A Multicentre, Randomized, Double-blind, Parallel Group, Placebo Controlled, 12-Week, Ph 2 Study to Evaluate the Effect of Tralokinumab on Airway Inflammation in Adults With Asthma Inadequately Controlled on Inhaled Corticosteroid (MESOS)
Phase: PHASE2
Conditions: Asthma
Sponsor: AstraZeneca

AstraZeneca4
Revised Clinical Stndy Protocol
Drug Substance
Study Code
Edition Number
Date
Tralokinumab (CAT-354)
0221 OCOOO14
2.0
15 January 20 16
A Multicentre,
Randomized,
Double-blind,
Parallel
Group,
Placebo
Controlled,
12-Week, Phase 2 Study to Evaluate
the Effect of Tralokinumab
on Airway
Inflammation
in Adults with Asthma
Inadequately
Controlled
on
Inhaled
Corticosteroid
(MESOS)
IND: 100,702
EudraCT
Number: 2015-000857-19
This submission document contains confidential commercial information, disclosure of which is prohibited
without providing advance notice to Astrazeneca and opportunity to object.
Tbe following Amendment(s) and Administrative Changes are included in this revised protocol:
Amendment No.
Date of Amendment
Local Amendment No:
Date of Local Amendment
16 July 2015
15 January 2016
Administrative
Change No.
Date of Administrative
Change
Local Administrative
Change No.
Date of Local
Administrative Change
2.9
PDF Edit
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca
Standard procedures.
The clinical study protocol is publicly registered and the results are
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in
compliance with prevailing laws and regulations.
09038820824b1ac1
29101/2016
11:14:57 AM

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
2(107)
PROTOCOL SYNOPSIS
A Multicentre, Randomized, Double-blind, Parallel Group, Placebo 
Controlled, 12-Week, Phase 2 Study to Evaluate the Effect of Tralokinumab 
on Airway Inflammation in Adults with Asthma Inadequately Controlled 
on Inhaled Corticosteroid (MESOS)
International Co-ordinating Investigator: Prof. Chris Brightling M.D.
The study will be conducted in collaboration with the United Kingdom Translational Research 
Partnership (TRP).
Study site(s) and number of subjects planned
Approximately 80 subjects will be randomized at approximately 20-25 study sites.
Study period
Phase of development
Estimated date of first subject enrolled
Q2 2015
2
Estimated date of last subject completed
Q4 2017
2
Study design
This multicentre, randomized, double-blind, parallel group, placebo-controlled, 12-week, 
phase 2 study will evaluate the effect of a 300 mg dose of tralokinumab administered 
subcutaneously every 2 weeks on airway inflammation in adults with asthma inadequately 
controlled on inhaled corticosteroids (ICS) with or without other controllers.
The subjects will be randomized to 12-week treatment with tralokinumab or placebo (1:1). 
After the end of treatment all subjects will be followed up for a period of 14 weeks.   
Objectives
Primary Objective:
Outcome Measure:
To evaluate the effect of tralokinumab on 
eosinophilic airway infiltration in adult
subjects with asthma inadequately 
controlled with ICS
Primary Outcome Variable:
The change, expressed as a ratio, in number of 
airway submucosal eosinophils per mm2
determined by microscopic evaluation of 
bronchoscopic biopsies from baseline up to week 
12

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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Primary Outcome Measure:
Ratio of tralokinumab to placebo at week 12
Secondary Objective:
Outcome Measure :
To evaluate the effect of tralokinumab on 
blood eosinophil levels in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variable:
The change, expressed as a ratio, in number of 
blood eosinophils from baseline up to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12
To evaluate the effect of tralokinumab on 
sputum eosinophil levels in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variable:
The change, expressed as a ratio, in number of 
differential sputum eosinophils from baseline up 
to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12
To evaluate the effect of tralokinumab on 
activation of eosinophils in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variables:
The change, expressed as a ratio, in blood and 
sputum free eosinophil cationic protein (ECP) 
concentrations from baseline up to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12
Safety Objective:
Outcome Variables:
To evaluate the safety and tolerability of 
tralokinumab in adult subjects with asthma 
inadequately controlled with ICS
Adverse Events/Serious Adverse Events
Vital signs 
Clinical chemistry/haematology/urinalysis 
parameters 
Electro cardiograms
Physical examinations

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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Exploratory Objectives:
Outcome Variables:
To evaluate the effect of tralokinumab on 
other biomarkers of airway inflammation 
in adult subjects with asthma inadequately 
controlled with ICS
The change, from baseline up to week 12 in 
number of eosinophils per mm2 of epithelium 
and airway smooth muscle bundle determined by 
light microscopy of bronchoscopic biopsies from 
baseline up to week 12
The change, from baseline up to week 12 in 
number of inflammatory cells per mm2 of 
epithelium, submucosa and airway smooth 
muscle bundle determined by light microscopy 
of bronchoscopic biopsies from baseline up to 
week 12  
!
CD3+, CD4+ and CD8+ 
lymphocytes,
!
Neutrophils,
!
Macrophages, 
!
Mast cells
Change from baseline up to week 12 in induced 
sputum biomarkers:
!
Number of inflammatory cells 
(neutrophils, lymphocytes and 
macrophages) and epithelial cells 
per mL,

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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!
Number of inflammatory cells 
(neutrophils, lymphocytes and 
macrophages) expressed as a 
percentage of total inflammatory 
cells,
!
Biomarkers which may include 
(but are not limited to) histamine, 
leukotrienes, Interleukin (IL) IL-
13, IL-5, IL-12, IL-31
Change from baseline up to week 12 in serum
biomarkers:
!
Which may include (but are not 
limited to) periostin, DPP4, 
eotaxin, MCP1, TARC, IL-5, IL-
33, STAT6, IL-13Rα2, 
MCP4/CCL13, TARC/CCL17, 
CLCA1, SERPINB2, biomarkers 
of tissue destruction, vascular 
adhesion molecules
Change from baseline up to week 12 in 
biomarkers obtained from nasosorption samples
(Optional)
Change from baseline up to week 12 in blood 
total IgE
Change from baseline up to week 12 in exhaled 
nitric oxide

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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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To evaluate the effect of tralokinumab on 
large airways remodelling in adult subjects 
with asthma inadequately controlled with 
ICS
Change from baseline up to week 12 in bronchial 
biopsy specimens 
!
Airway epithelial cell integrity 
(measured by light microscopy), 
!
Lamina reticularis and reticular 
basement membrane (RBM) 
thickening (measured by light 
microscopy),
!
Deposition of periostin in 
basement membrane,
!
Mucus glands and MUC5A,
!
Other biomarkers of tissue 
remodelling and/or destruction 
which may include but are not 
limited to α-SMA and collagen 
type IV, fibronectin, laminin 
tenascin and TGFβ and epithelial 
damage markers which may 
include caspase 3 and CC16/KL6,
!
Airway epithelial gene expression

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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Change from baseline up to week 12 in large 
airway dimensions and estimated airway
resistance determined from computed 
tomography (CT)
!
Morphometry parameters (lumen 
area, wall area and wall area %) 
for airway generations 3, 4 and 5 
(segmental, sub-segmental, sub-
sub-segmental),
!
Airway resistance for airway 
generations 3, 4 and 5 estimated 
based on lumen area,
!
Airway volume and resistance for 
entire airway tree (lobar or lung 
level) based on Functional 
Respiratory Imaging (FRI)
(Optional)

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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To evaluate the effect of tralokinumab on 
small airways obstruction in adult subjects
with asthma inadequately controlled with 
ICS
Change from baseline up to week 12 in 
!
Including (but not limited to) R5-
R20 and AX as evaluated by 
airwave oscillometry (AO),
!
Including (but not limited to) Sacin
by using multiple breath washout 
(MBW),
!
Air trapping expressed as 
percentage of the lung with 
expiratory density less than -856 
HU, and as expiratory-to-
inspiratory ratio of mean lung 
density on CT,
!
Regional matching of the 
inspiratory/expiratory CT scans to 
assess air trapping/small airway 
obstruction,
!
Extent of gas trapping determined
from physiologic testing by total 
lung capacity (TLC)/residual 
volume (RV), vital capacity 
(VC)/inspiratory capacity (IC), 
functional residual capacity (FRC)
To evaluate the effect of tralokinumab on 
asthma symptoms and other asthma control 
metrics in adult subjects with asthma 
inadequately controlled with ICS
Change from baseline up to week 12 in 
!
Daily asthma symptom scores 
(combined daytime and night-time 
score),
!
Rescue medication use,
!
Home peak expiratory flow (PEF) 
(morning and evening),
!
Number of night-time awakening 
due to asthma,
!
Asthma Control Questionnaire 6 
(ACQ6)

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
9(107)
To evaluate the effect of tralokinumab on 
lung function and bronchial hyper-
responsiveness in adult subjects with 
asthma inadequately controlled with ICS
Change from baseline up to week 12 in pre BD 
and post BD spirometry
!
Forced expiratory volume in 1 
second (FEV1),
!
FVC, 
!
Forced expiratory flow between 
25% and 75% of the forced vital 
capacity (FEF25-75%),
Change from baseline up to week 12 in
!
Airway Hyper-responsiveness 
(AHR) 
To evaluate the effect of tralokinumab on 
symptom metrics of rhinosinusitis in adult 
subjects with asthma inadequately 
controlled with ICS
Change from baseline up to week 12 in Sino-
Nasal Outcome Test -20 (SNOT-20) total score
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
Pharmacokinetic parameters: Trough 
Concentration (Ctrough)
Immunogenicity outcome variables: incidence 
rate of positive anti-drug antibodies and 
characterization of their neutralizing potential
To evaluate the effect of tralokinumab on  
Ribonucleic Acid (RNA) in samples 
obtained from adults subjects with asthma 
inadequately controlled with ICS. 
Target subject population
This study will enrol males and females, 18 to 75 years of age inclusive, with uncontrolled 
asthma requiring continuous treatment with ICS (≥ 250 mcg fluticasone dry powder 
formulation equivalents total daily dose) with or without other asthma controllers and willing 
to provide informed consent.
Duration of treatment
After initial enrolment and confirmation of entry criteria (Visit 1) subjects will proceed to a 
run-in period of 4 weeks during which their suitability for randomization will be confirmed.  
The subjects’ currently prescribed ICS and additional asthma controller medication will 
remain unchanged during the run-in and treatment period. 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
10(107)
Subjects who meet the eligibility criteria at visit 3c will be randomized to a 12-week treatment 
period and receive either tralokinumab or placebo as an investigational product (IP) in 
addition to their existing asthma controller medications. IP will be administered at weeks 0, 2, 
4, 6, 8 and 10. End of treatment (EOT) visit will be at week 12. Follow-up period for all 
subjects will be for 14 weeks with a telephonic follow-up visit at week 16. There will be an
on-site follow-up visit, only for women of child bearing potential at week 26 to also ascertain 
their pregnancy status. For all other subjects this will be a telephonic FU 2 visit.
Investigational product, dosage and mode of administration
Tralokinumab 300 mg (150 mg/mL), or placebo, will be administered to subjects via 
subcutaneous injection using 2 accessorized 1 mL. pre-filled syringes at the study site.
Statistical methods
The primary analysis of the efficacy endpoints will include all data captured during the double 
blind, treatment period (intent-to-treat approach). However, only subjects with complete data 
will be included in the primary analysis.
The primary efficacy objective will be evaluated through statistical testing of the within 
subject change from baseline to Week 12 in airway submucosal eosinophils. The null 
hypothesis test H0 will be: The ratio tralokinumab/placebo equals 1 and will be tested vs. H1: 
The ratio is not equal to 1. The test will be based on an analysis of covariance model. 
Covariates and factors included in the model will include at least treatment and baseline 
number of airway submucosal eosinophils.
The secondary variable of within subject change from baseline up to Week 12 in the activation 
of eosinophils in bronchial submucosa will be analysed using a similar model as for the 
primary variable. The secondary variables of within subject change from baseline up to Week 
12 in blood eosinophils and activation of eosinophils in blood and induced sputum will be 
analysed using a mixed model for repeated measures including at least treatment as a 
covariate.
The analyses will be performed by using log-transformed data and estimated geometric means 
and the ratio of geometric means with 95% confidence intervals will be presented.
The sample size is based on the primary endpoint; change from baseline to Week 12 in airway 
submucosal eosinophils. Given the assumed standard deviation of the log values in the two 
treatment groups are 1.62 and 1.82, it is estimated that 31 subjects in each treatment arm will 
be sufficient to achieve at least 80% power to detect a 3.5-fold difference versus placebo using 
a two-sided test at 5% significance level. With these assumptions the smallest difference that 
will yield a significant result is a 2.4-fold difference. The assumptions are based on the change 
in number of eosinophils per mm2 subepithelial tissue in bronchial biopsies in studies 
D5890C00003 (Budesonide/ formoterol) (Pavord ID et al 2009) and MI-CP166 (Laviolette M 
et al 2013).

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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It is assumed that a non-neglectable proportion of the subjects will not have an evaluable 
primary endpoint value due to failed biopsies. To account for this, 40 subjects will be 
randomized in each treatment arm.
The results for the exploratory variables will be summarized using descriptive statistics and 
graphical displays by treatment group. All safety parameters will be analysed descriptively. 
The safety analyses will be based on the safety analysis data set, defined as all subjects who 
received at least one dose of investigational product.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
12(107)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.......................................................................................12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................18
1.
INTRODUCTION .................................................................................................24
1.1
Background and rationale for conducting this study .............................................24
1.2
Rationale for study design, doses and control groups............................................25
1.3
Benefit/risk and ethical assessment........................................................................26
1.4
Study Design..........................................................................................................27
2.
STUDY OBJECTIVES..........................................................................................30
2.1
Primary objective...................................................................................................30
2.2
Secondary objectives .............................................................................................30
2.3
Safety objectives ....................................................................................................31
2.4
Exploratory objectives ...........................................................................................32
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................38
3.1
Inclusion criteria ....................................................................................................38
3.2
Exclusion criteria ...................................................................................................40
3.3
Subject enrolment and randomization ...................................................................42
3.4
Procedures for handling incorrectly enrolled or randomized subjects...................43
3.5
Methods for assigning treatment groups................................................................43
3.6
Methods for ensuring blinding...............................................................................43
3.7
Methods for unblinding..........................................................................................44
3.8
Restrictions ............................................................................................................45
3.9
Criteria for withdrawal from study ........................................................................45
3.9.1
Screen failures........................................................................................................45
3.9.2
Post-randomization ................................................................................................45
3.10
Discontinuation of the study..................................................................................47
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................48

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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4.1
Enrolment and run-in period..................................................................................53
4.1.1
Enrolment...............................................................................................................53
4.1.2
Run-in period .........................................................................................................53
4.1.3
Re-screening ..........................................................................................................54
4.2
Treatment period....................................................................................................54
4.3
Follow-up period....................................................................................................55
5.
STUDY ASSESSMENTS .....................................................................................56
5.1
Efficacy assessments..............................................................................................56
5.1.1
Bronchoscopy biopsy and bronchial brushing.......................................................56
5.1.1.1
Bronchial biopsy ....................................................................................................56
5.1.1.2
Bronchial brushing.................................................................................................56
5.1.2
Sputum induction...................................................................................................56
5.1.3
Nasosorption and nasal epithelial cells samples ....................................................57
5.1.4
Computed tomography...........................................................................................57
5.1.5
Multiple breath washout ........................................................................................57
5.1.6
Airwave oscillometry.............................................................................................58
5.1.7
Post-BD Whole body plethysmography ................................................................58
5.1.8
Spirometry..............................................................................................................58
5.1.8.1
General requirements.............................................................................................58
5.1.8.2
Spirometry technique.............................................................................................59
5.1.8.3
Assessments and analysis ......................................................................................59
5.1.8.4
Post-BD spirometry and FEV1 reversibility assessment........................................59
5.1.9
Airway hyper-responsiveness ................................................................................60
5.1.10
Home PEF testing ..................................................................................................60
5.1.11
Fractional exhaled nitric oxide...............................................................................60
5.1.12
Assessment of asthma exacerbation.......................................................................61
5.1.13
Serum biomarkers ..................................................................................................62
5.1.14
Whole blood eosinophils........................................................................................63
5.1.15
Total IgE ................................................................................................................63
5.1.16
Phadiatop (Allergy screen).....................................................................................63
5.1.17
RNA Transcriptomics ............................................................................................63
5.2
Safety assessments.................................................................................................63
5.2.1
Laboratory safety assessments...............................................................................63
5.2.2
Pregnancy test ........................................................................................................65
5.2.3
Physical examination .............................................................................................65
5.2.3.1
Complete physical examination.............................................................................65
5.2.3.2
Brief physical examination ....................................................................................66
5.2.4
ECG........................................................................................................................66
5.2.4.1
Resting 12-lead ECG .............................................................................................66
5.2.5
Vital signs ..............................................................................................................66
5.2.5.1
Pulse, blood pressure and respiration rate..............................................................66
5.2.5.2
Body temperature...................................................................................................67
5.2.6
Other safety assessments........................................................................................67

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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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5.2.6.1
Serology .................................................................................................................67
5.2.6.2
Infections................................................................................................................67
5.3
Other assessments ..................................................................................................67
5.3.1
Weight and height..................................................................................................67
5.3.2
Patient reported outcomes......................................................................................67
5.3.2.1
Asthma Daily Diary ...............................................................................................68
5.3.2.2
Asthma Control Questionnaire (ACQ-6)...............................................................69
5.3.2.3
Sino-Nasal Outcome Test - 20...............................................................................69
5.4
Pharmacokinetics ...................................................................................................69
5.4.1
Collection of samples.............................................................................................69
5.4.2
Determination of drug concentration.....................................................................70
5.4.3
Storage and destruction of pharmacokinetic samples............................................70
5.5
Immunogenicity.....................................................................................................70
5.6
Pharmacogenetics ..................................................................................................71
5.7
Biomarker analysis in future..................................................................................71
5.7.1
Storage, re-use and destruction of biological samples...........................................71
5.7.2
Labelling and shipment of biological samples.......................................................71
5.7.3
Chain of custody of biological samples.................................................................71
5.7.4
Withdrawal of consent for donated biological samples.........................................72
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................73
6.1
Definition of adverse events ..................................................................................73
6.2
Definitions of serious adverse event......................................................................73
6.3
Recording of adverse events ..................................................................................73
6.3.1
Time period for collection of adverse events.........................................................73
6.3.2
Follow-up of unresolved adverse events................................................................74
6.3.3
Variables ................................................................................................................74
6.3.4
Causality collection................................................................................................75
6.3.5
Adverse events based on signs and symptoms.......................................................75
6.3.6
Adverse events based on examinations and tests...................................................75
6.3.7
Hy’s Law................................................................................................................76
6.3.8
Disease progression ...............................................................................................76
6.4
Reporting of serious adverse events.......................................................................76
6.5
Overdose ................................................................................................................77
6.6
Pregnancy...............................................................................................................77
6.6.1
Maternal exposure..................................................................................................77
6.6.2
Paternal exposure...................................................................................................78
6.7
Management of IP related toxicities ......................................................................78
6.8
Study governance and oversight ............................................................................78
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................79

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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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7.1
Identity of investigational product(s).....................................................................79
7.2
Dose and treatment regimens.................................................................................80
7.3
Labelling ................................................................................................................81
7.4
Storage ...................................................................................................................81
7.5
Compliance ............................................................................................................81
7.6
Accountability........................................................................................................82
7.7
Concomitant and other treatments .........................................................................82
7.7.1
Restriction during and after the study....................................................................83
7.7.1.1
Asthma medication restrictions..............................................................................83
7.7.1.2
Restrictions before study visits..............................................................................84
7.7.1.3
Medication restrictions with study procedures ......................................................84
7.7.1.4
Other medication restrictions.................................................................................84
7.7.2
Other concomitant treatment..................................................................................85
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................86
8.1
Statistical considerations........................................................................................86
8.2
Sample size estimate..............................................................................................86
8.3
Definitions of analysis sets ....................................................................................86
8.3.1
Efficacy analysis set...............................................................................................86
8.3.2
Safety analysis set..................................................................................................87
8.3.3
PK analysis set .......................................................................................................87
8.3.4
PRO analysis set ....................................................................................................87
8.4
Outcome measures for analyses.............................................................................87
8.4.1
Definition of baseline and subject baseline analyses.............................................87
8.4.2
Primary outcome measure......................................................................................88
8.4.3
Secondary outcome measures................................................................................88
8.4.4
Exploratory outcome measures..............................................................................88
8.4.4.1
Other biomarkers of airway inflammation.............................................................88
8.4.4.2
Effect on large airways remodelling......................................................................89
8.4.4.3
Effect on small airways obstruction.......................................................................89
8.4.4.4
Effect on asthma symptoms and other asthma control metrics..............................89
8.4.4.5
Effect on rhinosinusitis symptom metrics..............................................................91
8.4.4.6
Effect on lung function and bronchial hyper-responsiveness................................91
8.4.4.7
Calculation or derivation of pharmacokinetics and immunogenicity 
variables .................................................................................................................91
8.4.5
Calculation or derivation of safety variable(s).......................................................92
8.4.5.1
Adverse events.......................................................................................................92
8.4.5.2
Other significant adverse events ............................................................................93
8.4.5.3
Laboratory variables ..............................................................................................93
8.4.5.4
ECGs......................................................................................................................94
8.4.5.5
Physical Examination.............................................................................................94
8.4.5.6
Vital signs ..............................................................................................................94

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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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8.5
Methods for statistical analyses .............................................................................95
8.5.1
Analysis of the primary variable (s).......................................................................95
8.5.2
Analysis of the secondary variable(s)....................................................................96
8.5.3
Subgroup analysis ..................................................................................................96
8.5.4
Interim analysis......................................................................................................96
8.5.5
Sensitivity analysis.................................................................................................96
8.5.6
Exploratory analysis...............................................................................................96
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................97
9.1
Training of study site personnel.............................................................................97
9.2
Monitoring of the study .........................................................................................97
9.2.1
Source data.............................................................................................................97
9.2.2
Study agreements...................................................................................................98
9.2.3
Archiving of study documents...............................................................................98
9.3
Study timetable and end of study...........................................................................98
9.4
Data management by AstraZeneca ........................................................................98
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................100
10.1
Ethical conduct of the study.................................................................................100
10.2
Subject data protection.........................................................................................100
10.3
Ethics and regulatory review................................................................................100
10.4
Informed consent .................................................................................................101
10.5
Changes to the protocol and informed consent form...........................................101
10.6
Audits and inspections .........................................................................................102
11.
LIST OF REFERENCES.....................................................................................103
LIST OF TABLES
Table 1
Study plan - Treatment and follow-up period ..........................................49
Table 2
Laboratory safety variables ......................................................................64
Table 3
Volume of blood to be drawn from each subject......................................64
Table 4
Identity of investigational product............................................................79
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................29

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
17(107)
Figure 2
Injection sites and rotation scheme...........................................................80
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional safety information
Appendix C
IATA 6.2 guidance document
Appendix D
Actions required in cases of combined increase of aminotransferase and 
total bilirubin – Hy’s Law
Appendix E
Maintenance therapy equivalence table
Appendix F
Anaphylaxis: definition, signs and symptoms, management
Appendix G
Restricted and prohibited medications
Appendix H
Post-BD spirometry and FEV1 reversibility assessment algorithm

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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
AAER
Annualized Asthma Exacerbation Rate
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-drug antibody
AE
Adverse Event
AHR
Airway Hyper-Responsiveness
ALARA
As Low As Reasonably Achievable
ALP
Alkaline Phosphatase
α-SMA
Alpha smooth muscle actin
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AO
Airwave Oscillometry
APFS
Accessorized Pre-filled Syringe
AST
Aspartate Aminotransferase
ATS/ERS
American Thoracic Society/European Respiratory Society
BAL
Broncho Alveolar Lavage
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BMI
Body Mass Index
BSP-1
Basophil specific protein -1
BUN
Blood Urea Nitrogen
CC16/KL6
Clara-cell 16
CCL
Chemokine (C-C motif) ligand
CD
Cluster of Differentiation
CLCA1
Calcium-activated chloride channel regulator 1
CO2
Carbon Dioxide
COPD
Chronic Obstructive Pulmonary Disease

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Abbreviation or 
special term
Explanation
CRP
C-Reactive Protein
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
CTDIvol
Volume CT dose index
DAE
Discontinuation of Investigational Product due to Adverse Event
DMP
Data Management Plan
DNA
Deoxyribonucleic acid 
DPP4
Dipeptidyl Peptidase-4
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
ECP
Eosinophil Cationic Protein
eCRF
Electronic Case Report Form
ED
Emergency Department
EG
Eosinophil granule
ePEF
Electronic Peak Expiratory Flow
ER
Emergency Room
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome device
EU
European Union
EXACA
Module name of case report form to capture asthma exacerbations
FENO
Fractional Exhaled Nitric Oxide
FEF25-75%
Forced Expiratory Flow between 25% and 75% of the Forced Vital 
Capacity
FEV1
Forced Expiratory Volume in 1 second
FRC
Functional Residual Capacity
FRI
Functional Respiratory Imaging
FSH
Follicle-Stimulating Hormone
FU
Follow-up

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Abbreviation or 
special term
Explanation
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GLI
The Global Lung Function Initiative
GMP
Good Manufacturing Practice
GRand
Randomization Code Generator - Computerized System
HCP
Healthcare professional
HIV
Human Immunodeficiency Virus
HU
Hounsfield Unit
Hz
Hertz
IATA
International Air Transport Association
IB
Investigator’s Brochure
IC
Inspiratory Capacity
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
Inhaled Corticosteroids
IgE
Immunoglobulin E
IL
Interleukin
IL-13Rα1
Interleukin 13 receptor subunit alpha-1
Il-13Rα2
Interleukin 13 receptor subunit alpha-2
IP
Investigational Product 
IPD
Investigational product discontinuation
IRB
Institutional Review Board
ICRP
International Commission on Radiological Protection
ISF
Investigator Study File
ITT
Intent-to-Treat
IUD/IUS
Intra Uterine Device / Intra Uterine System
IVRS
Interactive Voice Response System

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Abbreviation or 
special term
Explanation
IWRS
Interactive Web Response System
Kg
Kilogram
LABA
Long-Acting β2-Agonist
LCI
Lung Clearance Index
LTRA
Leukotriene Receptor Antagonists
MAb
Monoclonal Antibody
MBP
Major Basic Protein
MBW
Multiple Breath Washout
Mcg
Microgram
MCP-4/CCL13
Monocyte chemoattractant protein – 4 / Chemokine (C-C motif) ligand 13
μM
Micromolar
MCP
Monocyte Chemoattractant Protein
MCT
Methacholine Challenge Test
MedDRA
Medical Dictionary for Regulatory Activities
MG
Milligram
mGy
Milli Gray
ML
Millilitre
MMRM
Mixed-Model for Repeated Measures
MSv
Millisievert
MUC5A
Mucin 5A
nAB
Neutralizing Antibodies
NHLB
National Heart Lung and Blood Institute
OAE
Other significant adverse events
OCS
Oral Corticosteroids
PEF
Peak Expiratory Flow
PGx
Pharmacogenetic research
PI
Principal Investigator 
PK
Pharmacokinetics
PNT
Pneumotachometer

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Abbreviation or 
special term
Explanation
PNV
Predicted Normal Value
PRO
Patient Reported Outcome
PT
Preferred Term
Q2W
Every 2 Weeks
Q4W
Every 4 Weeks
RBM
Reticular Basement Membrane
RNA
Ribonucleic acid
RV
Residual Volume
SABA
Short-Acting β2-Agonist
Sacin
Index of acinar ventilation heterogeneity
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SDV
Source Data Verification
SERPINB2
Serpin peptidase inhibitor, clade B (ovalbumin), member 2
SI
Sputum Induction
SOC
System Organ Class
STAT6
Signal transducer and activator of transcription 6
TARC
Thymus and Activation Regulated Chemokine
TGFβ
Transforming growth factor beta
Th2
T Helper 2 Cells
TLC
Total Lung Capacity
TO
Lung Turnover
TRP
Translational Research Partnership
ULN
Upper Limit of Normal
UNS
Unscheduled
VCAM
Vascular Cell Adhesion Molecule
WBC
White blood cell

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Edition Number 2.0
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Abbreviation or 
special term
Explanation
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction 
and airway hyper-responsiveness, with a global prevalence of approximately 300 million 
patients (GINA 2014). 
The observed variability in clinical response to currently available asthma therapies may be 
related, in part, to distinctive inflammatory phenotypes (Wenzel SE 2012). IL-13 is a central 
mediator implicated in the key pathophysiologic features of asthma and its expression is up-
regulated in a sub-group of patients with severe asthma, despite the use of inhaled 
corticosteroid (ICS) therapy. IL-13 promotes airway hyper-responsiveness (AHR), smooth-
muscle proliferation and mucus production in animal models (Grunig G et al 1998, Lentsch 
AB et al 1999, Wills-Karp M et al 1998, Blanchard C et al 2005, May RD et al 2012). In cell 
culture, IL-13 up-regulates the production of eotaxin from airway epithelial cells (Li L et al 
1999) and decreases trans-epithelial resistance, an indicator of epithelial barrier function
(Saatian B et al 2013).  IL-13 is thought to play a role in activating eosinophils and may affect 
eosinophil movement from blood to tissue by inducing release of vascular adhesion molecules 
(Bochner BS et al 1995, Wardlaw AJ 1999, Woltmann G et al 2000). More recently, studies 
suggested a potential role for IL-13 produced from innate natural T cells in asthma 
exacerbations (Cormier SA, Kolls JK 2011, Holtzman MJ 2012, Chang YJ et al 2013). 
Tralokinumab specifically binds to IL-13 and blocks its interaction with both interleukin 13 
receptor subunit alpha-1 (IL-13Rα1) and subunit alpha-2 (IL-13Rα2), preventing IL-13 signal 
transduction. IL-13Rα2 may function solely as a decoy receptor, but a recently reported study 
from cell culture model systems suggest that it may have a role in IL-13 mediated signal 
transduction (Fichtner-Fiegl S et al 2006). Tralokinumab has been shown to have a wide array 
of effects which might prove beneficial in asthma management. In vitro, tralokinumab 
prevented activation, signalling activity and production of mediators in and from a number of 
cells implicated in the development of asthma, including airway smooth muscle and epithelial 
cells, fibroblasts, monocytes and B cells (May RD et al 2012). Tralokinumab reduced IL-13 
mediated eotaxin production, CD23 up-regulation and IgE production (May RD et al 2012). In 
a murine model, tralokinumab attenuated IL-13-induced leukocytic inflammation, airway 
hyper-responsiveness (AHR) and bronchoalveolar lavage (BAL) eosinophilia (Yang G et al 
2005, May RD et al 2012). In a cynomolgus monkey model tralokinumab prevented AHR and 
BAL eosinophilia after antigen challenge (May RD et al 2012). Periostin and dipeptidyl 
peptidase-4 (DPP4) may be biomarkers of an activated IL-13 pathway and may predict 
response to tralokinumab (Jia G et al 2012, Parulekar AD et al 2014, Brightling CE et al 
2014a).
Studies in patients with severe, uncontrolled asthma suggest that tralokinumab might provide 
a beneficial response.  In a phase 2a study (MI-CP199), tralokinumab at a dose of 300 mg 
administered subcutaneously (SC) every 2 weeks (the dose proposed for the phase 3 program) 
improved forced expiratory volume in one second (FEV1) when added to standard asthma 
controller medications. A subsequent phase 2b study (CD-RI-CAT-354-1049), in a patient 

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Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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population whose asthma was poorly controlled by high dose ICS/ long-acting β2 – agonist 
(LABA) confirmed that 300 mg of tralokinumab administered every two weeks significantly 
improved FEV1 over 52 weeks of treatment. Although the primary endpoint for this study, a 
reduction in the annualised asthma exacerbation rate (AAER) over 52 weeks was not met, 
there were trends for AAER reductions in several subgroups. A subpopulation reversible to 
bronchodilators on study entry had an observed AAER reduction.  A further reduction of 
AAER was observed in a subgroup of reversible subjects with evidence of increased IL-13 
activity i.e. elevated serum periostin or DPP4. Post-hoc analysis of a small (n=26) sub-study 
of CD-RI-CAT-354-1049 utilising quantitative computed tomography (CT),  showed 
significant improvements in sub-segmental airway lumen parameters with tralokinumab 
compared with placebo, added to ICS/LABA. In tralokinumab-treated subjects, higher 
baseline wall area % seems to be associated with better lung function improvement 
(Brightling CE et al 2014b).
An important unanswered question is whether tralokinumab improves asthma outcomes by 
reducing airway inflammation. An interesting observation in previous clinical trials has been 
that patients treated with tralokinumab had an increase in blood eosinophil levels.  Based on in 
vitro work which showed that tralokinumab decreased epithelial cell production of eotaxin 
and vascular cell adhesion molecule-1 (VCAM-1) (May RD et al 2012), this observation in 
humans suggested that tralokinumab might reduce airway inflammation in asthma by reducing 
eosinophil trafficking from the blood into the lung.  This study will test this hypothesis and 
will ask whether tralokinumab administered to subjects with uncontrolled asthma despite use 
of ICS, increases blood eosinophils but decreases airway submucosal eosinophil infiltration 
and reduces activated blood and airway submucosal eosinophils.
In addition, this study will address several exploratory questions.  First, assuming that airway 
inflammation is reduced by tralokinumab, radiographic and physiologic tests will be 
performed to determine if reduced airway inflammation results in measurable changes in both 
large airway and small airway function and size.  Second, this study will also address whether 
gene expression changes occur in the airways and the nose using tralokinumab and whether 
these changes might correspond to changes in airway inflammation. Third, the relationship 
between improvement in airway inflammation and both asthma symptoms and airway hyper-
responsiveness will be assessed.
1.2
Rationale for study design, doses and control groups
This multicentre, randomized, double-blind, parallel group, placebo-controlled, 12-week, 
phase 2 study will evaluate the effect of a 300 mg dose of tralokinumab administered 
subcutaneously (SC) every 2 weeks on airway inflammation in adults with asthma 
inadequately controlled on ICS (≥ 250 mcg fluticasone dry powder formulation equivalents 
total daily dose) with or without other asthma controller medications.
The rationale for this study is the need to understand the mechanism of effect of tralokinumab 
in improving asthma outcomes.  Pre-clinical work suggests that tralokinumab might reduce 

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airway inflammation, but information supporting this hypothesis in humans is currently 
lacking.  One of the hallmarks of airway inflammation in asthma is an influx of eosinophils 
into the bronchial submucosal layer (Djukanovic R 2001, Saetta M and Durato G 2001). Pre-
clinical studies suggest that tralokinumab might reduce eosinophil influx into the bronchial 
submucosal layer in asthma by affecting eosinophil trafficking and activation.  Thus, the 
primary outcome measure for this study will be the change, expressed as a ratio, in number of 
airway submucosal eosinophils per mm2 determined by microscopic evaluation of 
bronchoscopic biopsies from baseline up to week 12. Secondary outcomes will include blood
eosinophil numbers and evidence of activation of eosinophils in blood, sputum and airway 
submucosa.  In addition to these analyses, exploratory efforts will be made to understand 
whether the tralokinumab anti-inflammatory effect results in improvement in large airways 
remodelling and small airways obstruction.
In order to avoid bias, the study will be randomized and double-blinded. A placebo group will 
be included to ensure a control for comparison of effects.  The dose and dosing frequency for 
tralokinumab, 300 mg administered SC every two weeks, was determined by an analysis of 
data from both the phase 2a study (MI-CP199) and the phase 2b study (CD-RI-CAT-354-
1049). These studies demonstrated that tralokinumab 300 mg Q2W significantly increased 
FEV1. 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. The treatment phase will last 12 weeks 
because previous studies with biologics such as benralizumab (Laviolette M et al 2013) have 
confirmed a reduction in airway submucosal eosinophils with a similar treatment duration.  
Included patients will have uncontrolled asthma to increase the likelihood that there will be 
increased airway submucosal eosinophils at study start.
1.3
Benefit/risk and ethical assessment
There are few treatment options for subjects whose asthma remains uncontrolled on 
ICS/LABA (GINA 2014). 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 (for further details see the Investigator’s brochure). 
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. 

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Tralokinumab might reduce airway inflammation in asthma by reducing eosinophil trafficking 
from the blood into the lung. The purpose of this study is to test the hypothesis that 
tralokinumab reduces airway submucosal eosinophil infiltration in subjects with uncontrolled 
asthma despite use of ICS, and increases blood eosinophils but is associated with a decrease in 
activated eosinophils.
Because it is believed that the Th2 response may be of importance in the defence against 
helminthic parasitic infections, a theoretical risk for such infestations exists in patients treated 
with tralokinumab. IL-13 may also play a role in regulating tumours (Hallett MA 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 the exclusion of subjects with untreated parasitic 
infection and active or recent malignancy. 
Biopsies will be performed by qualified pulmonologists experienced in research 
bronchoscopies, and all due precautions will be taken to minimize the risk to subjects. 
Subjects will receive a sedative and local anaesthetic to reduce any discomfort. Subjects will 
be informed of the risks associated with bronchoscopy and bronchial biopsy procedure before 
participating in the study.
CT is incorporated into this study design with reference to the EU guidance (Directorate-
General – Environment, nuclear safety and civil protection 1998). The potential benefits of the 
study are expected to be Category IIB as described in the guidance document aimed directly at 
the diagnosis, cure, or prevention of disease. The use of CT involves ionizing radiation that 
increases the risk of radiogenic tumours in subjects.  Subjects will be informed of the risks 
associated with CT before entering the study. Because CT scans in this study may not offer 
direct individual benefit to the subject, a dose constraint has been applied based on the as low 
as reasonably achievable (ALARA) principle. The CT scan parameters in the study will be 
optimized to give a standardized x-ray exposure across the different scanners used in the trial. 
A target CTDIvol (volume CT dose index) of approximately 6 milli Gray (mGy) for the 
inspiratory scan and 3 mGy for the expiratory scan is required to achieve the noise index 
needed for the subsequent image analysis. With two visits and a scanned length of 30 cm this 
corresponds to an estimated radiation dose of 7.6 mSv based on ICRP60 (International 
Commission on Radiological Protection Publication 60) weighting factors (AAPM, 2008, 
ICRP, 1991). Allowing for some additional variation between scanners, patient geometries 
and calculation models, the total effective radiation dose for the study is estimated to be equal 
or less than approximately 10 milli Sievert (mSv). This dose is within the accepted radiation 
dose range for biological research (1-10 mSv; Directorate-General – Environment, nuclear 
safety and civil protection 1998).
1.4
Study Design
This multicentre, randomized, double-blind, parallel group, placebo-controlled, 12-week, 
phase 2 study will evaluate the effect of a 300 mg dose of tralokinumab administered SC

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every 2 weeks on airway inflammation in adults with asthma inadequately controlled on ICS
with or without other controllers.
The subjects will be randomized to 12-week treatment with tralokinumab or placebo (1:1). 
After the end of treatment all subjects will be followed up for a period of 14 weeks.
Target subject population
This study will enrol males and females, 18 to 75 years of age inclusive, with uncontrolled 
asthma requiring continuous treatment with ICS (≥ 250 mcg fluticasone dry powder 
formulation equivalents total daily dose) with or without other asthma controllers and willing 
to provide informed consent.
Duration of treatment
After initial enrolment and confirmation of entry criteria (Visit 1) subjects will proceed to a 
run-in period of 4 weeks during which their suitability for randomization will be confirmed.  
The subjects’ currently prescribed ICS and additional asthma controller medication will 
remain unchanged during the run-in and treatment period. 
Subjects who meet all the eligibility criteria at Visit 3c will be randomized to a 12-week 
treatment period and receive either tralokinumab or placebo as an investigational product (IP)
in addition to their existing asthma controller medications. IP will be administered at weeks 0, 
2, 4, 6, 8 and 10 (Visit 3c to Visit 8). End of treatment (EOT) visit will be at week 12 (Visit 
9). 
Post-treatment follow-up period for all subjects will be for 14 weeks after the EOT visit with a 
telephonic follow-up (FU) 1 visit (Visit 10, Week 16). There will be an on-site FU 2 visit 
(Visit 11, Week 26) only for WOCBP to also ascertain their pregnancy status. For all other 
subjects this will be a telephonic FU 2 visit
Investigational product, dosage and mode of administration
Tralokinumab 300 mg (150 mg/mL), or placebo, will be administered to subjects SC using 2 
accessorized 1 mL pre-filled syringes at the study site.
Subjects will be maintained on their currently prescribed ICS therapy and any additional 
asthma controller medications, without changes, from enrolment until the end of treatment 
period.

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Edition Number 2.0
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Figure 1
Study flow chart
Enrolment/
Run-in
  1:1
Tralokinumab 300 mg, SC every 2 weeks (n=40)
Placebo, SC every 2 weeks (n=40)
Visit 3c 1
Randomization
Week 0
Visit 9
End of 
Treatment
Week 12
Visit 4 to 8
12-week double-blind randomized
Treatment period
Week 0 up to Week 10
Visit 10, 112
Follow-up
Week 16, 26 2
Visit 1, 2, 3a, 
3b
Enrolment/
Run-in
Week -4, -2, -1
1. Due to multiplicity of assessments, Visit 3 is spread over 3 visits, Visit 3a, 3b and 3c. Visit 3c being the randomization visit when IP is administered for the 
first time.
2. WOCBP will have an on-site follow-up visit at Week 26 to also ascertain their pregnancy status.

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To evaluate the effect of tralokinumab on 
eosinophilic airway infiltration in adult 
subjects with asthma inadequately 
controlled with ICS
Primary Outcome Variable:
The change, expressed as a ratio, in number of 
airway submucosal eosinophils per mm2
determined by microscopic evaluation of 
bronchoscopic biopsies from baseline up to week 
12
Primary Outcome Measure:
Ratio of tralokinumab to placebo at week 12 to 
baseline
2.2
Secondary objectives
Secondary Objective:
Outcome Measure :
To evaluate the effect of tralokinumab on 
blood eosinophil levels in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variable:
The change, expressed as a ratio, in number of 
blood eosinophils from baseline up to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12 to 
baseline
To evaluate the effect of tralokinumab on 
sputum eosinophil levels in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variable:
The change, expressed as a ratio, in number of 
differential sputum eosinophils from baseline up 
to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12

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To evaluate the effect of tralokinumab on 
activation of eosinophils in adult subjects 
with asthma inadequately controlled with 
ICS
Outcome Variables:
The change, expressed as a ratio, in blood and 
sputum free eosinophil cationic protein (ECP) 
concentrations from baseline up to week 12
Outcome Measure:
Ratio of tralokinumab to placebo at week 12 to 
baseline
2.3
Safety objectives
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
tralokinumab in adult subjects with asthma 
inadequately controlled with ICS
Adverse events (AEs)/Serious adverse events 
(SAEs)
Vital signs
Electrocardiogram (ECG)
Clinical chemistry/haematology/urinalysis
parameters
Physical examination

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2.4
Exploratory objectives  
Exploratory Objectives:
Outcome Variables:
To evaluate the effect of tralokinumab on 
other biomarkers of airway inflammation 
in adult subjects with asthma inadequately 
controlled with ICS
The change, from baseline up to week 12 in 
number of eosinophils per mm2 of epithelium 
and airway smooth muscle bundle determined by 
light microscopy of bronchoscopic biopsies from 
baseline up to week 12
The change, from baseline up to week 12 in 
number of inflammatory cells per mm2 of 
epithelium, submucosa and airway smooth 
muscle bundle determined by light microscopy 
of bronchoscopic biopsies from baseline up to 
week 12  
!
CD3+, CD4+ and CD8+ 
lymphocytes,
!
Neutrophils,
!
Macrophages, 
!
Mast cells

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Change from baseline up to week 12 in induced 
sputum biomarkers:
!
Number of inflammatory cells 
(neutrophils, lymphocytes and 
macrophages) and epithelial cells 
per mL,
!
Number of inflammatory cells 
(neutrophils, lymphocytes and
macrophages) expressed as a 
percentage of total inflammatory 
cells,
!
Biomarkers which may include 
(but are not limited to) histamine, 
leukotrienes, Interleukin (IL) IL-
13, IL-5, IL-12, IL-31
Change from baseline up to week 12 in serum
biomarkers:
!
Which may include (but are not 
limited to) periostin, DPP4, 
eotaxin, MCP1, TARC, IL-5, IL-
33, STAT6, IL-13Rα2, 
MCP4/CCL13, TARC/CCL17, 
CLCA1, SERPINB2, biomarkers 
of tissue destruction, vascular 
adhesion molecules
Change from baseline up to week 12 in 
biomarkers obtained from nasosorption samples
(Optional)
Change from baseline up to week 12 in blood 
total IgE
Change from baseline up to week 12 in exhaled 
nitric oxide

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To evaluate the effect of tralokinumab on 
large airways remodelling in adult subjects 
with asthma inadequately controlled with 
ICS
Change from baseline up to week 12 in bronchial 
biopsy specimens 
!
Airway epithelial cell integrity 
(measured by light microscopy), 
!
Lamina reticularis and reticular 
basement membrane (RBM) 
thickening (measured by light 
microscopy),
!
Deposition of periostin in 
basement membrane,
!
Mucus glands and MUC5A,
!
Other biomarkers of tissue 
remodelling and/or destruction 
which may include but are not 
limited to α-SMA and collagen 
type IV, fibronectin, laminin 
tenascin and TGFβ and epithelial 
damage markers which may 
include caspase 3 and CC16/KL6,
!
Airway epithelial gene expression

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Change from baseline up to week 12 in large 
airway dimensions and estimated airway
resistance determined from computed 
tomography (CT)
!
Morphometry parameters (lumen 
area, wall area and wall area %) 
for airway generations 3, 4 and 5 
(segmental, sub-segmental, sub-
sub-segmental),
!
Airway resistance for airway 
generations 3, 4 and 5 estimated 
based on lumen area,
!
Airway volume and resistance for 
entire airway tree (lobar or lung 
level) based on Functional 
Respiratory Imaging (FRI)
(Optional)

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Edition Number 2.0
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To evaluate the effect of tralokinumab on 
small airways obstruction in adult subjects
with asthma inadequately controlled with 
ICS
Change from baseline up to week 12 in 
!
Including (but not limited to) R5-
R20 and AX as evaluated by 
airwave oscillometry (AO),
!
Including (but not limited to) Sacin
by using multiple breath washout 
(MBW),
!
Air trapping expressed as 
percentage of the lung with 
expiratory density less than -856 
HU, and as expiratory-to-
inspiratory ratio of mean lung 
density on CT,
!
Regional matching of the 
inspiratory/expiratory CT scans to 
assess air trapping/small airway 
obstruction,
!
Extent of gas trapping determined 
from physiologic testing by  total 
lung capacity (TLC)/residual 
volume (RV), vital capacity 
(VC)/inspiratory capacity (IC), 
functional residual capacity (FRC)
To evaluate the effect of tralokinumab on 
asthma symptoms and other asthma control 
metrics in adult subjects with asthma 
inadequately controlled with ICS
Change from baseline up to week 12 in 
!
Daily asthma symptom scores 
(combined daytime and night-time 
score),
!
Rescue medication use,
!
Home peak expiratory flow (PEF) 
(morning and evening),
!
Number of night-time awakening 
due to asthma,
!
Asthma Control Questionnaire 6 
(ACQ6)

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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To evaluate the effect of tralokinumab on 
lung function and bronchial hyper-
responsiveness in adult subjects with 
asthma inadequately controlled with ICS
Change from baseline up to week 12 in pre BD 
and post BD spirometry
!
Forced expiratory volume in 1 
second (FEV1),
!
FVC, 
!
Forced expiratory flow between 
25% and 75% of the forced vital 
capacity (FEF25-75%),
Change from baseline up to week 12 in
!
Airway Hyper-responsiveness 
(AHR) 
To evaluate the effect of tralokinumab on 
symptom metrics of rhinosinusitis in adult 
subjects with asthma inadequately 
controlled with ICS
Change from baseline up to week 12 in Sino-
Nasal Outcome Test -20 (SNOT-20) total score
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
Pharmacokinetic parameters: Trough 
concentration (Ctrough)
Immunogenicity outcome variables: incidence 
rate of positive anti-drug antibodies and 
characterization of their neutralizing potential
To evaluate the effect of tralokinumab on 
Ribonucleic Acid (RNA) in samples 
obtained from adult subjects with asthma 
inadequately controlled with ICS.

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Study Code D2210C00014
Edition Number 2.0
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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 (including 
withholding of any asthma medications required for procedures) for subjects who 
are at, or over the age of majority (as per local law). 
2.
Female or male, ages 18 to 75 years, inclusively at time of enrolment (Visit 1).  
3.
Women of childbearing potential (WOCBP) (after menarche) must use a highly 
effective form of birth control (confirmed by the Investigator). Highly effective 
forms of birth control includes: true sexual abstinence (‘true sexual abstinence’ is 
defined as abstinence that is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-
ovulation methods] and withdrawal are not considered highly effective methods of 
contraception), a vasectomised sexual partner, female sterilization by tubal 
occlusion, Implanon® , any effective intrauterine device/system (IUD/IUS), Depo-
Provera™ injections, oral contraceptive, or Nuvaring™(if approved for use as per 
local regulations). WOCBP must agree to use highly effective method of birth 
control, as defined above, from enrolment (Visit 1), throughout the study duration 
and within 16 weeks after last dose of investigational product (IP), and have a 
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 
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).

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Study Code D2210C00014
Edition Number 2.0
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5.
Documented physician-diagnosed asthma for at least 12 months prior to enrolment 
(Visit 1) with the subject having received an asthma controller regimen requiring 
treatment with ICS (minimum dose of ≥250μg fluticasone propionate via dry 
powder inhaler equivalents total daily dose) alone or in combination ≥ 6 months and 
that has been taken at a stable dose for at least 1 month prior to enrolment (Visit 1).
In order to aid the assessment, ICS equivalents for fluticasone propionate dry 
powder, are presented in Appendix E. 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.
6.
Additional maintenance asthma controller medications are allowed according to 
standard practice of care. These medications must be given at a stable dose for at 
least 1 month prior to Visit 1. Furthermore, after randomization, the subject's 
background maintenance medication for asthma shall remain unchanged throughout 
the study.
7.
At enrolment (Visit 1) the subject must have a predicted normal value (PNV) for the 
pre-bronchodilator (BD) FEV1 >50% and more than 1L. If this criterion is not met at 
Visit 1, the criterion must be met at Visit 2. Prior to the lung function measurement, 
the subject should withhold their BD for the effect duration specific to the BD (see 
7.7.1.2 and Appendix G).
8.
A post-BD reversibility in FEV1 of ≥12% and ≥200 mL at enrolment (Visit 1). If 
this criterion is not met at Visit 1, the criterion must be met at Visit 2.  Prior to the 
lung function measurement, the subject should withhold their BD for the effect 
duration specific to the BD (see 7.7.1.2 and Appendix G).
Prior to randomization at Visit 3c, subjects should fulfil the following inclusion criteria:
9.
For WOCBP only: have a negative urine pregnancy test prior to administration of 
the IP.
10.
No requirement for a change in the subject’s ICS, other asthma controller 
medications and/or the requirement to add asthma controller medications during the 
run-in period.
11.
Ability to perform acceptable inhaler and spirometry techniques and use peak flow 
meter as judged by the investigator.
12.
Minimum 70% compliance with usual asthma controller (ICS and any other) 
medications and eDiary completion between Visit 1 and Visit 2. Compliance is 
defined as completing all elements of eDiary for any 10 mornings and evenings of 
the last 14 days between visits as reported by the subject in the eDiary.
13.
Asthma Control Questionnaire-6 (ACQ-6) ≥ 1.5 at Visit 1 or Visit 2.

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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
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14.
Successful bronchial biopsy procedure as judged by the investigator. 
3.2
Exclusion criteria
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
1.
History of interstitial lung disease, chronic obstructive pulmonary disease (COPD), 
or other clinically significant lung disease other than asthma that in the opinion of 
the investigator may compromise the well-being of the subject or study end point 
assessments at the start of the study.
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 either not stable or 
could in the opinion of the Investigator:
∀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 (see 
Table 4).
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 to 
enrolment (Visit 1) or during the run-in period. 
7.
Tuberculosis requiring treatment within the 12 months prior to enrolment (Visit 1).
8.
Any clinically significant findings in physical examination, vital signs, 
electrocardiogram (ECG), CT scan, haematology, clinical chemistry, or urinalysis 
during the enrolment or 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 
(Visit 1), or a condition associated with poor compliance as judged by the 
Investigator.

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Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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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 (Visit 1), 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 (Visit 1)) 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 with the exception of:
∀
Subjects who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix 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 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, and intramuscular long-acting depo 
corticosteroids) within 3 months prior to enrolment (Visit 1). 
15.
Chronic use of oral corticosteroids (OCS).
16.
Subjects unable to safely undergo elective, flexible, fibreoptic bronchoscopy. 
17.
Subjects who have been hospitalised or required OCS within 6 weeks of the 
enrolment visit or had a history of more than three exacerbations requiring 
corticosteroid treatment in the previous year or history of intubation/ICU in the 
previous year.
18.
Receipt of immunoglobulin or blood products within 30 days prior to enrolment 
(Visit 1).
19.
Receipt of any marketed (e.g., omalizumab) or investigational biologic agent within 
4 months or 5 half-lives prior to the enrolment (Visit 1), whichever is longer.
20.
Receipt of live attenuated vaccines within 30 days prior to the enrolment (Visit 1) 
and the subject agrees not to have live attenuated vaccines during the study 
including the follow-up period.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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∀
Receipt of inactive/killed vaccinations (e.g., inactive influenza) are allowed, 
provided they are not administered within 5 days before/after any dosing visit.
21.
Receipt of any investigational non-biologic agent within 30 days or 5 half-lives 
prior to enrolment (Visit 1), whichever is longer.
22.
Previous receipt of tralokinumab (CAT-354).
23.
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.
24.
Current use of any oral or ophthalmic non-selective β-adrenergic antagonist (e.g.,
propranolol).
25.
Current use of five-lipoxygenase inhibitors (e.g., Zileuton) or roflumilast.
26.
Subjects who have undergone bronchial thermoplasty.
27.
Major surgery within 8 weeks prior to the enrolment (Visit 1), or planned in-patient 
surgery or hospitalization during the study period.
28.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 2.5 
times the upper limit of normal (ULN) at enrolment (Visit 1).
29.
Pregnant, currently breast-feeding, or lactating women.
30.
Previous randomization in the present study.
31.
Concurrent enrolment in another clinical study where the subject is receiving an IP.
32.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
33.
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.
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.
3.3
Subject enrolment and randomization
Investigator(s) should keep a record, the 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.

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Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject or their legal 
representative before any study specific procedures are performed.
2.
Assign potential subject a unique enrolment number, beginning with ‘E’ via the 
Interactive Web Response System/ Interactive Voice Response System 
(IWRS/IVRS) at Visit 1.
3.
Determine subject eligibility. See Section 0.
4.
Assign the eligible subject unique randomization code via IWRS/IVRS at Visit 3c.
Subjects will be allocated to receive tralokinumab or placebo in a 1:1 ratio (i.e. 40 subjects on 
tralokinumab versus 40 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.
3.4
Procedures for handling incorrectly enrolled or randomized 
subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  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.
When 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 as subjects become eligible for 
randomization. The randomization code will be assigned from a randomization list prepared 
by an internal AstraZeneca computerized system (GRand). 
3.6
Methods for ensuring blinding
This is a double-blind study in which tralokinumab and placebo are visually distinct from each 
other. 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 

Revised Clinical Study Protocol
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Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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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 
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:
!
IVRS/IWRS Vendor
!
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 contract research organization 
(CRO) handling data, will have access to unblinded information during the conduct of the 
study, with the exception of the Supply Chain Study Management department and the Patient 
Safety department at AstraZeneca.
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 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.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
subject have been made and documented.
3.8
Restrictions
Fertile and sexually active female subjects should use highly effective contraceptive methods 
throughout the study and for at least 16 weeks (5 half-lives) after last administration of the IP. 
Subjects must abstain from donating blood or plasma from the time of informed consent and 
up to 16 weeks (5 half-lives) after last dose of IP. 
3.9
Criteria for withdrawal from study
3.9.1
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 
criteria).  This reason for study withdrawal is only valid for screen failures, and not 
randomized subjects.
3.9.2
Post-randomization
After randomization and receiving IP, subjects are free to discontinue IP and withdraw from 
the study at any time without prejudice to further treatment.  A subject that decides to 
discontinue the IP and withdraw from the study 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
6.3). 
Subjects will be withdrawn from the study 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 as judged by the Investigator or 
AstraZeneca
5.
Pregnancy 

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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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
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%)
The Principal Investigator will perform all the possible observation(s), test(s) and 
evaluation(s) including completion of questionnaires if any, as per End of Treatment (EOT) 
assessments mentioned in Table 1 as soon as possible. Investigator will give appropriate 
medication and take all possible measures for the safety of the subject. They will also 
immediately inform AstraZeneca of the withdrawal. Subject will then be followed up for 
additional 16 weeks from the last dose of IP, unless the subject withdraws consent for any 
further follow-ups. During follow-up, the Investigator will perform all possible assessments in 
accordance with schedule provided in Table 1. 
The reason for premature study withdrawal will be documented in the source documentation 
and recorded in the electronic case report form (eCRF). All discontinued subjects must return 
the electronic patient reported outcome (ePRO) device (eDiary) and electronic ePEF devices. 
Early termination of IP treatment, will be registered via the IWRS/IVRS for each subject.
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., study of markers of asthma, identifying potential new drug targets for asthma, or for 
                                                
1 A subject is considered lost to follow up when any of the following attempts of contact are failed: at least 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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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
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assay development purposes), the subject will not be withdrawn from the study. For details 
please see Section 5.7.4.
3.10
Discontinuation of the study
The entire study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed 
at undue risk because of clinically significant findings that:
∀
are assessed as causally related to study drug, 
∀
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the eCRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.

Revised Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
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4.
STUDY PLAN AND TIMING OF PROCEDURES 

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Study Code D2210C00014
Edition Number 1.0
Date 15 January 2016
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Table 1
Study plan - Treatment and follow-up period
Assessment/activity
Enrolment
Run-in
Treatment
EOT iv
FU 
1v
FU 
2vi
UNSvii
V1i
V2
V3aiii
V3biii
V3c
V4
V5
V6
V7
V8
V9
V10
V11
-4w
-2w
-7d
-5d
0
2w
4w
6w
8w
10w
12w
16w
26w
Visit window ii (days)
N/A
+3
±2
±2
0
±3
±3
±3
±3
±3
±7
±7
±7
N/A
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics
X
Medical/Surgical and asthma history
X
Weight, Height
X
Asthma Daily Diary and PEF  
adherence check
X
X
X
X
X
X
X
X
X
X
ACQ-6 at the site
X
X
X
X
X
SNOT-20 at the site
X
X
Urine pregnancy test (dipstick) viii
X
X
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma exacerbation
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
Randomization 
X
Vital Signs ix
X
X
X
X
X
X
X
X
X
Local ECG 
X
X
Complete physical examination
X
X
X

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Study Code D2210C00014
Edition Number 1.0
Date 15 January 2016
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Assessment/activity
Enrolment
Run-in
Treatment
EOT iv
FU 
1v
FU 
2vi
UNSvii
V1i
V2
V3aiii
V3biii
V3c
V4
V5
V6
V7
V8
V9
V10
V11
-4w
-2w
-7d
-5d
0
2w
4w
6w
8w
10w
12w
16w
26w
Visit window ii (days)
N/A
+3
±2
±2
0
±3
±3
±3
±3
±3
±7
±7
±7
N/A
Brief physical exam
X
X
X
X
X
X
Clinical chemistry
X
X
X
Haematology 
X
X
X
X
X
Serology (hepatitis B,C; HIV-1,2)
X
Serum pregnancy test
X
FSH x
X
Serum biomarkers 
X
X
X
Total IgE
X
X
X
Phadiatop
X
RNA Transcriptomics xi
X
X
X
X
Tralokinumab PK xii
X
X
Tralokinumab ADA/nAb xii
X
X
FENO
X
X
X
Nasosorption and nasal epithelial 
cells sampling
X
X
Pre- BD, spirometry
X
Xxiii
X
X
X
Post-BD, spirometry
X
Xxiii
Xxiv
Xxiv
Post-BD, whole body 
plethysmography (WBP)
X
X

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Assessment/activity
Enrolment
Run-in
Treatment
EOT iv
FU 
1v
FU 
2vi
UNSvii
V1i
V2
V3aiii
V3biii
V3c
V4
V5
V6
V7
V8
V9
V10
V11
-4w
-2w
-7d
-5d
0
2w
4w
6w
8w
10w
12w
16w
26w
Visit window ii (days)
N/A
+3
±2
±2
0
±3
±3
±3
±3
±3
±7
±7
±7
N/A
Airwave oscillometry (AO)
Xxv
X
X
Multiple breath washout (MBW)
Xxv
X
X
AHR
X
X
Computed tomography (CT) 
X
Xxix
Sputum induction xvi
Xxv
X
X
X
Bronchoscopy/biopsy/brushing 
Xxvii
Xxix
Administration of IP xviii
X
X
X
X
X
X
For restrictions for withholding asthma medications before visits see Section 7.7.1.2. Asthma medications should not be withheld on visits when 
bronchoscopy is scheduled.
i.
Visit 1 can be performed over more than one day, within a 3-working day window, with the exception of documentation of informed consent which can 
be completed up to 30 days prior to Visit 1.
ii.
All visits are to be scheduled from the date of randomization, not from the date of the previous visit.
iii.
All pulmonary assessments performed during V3 (a, b & c) may be performed over a 7-working day window, with a suggested order of FENO, AO, 
MBW and Pre-BD spirometry if performed on the same day. CT Scan assessment should precede sputum induction if performed on same day. 
iv.
Based on investigator’s judgement and site resources, EOT assessments will be performed over more than one day, within a 7-working day window. The 
sequence of pulmonary assessments during the EOT visit should be performed in the same order as completed at Visits 3a, 3b and 3c. (Refer to footnote 
iii).
v.
This will be a telephonic follow-up visit. Depending on investigator’s judgement, subject may be called for an on-site visit for further evaluation.
vi.
On-site FU 2 visit will be performed only for WOCBP to also ascertain their pregnancy status. For all other subjects this will be a telephonic FU 2 visit.
vii.
At unscheduled visits for assessing an asthma exacerbation, the assessment/activity listed above is only the minimum needed to be performed. Other 
unscheduled visits may be initiated as needed, and assessments performed as per investigator’s judgement.
viii.
For WOCBP urine pregnancy test (dipstick) is to be done at the centre and confirmed ‘negative’ prior to IP administration when scheduled.
ix.
Vital signs will be recorded pre-dose on the days of IP administration. Subjects will be observed 2 hours post IP administration for Visits 3c through
Visit 6.  For all later visits where IP is administered, subjects will be observed for a minimum of 1 hour. Additional assessments may be performed as 
per investigator’s judgement.
x.
FSH test is performed only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for ≥12 month.

Revised Clinical Study Protocol
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xi.
RNA samples will be obtained from the peripheral blood collected for haematology assessments, nasal epithelial cells and from bronchial brushing 
samples.
xii.
Blood samples for PK and ADA/nAb evaluations will be collected before the administration of IP. In case of any acute reaction following IP 
administration, additional blood samples will be drawn. For details see Section 6.7.
xiii.
Pre and post-BD spirometry to assess FEV1 and its reversibility will be performed at Visit 2 only if eligibility criteria is not met at Visit 1.
xiv.
V3a and Visit 9 (EOT) Post-BD spirometry assessments will be performed as outlined in Appendix H. But it will stop at the end of Step 1 (i.e. using up 
to 4 inhalations of salbutamol).
xv.
AO, MBW and Sputum induction completed at Visit 2 will be training assessments to ensure the subjects are familiar with the procedures. They can be 
completed over more than one day, within a 3-working day window, with a suggested order of AO, MBW, Spirometry and Sputum induction if 
performed on the same day.
xvi.
V6 and EOT sputum assessment should only be performed if either V2 or V3 sputum sample is available for assessment.
xvii.
Depending on investigator’s judgement, bronchoscopy along with biopsy and bronchial brushing can be performed up to 3 days before or on the day of 
randomization Visit 3c.
xviii.
IP will be administered after performing all the visit specific assessments.
xix. EOT Bronchoscopy and CT scans will be performed only if baseline data were of good quality as confirmed by central analysing facility.

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4.1
Enrolment and run-in period
4.1.1
Enrolment
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).
With the exception of documentation of informed consent 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 bronchodilator medications withheld in 
accordance with the instruction manual provided for the study. The registration of the 
subject’s enrolment via IWRS/IVRS should occur on the day when the subject’s 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 and exacerbation history. 
Spirometry will also be performed at Visit 1. Subjects must have a pre-BD FEV1 value > 50% 
of their PNV and >1 L. Should this criterion not be met or cannot be performed at Visit 1, 
subjects must fulfil it at Visit 2 in order to proceed in the study. If not, the subject will be 
screen failed.
Subjects must have a post-BD reversibility in FEV1 of ≥12% and ≥200 mL at enrolment (Visit 
1). If this criterion is not met at Visit 1, the criterion must be met at Visit 2, failing which the 
subject will be screen failed.
Other study assessments and procedures to be performed at enrolment Visit 1 are mentioned 
in Table 1.
A record of physician-diagnosed asthma, ICS and other asthma controllers use is required 
source documentation. Current, regular use of an ICS at a stable dose for at least 1 month prior 
to enrolment (Visit 1) must be documented in the source data. This documentation may be in 
the form of a recent, active medication list as per a healthcare professional (HCP) note, or 
filled prescription.
After confirmation of initial entry criteria the subject will be supplied with an electronic 
handheld peak expiratory flow (ePEF) meter to monitor home lung function, and an electronic 
diary (eDiary) to record asthma symptoms and complete relevant questionnaires (see Section 
5.3.2 for further details).
4.1.2
Run-in period
All subjects meeting eligibility criteria at Visit 1 will enter into a 4-week run-in period. After 
2 weeks subject will come back to the site for Visit 2. Subjects will continue on their current 

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ICS and other maintenance asthma controller medications (if applicable) with no changes 
during the run-in period.
Subjects who do not comply with the eDiary completion will be given a one-time option to 
reschedule a study visit within 72 hours. Compliance is defined as completing all required 
elements of eDiary for any 10 mornings and 10 evenings of the last 14 days before the visit. 
Subject must comply with eDiary compliance between Visit 1 and 2, before being randomized 
into the treatment period otherwise this will result in screen failure.
Assessments and procedures to be performed during the run-in period at Visit 2, 3a and 3b are 
as per Table 1. Post-BD spirometry evaluation will be performed at Visit 2, only if required 
inclusion criteria were not met at Visit 1. Subject will be screen failed if the inclusion criteria 
are not met. Subject will also perform multiple breath washout (MBW), airwave oscillometry 
(AO) and sputum induction (SI) as training manoeuvres at Visit 2. 
4.1.3
Re-screening
Subjects who experience an asthma exacerbation, have respiratory infections requiring 
antibiotics or antiviral medication during the run-in period should be screen failed. They may 
be re-screened no sooner than 30 days after their last dose of systemic agents (including 
steroids) administered to control the episode.
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, 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).
Any re-screened subject will be re-enrolled and reassigned their originally assigned enrolment 
number after signing a new informed consent form (ICF) and after all Visit 1 assessments 
have been performed as listed in Table 1.
Re-enrolment is only allowed once for any subject, regardless of whether this is due to an 
exacerbation or infection. Subjects may be re-screened no later than 3 months after failing the 
initial enrolment. But the subject may not be re-screened if any other eligibility criteria have 
not been met.
4.2
Treatment period
The randomized treatment period begins at Visit 3c (Week 0) till Visit 8 (Week 10) with End 
of treatment (EOT) visit at Visit 9 (Week 12). Subject’s eligibility to continue in the study will 
be once again confirmed before randomization during Visit 3c (see Section 3.1 and 3.2). 
Assessments and procedures to be performed during the treatment period are as per Table 1.
Subjects confirmed to be eligible will be randomized in a 1:1 ratio to receive either 
tralokinumab 300 mg or placebo every two weeks throughout the treatment period. The first 

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dose of the IP will be administered at Visit 3c after the subject’s randomization via 
IVRS/IWRS.
Following randomization the subject will receive the double-blind treatment for 12 weeks, 
with the last dose of tralokinumab /placebo administered at Visit 8 (Week 10).
Subjects will continue on their current ICS and other maintenance asthma controller 
medications (if applicable) with no changes during the entire treatment period.
4.3
Follow-up period
Post-treatment follow-up period to assess any ongoing safety issues and any potential 
prospective AEs for all subjects will be for 14 weeks after the EOT visit with a telephonic FU 
1 visit (Visit 10, Week 16). There will be an on-site FU 2 visit (Visit 11, Week 26) only for 
WOCBP to also determine their pregnancy status.  For all other subjects this will be a 
telephonic FU 2 visit. Assessments and procedures to be performed during the follow-up 
period are as per Table 1.

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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 the 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 study completion.
5.1
Efficacy assessments
5.1.1
Bronchoscopy biopsy and bronchial brushing
Bronchoscopy along with bronchial biopsy and brushing, will be performed in accordance 
with the schedule provided in Table 1. Details for conducting bronchoscopy, bronchial biopsy 
and bronchial brushing will be described in a separate manual of procedures. 
5.1.1.1
Bronchial biopsy
Bronchial biopsy will be performed in accordance with the schedule provided in Table 1. 
Details for conducting bronchial biopsy will be described in a separate manual.
Samples will be analysed at a central facility designated by AstraZeneca. Details of 
assessment and analysis parameters will be described in a separate manual
5.1.1.2
Bronchial brushing
During bronchoscopy, bronchial brushing will be obtained. Details for sample collection, 
handling, processing, storage and transportation will be described in a separate manual.
Samples will be analysed at a central facility designated by AstraZeneca. Details of 
assessment and analysis of parameters including airway epithelium gene expression and 
transcriptomics will be described in a separate manual.
5.1.2
Sputum induction
The aim of sputum induction is to obtain satisfactory samples of sputum originating from the
airways. Sputum induction will be performed in accordance with the schedule provided in 
Table 1. Visit 2 assessment will be a training manoeuvre for the subjects. A detailed procedure
for inducing sputum will be described in a separate manual. Attempts will be made to perform 
sputum induction as close to the baseline assessment time at each of the scheduled visits. 
Detailed procedures for sample processing, storage and transportation will be described in a 
separate manual.

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Details of assessment and analysis of parameters including inflammatory and epithelial cell 
counts, biomarkers which may include (but are not limited to) histamine, leukotrienes, IL-13, 
IL-5, IL-12, IL-31 and ECP will be described in a separate manual.
5.1.3
Nasosorption and nasal epithelial cells samples
The nasosorption procedure is a quick and simple technique for sampling nasal secretions.
Samples of nasal epithelial cells will also be obtained for gene expression profiling and 
transcriptomics.
Nasosorption and nasal epithelial cells samples will be obtained in accordance with the 
schedule provided in Table 1. Detailed procedures for obtaining, processing, storing, 
transporting and analysing the samples will be described in a separate manual.
5.1.4
Computed tomography
Chest CT will be performed in accordance with the schedule provided in Table 1. Detailed
procedures for the acquisition, storage, anonymization and transfer of the CT image data will 
be described in a separate manual. 
Details for the analysis of the CT image data to obtain parameters for large airway 
morphometry, air trapping and functional imaging will be described in a separate imaging 
biomarker document.
The CT scans will be assessed clinically at each site, and the Principal Investigator is 
responsible for the clinical reporting of findings and its subsequent management. Clinically 
significant findings not related to asthma, will be reported as medical history or AEs by the 
investigator (also refer Section 6.3.6).
5.1.5
Multiple breath washout
Multiple breath washout (MBW) assesses ventilation distribution inhomogeneity during tidal 
breathing from functional residual capacity (FRC), by examining inert gas clearance over a 
series of breaths. MBW is included in this study as a specific small airway marker to evaluate 
treatment effect on small airway physiology.  
Detailed procedure for performing MBW will be described in a separate manual. Subjects will 
be encouraged to breathe normally and comfortably through a pneumotachometer (PNT) via a 
mouthpiece. Each test will consist of two phases (wash-in and wash-out). Concentrations of 
gas in expired breath will be measured continuously using the gas analyser connected to the 
mouth piece. An acceptable trial should show a regular breathing pattern, without leaks from 
the mouthpiece, with complete wash-in and washout phases.
MBW procedures will be performed in accordance with the schedule provided in Table 1. 
Visit 2 assessment will be a training manoeuvre for the subjects. 
Number of parameters including Sacin (index of acinar ventilation heterogeneity) will be 
derived from the raw MBW data using custom software.

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5.1.6
Airwave oscillometry
Airwave oscillometry (AO) is a non-invasive lung function test included in this study to 
evaluate treatment effect on small airway physiology. 
A calibrated system will be used for measurements. Detailed procedures for performing, 
recording and analysing AO data will be described in a separate manual.
AO evaluation will be performed in accordance with the schedule provided in Table 1. 
Assessment at Visit 2 will be a training manoeuvre for the subjects. 
By measuring subject’s airflow and response to sound waves, frequency-dependent resistance 
and reactance will be calculated by the AO system software. A signed and dated copy of the 
results printout from the equipment must be kept at the study site for SDV. The printout must 
be marked with the study code, subject enrolment code, date and time of measurement, and 
visit number. Number of parameters including (but not limited to) R5, R20 and AX for each 
trial will be recorded and analysed.
5.1.7
Post-BD Whole body plethysmography
Whole body plethysmography (WBP) to assess lung volumes will be performed post-BD in 
accordance with the schedule provided in Table 1. Prior to assessment, subject will be asked 
to inhale 100 micrograms of salbutamol using a metered dose inhaler and a valved spacer 
device. This procedure will be repeated 4 times. WBP assessment should be performed within 
15-60 minutes post bronchodilation.
Lung volume subdivisions which include total lung capacity (TLC), residual volume (RV), 
vital capacity (VC), inspiratory capacity (IC) and FRC will be performed at study sites by the 
investigator or qualified designee according to American Thoracic Society /European 
Respiratory Society (ATS/ERS) guidelines (Wanger J et al 2005) and in accordance with 
applicable SOP and clinical standards of care at investigational sites. The test will be 
performed by trained pulmonary function technicians with experience performing this 
assessment. 
Each site will be allowed to use their own body boxes for this assessment. A signed and dated 
copy of the results printout from the equipment must be kept at the study site for SDV. The 
printout must be marked with the study code, subject enrolment code, date and time of
measurement, and visit number.
5.1.8
Spirometry
5.1.8.1
General requirements
Pre and post BD pulmonary function will be measured by spirometry at the study site using 
equipment provided by a central vendor. For all the remaining assessments (such as sputum 
induction, airway hyper-responsiveness) involving spirometry, sites will use their own local 
equipment. Spirometry will be performed by the Investigator or authorized delegate according 
to ATS/ERS guidelines (Miller MR et al 2005).

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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.
Pre-BD spirometry testing must be performed 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 baseline Pre-BD spirometry (Visit 3a) was performed. 
5.1.8.2
Spirometry technique
Detailed procedure for performing spirometry will be described in a separate instruction 
manual. A signed and dated copy of the pre- and post- BD spirogram 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 
PNV values and are pre-programmed into the spirometer (Quanjer PH et al 2012). 
FEV1, expressed as percent of the PNV, will be calculated as follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100
5.1.8.3
Assessments and analysis
FVC, FEV1, forced expiratory flow between 25% and 75% of the FVC (FEF25–75%) is taken 
from the forced expiration with the largest sum of FEV1 and FVC. The absolute measurement 
(for FEV1), and the percentage of PNV (Quanjer PH et al 2012) will be recorded. 
5.1.8.4
Post-BD spirometry and FEV1 reversibility assessment
Post-BD spirometry procedures will be performed according to the schedule provided in Table 
1 and will be described in separate instruction manuals. Up to a maximum of 8 inhalations of 
salbutamol (100 μg metered dose) will be used as bronchodilator (Sorkness RL et al 2008). It 
is highly recommended to use a spacer device for this procedure. Nebulizer should not be 
used. The algorithm for reversibility assessment is outlined in Appendix H. A lower total dose 
(e.g., 2 inhalations instead of 4 in the first round of puffs, and/or a total of less than 8 puffs), 
can be used if there is a concern about any effect on the subject’s heart rate, tremor or safety; 
the reason  should be noted in the subject’s medical record. Post-BD spirometry to assess 
FEV1 reversibility will be performed at Visit 2 only if eligibility criteria are not met at Visit 1.
It is acceptable to stop the reversibility assessment procedure once the criteria for reversibility 
are met.
The highest pre- and post-BD FEV1 will be used to determine reversibility.

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Reversibility is calculated as follows:
% Reversibility = (post-BD FEV1- pre-BD FEV1) × 100/pre-BD FEV1
V3a and Visit 9 (EOT) Post-BD spirometry assessments will be performed as outlined in 
Appendix H. But it will stop at the end of Step 1 (i.e. using up to 4 inhalations of salbutamol).
5.1.9
Airway hyper-responsiveness
Airway hyper-responsiveness (AHR) will be assessed, according to the schedule provided in 
Table 1, by methacholine challenge test (MCT). MCT will be performed in accordance with 
the ATS Guideline (ATS Guideline 1999) and applicable SOP and clinical standards of care at 
investigational sites. 
Signed and dated worksheets from the measurements will be kept in the ISF for source data 
verification (SDV). If a worksheet cannot be printed, required measurements will be recorded 
in the subject’s medical records for SDV.
5.1.10
Home PEF testing
An electronic hand-held peak expiratory flow (ePEF) meter will be provided to the subject at 
Visit 1. ePEF meter will be paired with an eDiary which will record, store and send the 
readings via a cellular network. 
Home PEF testing will be performed by the subject in the morning upon awakening (prior to 
taking their AM asthma controller) and in the evening at bedtime (prior to taking their PM 
asthma controller). For details see Section 7.7.1.1 and Appendix G. Recording of home PEF 
should start from the evening of Visit 1 until the morning of Visit 9 (Week 12) using an ePEF 
meter device.
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.
5.1.11
Fractional exhaled nitric oxide
Fractional exhaled nitric oxide (FENO) measurements will be performed in accordance with 
the schedule provided in Table 1. 
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.

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FENO will be measured using an electrochemical sensor.  Information concerning the 
specifications and use of the analyser will be provided in a separate instruction manual. The 
standard single exhalation technique recommended by the ATS will be followed (Dweik RA 
et al 2011). 
Signed and dated printouts from the measurements will be kept in the ISF for SDV. Printouts 
will be marked with the study code, subject enrolment/ randomization code, date and time of 
measurement and visit number. 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 equipment 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.
5.1.12
Assessment of asthma exacerbation
Assessment of asthma exacerbation will be performed in accordance with the schedule 
provided in Table 1. 
For the purpose of the study, an asthma exacerbation will be defined as a worsening of asthma 
that leads to any of the following:
∀A temporary bolus/burst of systemic corticosteroids for at least 3 days to treat symptoms of 
asthma worsening; a single depo-injectable dose of corticosteroids will be considered 
equivalent to a 3-day bolus/burst of systemic corticosteroids
∀An emergency room or urgent care visit (defined as evaluation and treatment for <24 hours 
in an emergency department or urgent care centre) due to asthma that required systemic
corticosteroids (as per the above)
∀An in-patient hospitalization (defined as admission to an inpatient facility and/or evaluation 
and treatment in a healthcare facility for ≥ 24 hours) due to asthma
Worsening of asthma is defined as new or increased symptoms and/or signs (examination or 
lung function) that can be either concerning to the subject (subject-driven) or related to an 
asthma daily diary alert (diary-driven). Baseline values for diary-driven alerts will be the 
mean of measures collected between Visits 1 and 2.
The eDiary will be programmed to alert both the subject and study centre when certain pre-
specified worsening thresholds are crossed including:
∀Decrease in morning peak flow ≥20% on at least 2 consecutive days compared with 
baseline, and/or
∀An increase in rescue medication use of 4 or more puffs, or use of one new or additional 
nebulized β2 agonist on at least 2 consecutive days compared with the average use during 
baseline, and/or

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∀An increase of 2 nocturnal awakenings due to asthma over a 7 day period compared with 
the average during baseline, 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 baseline average or the 
highest possible score (daily score of 6), on at least 2 consecutive days
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the Investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. Events that are not supported by any 
objective assessment will be deemed not to be a protocol-defined exacerbation.
An asthma exacerbation that occurs ≤ 7 days of the last dose of systemic steroids, prescribed 
for a prior exacerbation, will be counted as the same exacerbation event.
Subjects who experience an exacerbation during the run-in period should be screen failed and 
may be considered for re-screening. Discontinuation due to an exacerbation after 
randomization (Visit 3c) is not mandatory and subjects may remain on the investigative 
product at PI’s discretion. A stable period of 6 weeks is recommended between the last dose 
of systemic steroids for treating an asthma exacerbation and the EOT bronchoscopy. For such 
subjects, the timing of EOT bronchoscopy assessments should be discussed and agreed upon 
with AstraZeneca study physician.
Reasonable attempts should be made by the Investigator to bring the subject into the study 
centre for evaluation of a diary alert or subject initiated asthma worsening, particularly when it 
results in additional treatment being prescribed. Study centre evaluations for asthma 
worsening may occur as an unscheduled (UNS) visit or as part of an ordinary centre 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 centres (e.g., 
by the primary care HCP or at an ED/hospital) and details entered into the exacerbation eCRF 
(EXACA module) in a timely fashion. Changes in concomitant medication due to an 
exacerbation must be recorded in the appropriate module of the eCRF.
5.1.13
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, DPP4, 
Eotaxin, ECP, monocyte chemoattractant protein 1 (MCP1), thymus and activation regulated 
chemokine (TARC), IL-5, IL-33, signal transducer and activator of transcription 6 (STAT6), 
IL-13Rα2, MCP4/chemokine (C-C motif) ligand 13(CCL13), TARC/CCL17, calcium-
activated chloride channel regulator 1 (CLCA1), serpin peptidase inhibitor, clade B 
(ovalbumin), member 2 (SERPINB2), biomarkers of tissue destruction, vascular adhesion 
molecules. Instructions for sample collection, processing, storage, shipment and analysis will 
be provided in a separate laboratory manual provided to the sites. 

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5.1.14
Whole blood eosinophils
Samples for assessment of blood eosinophils will be collected as haematology samples 
according to the schedule in Table 1. Blood eosinophil count will be obtained from the total 
and differential white blood cell (WBC) counts. Instructions for sample collection, processing, 
storage, shipment and analysis will be provided in a separate laboratory manual provided to 
the sites.
5.1.15
Total IgE
Testing for total IgE will be performed as per schedule in Table 1. The analysis for this test 
will be managed by the central laboratory. Instructions for sample collection, processing, 
storage, and shipment will be provided in a separate laboratory manual provided to the sites.
5.1.16
Phadiatop (Allergy screen)
Testing for phadiatop in blood (allergy screening test) will be performed as per schedule in
Table 1.  The analysis for this test will be managed by the central laboratory. Instructions for 
sample collection, processing, storage, and shipment will be provided in a separate laboratory 
manual provided to the sites.
5.1.17
RNA Transcriptomics
Transcriptomic analysis will be performed on the ribonucleic acid (RNA) sample obtained 
from peripheral blood samples, nasal epithelial cells and from bronchial brushing as per 
schedule in Table 1. All the samples will be analysed at a central facility. Instructions for 
sample collection, processing, storage, shipment and analyses will be provided in a separate 
manual of procedures provided to the sites.
The results from the analysis related to all exploratory objectives may be reported either 
in the CSR itself or as an addendum, or separately in a scientific report or publication as 
appropriate.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at visits in accordance with the schedule outlined in Table 1.  Fasting is not 
required before the collection of blood and urine samples. For dosing visits, all samples will 
be taken prior to the administration of IP.
The laboratory variables measured are outlined in Table 2.

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Table 2
Laboratory safety variables
Tests
Variables
Haematology/Haemostasis (whole blood)
Haemoglobin, Red blood cell (RBC) count, Leukocyte 
count, Leukocyte differential count (absolute count), 
Platelet count, Haematocrit, Mean corpuscular volume
Clinical chemistry (Serum)
Alkaline phosphatase (ALP), Alanine transaminase 
(ALT), Aspartate transaminase (AST), Bilirubin (Total), 
Blood urea nitrogen, Calcium (Total), Carbon dioxide 
(CO2), Chloride, Creatinine, Creatinine kinase, C-
Reactive Protein (CRP), Gamma-glutamyl transpeptidase 
(GGT), Glucose, Phosphorus, Potassium, Sodium, Total 
cholesterol, Uric acid
Urine (Dipstick)
Nitrite, Bilirubin, Glucose, Blood, Protein, Ketones
Urine 1
Microscopy, Casts, Culture (as required)
1.
Urine samples will be collected 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. 
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.
NB. In case a subject shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN please 
refer to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law’, for further instructions.
The total volume of blood that will be collected from each subject during the study is 
presented in Table 3.
Table 3
Volume of blood to be drawn from each subject
Assessment3
Sample volume 
(mL)
No. of samples
Total volume2
(mL)
Safety
Clinical chemistry
2.5
2
5
Haematology
2
4
8
FSH, β-HCG1
1
1
1
Serology
7.5
1
7.5
IgE
2.5
3
7.5

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Assessment3
Sample volume 
(mL)
No. of samples
Total volume2
(mL)
Phadiatop
2.5
1
2.5
Serum biomarkers
16
3
48
PK
3.5
2
7
ADA/nAb
3.5
2
7
Total
93.5
1.
Female subjects only
2.
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 subject over the course of the study will not exceed 450 ml.
3.
Timing of assessments as per Table 1
5.2.2
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 β-human chorionic gonadotropin (ß-HCG) – the test done at enrolment (Visit 
1) only, for WOCBP (analysed 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 in accordance 
with the schedule outlined in Table 1 using a dipstick. Positive urine test result must be 
confirmed with serum β-HCG.
5.2.3
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.
5.2.3.1
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.

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5.2.3.2
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.
5.2.4
ECG
All ECG assessments must be performed using site’s electrocardiogram (ECG) device
according to the clinical standards of care at the site. ECGs will be performed prior to blood 
drawing, spirometry and IP administration, in accordance with schedule provided in Table 1.
For all subjects, the printouts of the ECG 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). Any new finding(s) judged as clinically significant by the 
Investigator, will be reported as an AE as described in Section 6.1.
5.2.4.1
Resting 12-lead ECG
A 12-lead ECG will be taken in supine position, after the subject has been resting for at least 5 
minutes. Heart rate, P and QRS durations, PR, QT and QTc intervals will be recorded from 
the standard lead of the ECG.
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the Investigator’s interpretation and that provided by the ECG 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 ECG 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 ECG assessments throughout 
the subject’s participation in the study.
5.2.5
Vital signs
Vital signs (i.e., pulse, blood pressure, respiration rate and body temperature) will be obtained 
in accordance with the schedule provided in Table 1. Vital signs will be taken prior to blood 
drawing and IP administration. At Visits 3c 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. 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.
5.2.5.1
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 a seated position. Pulse rate will be obtained 
prior to blood pressure measurement if measured manually.

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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.
5.2.5.2
Body temperature
Body temperature will be measured in degrees Celsius prior to IP administration, in 
accordance with local standards.
5.2.6
Other safety assessments
5.2.6.1
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.
5.2.6.2
Infections
Subjects experiencing serious infections, defined as life-threatening infections, infections 
requiring hospitalization, or infections requiring treatment with antiviral medications, 
intravenous antibiotics or medications for helminth parasitic infections or that lead to a 
permanent discontinuation of study drug should be noted in the infection module in the eCRF.
5.3
Other assessments
5.3.1
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.
5.3.2
Patient reported outcomes
Patient reported outcomes (PRO) data will be captured using an ePRO device (eDiary) and 
also by using paper based tool. Site personnel will be trained on using the eDiary. Detailed
procedures for using eDiary and training the subjects will be described in a separate 
instruction manual. Subjects will be trained on at-home use of the eDiary and paired ePEF 
meter at Visit 1. Training will include explanation of device functionality and proper use of 
the ePEF meter. 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 eDiary. Subjects will be provided with 
information on device use and issue resolution (e.g., helpdesk numbers) to conclude the 
training. The site staff will set assessment reminder alarms on the device. At-home PRO 
assessment will start the evening of Visit 1. Subjects will be asked to bring the device back at 
each study visit. Additional details concerning the assessments can be found in the subsequent 
sections (see Sections 5.3.2.1 to 5.3.2.3).

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5.3.2.1
Asthma Daily Diary
The Asthma Daily Diary will be completed each day from the evening of Visit 1 to the 
morning of Visit 9. The Asthma Daily Diary will include the following daily recordings: 
morning and evening home PEF data (obtained from the ePEF meter), asthma symptoms, 
inhalations of rescue medication, nights with awakenings due to asthma symptoms, 
maintenance medication compliance. There will be triggers in the eDiary to alert the subjects 
to signs of worsening of asthma and to contact their physician, please refer to Section 5.1.12.
The subject should contact the investigator 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 5.1.10.
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 1 until the 
morning of Visit 9.
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 
evening) beginning the evening of Visit 1 until the morning of Visit 9. 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 1 until the morning of Visit 9, 
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 compliance will be captured daily from the evening of Visit 1 until 
the morning of Visit 9. Maintenance medication will be recorded in the Asthma Daily Diary. 

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The maintenance medication question will ask about compliance with regularly scheduled 
asthma medications.
5.3.2.2
Asthma Control Questionnaire (ACQ-6)
The Asthma Control Questionnaire (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. Subjects will be instructed to count each use of nebulizer as 2 puffs of inhalers.
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 EF et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful.
ACQ-6 will be completed at the study site using eDiary in accordance with the schedule 
provided in Table 1.
5.3.2.3
Sino-Nasal Outcome Test - 20
Sino-Nasal Outcome Test – 20 (SNOT-20) is a health-related and disease specific instrument 
for assessing quality of life for rhinosinusitis. This questionnaire contains 20 questions divided 
across five subgroups (nasal symptoms, paranasal symptoms, sleep-related symptoms, and 
social and emotional impairment). Subjects will rate their experiences during the previous 2 
weeks and score each question on a six-point scale (0-no problem, 5-most serious problem) 
and in addition, they will mark which of the five items they consider to be the most important.
Total score will be calculated for each assessment. SNOT-20 will be completed by the subject 
at study site using a paper based tool in accordance with the schedule provided in Table 1.
Completed paper questionnaires will be kept in subject’s chart for SDV and data from the 
questionnaire transcribed into the respective fields of eCRF.
5.4
Pharmacokinetics
5.4.1
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 3.
5.4.2
Determination of drug concentration
Samples for determination of tralokinumab concentration in serum will be analyzed by central 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method. Details of the 
analytical method used will be described in a bioanalytical report. A summary of 
pharmacokinetics (PK) analysis results will be reported in the CSR; details of the PK analysis 
will be reported separately in a bioanalytical report.
5.4.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples will be retained for future use at AstraZeneca, or designee, for a 
maximum of 15 years following the date of Last Subject’s Last Visit. They 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 CSR 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 and in Section 5.7).
5.5
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 analyses 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 as per 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 further tested in the 
confirmatory step. Samples confirmed positive for ADA in the confirmatory step will undergo 
endpoint titer determination and will be analysed for the presence of nAb. 

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Neutralizing antibodies
Neutralizing antibodies will be assessed as per Table 1 according to the tiered testing scheme 
outlined above, as well as at any discontinuation, as indicated. 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.
5.6
Pharmacogenetics
Not applicable.
5.7
Biomarker analysis in future
The subject’s consent to the use of donated biological samples for future analysis purpose is 
mandatory.  
Biological samples (e.g., sputum, nasal secretions, blood, plasma, serum, bronchial tissue) will 
be collected and may be analysed in future for additional exploratory biomarkers to assess 
correlations with disease activity, effects of study drug, clinical outcomes and toxicity.
5.7.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication. The results of this biomarker research may be pooled with biomarker data from 
other studies with the study drug to generate hypotheses to be tested in future research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that biological 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 are not shipped and no further samples will be taken from the 
subject unless agreed with AstraZeneca and appropriate labelling, shipment and containment 
provisions are approved.
5.7.3
Chain of custody of biological samples
A full chain of custody is 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 and/or disposal 
(where appropriate) and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.

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AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory/service providers.
Samples retained for further use are registered in the AstraZeneca Biobank during the entire 
life cycle. 
5.7.4
Withdrawal of consent for donated biological samples
If a subject withdraws consent to the use of donated biological samples for future analysis 
purpose, the samples will be disposed of/destroyed, and the action documented.  If samples 
are already analysed, AstraZeneca is not obliged to destroy the results of this research.
Subjects who withdraw their consent for the use of their donated samples for future 
exploratory use, will be allowed to continue in the study.
The Principal Investigator:
∀
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
documented in subject’s source documentation and notified immediately to 
AstraZeneca
∀
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
∀
Ensures the laboratory(ies)/facility(ies) holding the samples is/are informed about 
the withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site
∀
Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the central laboratory(ies)/facility(ies) holding the samples is/are 
informed about the withdrawn consent immediately and that samples are disposed 
of/destroyed and the action documented and returned to the study site.

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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 adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study period (i.e., run-in, treatment, 
follow-up), that fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
∀
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
∀
Is a congenital abnormality or birth defect
∀
Is an important medical event that may jeopardise the 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 will be collected from the time the subject signs the informed consent form, 
throughout the treatment period and till end of follow-up period at FU 2 Visit.

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6.3.2
Follow-up of unresolved adverse events
AEs that are unresolved at the time of telephonic FU 2 Visit (or on-site FU 2 visit 
for WOCBP) will be followed up by the Investigator for as long as medically 
indicated, but without further recording in the eCRF. If deemed necessary and 
depending on their judgement, Principal Investigator may even call the subject for 
an on-site visit for further evaluation. 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
Variables 
The following variables will be collected 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 investigational product
∀
Outcome.
*Intensity rating scale:
1 mild (awareness of sign or symptom, but easily tolerated)
2 moderate (discomfort sufficient to cause interference with normal activities) 
3 severe (incapacitating, with inability to perform normal activities)
In addition, the following variables (if applicable) will be collected in eCRF for SAEs:
∀
Date AE met criteria for serious AE
∀
Date Investigator became aware of serious AE
∀
AE is serious due to
∀
Date of hospitalisation
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to Study procedure(s)
∀
Description of AE.

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It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between investigational product and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B 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 had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any untoward findings or events encountered during or after the conduct of study procedures 
that are not related to the disease under investigation will be reported as an AE(s)/SAE(s).

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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 D 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:
o
the sign or symptom is serious according to definitions, see Section 6.2
o
the subject discontinues the study due to the sign or symptom, and/or
o
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 5.1.12.
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 have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.

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For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is 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 recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module. An overdose without associated 
symptoms is only reported on the Overdose eCRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representative(s)
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative(s) 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 investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication.  Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs.  Elective abortions without 
complications should not be handled as AEs.  The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the subject was discontinued from the study.

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If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representative(s) within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative(s) will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The 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 
when IP is being administered.  Study site personnel must be trained to recognize and treat 
anaphylaxis (Lieberman P et al 2010). Details on anaphylaxis management are provided in 
Appendix F.
Anaphylaxis will be defined as serious reaction that is rapid in onset and may cause death
(Sampson HA 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.
In order to help understand the potential drug-relatedness of any acute reaction, a blood
sample should be drawn during the event for anti-drug antibody/neutralizing anti-body
(ADA/nAb) testing. 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 sample will be tested at the local lab or central 
laboratory where applicable.
6.8
Study governance and oversight
Not applicable.

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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
The IP will be manufactured in accordance with Good Manufacturing Practice (GMP).
Tralokinumab and placebo administered in the study will be a clear to opalescent, colorless to 
yellow solution free from, or practically free, from visible particles.
Subjects will be randomized in a 1:1 ratio to receive 300 mg tralokinumab or placebo every 2 
weeks.
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 4.
Table 4
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) 
polysorbate-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 pre-filled 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 pre-filled syringe sub-assembly (PFS-SA; 1 mL fill volume, pre-filled 
syringe barrel with a 27 gauge thin wall, 1/2 inch long staked in needle, rigid needle shield, 
plunger stopper) and a safety device.

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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. IP will be administered after performing all other visit specific 
assessments.
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. 
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.

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After IP administration
At Visits 3c 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.
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:
o
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)
o
The subject, in the opinion of the Investigator, is experiencing an acute or 
emerging asthma exacerbation
o
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 Good 
Manufacturing Practice (GMP) and local regulatory guidelines.  The labels will fulfil GMP 
Annex 13 requirements for labelling.  Label text will be translated into local language as 
applicable.
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:
o
Temperature excursion upon receipt or during storage at the study site,
o
Damaged kit upon receipt, or
o
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 drug provided for this study will be used only as directed in the study 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 site should contact the unblinded AstraZeneca monitor to 
initiate a product complaint process according to applicable guidelines.
7.7
Concomitant and other treatments 
Information about any treatment in the 3 months prior to the date of the informed consent 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 and recorded in the eCRF.
Maintenance of asthma controller medication 
All subjects are required to be treated with a stable dose of ICS corresponding to ≥250 μg 
fluticasone propionate dry powder formulation equivalents (as outlined in Appendix E) total 
daily dose for at least 1 month prior to Visit 1 and during the treatment period. Subjects may 
also receive other physician prescribed asthma controller medications. The maintenance 
asthma controller therapy should be maintained at a stable dose from Visit 1 until the end of 
the treatment period.
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 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.
As theophylline has narrow therapeutic window, please note that subjects on maintenance 
treatment with theophylline should have blood concentration levels within therapeutic range 

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documented before Visit 1. 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. Investigator can use their 
clinical judgement about the therapeutic range of theophylline levels on the basis of sampling 
time and other factors that may impact the results.
Rescue medication 
Salbutamol, albuterol, or levalbuterol will be used as rescue medication during the study in the 
event of a worsening of asthma symptoms. 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.
7.7.1
Restriction during and after the study
7.7.1.1
Asthma medication restrictions
Use of short-acting β2-agonists (SABA)
Regularly scheduled SABA use in the absence of any asthma symptoms is discouraged from 
enrolment (Visit 1) 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 discouraged, except as 
urgent treatment during an asthma exacerbation.  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 
enrolment and throughout the study duration.
Use of long-acting β2-agonists (LABA) as a reliever
The use of LABA as a reliever (e.g., Symbicort maintenance and reliever treatment) is not 
allowed from enrolment 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 medications should be stabilized at least 1 month prior to the subject 
entering the study. Should the subject be taking the once daily BD or theophylline in the 

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evening, it is advised that the Investigator ask the subject to reschedule their BD or 
theophylline regimen to morning use, if there are no medical reasons to prevent this change.
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. 
7.7.1.2
Restrictions before study visits
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 pulmonary assessment should be noted in the record.
Asthma medication restrictions for scheduled visits
Subjects should be instructed not to take their usual asthma controller medication prior to 
scheduled study visits (Except on visits when bronchoscopy is scheduled). Subjects should be 
advised to bring their scheduled asthma medications along with them to study site and take 
them after the study visit assessments as per Table 1 are complete. Following restrictions 
apply for scheduled visits:
!
Use of SABA within 6 hours
!
Use of twice daily LABA or ICS/LABA within 12 hours
!
Use of once daily LABA within 24 hours
!
Use of theophylline and once daily BD within 48 hours
If the above restrictions are not adhered to Investigator should reschedule the study visit.
However, for Visits 4, 5, 7 and 8, Investigator can decide if the same restriction should apply.
7.7.1.3
Medication restrictions with study procedures
Details of permitted use and restrictions of medications before, during and after study 
procedures, if any are provided along with procedure details in a separate manual.
7.7.1.4
Other medication restrictions
Use of any off-label medications, for example medications locally approved for Chronic 
Obstructive Pulmonary Disease but not for asthma, are also not allowed from 30 days prior to 
Visit 1 and throughout the study.
Use of immunosuppressive medication including oral corticosteroids is not allowed.

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Receipt of live attenuated vaccines within 30 days prior to enrolment (Visit 1) 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 any new allergen immunotherapy during the study. However, 
allergen immunotherapy initiated at least 30 days prior to Visit 1, may be continued provided 
there is no dose change and there is a span of at least 5 days between the immunotherapy and 
IP administration.
Subjects should not take any other excluded medications including Oral or ophthalmic non-
selective β-adrenergic antagonist (e.g., propranolol).
A table with medication-related restrictions is presented in Appendix G.
7.7.2
Other concomitant treatment
Subjects should not undergo bronchial thermoplasty during the study. Other medication other 
than that described above, which is considered necessary for the subject’s safety and 
wellbeing, may be given at the discretion of the Investigator and recorded in the appropriate 
sections of the eCRF.

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8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to database lock and 
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 database lock 
and protocol violators identified.
8.2
Sample size estimate
The study is powered to show a reduction in airway submucosal eosinophils, from baseline to 
week 12 for tralokinumab, versus placebo in the overall study population.
The sample size is based on the primary endpoint; change from baseline to Week 12 in airway 
submucosal eosinophils. Given the assumed deviation of the log values in the two treatment 
groups are 1.62 and 1.82, it is estimated that 31 subjects in each treatment arm will be 
sufficient to achieve at least 80% power to detect a 3.5-fold difference versus placebo using a 
two-sided test at 5% significance level. With these assumptions the smallest difference that 
will yield a significant result is a 2.4-fold difference. The assumptions are based on the change 
in number of eosinophils per mm2 subepithelial tissue in bronchial biopsies in studies 
D5890C00003 (Budesonide/ formoterol) (Pavord ID et al 2009) and MI-CP166 (Laviolette M 
et al 2013). Though there are some differences between the design of these studies and 
MESOS, they are considered the most relevant available studies.
It is assumed that a non-neglectable proportion of the subjects will not have an evaluable 
primary endpoint value due to failed biopsies. To account for this, 40 subjects will be
randomized in each treatment arm.
8.3
Definitions of analysis sets
All efficacy analyses will be performed using an ITT approach based on the full analysis set.
It should however be noted that only subjects with complete data will be included in the 
primary analysis. For consistency, demographic and baseline characteristics will be presented 
using the full analysis set. Safety objectives will be analysed based on the Safety population.
All 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.
8.3.1
Efficacy analysis set
Full analysis set: All subjects randomized and receiving any investigational product will be 
included in the full analysis set, irrespective of their protocol adherence and continued 
participation in the study. Subjects will be assigned according to their randomized treatment, 
irrespective of whether or not they have prematurely discontinued. Subjects who withdraw 
consent to participate in the study will be included up to the date of their study termination. 

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All efficacy analyses will be based on the full analysis set and analysed according to the ITT 
principle.
8.3.2
Safety analysis set
Safety analysis set (Safety): All subjects who received any investigational product 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. PK blood samples are assumed not to be affected by factors such as protocol 
deviations (eg, 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
Definition of baseline and subject baseline analyses
The baseline for outcome variables based on efficacy biomarkers is defined as value recorded 
at the Visit 3 (a, b or c); if a measurement is not scheduled to be measured at Visit 3 or if the 
Visit 3 measurement is missing, the last non-missing value before Visit 3 will be used as 
baseline instead.
The baseline for ACQ-6 and SNOT-20 will be captured using an eDiary and paper based tool 
respectively at Visit 3c. Baseline for Asthma Daily Diary variables will be the mean for data 
collected between Visit 1 and 2. If more than 7 daily measures/scores (>50%) within a period 
is missing, then the bi-weekly mean for that period is set to ‘missing’.
For laboratory data and physical examination, baseline will be defined as the latest non-
missing assessment prior to first dose (Visit 3c).
Absolute change from baseline outcome variables is computed as (post-randomization value –
baseline value). 
Percent change from baseline is computed as 100 x 1((post-randomization value – baseline 
value) / baseline value) %. 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.
The ratio post-randomization value / baseline value will also be computed when stated below.

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8.4.2
Primary outcome measure
The change, expressed as a ratio, in number of airway submucosal eosinophils per mm2
determined by microscopic evaluation of bronchoscopic biopsies from baseline (Visit 3c) to 
week 12 (Visit 9) i.e. (Visit 9/Visit 3c) will compared between treatments. 
An absolute change variable is considered as a supportive variable to the primary variable.
8.4.3
Secondary outcome measures
∀
The change, expressed as ratio, in blood eosinophil counts levels from baseline up to 
week 12. 
∀
The change, expressed as a ratio, in number of differential sputum eosinophils from 
baseline up to week 12.
∀
The change, expressed as a ratio, in blood and sputum free eosinophils cationic protein 
(ECP) from baseline up to week 2.
Absolute change variables are considered as supportive variables as well as the change in 
sputum eosinophils as percentage number of inflammatory cells.
8.4.4
Exploratory outcome measures
8.4.4.1
Other biomarkers of airway inflammation
∀
Change from baseline to week 12 in number of eosinophils per mm2 of epithelium and 
airway smooth muscle bundle
∀
Change from baseline to week 12 in inflammatory cell counts/mm2 of epithelium, 
submucosa and airway smooth muscle bundle for:
o
CD3+, CD4+, CD8+ lymphocytes,
o
Neutrophils,
o
Macrophages, 
o
Mast cells, 
∀
Change from baseline to week 12 in induced sputum for:
o
Number of neutrophils, lymphocytes and macrophages per mL
o
Number of neutrophils, lymphocytes and macrophages as percentage number 
of inflammatory cells
o
Soluble biomarkers including (but not limited to) histamine, leukotrienes, IL-
13, IL-5, IL-12, IL-31
∀
Change from baseline to week 12 in serum:
o
Biomarkers which may include (but are not limited to) periostin, DPP4, 
eotaxin, MCP1, TARC, IL-5, IL-33, STAT6, IL-13Rα2, MCP4/CCL13, 
TARC/CCL17, CLCA1, SERPINB2 and other  standard biomarkers of tissue 
destruction, vascular adhesion molecules
∀
Change from baseline to week 12 in biomarkers from nasosorption samples
∀
Change from baseline to week 12 in blood total IgE
∀
Change from baseline to week 12 in exhaled nitric oxide

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8.4.4.2
Effect on large airways remodelling
Change from baseline to week 12 in:
∀
Airway epithelial cell integrity, 
∀
Lamina reticularis and reticular basement membrane thickening, 
∀
Deposition of periostin in basement membrane
∀
Mucus glands, MUC5A, 
∀
Biomarkers of tissue remodelling and/or destruction which may include but are not 
limited to α-SMA and collagen type IV, fibronectin, laminin tenascin and TGFβ and 
epithelial damage markers which may include caspase 3 and CC16/KL6
∀
Airway epithelial gene expression
∀
Large airway dimensions and estimated airway resistance determined from CT
8.4.4.3
Effect on small airways obstruction
Change from baseline to week 12 in:
∀
R5-R20 and AX as evaluated by AO 
∀
Sacin by using MBW
∀
Air trapping expressed as percentage of the lung with expiratory density less than -856 
HU, and as expiratory-to-inspiratory ratio of mean lung density on CT
∀
Regional matching of the inspiratory/expiratory CT scans to assess air trapping/small 
airway obstruction
∀
Extent of gas trapping determined from physiologic testing by TLC/RV, VC/IC, FRC
8.4.4.4
Effect on asthma symptoms and other asthma control metrics
For asthma symptom score, rescue medication use and home PEF, biweekly means will be 
calculated. A biweekly mean is calculated as the sum of all non-missing daily measures/scores 
over 14 sequential days divided by the number of non-missing daily measures/scores.  For 
nights with awakenings due to asthma, the bi-weekly mean will be the percentage of times the 
subject answered “yes” to ‘did your asthma cause you to wake up’ and “yes” to ‘did you use 
rescue medication upon awakening’. If more than 7 daily measures/scores (>50%) within a 
period is missing, then the bi-weekly mean for that period is set to ‘missing’.
Percent change from baseline will be calculated as described in Section 8.4.1.
Mean daily 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 

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night-time asthma symptom score on a given day then the total score for that day will be set to 
missing.
The 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’. 
Rescue 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.
The number of inhalations (puffs) per day will be calculated as follows:
Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of day 
inhaler puffs + 2 x [number of day nebulizer times].  
Biweekly mean number of inhalations (puffs) per day will be calculated as the outcome 
variable.
Nights with awakening due to asthma
The total biweekly number of nights with awakening due to asthma that required rescue 
medication will be calculated as the outcome variable.
Home peak expiratory flow (morning and evening)
Biweekly mean absolute changes from baseline in morning and evening PEF will be 
calculated.
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 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

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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 main outcome variable for the ACQ-6 will be the ACQ-6 
score, 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
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
8.4.4.5
Effect on rhinosinusitis symptom metrics
Using the SNOT-20 questionnaire , subjects are asked to recall their experiences during the 
previous 2 weeks and to score each of the 20 questions on a 6-point scale ranging from 0 (no 
problem) to 5 (problem as bad as it can get).
The total score is calculated for all the questions answered. 
The main outcome variable for the SNOT-20 will be the change in total score from baseline to 
week 12. The change from baseline will be derived as post-randomization score minus 
baseline score, there will be no imputation for missing values.
8.4.4.6
Effect on lung function and bronchial hyper-responsiveness
∀
Change from baseline to week 12 in Pre and Post BD FEV1,FVC, FEF25-75% 
o
FEV1, FVC and FEF25-75% variables will be calculated based on the pre BD 
and post BD measurements.
∀
Change from baseline to week 12 in AHR 
o
Percent change and absolute change from baseline (supportive variable) will be 
calculated as described in Section 8.4.1.
8.4.4.7
Calculation or derivation of pharmacokinetics and immunogenicity variables
Blood samples (processed to serum) for pharmacokinetic and immunogenicity assessments 
will be collected from all subjects in accordance with schedule in Table 1. ADA assessments 
will be conducted utilizing a tiered approach (screen, confirm, titer). These validated methods 

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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 that confirm positive for ADA will also be tested for nAb activity. 
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.
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 association of ADA status across the study (positive vs. negative) with AEs/SAEs may be 
evaluated. 
Neutralizing antibody evaluations will be conducted on those serum samples that test positive 
for ADA at end of treatment and also during the study follow up period.  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.  Samples positive for nAb to 
tralokinumab are then titered to determine relative amounts of nAb present in each test 
sample.
8.4.5
Calculation or derivation of safety variable(s)
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline to each post-baseline time point where scheduled assessments were 
made will be calculated for relevant measurements. 
8.4.5.1
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).
Adverse event 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
o
(onset date > the last day of study treatment + 2 weeks and ≤ the last day of 
study treatment + 16 weeks)

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∀
AEs occurring post-treatment (onset date > the last day of study treatment + 16
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.
8.4.5.2
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 haematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
8.4.5.3
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 in Section 5.2.1, will be collected. Laboratory 
data will be reported in SI units.
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent on treatment assessment will be calculated as described in Section 8.4.1. 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), positive (+), or strongly positive (++, +++, 
or >+++) 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.
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.

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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
8.4.5.4
ECGs
Twelve-lead ECG 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.
8.4.5.5
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 5.2.3. 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 3c) complete physical examination will be 
recorded as normal or abnormal. Each component of the follow-up 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.
8.4.5.6
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 sign variables between baseline and each subsequent scheduled assessment 
will be calculated as described in 8.4.1. 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 BMI = kg/m2.

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8.5
Methods for statistical analyses
The main focus for the statistical analyses is to compare tralokinumab to placebo with regards 
to primary key secondary, and safety objectives.
The analysis of the study endpoints will include all data captured during the 12-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 to study participation. 
The statistical analyses will compare tralokinumab to placebo. 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, standard deviation (SD), geometric 
mean, SD of log values, median, and range. All data will be listed and data listings will be 
sorted by treatment and subject number.
The primary and secondary variables will be analysed using geometric means. Geometric 
mean is often used to evaluate data covering several orders of magnitude, and for evaluating 
ratios, percentages, or other data sets bounded by zero. A geometric mean, unlike an 
arithmetic mean, tends to dampen the effect of very high or low values, which might bias the 
mean if an arithmetic mean was calculated. The geometric mean is also a log-transformation 
of data to enable meaningful statistical evaluations; it accounts for some of the expected 
skewness in the data, but with the possibility to use a parametric analysis with a p-value 
directly linked to the confidence interval for the treatment effect. Both the difference in 
number of cells and the %change or ratio will be reported, but the statistical analysis will only 
be based on the ratio. Nonparametric analyses will be applied as sensitivity analyses.
All hypothesis testing will be reported using 2-sided tests. Nominal p-values will be reported 
for primary and secondary variables i.e., no adjustment of multiplicity will be performed. P-
values will be rounded to 3 decimal places.
8.5.1
Analysis of the primary variable (s)
The primary efficacy objective will be evaluated through statistical testing of the within 
subject change from baseline to week 12 in airway submucosal eosinophils. The null 
hypothesis test H0 will be: The ratio tralokinumab/placebo equals 1 and will be tested vs. H1:
The ratio is not equal to 1.
The primary variable of within subject change from baseline to Week 12 in airway 
submucosal eosinophils will be analysed using an analysis of covariance (ANCOVA)
including at least baseline value and treatment as covariates. The analysis will be performed 
by using log-transformed data and estimated geometric means and the ratio of geometric 
means with 95% confidence intervals will be presented.

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If the change from baseline for a subject is zero, the value will be replaced by half the smallest 
observed value among the subjects with non-zero values, before doing the logarithmic 
transformation. 
Available values at both baseline and week 12 are required for a subject to be included in the 
analysis and it is unlikely that a subject with a missing baseline value will undergo a second 
biopsy.
8.5.2
Analysis of the secondary variable(s)
The secondary variables of within subject change from baseline up to Week 12 in blood and 
sputum eosinophils and blood and sputum free eosinophil cationic protein (ECP) will be 
analysed using a mixed model for repeated measures (MMRM) including at least treatment as 
covariate. The analysis will be performed by using log-transformed data.
8.5.3
Subgroup analysis
Potential sub-group analyses are currently under discussion and will then be conducted for the 
primary, secondary as well as selected CT and lung function parameters.
8.5.4
Interim analysis
Not applicable.
8.5.5
Sensitivity analysis
For the primary and secondary variables, non-parametric analysis methods will be applied as 
sensitivity analyses.
It is likely that some biopsy specimens will not be evaluable. Also, due to the invasive 
procedures performed, it is likely that some subjects will withdraw from the study. We cannot 
rule out that there is a relationship between unobserved values and the likelihood of data being 
missing and therefore the effect of missing data will be assessed using multiple imputations 
and a range of assumptions for the missing data.
Full details of the sensitivity analyses will be pre-specified in SAP and documented prior to 
database lock of the studies.
8.5.6
Exploratory analysis 
Exploratory variables will be summarized using descriptive statistics and graphical displays.
How changes in biomarkers correlate with changes in airway inflammation and remodelling 
will be explored graphically.

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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 staff and also train them in 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 given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will 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 contacts with the study site, 
including visits to:
∀
Provide information and support to the Investigator(s)
∀
Confirm that facilities remain acceptable
∀
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples and CT image data 
are handled in accordance with the instruction manuals and that study drug accountability 
checks are being performed
∀
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (e.g., clinic charts)
∀
Ensure withdrawal of informed consent 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(s) will be available between visits if the Investigator(s) or 
other staff at the site needs 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.

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9.2.2
Study agreements
The Principal Investigator at each 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 CSA, the terms of Clinical Study Protocol shall 
prevail with respect to the conduct of the study and the treatment of subjects and 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 Q2, 2015 and to end by Q4, 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.
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 be 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 

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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 are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca.
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., eDiary, IVRS/IWRS, etc.) 
will be tested/validated as necessary. External data reconciliation will be done with the 
clinical database as applicable.

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10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with 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 Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the Informed Consent Form (ICF) and any other 
written information and/or materials to be provided to the subjects.  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 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, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, ECs/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 
investigational product.  AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.

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10.4
Informed consent
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
∀
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study
∀
Ensure the original, signed ICFs are stored in the Investigator’s Study File
∀
Ensure a copy of the signed ICF is 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 form that is approved by an EC/IRB.
10.5
Changes to the protocol and informed consent form
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 EC/IRB, see Section 10.3.
If a protocol amendment requires a change to a site’s ICF, AstraZeneca and the site’s EC/IRB 
are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB.

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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, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The Investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the site.

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11.
LIST OF REFERENCES
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Report of AAPM Task Group 23 of the Diagnostic Imaging Council CT Committee. College 
Park, MD: AAPM; 2008.
ATS Guideline 1999
American thoracic society. Guidelines for methacholine and exercise challenge testing-1999. 
Am J Respir Crit Care Med 2000: Vol 161: pp 309-329. 
Blanchard C et al 2005
Blanchard C, Mishra A, Saito-Akei H, Monk P, Anderson I, Rothenberg ME. Inhibition of 
human interleukin-13-induced respiratory and oesophageal inflammation by anti-human-
interleukin-13 antibody (CAT-354). Clin Exp Allergy 2005: Aug: 35(8):1096-103.
Bochner BS et al 1995
Bochner BS, Klunk DA, Sterbinsky SA, Coffman RL, Schleimer RP. IL-13 selectively 
induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol 
1995: Jan 15; 154 (2):799-803. 
Brightling CE et al 2014a 
C. E. Brightling, D. She, K. Ranade, E. Piper. Efficacy and safety of Tralokinumab, an anti-Il-
13 monoclonal antibody, in a Phase 2b study of uncontrolled severe asthma. Am J Respir Crit 
Care Med 2014: 189; A6670. Online abstract issue. www.atsjournals.org.  
Brightling CE et al 2014b 
C. E. Brightling, L. Nordenmark, M. Jain, E. Piper, D. She, M. Braddock, G. Colice, G. 
Tornling. Effect of anti-IL-13 treatment on airway dimensions in severe asthma. Abstract 
submitted to ATS 2015.
Chang YJ et al 2013
Chang YJ, DeKruyff RH, Umetsu DT. The role of type 2 innate lymphoid cells in asthma. J 
Leukoc Biol. 2013: Nov; 94(5):933-40.
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Edition Number 1.0
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Edition Number 1.0
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Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 15 January 2016
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Clinical Study Protocol Appendix B
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2 (3)
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS
ADVERSE EVENT (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation
!
Development of drug dependency or drug abuse

Clinical Study Protocol Appendix B
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
3 (3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?
!
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

Clinical Study Protocol Appendix C
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document

Clinical Study Protocol Appendix C
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2(3)
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm). For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005).  Infectious substances are now classified either as Category A, Category B or Exempt.  
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm)
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable

Clinical Study Protocol Appendix C
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
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!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times.  The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

Clinical Study Protocol Appendix D
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2(7)
TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................2
1.
INTRODUCTION ...................................................................................................3
2.
DEFINITIONS.........................................................................................................3
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES...................................4
4.
FOLLOW-UP ..........................................................................................................5
4.1
Potential Hy’s Law Criteria not met ........................................................................5
4.2
Potential Hy’s Law Criteria met ..............................................................................5
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW CASES...............5
6.
REFERENCES ........................................................................................................7

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
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1.
INTRODUCTION
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met.  HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the Investigational 
Medicinal Product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2.
DEFINITIONS
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP).

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
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Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the
elevations in transaminases and TBL must occur.
3.
IDENTIFICATION OF POTENTIAL HY’S LAW CASES
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3xULN
!
AST ≥ 3xULN
!
TBL ≥ 2xULN
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
identification criteria are met, where this is the case the Investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory
!
Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits (including 
both central and local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
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!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see Section 2 of this Appendix 
for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory CRF
4.
FOLLOW-UP
4.1
Potential Hy’s Law Criteria not met
If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2
Potential Hy’s Law Criteria met
If the patient does meet PHL criteria the Investigator will:
!
Notify the AstraZeneca representative who will then inform the central Study Team 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
!
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the Hy’s law lab kit should be used
!
Complete the three Liver CRF Modules as information becomes available 
!
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures
5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
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No later than 3 weeks after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP.  The AstraZeneca Medical Science Director and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
If there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF
!
If the alternative explanation is an AE/SAE, record the AE /SAE in the CRF 
accordingly and follow the AZ standard processes
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above
!
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to 
determine whether HL criteria are met.  Update the SAE report according to the 
outcome of the review

Clinical Study Protocol Appendix D
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
7(7)
6.
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf

Clinical Study Protocol Appendix E
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix E
Maintenance Therapy Equivalence Table

Clinical Study Protocol Appendix E
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2(2)
Clinical Study Protocol Appendix E
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix E
Maintenance Therapy Equivalence Table
Estimated daily doses for inhaled corticosteroids.
Asthma Therapy 
Total Daily Dose (μg/day)
Inhaled Corticosteroid
Low / Medium1
High
Beclomethasone dipropionate 
500 - 1000
>1000 - 2000
Beclomethasone HFA
240 - 480
>480
Beclomethasone dipropionate (Fostair)
200 - 400
>400 - 800
Ciclesonide 
160 - 320
>320 - 1280
Triamcinolone acetonide 
1000 - 2000
>2000
Flunisolide 
1000 - 2000
>2000
Fluticasone furoate
100
200
Fluticasone propionate 
250 - 500
>500 - 1000
Fluticasone propionate HFA
364 - 440
>440
Budesonide
Budesonide, if as delivered dose (e.g. Symbicort)
400 - 800
320 - 640
>800 - 1600
>640 – 1280
Mometasone furoate 
200 - 400
>=800
                                                
1 The acceptable ICS dose for this study is equal to or above the bolded dose.

Clinical Study Protocol Appendix F
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix F
Anaphylaxis: definition criteria, signs and symptoms, and management

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2(5)
1.
INTRODUCTION
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organization has categorized anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic [IgE-mediated and non-IgE-mediated (e.g., IgG and immune 
complex mediated) and nonimmunologic (Johansson SGO et al, 2004). The clinical criteria 
for defining anaphylaxis for this study are listed in section 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in section 3. Appropriate drugs, 
such as epinephrine, antihistamines, corticosteroids, etc, and medical equipment to treat 
anaphylactic reactions must be immediately available at study sites, and study personnel 
should be trained to recognize and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the patient as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase.
2.
CLINICAL CRITERIA FOR DEFINING ANAPHYLAXIS AND 
IMMUNE COMPLEX DISEASE
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING:
(a)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(b)
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (e.g., 
hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula)
(b)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
3(5)
(c)
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
(d)
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that patient’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-
antibody or antigen-antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness and nephritis is common.
3.
SIGNS AND SYMPTOMS AND MANAGEMENT OF ACUTE 
ANAPHYLAXIS
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur: 
- Diffuse erythema
- Pruritus
- Urticaria and/or angioedema
- Bronchospasm
- Laryngeal edema
- Hypotension
- Cardiac arrhythmias
- Feeling of impending doom
- Unconsciousness
- Shock
Other earlier or concomitant signs and symptoms can include:
- Itchy nose, eyes, pharynx, genitalia, palms, and soles
- Rhinorrhea

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
4(5)
- Change in voice
- Metallic taste
- Nausea, vomiting, diarrhea, abdominal cramps and bloating
- Lightheadedness
- Headache
- Uterine cramps
- Generalized warmth
4.
MANAGEMENT OF ACUTE ANAPHYLAXIS
4.1
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness
4.2
Possibly appropriate, subsequent measures depending on response 
to epinephrine
(a)
Place patient in recumbent position and elevate lower extremities
(b)
Establish and maintain airway
(c)
Administer oxygen
(d)
Establish venous access
(e)
Normal saline IV for fluid replacement
4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a)
Consider epinephrine infusion
(b)
Consider H1 and H2 antihistamines
(c)
Consider nebulized β2 agonist [e.g., albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
5(5)
(d)
Consider systemic corticosteroids
(e)
Consider vasopressor (e.g. dopamine)
(f)
Consider glucagon for patient taking β-blocker
(g)
Consider atropine for symptomatic bradycardia
(h)
Consider transportation to an emergency department or an intensive care facility
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.
Johansson SGO et al, 2004
Johansson SGO et al. Revised nomenclature for allergy for global use: Report of the 
Nomenclature Review Committee of the World Allergy Organization, October 2003. (J 
Allergy Clin Immunol. 2004; 113: 832-6.

Clinical Study Protocol Appendix G
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
1.0
Date
26 February 2015
Appendix G
Restricted and prohibited medications

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
2(5)
PROHIBITED AND RESTRICTED MEDICATIONS
Asthma medication restrictions
Medication
Prohibited/restricted
Details
Maintenance treatment with 
long-acting bronchodilators 
(including ICS/LABA
combinations)
Restricted
Changes in dose and regimen should 
not be done from enrolment and 
throughout the study treatment 
(unless there is a medical need as 
judged by the Investigator)
Usual ICS/LABA should not be taken 
prior to scheduled study visits defined 
in the protocol and home lung 
function assessments (to be 
administered once assessments are 
completed)
Subjects should be instructed not to 
use their twice daily LABA within 12
hours of the scheduled site visit. For 
once daily LABA a 24 hour washout 
period is required
Subjects will not need to washout of 
their asthma medications for 
unscheduled visits due to asthma 
worsening

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
3(5)
Short acting β2-agonists 
(SABA)
Restricted
Regular scheduled use not allowed 
from enrolment through the study 
duration
Rescue use of SABA administered 
via nebulization is discouraged, 
except as urgent treatment during an 
asthma exacerbation
SABA should not be used within 6 
hours prior to scheduled study visits 
defined in the protocol and home lung 
function assessments with the 
exception of any unscheduled visits 
due to asthma worsening and home 
lung function assessments
Additional Maintenance 
Controllers
Allowed with 
restriction
Stable dose for 1 month prior to Visit 
1; stable dose during the treatment 
period
Subjects on theophylline should have 
blood concentration levels within 
therapeutic range documented before 
Visit 1
Subjects should be instructed not to 
use additional once daily 
bronchodilators within 48 hours of 
the scheduled study visits defined in 
the protocol with the exception of any 
unscheduled visits due to asthma 
worsening
Short acting anticholinergics 
(e.g. ipratropium)
Restricted
Not allowed from enrollment and 
throughout the study as a rescue 
treatment for worsening asthma 
symptoms outside of managing an 
asthma exacerbation event 
May be used for managing an asthma 
exacerbation event

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
4(5)
Long-acting β-agonists as a 
reliever (e.g. Symbicort 
Maintenance and Reliever 
Treatment)
Prohibited
Not allowed from enrolment and 
throughout the study duration
Zileuton
Prohibited
Not allowed 30 days prior to Visit 
1;during treatment period
Other medication restrictions
Medication
Prohibited/restricted
Details
Live Attenuated Vaccines
Prohibited
Not allowed 30 days prior to Visit 1;
during treatment period and 4 months 
(5 half-lives) after the last dose of the 
investigational product
Inactive/killed vaccinations
(e.g. inactive influenza) 
Restricted
Allowed provided they are not 
administered within 5 days before or 
after any study visit
Any immunomodulators or 
immunosuppressives 
(including long-acting depo 
corticosteroids)
Prohibited
Not allowed 3 Months or 5 Half Lives 
(whichever is longer) prior to Visit 1;
during treatment period; 3 Months or 5 
Half Lives (whichever is longer) after 
the last dose of the investigational 
product
Blood products or 
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to Visit 1; 
during treatment period
Any marketed (eg 
omalizumab) or 
investigational biologic 
treatment
Prohibited
Not allowed 4 months or 5 half-lives 
(whichever is longer) prior to Visit 1; 
during treatment period; 4 months or 5 
half-lives (whichever is longer) after 
the last dose of the investigational 
product
Other investigational 
products (including 
investigational use of an 
Prohibited
Not allowed 30 Days or 5 Half Lives 
(whichever is longer) prior to Visit 1; 
during treatment period

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 1.0
Date 26 February 2015
5(5)
Medication
Prohibited/restricted
Details
approved drug)
Allergen Immunotherapy
Restricted
Allowed if on stable therapy for at 
least 30 days prior to Visit 1; no 
anticipated changed during treatment 
period and provided there is a span of 
at least 5 days between the 
immunotherapy and IP administration
Herbal remedies for the 
treatment of allergic, 
inflammatory, or respiratory 
diseases
Prohibited
Not allowed 30 days prior to Visit 
1;during treatment period
Roflumilast 
Prohibited
Not allowed 30 days prior to Visit 
1;during treatment period
Oral or ophthalmic non-
selective β-adrenergic 
antagonist (e.g. propranolol)
Prohibited
Patients currently using any oral or 
ophthalmic non-selective β-adrenergic 
antagonist at the time of enrolment are 
not eligible for the study
Not allowed during treatment period
Medications not currently 
licensed for use in the 
treatment of asthma, for 
example medications 
approved for Chronic 
Obstructive Pulmonary 
Disease and not part of 
current standard of care
Prohibited
Not allowed 30 days prior to Visit 1; 
Not allowed throughout the duration 
of the study

Clinical Study Protocol Appendix H
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00014
Edition Number
2.0
Date
15 January 2016
Appendix H
Post-BD spirometry and FEV1 reversibility assessment algorithm

Clinical Study Protocol Appendix H
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
2(3)
POST-BD SPIROMETRY AND FEV1 REVERSIBILITY ASSESSMENT 
ALGORITHM
1. Verify with the subject that the medication restrictions for performing spirometry 
assessment have been met. For details please see sections 5.1.8 and 7.7.1.
2. Complete the initial (pre-BD) FEV1 measurement (refer section 5.1.8).
The standard metered dose for each inhalation of bronchodilator in the reversibility 
assessment is salbutamol 100μg.
Step 1: FEV1 measurement after 4 bronchodilator inhalations  
For administration of salbutamol, the subject will:
i.
Perform a gentle, complete expiration 
ii.
Inhale Dose 1 of bronchodilator to total lung capacity (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 FEV1 is measured following the technique described in 
section 5.1.8.
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.
Step 2: FEV1 measurement following a further 2 (total of 6) bronchodilator inhalations
The subject will repeat the inhalation procedures for Dose 5 and Dose 6, resting for 15 – 20 
minutes after Dose 6.  (See Step 1 above for instructions).
After resting for the 15 – 20 minutes FEV1 will be measured following the technique 
described in Section 5.1.8.  
This is the end of the reversibility assessment if either of the following occur: 
-
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% but the criterion for reversibility has not yet been met.

Clinical Study Protocol Appendix H
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00014
Edition Number 2.0
Date 15 January 2016
3(3)
Step 3: FEV1 measurement following a further 2 (total of 8) bronchodilator inhalations
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 the 15 – 20 minutes FEV1 will be measured following the technique 
described in Section 5.1.8. 
The reversibility assessment is now complete.
V3a and V9 (EOT) Post-BD spirometry assessment will stop at the end of Step 1.