
onset date > the last day of study treatment + 2 weeks and  ≤  the last day of 
study treatment +  22 weeks ; this is only applicable for subjects that 
prematurely discontinued treatment

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!
AEs occurring post-treatment (onset date > the last day of study treatment + 22 weeks; 
this is only applicable for subjects that prematurely discontinued treatment)
The timing of AEs will be assigned to the period in which they first occurred. If an AE has a 
missing onset date, then unless the stop date of the AE indicates otherwise, this will be 
considered an on treatment event. 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 an on treatment 
AE.
8.4.4.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations due to AEs. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR.
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
8.4.4.3
Laboratory variables
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
parameters will be taken at the times detailed in the CSP, and will be assessed in a central 
laboratory. The parameters outlined in Table 2, Table 3, Table 4 and Table 5 in Section 
5.1.6.1, will be collected. Laboratory data will be reported in SI units.
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent scheduled assessment will be calculated. Baseline is defined as the last available 
value measured prior to the first dose of randomized treatment. The change from baseline is 
defined as the treatment period value minus the baseline period value. There will be no 
imputation for missing values.
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 AstraZeneca extended 
reference ranges will be used for laboratory variables (where they exist). 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. 
For the purposes of haematology, clinical chemistry and urinalysis shift tables, baseline will 
be defined as the latest non-missing assessment prior to first dose, and on-treatment will be 
defined as the latest non-missing assessment whilst the subject is ongoing on treatment.

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For the liver function tests: AST, ALT, ALP, GGT and total bilirubin, the multiple of the 
AstraZeneca ULN (not extended) 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.
Subjects who meet any of the following criteria at any point during the study will be flagged:
Multiple = Value / ULN
i.e., if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2.
Subjects who meet any of the following criteria at any point during the study will be flagged:
!
AST ≥ 3x ULN
!
ALT ≥ 3x ULN
!
TBL ≥ 2xULN
8.4.4.4
dECGs
Twelve-lead dECG measurements will be recorded in accordance with the protocol, with the 
baseline visit being defined as Visit 1.
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.
8.4.4.5
Physical examination
Complete and brief physical examinations will be performed at time points specified in Table 1. 
What is included in the assessment will be dependent on whether the examination is complete 
or brief, as described in Section 5.1.7. For the brief physical examination, only information on 
whether the assessment was performed or not will be recorded.
Each component of the baseline visit (i.e., Visit 3) complete physical examination will be 
recorded as normal or abnormal. Each component of the follow-up complete physical 
examinations will be recorded as normal, same as baseline, or new/aggravated.
Any new finding(s), or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE.
8.4.4.6
Vital signs
Pre-dose vital signs (pulse, systolic blood pressure, diastolic blood pressure, respiration rate 
and body temperature) will be obtained in accordance with the schedule provided in Table 1.
Changes in vital signs variables between baseline and each subsequent scheduled assessment 
will be calculated. Baseline will be defined as the last value prior to the first dose of 

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randomized treatment. The change from baseline will be defined as the treatment period value 
minus the baseline period value. There will be no imputation for missing values.
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). All values (absolute and 
change) falling outside the reference ranges will be flagged.
Body mass index (BMI) will be calculated from the height (in meters) and weight (in 
kilograms) as follows: 
BMI = kg/m2
8.4.5
Calculations or derivation of Pharmacokinetic and Immunogenicity variables
Blood samples (processed to serum) for pharmacokinetic and immunogenicity assessments 
will be collected from all subjects at baseline prior to first IP administration at Visit 3, at 
multiple time points before IP administrations during the treatment period, and at selected 
time points in the follow-up phase of the study. Anti-drug antibodies assessments will be 
conducted utilizing a tiered approach (screen, confirm, titer). These validated methods are 
conducted using a bridging assay format and statistically determined floating screening assay 
cut point factor and confirmatory assay cut point. The minimal sample dilution is 1:13. Titer 
values are reported as the reciprocal of the highest dilution that yields a value above the cut 
point. Samples from pre-defined study time points that confirm positive for ADA will also be 
tested for neutralizing ADA/nAb activity. Both ADA and nAb will be summarized using 
descriptive statistics as described in Section 8.5.9.
Pharmacokinetics and immunogenicity of tralokinumab:
Tralokinumab serum concentrations will be tabulated by time along with descriptive statistics.  
Population PK modelling may also be performed to better characterize the PK of 
tralokinumab, but will be reported separately from the CSR. 
The incidence rate of ADA to tralokinumab will be reported by tralokinumab treatment group. 
If possible and if relevant, the impact of ADA occurrence on the PK and PD and safety will be 
summarized in the CSR.
8.5
Methods for statistical analyses
The main focus for the statistical analyses is to compare tralokinumab to placebo in the two 
pre-defined populations, all subjects and biomarker positive subjects, with regards to primary, 
key secondary, and safety objectives.
The analysis of the study endpoints will include all data captured during the 52-week double-
blind treatment period. This includes data regardless of whether study treatment was 
prematurely discontinued or delayed, and/or irrespective of protocol adherence, unless the 
subject withdraws consent or assent to study participation. The statistical analyses will 
compare tralokinumab to placebo.

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Summary data will be presented in tabular format by treatment. Categorical data will be 
summarized by the number and percentage of subjects 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 
  
subject number. 
All hypothesis testing will be reported using 2-sided tests. P-values will be rounded to 4
decimal places.
8.5.1
Testing strategy for primary and key secondary objectives
The pre-defined hierarchical testing strategy for testing of the primary and key secondary 
hypothesis in the primary populations described below, gives global strong control of the 
Type I error (FWER). 
Step 1: The primary endpoint in the biomarker positive population will be tested two-sided at 
α=0.05
Step 2: If a significant treatment effect is shown with regards to the primary endpoint in the 
biomarker positive population in Step 1, then the key secondary endpoint, percent change 
from baseline in pre-dose/pre-BD FEV1 at Week 52 vs. placebo will be tested two-sided at 
α=0.05 within that population using the hierarchical testing approach. Otherwise, testing will 
stop. All subsequent results within the hierarchy will be declared non-significant.
Step 3: If a significant treatment effect is shown with regards to the key secondary endpoint 
percent change from baseline in pre-dose/pre-BD FEV1 at Week 52 vs. placebo in the 
biomarker positive population in Step 2, then the next key secondary endpoint, change from 
baseline in AQLQ(S)+12 at Week 52 vs. placebo will be tested two-sided at α=0.05 within 
that population using the hierarchical testing approach. Otherwise, testing will stop. All 
subsequent results within the hierarchy will be declared non-significant.
Step 4: If a significant treatment effect is shown with regards to the key secondary endpoint 
change from baseline in AQLQ(S)+12 at Week 52 vs. placebo in the biomarker positive 
population in Step 3, then the next key secondary endpoint, change from baseline in ACQ-6 at 
Week 52 vs. placebo will be tested two-sided at α=0.05 within that population using the 
hierarchical testing approach. Otherwise, testing will stop. All subsequent results within the 
hierarchy will be declared non-significant.
Step 5: If a significant treatment effect is shown with regards to the key secondary endpoint 
of change from baseline in ACQ-6 at Week 52 vs placebo in the biomarker positive 
population, then the key secondary endpoint of change from baseline in bi-weekly mean daily 
asthma symptom score at Week 52 vs placebo in the biomarker positive population and the 
primary endpoint in the all subjects population will be tested using a Bonferroni approach at 
significance α. Hence, each of the two endpoints will be tested at significance level α/2 
(=0.025). If at least one significant treatment effect is shown at this step, testing will continue 

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to step 6. Otherwise, testing will stop. All subsequent results within the hierarchy will be 
declared non-significant.
Step 6: Percent change from baseline in pre-dose/pre-BD FEV1 at Week 52 vs. placebo in the 
all subjects population will only be tested if at least one significant treatment effect is shown 
at step 5. There are two different outcomes in Step 5 that could result in testing the hypothesis 
for FEV1:
(a)
If both comparisons in step 5 exhibits significance, then FEV1 in the all subjects 
population is testable and will be tested at significance level α (=0.05).
(b)
If only one of the hypotheses in step 5 exhibits significance, then FEV1in the all 
subjects population is testable and will be tested at significant level α/2 (=0.025).
Step 7: If a significant treatment effect is shown with regards to percent change from baseline 
in pre-dose/pre-BD FEV1 at Week 52 vs. placebo in the all subjects population then change 
from baseline in AQLQ(S)+12 at Week 52 vs placebo will be tested using the significance 
level used in step 6 (α (=0.05) if outcome (a) from Step 5, or α/2 (=0.025) if outcome (b) from 
step 5). Otherwise, testing will stop. All subsequent results within the hierarchy will be 
declared non-significant.
Step 8: If a significant treatment effect is shown with regards to change from baseline in 
AQLQ(S)+12 at Week 52 vs placebo in the all subjects population then change from baseline 
in ACQ-6 at Week 52 vs placebo will be tested using the significance level used in step 7 (α 
(=0.05) if outcome (a) from Step 5, or α/2 (=0.025) if outcome (b) from step 5). Otherwise, 
testing will stop. All subsequent results within the hierarchy will be declared non-significant.
Step 9: If a significant treatment effect is shown with regards to change from baseline in 
ACQ-6 at Week 52 vs placebo in the all subjects population then change from baseline in bi-
weekly mean daily asthma symptom score vs placebo will be tested using the significance 
level used in step 8 (α (=0.05) if outcome (a) from Step 5, or α/2 (=0.025) if outcome (b) from 
step 5). Otherwise, testing will stop. All subsequent results within the hierarchy will be 
declared non-significant.
8.5.2
Sensitivity analyses
The interpretation of exacerbation data post-discontinuation of treatment is likely to be 
confounded by reduced quality of objective confirmation of deterioration, and by the use of 
subsequent therapies. Sensitivity analyses for the primary endpoint will be carried out to 
explore the impact of this, e.g. exclusion of data post-discontinuation of treatment.
Sensitivity analyses for the primary endpoint and the key secondary endpoints based on 
different missing data mechanism assumptions including those expected to be more 
conservative such as missing not at random will be used to explore the robustness of any 
treatment effect, including multiple imputation approaches. Full details of the sensitivity 
analyses will be pre-specified in SAP and documented prior to database lock of the studies.

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8.5.3
Subject disposition, demography data and subjects characteristics
Subject disposition will be summarized using the all subjects analysis set. 
The number of enrolled subjects will be summarized. The number and percentage of subjects 
within each treatment group will be presented by the following categories; randomized, not 
randomized (and reason), received study treatment, didn’t 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 and biomarker positive and negative populations.
Various 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 subjects 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.
8.5.4
Exposure
Exposure to IP will be summarized by treatment group, for the safety analysis set and 
biomarker positive and negative populations.
8.5.5
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 subject’s rights, safety, or well-being include:
•
Subjects who do not meet the inclusion criteria
•
Subjects who do not meet the randomization criteria
•
Subjects who meet any of the exclusion criteria
•
Subjects who use one or more disallowed medication (for any reason, unless otherwise 
specified) during the randomized treatment period 

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•
Subjects who received the incorrect study treatment or study dose at any time during 
the 52-week double-blind treatment period
•
Subjects who developed withdrawal criteria during the study but were not withdrawn
8.5.6
Analysis of the primary variable
The primary efficacy variable is the AAER and the primary analysis is to compare the AAER 
for tralokinumab with placebo in the two subject populations based on the full analysis 
population (‘all subjects’ and biomarker positive population).
For each population the primary objective will be evaluated through the hypothesis test:
H0: rate ratio (tralokinumab/placebo) equals 1 vs.
H1: rate ratio does not equal 1. 
The AAER in the tralokinumab group will be compared to that seen in the placebo group 
using a negative binomial model. The response variable in the model will be the number of 
asthma exacerbations experienced by a subject, over the 52-week double-blind treatment 
period. Covariates and factors included in the model will include at least treatment and the 
stratifying variables. The logarithm of the subject’s corresponding follow-up time will be used 
as an offset variable in the model to adjust for subjects having different exposure times during 
which the events occur.
The standard parameterization approach (NB2) of the Negative Binomial model will be 
applied (Hilbe 2011).
The estimated treatment effect (i.e., the rate ratio of tralokinumab versus placebo), 
corresponding 95% confidence interval (CI), and two-sided p-value for the rate ratio will be 
presented. In addition, the AAER and the corresponding 95% CI within each treatment group 
will be presented.
The individual exacerbation criteria (ER or urgent care visits due to asthma that required 
systemic corticosteroids, hospitalization due to asthma, or use of systemic corticosteroids) will 
also be summarized descriptively.
8.5.7
Analysis of secondary variable(s)
All efficacy secondary objectives will be analyzed based on the full analysis population in 
both populations (‘all subjects’ and biomarker positive populations).
8.5.7.1
Lung Function
The key secondary outcome variable for lung function is: Percent change from baseline in 
pre-dose/pre BD FEV1.

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The percent change from baseline in pre-dose/pre-BD FEV1 at Week 52 will be compared 
between tralokinumab and placebo using a repeated measures analysis on all subjects with a 
baseline pre-dose/pre-BD FEV1 measurement in the full analysis set. 
The dependent variable will be the percent change from baseline in pre-BD FEV1 at post-
baseline protocol-specified visits (up to the EOT visit). Treatment group and the variables 
used in the stratified randomization will be included as independent variables. Visit will be 
fitted as a categorical variable, and 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:
Percent change in FEV1 = Treatment group +stratifying variables + visit + treatment*visit
Results will be presented in terms of LSMEANS, treatment differences in LSMEANS, 95% 
confidence intervals and p-values. Summary statistics of the change from baseline for all visits 
in the FEV1 at study site will be produced by treatment group.
8.5.7.2
Asthma symptoms
The key secondary outcome variable: Change from baseline in bi-weekly mean daily 
asthma symptom score (combined daytime and night-time score as captured in the Asthma 
Daily).
The change from baseline in asthma symptom total score, daytime score, and night-time score 
at Week 52 will each be summarized and analyzed using the repeated measurement approach 
defined for change from baseline in pre-dose/pre-BD FEV1, as described in Section 8.4.2.4. 
Included in the model will also be the baseline mean daily asthma symptom score.
8.5.7.3
Asthma specific health-related quality of life
The key secondary outcome variable: Change from baseline in AQLQ(s)+12 total score.  
The change in mean score from baseline for AQLQ(S)+12 at Week 52 will be summarized 
and analyzed using the repeated measurement approach defined for change from baseline in 
pre-dose/pre-BD FEV1, as described in Section 8.4.2.4. Included in the model will also be the 
baseline AQLQ(s)+12 total score.
Supportive outcome variable: AQLQ(S)+12 responder (yes/no) 
Responder variables AQLQ(S)+12 (yes/no) will be analyzed using a logistic regression model 
with covariates of at least treatment, stratifying variables, and baseline value.
The number and percentage of subjects with AQLQ(s)+12 total score changes ≥ 0.5 will be 
summarized by treatment (identified as a large meaningful change). Additionally, the number 
and percentage of subjects achieving an improvement, no change, or deterioration will be 
summarized by treatment as per Section 8.4.3.5.

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Supportive outcome measure: change from baseline to overall post-baseline mean of 
AQLQ(S)+12.
8.5.7.4
ACQ-6 defined asthma control
The key outcome variable: Change from baseline in ACQ-6.
Change in mean score from baseline for ACQ-6 will be summarized and analyzed using the 
repeated measurement approach defined for change from baseline in pre-dose/pre-BD FEV1, 
as described in Section 8.4.2.4. Included in the model will also be the baseline ACQ-6 mean 
score.
Supportive outcome variable: ACQ-6 responder (yes/no).
Responder variables ACQ-6 (yes/no) will be analyzed using a logistic regression model with 
covariates of at least treatment, stratifying variables, and baseline value.
The number and percentage of subjects achieving mean ACQ-6 ≤ 0.75, 0.75 < mean ACQ-6 
<1.5 and mean ACQ-6 of ≥ 1.5 at EOT will be summarized by treatment. Additionally, the 
number and percentage of subjects achieving an improvement, no change, or deterioration as 
per Section 8.4.3.4, ACQ-6 will also be summarized by treatment. 
Supportive outcome measure: change from baseline to overall post-baseline mean of ACQ-
6.
8.5.7.5
Other endpoints associated with asthma exacerbations
Proportion of subjects with ≥ 1 asthma exacerbation
The proportion of subjects with ≥1 asthma exacerbation during the 52 weeks of treatment will 
be addressed as a supportive variable to the primary objective. The proportion of subjects in 
the active tralokinumab arm will be compared with the proportion in the placebo group in both 
populations using a Cochran–Mantel–Haenszel test controlled for stratifying variables.
The results of the analyses will be presented as weighted difference in the proportion of 
subjects who have ≥1 asthma exacerbation, together with associated 95% CI and 2-sided p-
value for each active dose regimen versus placebo. The number and percentage of subjects 
with ≥1 asthma exacerbation will also be summarized by randomized treatment for both 
populations.
Time to first asthma exacerbation
Time to first asthma exacerbation will be analyzed as another supportive efficacy variable to 
the primary objective to explore the extent to which treatment with tralokinumab delays the 
time to first exacerbation compared with placebo. A Cox proportional hazard model will be 
fitted to data with including treatment and at least stratifying variables as covariates.
Results of the analysis will be summarized as hazard ratios, 95% confidence intervals and p-
values.

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Time to first asthma exacerbation will be displayed graphically using a Kaplan-Meier plot. 
The median time to event will be summarized by randomized treatment, if there is sufficient 
uncensored data available to calculate these median values. The percentage of subjects who 
are exacerbation free at 22 and 44 Weeks will be estimated for each treatment group.
8.5.7.6
Emergency room or urgent care visits and hospitalizations due to asthma
Annual rate of asthma exacerbations that are associated with an ER or urgent care visit or a 
hospitalization will be analyzed using a similar negative binomial model as outlined for the 
primary efficacy variable in Section 8.5.6.
8.5.7.7
Health care resource utilization and productivity loss due to asthma
WPAI-CIQ
The WPAI+CIQ data will be summarized by treatment, including the 4 types of scores: 
absenteeism, presenteeism, work/class productivity loss, and activity impairment described. 
The number and percentage of subjects with asthma specific resource utilization (defined in 
Section 8.4.3.8) will be presented by treatment group.
8.5.7.8
Asthma symptom, general health-related quality of life and asthma control
This section specifies analyses addressing the secondary objectives other than the key 
secondary objectives described in Sections 8.5.7.2, 8.5.7.3 and 8.5.7.4.
Nights with awakening due to asthma
The number of nights with awakening due to asthma and requiring rescue medication will be 
summarized and analyzed in the same way as rescue medication use, below.
Rescue medication use
Total rescue medication use (average puffs/day) will be analyzed as the response variable by 
fitting a linear model to the data. Treatment group will be fitted as the explanatory variable, 
and at least stratifying variables will be fitted as covariates.  The results will be presented in 
terms of LSMEANS, difference between treatments in LSMEANS and 95%CI. The number 
and percentage of subjects within each treatment group who received rescue medication will 
be summarized by visit.
Home PEF (morning and evening)
Change from baseline in morning and evening PEF at Week 52 will each be summarized and 
analyzed using a similar model as the model for change from baseline in pre dose/pre-BD 
FEV1, as described in Section 8.5.7.1
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The EQ-5D-5L responses from each dimension and the visual analogue scale (VAS) will be 
summarized by treatment group and period. Shift tables will be produced for each dimension, 
and the change from baseline in VAS will be summarized with descriptive statistics by visit.

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8.5.8
Safety and tolerability
All safety variables will be summarized using the safety analysis set and biomarker positive 
and negative populations, and data presented according to treatment received.
8.5.8.1
Adverse events
AEs will be summarized separately for the treatment and follow-up periods, as defined in 
Section 6.3. AEs occurring during the run-in period, or occurring post-treatment (as per the 
definition above) will be listed, but not summarized.
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; AEs, SAEs, deaths due to AE, DAEs, 
and other significant adverse events (OAEs). 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 summarized by SOC and PT assigned to the event using MedDRA. 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 summarized 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). SAEs, OAEs, 
DAEs, and deaths will also be summarized in separate tables.
The rate of AEs per person-years at risk, calculated as (number of subjects reporting 
AE)/(total time at risk of AE), will also be reported. Rates will typically be expressed in terms 
of events per 100 subject-years.
Separate listings of subjects with AEs, SAEs, death due to AE, or discontinuations due to AEs 
will be presented.
8.5.8.2
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, in both primary 
populations. 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.
AstraZeneca defined extended 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 maximum/minimum on-treatment value, as applicable for each 
parameter.

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Shift plots showing each individual subject’s laboratory value at baseline and at 
maximum/minimum 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 AstraZeneca defined reference ranges will also be displayed on the shift plots.
Data for subjects who have treatment-emergent changes outside the predefined criteria will be 
presented. This data presentation will include all visits for this subset of subjects.
The frequency of changes with respect to normal ranges between baseline and each post-
treatment time point will be tabulated. Frequencies of clinically noteworthy values (using 
AstraZeneca defined reference ranges) occurring during the clinical study will also be given.
In order to identify potential Hy’s Law cases, maximum post baseline total bilirubin will be 
plotted against maximum post baseline ALT, expressed as multiples of ULN. This plot will be 
repeated to show maximum post baseline total bilirubin 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 total bilirubin and at 3xULN for ALT/AST. 
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 total bilirubin, at any time may be explored further graphically using individual 
subject profile plots.
For urinalysis data, a shift table will be generated to present changes from baseline to EOT. 
The number of subjects with treatment-emergent changes will also be summarized. Here, 
treatment-emergent changes are defined as None/Trace at baseline to Positive, at any visit 
after baseline.
Any data outside the AstraZeneca normal and extended reference ranges will be explicitly 
noted on the listings that are produced.
8.5.8.3
dECGs
The Investigator’s assessment of the 12-lead dECG (normal or abnormal) will be listed for all 
subjects, along with detailing whether any abnormalities were clinically significant or not.
The number and percentage of subjects with clinically significant abnormal dECGs will be 
summarized by treatment group and visit.
8.5.8.4
Physical Examination
Shift tables (normal, abnormal) of baseline versus EOT will be generated, presenting the 
assessment for each component of the complete physical examination separately.

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Listings of abnormal results will be produced.
8.5.8.5
Vital Signs
Vital signs data will be presented in the same way as described in Section 8.5.8.2 for the 
clinical laboratory data, and will be presented using AstraZeneca defined reference ranges, 
and clinically important change criteria.
All recorded vital signs data will be listed.
8.5.8.6
Analysis of Immunogenicity variables
ADA status (positive vs negative) at each visit will be summarized by treatment group. 
Descriptive statistics including number of subjects, mean, standard deviation, median, and 
range of the actual ADA titers by treatment group and visit, where possible, will be provided. 
The ADA status across the study for each subject will also be classified and summarized by 
treatment group. The association of ADA status across the study with AEs/SAEs may be 
evaluated. In addition, the association of ADA titers (≥median titer in positive subjects vs. < 
median titer) with AE/SAEs may be evaluated for ADA-positive treated subjects only. The 
ADA-positive subjects across the study may also be divided into persistent positive versus 
transient positive. A subject will be considered as persistent positive if he/she has positive 
ADAs for at least two consecutive visits (with ≥ 16 weeks between the first and last positive 
value). Otherwise, the subject will be considered as transient ADA positive. The associations 
between ADA and AE/SAEs may be summarized for both persistent positive subjects versus 
transient positives subjects. 
Neutralizing antibody evaluations will be conducted on confirmed ADA positive samples.  
The test sample is deemed positive or negative for the presence of nAb to tralokinumab 
relative to a pre-determined (in assay validation), statistically derived cut point.  
For ADA, all subjects will be shown in the data listing.
8.5.9
Analysis of pharmacokinetics
All analyses of pharmacokinetics variables will be based on the PK data set, all analyses on 
Immunogenicity variables will be based on the safety analysis set.
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed serum trough (predose) concentrations, Ctrough. Empirical evaluation of potential 
impact of demographic covariates and ADA on Ctrough may be conducted.   
The PK data may be merged with those from other clinical studies for a population-based 
meta-analysis. If performed, results of the meta-analysis will be presented in a separate 
pharmacometrics report outside of the CSR.
8.5.10
Interim analysis
No interim analysis is planned for this study.

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A blinded sample size re-estimation will be performed before last subject enrolled in the 
study. The analysis will be performed by AstraZeneca or its representatives. A detailed 
description on this will be included in the statistical analysis plan.
8.5.11
Exploratory analysis
The analysis of exploratory objectives will be specified in the statistical analysis plan.
8.5.11.1
Baseline biomarker levels as predictive variables for treatment effect
The utility of subject’s baseline biomarker level (e.g. blood eosinophils, DPP4) as predictive 
continuous biomarkers for treatment effect on asthma exacerbation rate and asthma symptom 
control will be explored. A detailed description of the planned exploratory analyses will be 
given in the statistical analysis plan.  
 
 
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject 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 site staff, and also train them on any study specific procedures, the WBDC and 
IVR/IWR systems, ePRO and ePEF devices, spirometers, and any other system(s) that may be 
utilised in the study.
The Principal Investigator will ensure that appropriate training relevant to the study is 
provided 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 ensure that a record of all individuals involved in the study 
(medical, nursing and other staff) is maintained.
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contact with the study site, 
including site visits to:
!
Provide information and support to the Investigator(s)
!
Confirm that facilities remain acceptable

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!
Confirm that the investigational site team is adhering to the protocol, data are being 
accurately and timely recorded in the CRFs, 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 subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent or assent of participating subjects. This will 
require direct access to all original records for each subject (e.g., clinic/hospital charts)
!
Ensure withdrawal of informed consent or assent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed of/destroyed 
accordingly, and the action is documented, and reported to the subject.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
personnel at the site require information and advice about the study conduct.
9.2.1
Source data
Please refer to the Clinical Study Agreement (CSA) for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the site should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study.  In the event of any inconsistency 
between this Clinical Study Protocol and the Clinical Study, the terms of Clinical Study 
Protocol shall prevail with respect to the conduct of the study and the treatment of subjects.  In 
all other respects, not relating to study conduct or treatment of subjects, the terms of the CSA 
shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled.
9.2.3
Archiving of study documents
The Investigator should follow the principles and terms outlined in the CSA pertaining to the 
archival of study documents.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last subject undergoing the study’.
The study is expected to start in Q4, 2014 and to end by Q3, 2017.
The study may be terminated at individual sites if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow.  AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with tralokinumab.

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9.4
Data management by AstraZeneca
Data management will be performed by the AstraZeneca Data Management Centre according 
to the Data Management Plan (DMP). Quality control procedures will be applied to each stage 
of data handling to ensure that all data are reliable and have been processed correctly. The 
DMP will also clarify the roles and responsibilities of the various functions and personnel 
involved in the data management process.
Data will be entered in the WBDC system at the study site.
Site personnel will be trained on use of the WBDC system and will be responsible for entering 
data on the observations, tests and assessments specified in the protocol into the WBDC 
system. eCRF Instructions will be provided to the personnel at the study site as guidance for 
performing data entry. Data entered in the WBDC system will be immediately saved to a 
central database and all changes will tracked in the system’s audit trail. All data will be Source 
Data Verified (SDV) by an AstraZeneca site monitor (or representative), reviewed /queried 
and updated as needed. 
Data queries will be raised for inconsistent, impossible, or missing data, and must be resolved 
in a timely manner. Clean file occurs when all data have been declared clean and signed off by 
all investigators. Data will be frozen and then locked to prevent further data entry/editing. Any 
treatment revealing data may thereafter be added and the final database will be locked. A copy 
of the eCRFs will be provided to and archived at the study site when the study has been 
locked.
Data collected through third party sources will be obtained and reconciled against study data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA.  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  All coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Centre. 
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports will be produced and reconciled with the Subject Safety database 
and/or the investigational site. 
Data Management of genotype data
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 samples.  The results from this genetic research may be 
reported in the CSR for the main study, or in a separate report as appropriate.
Genotype data will be transferred to the clinical database, and merged with the clinical data 
from the main study, prior to the statistical analysis and reporting of the study.

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Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
Management of external data
Data Management will determine the format of the data to be received from external vendors 
and coordinates the flow of data to an external environment or clinical database (as 
applicable).
Data Management will ensure that the data collection tool (e.g., ePRO diary, IVRS/IWRS, 
etc.) will be tested/validated as necessary. External data reconciliation will be done with the 
clinical database as applicable.
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 International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Subject data protection
The Informed Consent or assent Form(s) will incorporate (or, in some cases, be accompanied 
by a separate document incorporating) wording that complies with relevant data protection 
and privacy legislation.
10.2.1
Pharmacogenomic data
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician or any other third party, unless 
required to do so by law.
Precautions will be taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.

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10.3
Ethics and regulatory review
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the subject’s ICF (and assent form for subjects under 
the age of majority), and any other written information and/or materials to be provided to a 
subject.  The Investigator will ensure the distribution of these documents to the applicable 
EC/IRB, and to the study site staff.
The opinion of the EC/IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrolment of any subject into the study. 
The EC/IRB should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the ICF (and/or assent form for subjects 
under the age of majority) that are needed to meet local requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF (and assent form for subjects under the age of majority), should be 
approved by the national regulatory authority or a notification to the national regulatory 
authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, ECs/IRBs and Principal Investigators with 
safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
10.4
Informed consent and assent
The Principal Investigator(s) at each site will:
!
Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study
!
Ensure each subject is notified that they are free to discontinue from the study at 
any time
!
Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided

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!
Ensure each subject provides signed and dated informed consent (and assent form 
for subjects under the age of majority) before conducting any procedure specifically 
for the study
!
Ensure the original, signed ICFs (and assent form for subjects under the age of 
majority) are stored in the Investigator’s Study File
!
Ensure copies of the signed ICFs (and assent form for subjects under the age of 
majority) are given to the subject
!
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are 
described in the informed consent or assent form that is approved by an Ethics 
Committee.
10.5
Changes to the protocol and informed consent or assent forms
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator and AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant EC/IRB 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 ECs/IRB, see Section 10.3.
If a protocol amendment requires a change to a site’s ICF (and/or assent form for subjects 
under the age of majority), AstraZeneca and the site’s EC/IRB are to approve the revised ICF 
(and/or assent form for subjects under the age of majority) before the revised form(s) is/are 
used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the site, 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, 
analyzed, and accurately reported according to the protocol, GCP, ICH guidelines, and any 

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applicable regulatory requirements.  The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the site.

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11.
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