A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Reducing Oral Corticosteroid Use in Adults and Adolescents With Oral Corticosteroid Dependent Asthma (TROPOS)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca



Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
2 (130)
PROTOCOL SYNOPSIS
A Multicentre, Randomized, Double-blind, Parallel Group, Placebo 
Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of 
Tralokinumab in Reducing Oral Corticosteroid Use in Adults and 
Adolescents with Oral Corticosteroid dependent Asthma (TROPOS)
International Co-ordinating Investigator: 
Study site(s) and number of subjects planned
Approximately 120 subjects will be randomized at approximately 75 study centers worldwide.
Study period
Phase of development
Estimated date of first subject enrolled
Q1 2015
3
Estimated date of last subject completed
Q4 2017
3
Study design
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the efficacy and safety of a fixed 300 mg dose of tralokinumab administered 
subcutaneously every 2 weeks in adult and adolescent subjects with oral corticosteroid 
dependent asthma.
Approximately 120 subjects will be randomized to tralokinumab or placebo (1:1) globally 
from about 75 study centers. All subjects will be stratified at randomization by age group 
(adults versus adolescents). Adult subjects will also be stratified at randomization by the 
baseline oral corticosteroid dose (≤10 mg versus > 10 mg prednisone or prednisolone).
After the initial enrolment (Visit 1) and confirmation of entry criteria subjects will, depending 
on their recent asthma and oral corticosteroid medication history, enter either:
-
a 2-week run-in period (if there has been a documented failure of oral corticosteroid
dose reduction within 6 months prior to Visit 1, and after discussion with the sponsor 
study physician) (see section 4.1.1 and 4.1.2), or
-
a 2-week run-in period plus an 8-week optimization period to establish a minimum 
effective dose of the prescribed oral corticosteroid (established by dose titration every 
two weeks).  

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
3 (130)
Subjects who fulfill the eligibility criteria will be randomized to a 40-week treatment period. 
The last dose of tralokinumab or placebo will be given at week 38 with the end of treatment 
visit at week 40. Subjects will be maintained on their currently prescribed inhaled 
corticosteroid plus long-acting beta-2 agonist and any additional asthma controller medication, 
without change, from enrolment, throughout the run-in/optimization and treatment periods.
There are three phases in the 40-week treatment period following randomization where 
subjects will be administered study drug.
!
Induction phase – from week 0 to up to week 12 where subjects should remain on their 
optimized oral corticosteroid dose.
!
Oral corticosteroid reduction phase – from week 12 up to week 32, oral corticosteroid
dose reduction can be started at week 12 with the possibility of dose titration every 4 
weeks.
!
Maintenance phase – after the week 32 visit to week 40, subjects should remain on the 
oral corticosteroid dose reached at week 32 or remain on complete oral corticosteroid 
elimination. 
Post treatment safety follow up visits will be performed at Week 44 and Week 54.
Objectives
Primary Objective:
Outcome Measures:
To evaluate the effect of tralokinumab 
compared to placebo in reducing the 
prescribed, oral corticosteroid maintenance 
dose in adult and adolescent subjects with 
asthma requiring chronic treatment with 
maintenance oral corticosteroids in 
addition to inhaled corticosteroid plus 
long-acting β2-agonist 
Primary outcome variable: Percent change 
from baseline in the daily, average, oral 
corticosteroid dose at week 40 post 
randomization while not losing  asthma control
Primary outcome measure: Percent difference 
vs. placebo at Week 40 post randomization

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
4 (130)
Secondary Objectives:
Outcome Measures:
To evaluate the effect of tralokinumab 
compared to placebo on the proportion of 
subjects with the prescribed, oral 
corticosteroid maintenance dose ≤5 mg in 
adult and adolescent subjects with asthma 
requiring chronic treatment with 
maintenance oral corticosteroids in 
addition to inhaled corticosteroid plus 
long-acting β2-agonist 
Difference vs. placebo in the proportion of 
subjects with final daily average oral 
corticosteroid dose ≤5 mg at Week 40 post 
randomization
To evaluate the effect of tralokinumab 
compared to placebo on the proportion of 
subjects with at least 50% reduction in 
their prescribed, oral corticosteroid 
maintenance dose in adult and adolescent 
subjects with asthma requiring chronic 
treatment with maintenance oral 
corticosteroids in addition to inhaled 
corticosteroid plus long-acting β2-agonist 
Difference vs. placebo in the proportion of 
subjects with ≥50% reduction in average daily 
oral corticosteroid dose at Week 40 post 
randomization

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
5 (130)
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
tralokinumab
!
Adverse Events/Serious Adverse Events
!
Vital signs
!
Digital electrocardiograms
!
Clinical chemistry/haematology/urinalysis
!
Physical examinations
Exploratory Objectives:
Outcome Measures:
To evaluate the effect of tralokinumab 
versus placebo in overall oral 
corticosteroid exposure
Overall oral corticosteroid exposure measured by 
the area under the dose curve
To evaluate the effect of tralokinumab 
versus placebo in the proportion of 
subjects that have decreased their daily 
average prescribed, oral corticosteroid dose
Change from baseline daily average oral 
corticosteroid dose classified as:
1. 100% reduction (no OCS)
2. ≥ 90% to < 100% reduction
3. ≥ 75% to < 90% reduction
4. ≥ 50% to < 75% reduction
5. > 0% to < 50% reduction
6. no change in average OCS dose
7. increased average OCS dose
To evaluate the effect of tralokinumab 
compared with placebo on asthma 
exacerbations.
Outcome variable: The annualised asthma 
exacerbation rate up to Week 40.    
Outcome measure: Asthma exacerbation rate 
reduction
To evaluate the effect of tralokinumab 
compared with placebo on lung function 
Outcome variables: Percent change from 
baseline in pre-bronchodilator forced expiratory 
volume in 1 second, Forced Vital Capacity and 
Forced Expiratory Flow between 25% and 75% 
of the Forced Vital Capacity
Outcome measure: Percent difference vs. 
placebo at Week 12 and 40

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
6 (130)
To evaluate the effect of tralokinumab 
compared with placebo on asthma 
symptoms and other asthma control 
metrics
Outcome variables:
-
Change from baseline in bi-weekly mean 
daily asthma symptom score (combined 
daytime and night-time score as captured 
in the Asthma Daily Diary). 
-
Change from baseline in rescue 
medication use 
-
Change from baseline in home peak 
expiratory flow (morning and evening) 
-
Change from baseline in the number of 
night-time awakening due to asthma 
-
Change from baseline in Asthma Control 
Questionnaire 6
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
asthma specific health-related quality of 
life
Outcome variable: Change from baseline in 
Standardised Asthma Quality of Life 
Questionnaire for 12 Years and Older total score 
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
health related quality of life.
Outcome variable: European Quality of Life 5 
Dimension 5 Level Questionnaire
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
health care resource utilization and 
productivity loss due to asthma
Outcome variables:
!
Asthma specific resource utilization (e.g., 
unscheduled physician visits, unscheduled 
phone calls to physicians, use of other 
asthma medications)
!
Work Productivity and Activity Impairment 
Questionnaire and Classroom Impairment 
Questionnaire scores
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
7 (130)
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
Outcome variables:
!
Pharmacokinetic parameters: Ctrough at 
steady-state
!
Immunogenicity outcome variables: 
incidence rate of positive anti-drug 
antibodies and characterization of their 
neutralizing potential
To evaluate the change from baseline of   
biomarkers that may be associated with up-
regulation of interleukin-13
To evaluate the relationship between 
baseline biomarkers and the effect of 
tralokinumab on oral corticosteroid dose 
reduction and clinical efficacy
To evaluate the impact of oral 
corticosteroid optimization on biomarkers
Biomarkers will include: 
!
Periostin
!
Dipeptidyl peptidase-4
!
Blood eosinophils 
!
Total serum Immunoglobulin E
!
Fractional exhaled nitric oxide
Other specific blood biomarkers may also be 
analyzed.
Target subject population
Male and female adults and adolescents, 12-75 years of age inclusive with diagnosed asthma 
willing to provide informed consent and requiring continuous treatment with inhaled 
corticosteroids (≥ 500 mcg fluticasone dry power formulation equivalents total daily dose) 
plus long-acting β2-agonist and  chronic treatment with maintenance oral corticosteroid 
therapy.
Duration of treatment
Following an initial enrolment (Visit 1), depending on recent asthma and oral corticosteroid 
medication history, subjects will enter either a 2 week run-in period or a 2-week run-in period 
plus an 8-week oral corticosteroid dose optimization period. The first dose of 
tralokinumab/placebo will be administered at Week 0. Subjects will receive tralokinumab or 
placebo every two weeks over a 40-week treatment period.

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
8 (130)
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 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).
The primary efficacy objective will be evaluated through the null hypothesis test H0: 
Difference in percentage reduction in the prescribed, oral corticosteroids (tralokinumab-
placebo) equals 0 vs. H1: difference not equal to 0. The test will be based on an analysis of 
covariance model. Covariates and factors included in the model will include at least treatment, 
age group and baseline oral corticosteroid dose. 
For binary variables based on oral corticosteroid dose, the proportion in the tralokinumab 
group will be compared with the proportion in the placebo group using a Cochran–Mantel–
Haenszel test controlling for age group and baseline oral corticosteroid dose. Continuous 
variables related to lung function, symptoms, health-related quality of life and Asthma Control 
Questionnaire-6 will primarily be analyzed using a repeated measures analysis approach 
including at least treatment, baseline value and stratifying variables as the explanatory 
variables. 
Asthma exacerbation rates will be analyzed using negative binomial models with the 
covariates of treatment, stratifying variables and number of exacerbations in the year before 
the study.
The sample size is based on the primary endpoint; percentage change in oral corticosteroid 
dose. Given an assumed standard deviation of 80% it is estimated that 55 subjects in each 
treatment arm will be sufficient to achieve at least 90% power to detect a true difference 
versus placebo of 50% using a two-sided test at 5% significance level.
The results for the exploratory variables will be summarized using descriptive statistics and 
confidence intervals by treatment group.
All safety parameters will be analyzed descriptively.  The safety analyses will be based on the 
safety analysis data set, defined as all subjects who received at least one dose of 
investigational product.

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
9 (130)
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................16
1.
INTRODUCTION .................................................................................................20
1.1
Background and rationale for conducting this study .............................................20
1.2
Rationale for study design, doses and control groups............................................21
1.3
Benefit/risk and ethical assessment........................................................................22
1.4
Study Design..........................................................................................................23
2.
STUDY OBJECTIVES..........................................................................................27
2.1
Primary objective...................................................................................................27
2.2
Secondary objectives .............................................................................................27
2.3
Safety objectives ....................................................................................................28
2.4
Exploratory objectives ...........................................................................................28
3.
SUBJECT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL......................30
3.1
Inclusion criteria ....................................................................................................30
3.2
Exclusion criteria ...................................................................................................33
3.3
Subject enrolment and randomization ...................................................................37
3.4
Procedures for handling incorrectly enrolled or randomized subjects...................37
3.5
Methods for assigning treatment groups................................................................37
3.6
Methods for ensuring blinding...............................................................................38
3.7
Methods for unblinding..........................................................................................39
3.8
Restrictions during and after the study ..................................................................39
3.9
Discontinuation of investigational product............................................................39
3.9.1
Procedures for discontinuation of a subject from investigational product ............39
3.10
Criteria for withdrawal...........................................................................................42
3.10.1
Screen failures........................................................................................................42
3.10.2
Withdrawal of the informed consent or assent.......................................................42

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
10 (130)
4.
STUDY PLAN AND TIMING OF PROCEDURES.............................................43
4.1
Enrolment and run-in/optimization period.............................................................52
4.1.1
Run-in period (Visit 1 – Visit 2)............................................................................52
4.1.2
OCS Optimization period (Visit 2 – Visit 5) .........................................................54
4.1.3
Re-screening ..........................................................................................................55
4.2
Randomized treatment period (Visit 6 – Visit 26).................................................56
4.2.1
Induction Phase......................................................................................................56
4.2.2
Reduction Phase.....................................................................................................56
4.2.3
Maintenance Phase.................................................................................................57
4.3
Follow-up period....................................................................................................57
5.
STUDY ASSESSMENTS .....................................................................................57
5.1
Efficacy assessments..............................................................................................57
5.1.1
Assessment of OCS dose .......................................................................................57
5.1.2
OCS dose titration..................................................................................................58
5.1.3
Assessment of asthma exacerbations.....................................................................61
5.1.4
Spirometry..............................................................................................................62
5.1.4.1
Reversibility test and post-BD FEV1 efficacy assessment ....................................65
5.1.5
Home PEF testing ..................................................................................................66
5.1.6
Safety assessments.................................................................................................67
5.1.6.1
Laboratory safety assessments...............................................................................67
5.1.6.2
Pregnancy Test.......................................................................................................72
5.1.7
Physical examination .............................................................................................72
5.1.7.1
Complete physical examination.............................................................................72
5.1.7.2
Brief physical examination ....................................................................................73
5.1.8
dECG......................................................................................................................73
5.1.8.1
Resting 12-lead dECG ...........................................................................................73
5.1.9
Vital signs ..............................................................................................................73
5.1.10
Other safety assessments........................................................................................74
5.1.10.1
Serology .................................................................................................................74
5.1.10.2
Infections................................................................................................................74
5.2
Other assessments ..................................................................................................74
5.2.1
Weight and height..................................................................................................74
5.2.2
Patient reported outcomes......................................................................................75
5.2.2.1
Asthma Daily Diary ...............................................................................................75
5.2.2.2
Asthma Control Questionnaire (ACQ-6)...............................................................76
5.2.2.3
Standardised Asthma Quality of Life Questionnaire for 12 Years and Older 
(AQLQ(S)+12).......................................................................................................77
5.2.2.4
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ).....................................................................77
5.2.2.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L) ................................78
5.2.2.6
Health care resource utilization..............................................................................78
5.3
Pharmacokinetics and Immunogenicity.................................................................78

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
11 (130)
5.3.1
Collection of samples.............................................................................................78
5.3.2
Determination of drug concentration.....................................................................79
5.3.3
Storage and destruction of pharmacokinetic samples............................................79
5.3.4
Immunogenicity.....................................................................................................79
5.3.5
Total IgE ................................................................................................................80
5.3.6
Phadiatop (Allergy Screen)....................................................................................80
5.4
Pharmacodynamics ................................................................................................80
5.4.1
Serum biomarkers ..................................................................................................80
5.4.2
Level of fractional exhaled nitric oxide.................................................................80
5.5
Pharmacogenetics (Not Applicable) ......................................................................81
5.6
Biomarker analysis.................................................................................................81
5.6.1
Storage, re-use and destruction of biological samples...........................................81
5.6.2
Labelling and shipment of biological samples.......................................................82
5.6.3
Chain of custody of biological samples.................................................................82
5.6.4
Withdrawal of Informed Consent or Assent for donated biological samples........82
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................83
6.1
Definition of adverse events ..................................................................................83
6.2
Definitions of serious adverse event......................................................................83
6.3
Recording of adverse events ..................................................................................84
6.3.1
Time period for collection of adverse events.........................................................84
6.3.2
Follow-up of unresolved adverse events................................................................84
6.3.3
Adverse event variables .........................................................................................84
6.3.4
Assessment of causality .........................................................................................85
6.3.5
Adverse events based on signs and symptoms.......................................................85
6.3.6
Adverse events based on examinations and tests...................................................86
6.3.7
Hy’s Law................................................................................................................86
6.3.8
Disease progression ...............................................................................................86
6.4
Reporting of serious adverse events.......................................................................87
6.5
Overdose ................................................................................................................87
6.6
Pregnancy...............................................................................................................88
6.6.1
Maternal exposure..................................................................................................88
6.6.2
Paternal Exposure ..................................................................................................88
6.7
Management of IP related toxicities ......................................................................88
6.8
Study governance and oversight ............................................................................89
6.8.1
Independent Adjudication Committee ...................................................................89
6.8.2
Data and safety monitoring board..........................................................................90
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................90
7.1
Identity of investigational product(s).....................................................................90
7.2
Dose and treatment regimens.................................................................................91

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
12 (130)
7.3
Labelling ................................................................................................................94
7.4
Storage ...................................................................................................................94
7.5
Compliance ............................................................................................................94
7.6
Accountability........................................................................................................94
7.7
Concomitant and other treatments .........................................................................95
7.7.1
Concomitant medications.......................................................................................95
7.7.2
Restrictions during and after the study ..................................................................96
7.7.2.1
Asthma medication restrictions..............................................................................96
7.7.2.2
Other medication restrictions.................................................................................98
7.7.2.3
Bronchial Thermoplasty.........................................................................................98
7.7.3
Other treatments.....................................................................................................98
8.
STATISTICAL ANALYSES BY ASTRAZENECA............................................98
8.1
Statistical considerations........................................................................................98
8.2
Sample size estimate..............................................................................................99
8.3
Definitions of analysis sets ....................................................................................99
8.3.1
Efficacy analysis set...............................................................................................99
8.3.2
Safety analysis set..................................................................................................99
8.3.3
PK analysis set .....................................................................................................100
8.3.4
PRO analysis set ..................................................................................................100
8.4
Outcome measures for analyses...........................................................................100
8.4.1
General Definitions..............................................................................................100
8.4.1.1
Definition of baseline and subject baseline variables..........................................100
8.4.1.2
Visit and period windows ....................................................................................100
8.4.2
Calculation or derivation of efficacy variables....................................................101
8.4.2.1
Percentage reduction from baseline in prescribed oral corticosteroid dose.........101
8.4.2.2
The proportion of subjects with average final prescribed OCS dose ≤5.0 
mg daily ...............................................................................................................102
8.4.2.3
Proportion of subjects with ≥50% reduction from baseline in the prescribed 
oral corticosteroid dose........................................................................................102
8.4.2.4
Area under the prescribed oral corticosteroid dose curve....................................102
8.4.2.5
Proportion of subjects in different categories of reduction from baseline in 
oral prescribed corticosteroid dose ......................................................................102
8.4.2.6
Proportion of subjects with ≥25% reduction from baseline and with 
average final OCS dose ≤5.0 mg daily. ...............................................................103
8.4.2.7
Proportion of subject with ≤5.0 mg reduction from baseline in oral 
corticosteroid dose ...............................................................................................103
8.4.2.8
Exacerbation rate..................................................................................................103
8.4.2.9
Time to first exacerbation ....................................................................................104
8.4.2.10
Proportion of subjects with ≥ 1 asthma exacerbation during 40 weeks of 
treatment ..............................................................................................................104
8.4.2.11
Annualised asthma exacerbation rate associated with an ER or urgent care 
visit or a hospitalization.......................................................................................104

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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8.4.2.12
Lung Function Variables......................................................................................105
8.4.2.13
Diary Based Variables .........................................................................................105
8.4.2.14
Asthma Control Questionnaire (ACQ-6).............................................................106
8.4.2.15
Asthma Quality of Life Questionnaire for 12 Years and Older...........................107
8.4.2.16
European quality of life-5 dimensions-5 levels (EQ-5D-5L) ..............................107
8.4.2.17
Health care resource utilization............................................................................108
8.4.2.18
The Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions (WPAI+CIQ).................................................108
8.4.3
Calculation or derivation of safety variable(s).....................................................109
8.4.3.1
Adverse events.....................................................................................................109
8.4.3.2
Other significant adverse events ..........................................................................110
8.4.3.3
Laboratory variables ............................................................................................110
8.4.3.4
dECGs..................................................................................................................111
8.4.3.5
Physical Examination...........................................................................................111
8.4.3.6
Vital signs ............................................................................................................111
8.4.4
Calculations or derivation of Pharmacokinetic and Immunogenicity 
variables ...............................................................................................................112
8.5
Methods for statistical analyses ...........................................................................112
8.5.1
Testing strategy for primary and key secondary objectives.................................112
8.5.2
Sensitivity analyses..............................................................................................113
8.5.3
Subject disposition, demography data and subjects characteristics.....................113
8.5.4
Exposure ..............................................................................................................114
8.5.5
Violations and deviations.....................................................................................114
8.5.6
Analysis of the primary variable..........................................................................114
8.5.7
Analysis of secondary variable(s)........................................................................115
8.5.7.1
The proportion of subjects with average final prescribed OCS dose ≤5.0 
mg daily ...............................................................................................................115
8.5.7.2
Proportion of subjects with ≥50% reduction from baseline in prescribed 
oral corticosteroid dose........................................................................................115
8.5.8
Analysis of supportive and exploratory variables................................................115
8.5.8.1
Area under the in prescribed oral corticosteroid dose curve................................115
8.5.8.2
Proportion of subjects in different categories of reduction from baseline in 
oral corticosteroid dose........................................................................................115
8.5.8.3
Proportion of subjects with ≥25% reduction from baseline and with 
average final prescribed OCS dose ≤5.0 mg daily...............................................116
8.5.8.4
Proportion of subjects with ≤5.0 mg reduction from baseline in oral 
corticosteroid dose ...............................................................................................116
8.5.8.5
Exacerbation rate..................................................................................................116
8.5.8.6
Other endpoint associated with asthma exacerbations.........................................116
8.5.8.7
Emergency room or urgent care visits and hospitalizations due to asthma .........117
8.5.8.8
Lung Function......................................................................................................117
8.5.8.9
Asthma symptoms................................................................................................117
8.5.8.10
Asthma symptom, general health-related quality of life and asthma control ......118
8.5.8.11
ACQ-6 defined asthma control ............................................................................118
8.5.8.12
Asthma specific health-related quality of life......................................................118

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
14 (130)
8.5.8.13
European quality of life-5 dimensions-5 levels (EQ-5D-5L) ..............................119
8.5.8.14
Health care resource utilization and productivity loss due to asthma..................119
8.5.9
Safety and tolerability..........................................................................................119
8.5.9.1
Adverse events.....................................................................................................119
8.5.9.2
Laboratory data ....................................................................................................120
8.5.9.3
dECGs..................................................................................................................121
8.5.9.4
Physical Examination...........................................................................................121
8.5.9.5
Vital Signs............................................................................................................121
8.5.9.6
Analysis of Immunogenicity variables ................................................................121
8.5.10
Analysis of pharmacokinetics..............................................................................122
8.5.11
Interim analysis....................................................................................................122
8.5.12
Exploratory analysis.............................................................................................122
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ........................122
9.1
Training of study site personnel...........................................................................122
9.2
Monitoring of the study .......................................................................................123
9.2.1
Source data...........................................................................................................123
9.2.2
Study agreements.................................................................................................123
9.2.3
Archiving of study documents.............................................................................123
9.3
Study timetable and end of study.........................................................................123
9.4
Data management by AstraZeneca ......................................................................124
10.
ETHICAL AND REGULATORY REQUIREMENTS.......................................125
10.1
Ethical conduct of the study.................................................................................125
10.2
Subject data protection.........................................................................................125
10.3
Ethics and regulatory review................................................................................125
10.4
Informed consent and assent................................................................................126
10.5
Changes to the protocol and informed consent or assent forms ..........................126
10.6
Audits and inspections .........................................................................................127
11.
LIST OF REFERENCES.....................................................................................128
LIST OF TABLES 
Table 1
Study Plan – Enrolment/Run-in/OCS optimization period ......................43
Table 2
Study plan – Treatment and follow-up period..........................................46
Table 3
OCS dose titration schedule during the optimization period (V2 –
V4)............................................................................................................60
Table 4
OCS dose titration schedule recommended during the reduction 
phase (V12-V20) a,b..................................................................................60

Clinical Study Protocol
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Edition Number 4.0
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Table 5
List of safety laboratory tests....................................................................68
Table 6
Clinical chemistry tests schedule..............................................................68
Table 7
Haematology/Haemostasis (whole blood) schedule.................................70
Table 8
Urinalysis schedule...................................................................................71
Table 9
Volume of blood to be drawn from each subject......................................71
Table 10
Identity of investigational product............................................................91
LIST OF FIGURES
Figure 1
Study flow chart (subjects with documented failure of OCS 
reduction within 6 months prior to Visit 1)..............................................25
Figure 2
Study flow chart (subjects undergoing dose optimization) ......................26
Figure 3
Injection sites and rotation scheme...........................................................93
LIST OF APPENDICES 
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

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Study Code D2210C00013
Edition Number 4.0
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-drug antibody
AE
Adverse Event
AAER
Annual Asthma Exacerbation Rate
AERR
Asthma Exacerbation Reduction Rate
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APFS
Accessorized Pre-filled Syringe
AQLQ(S)+12
Standardised Asthma Quality of Life Questionnaire for 12 Years and 
Older
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS/ERS
American Thoracic Society/European Respiratory Society
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood Urea Nitrogen
CO2
Carbon Dioxide
COPD
Chronic Obstructive Pulmonary Disease
CSA
Clinical Study Agreement
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
dECG
Digital Electrocardiogram
DPP4
Dipeptidyl Peptidase-4
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC)

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Edition Number 4.0
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Abbreviation or 
special term
Explanation
eCRF
Electronic Case Report Form
ED
Emergency Department
ER
Emergency Room
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome device
EQ-5D-5L
European Quality of Life - 5 Dimensions - 5 Level
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
FSH
Follicle-Stimulating Hormone
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
HRU
Healthcare resource utilisation
IATA
International Air Transport Association
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICI
If a study is conducted in several countries the International Co-
ordinating Investigator is the Investigator co-ordinating the 
investigators and/or activities internationally. 
ICS
Inhaled Corticosteroids
IgE
Immunolglobulin E

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Abbreviation or 
special term
Explanation
IL
Interleukin
IL-13
Interleukin-13 
IP
Investigational Product 
IPD
Investigational product discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
ITT
Intent-to-Treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LABA
Long-Acting β2-Agonist
LTRA
Leukotriene Receptor Antagonists
MAb
Monoclonal Antibody
MedDRA
Medical Dictionary for Regulatory Activities
nAB
Neutralizing Antibodies
OAE
Other significant adverse events
OCS
Oral Corticosteroids
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PK
Pharmacokinetic(s)
PNV
Predicted Normal Value
PRO
Patient Reported Outcome
PT
Preferred Term
Q2W
Every 2 Weeks
Q4W
Every 4 Weeks
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SOC
System Organ Class

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Abbreviation or 
special term
Explanation
Th2
T Helper 2 Cells
TLC
Total Lung Capacity
ULN
Upper Limit of Normal
UNS
Unscheduled
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential
WPAI+CIQ
Work Productivity and Activity Impairment Questionnaire and 
Classroom Impairment Questionnaire 

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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction 
and airway hyperresponsiveness, with a global prevalence of approximately 300 million 
patients (GINA 2014). 
Approximately 5% to 10% of asthma patients have severe asthma, many of whom may be 
inadequately controlled by inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) 
in combination with additional controller therapies (Bateman et al 2010). These patients are at 
risk of asthma exacerbations, have a large medical need, and represent the greatest economic 
burden (Accordini et al 2006).
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012). There is 
considerable evidence that interleukin-13 (IL-13) is a key mediator in the pathogenesis of 
asthmatic disease. IL-13 is secreted predominantly by CD4+ T-helper 2 (Th2) cells and IL-13 
receptors are expressed on a number of cell types including those involved in the pathogenesis 
of asthma (Hershey 2003). There is evidence to support that IL-13 can increase development 
of airway hyperresponsiveness (Wardlaw et al 1988), potentiate bronchoconstriction 
(Grunstein et al 2002), increase the number of mucus-secreting cells and promote airway 
fibrosis in asthma (Wills-Karp et al 1998).
Tralokinumab is a human recombinant monoclonal antibody (MAb) of the immunoglobulin 
G4 subclass that specifically binds human IL-13, blocking interactions with the IL-13 
receptor. Tralokinumab is in development for the treatment of severe asthma. A phase 2a 
study (MI-CP199) provided evidence of improvement of lung function, forced expiratory 
volume in 1 second (FEV1), following the addition of subcutaneous (SC) tralokinumab to 
standard asthma controller medications. Doses of 300 and 600 mg every 2 weeks of 
tralokinumab both resulted in comparable improvements in FEV1 that were greater than that 
observed with a 150 mg dose (Piper et al 2013). Because low pre-bronchodilator (BD) FEV1
has been identified as a strong independent predictor of subsequent asthma exacerbations, it is 
plausible that the addition of tralokinumab will reduce the rate of asthma exacerbations,
improving lung function (Reddel et al 2009). 
In a phase 2b (CD-RI-CAT-354-1049) study with tralokinumab in adults with uncontrolled, 
severe asthma requiring high dose ICS and LABA, the efficacy and safety of 2 different 
treatment regimens of tralokinumab (300 mg every 2 weeks (Q2W) or, 300 mg Q2W for 12 
weeks, followed by a 300 mg every 4 weeks (Q4W) maintenance dosing [Q2/4W]) vs. 
placebo, was evaluated over a treatment period of 52 weeks. The primary endpoint for this 
study was the annualised asthma exacerbation rate (AAER) over 52 weeks, with secondary 
endpoints including pulmonary function, patient reported outcomes, including asthma 
symptoms. In the overall intent-to-treat (ITT) phase 2b population, an increase from baseline 

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in pre-BD FEV1 to the end of treatment was seen with the Q2W dosing regimen, but not with 
the Q2/4W dosing regimen. 
In this phase 2b study, a subpopulation reversible to bronchodilators on study entry (FEV1
reversibility ≥ 12% and ≥200 ml in FEV1) had an observed AAER reduction that was greater 
for the tralokinumab 300 mg Q2W cohort versus the Q2/4W cohort. A further reduction of 
AAER was observed in a subgroup of reversible subjects with high (> median) serum 
periostin or dipeptidyl peptidase-4 (DPP4), biomarkers induced by IL-13. The AAER
efficacy signal observed in this biomarker-positive and reversible sub-group appeared to be 
somewhat attenuated in the presence of oral corticosteroid (OCS) co-medication
(approximately 17% of patients in the ITT population were on OCS), although there was no 
clear explanation for this (for further details see the Investigator’s brochure). However, since 
patients who required treatment with maintenance OCS are a distinct population, in the Phase 
III program they will be studied in this separate OCS sparing study.
OCS are effective agents for controlling airway inflammation in asthma and are indicated for 
severe persistent asthma, as outlined in Step 5 of the Global Initiative for Asthma (GINA 
2014) guidelines. Since long-term treatment with OCS use can result in adverse reactions such 
as osteoporosis, diabetes, cataract and growth retardation in children, a major objective in this 
population is to reduce their overall exposure to OCS thereby minimising adverse events. 
IL-13 over-expression as detected in sputum, in peripheral blood-derived T cells and in 
bronchial biopsy samples is a signature of patients with severe asthma (Saha et al 2008, 
Siddiqui et al 2009). Moreover, in severe, asthmatic patients who have an active IL-13 axis, 
cessation of OCS treatment caused an increase in IL-13 expression, which was not observed in 
patients who did not have an active IL-13 axis (MedImmune data on file). Therefore, patients 
who have an active IL-13 axis, as defined by high periostin and/or DPP4 levels, including 
patients on maintenance OCS, may benefit from treatment with tralokinumab. Given the need 
to reduce the requirement of OCS in patients with severe asthma, treatments that may allow 
tapering of OCS without loss of control are needed.  To date, no clinical study has been 
conducted in severe asthmatic patients on maintenance OCS with agents that attenuate IL-13 
signaling in a regime. The purpose of the present study is therefore to demonstrate the ability 
of tralokinumab versus placebo in reducing OCS use in adults and adolescents with asthma 
requiring treatment with maintenance OCS in combination with ICS/LABA with or without 
other asthma controller therapy.
1.2
Rationale for study design, doses and control groups
This is a global study designed to evaluate the efficacy and safety of a fixed 300 mg dose of 
tralokinumab administered subcutaneously every 2 weeks in asthma subjects who are on 
maintenance OCS and ICS/LABA therapy, with or without additional asthma controller(s). 
Subjects will be dosed every two weeks throughout a 40 week treatment period. 
The primary efficacy measure will be based on the percentage change from baseline in the 
prescribed, daily, average OCS dose at week 40 post randomization while not losing asthma 
control. In order to avoid bias, the study is to be randomized and double-blinded, with

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stratification by age group (adults versus adolescents) and for adult subjects only by the 
baseline OCS dose (≤ 10 mg versus >10 mg prednisone or prednisolone). Analysis of data 
from both the phase 2a study MI-CP199 and the phase 2b study (CD-RI-CAT-354-1049), has 
demonstrated a clinically relevant effect on FEV1 from tralokinumab 300 mg Q2W. In 
contrast, only limited, if any, improvement was observed with 150 mg Q2W (in study 
MICP199) 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. Therefore the dose of 300 mg Q2W has been 
selected for evaluation in this study.
Pharmacokinetic (PK) evaluations in adolescents with asthma confirm that the same dose as
for adults is applicable and since it is expected that adolescent subjects (12-17 years of age)
will respond similarly to adults, adolescents will therefore be included as part of the study 
population. 
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. OCS, leukotriene 
inhibitors (LTRAs), and xanthenes) is limited. Anti-immunoglobulin E (IgE) therapy (ie, 
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. In the 24 week phase 2a study (MI-CP199) tralokinumab
at a dose of 300 mg SC every 2 weeks (the dose proposed for the phase 3 programme)
improved FEV1 when added to standard asthma controller medications.  In addition the 
efficacy of tralokinumab has been studied in a 1 year long phase 2b study (CD-RI-CAT-354-
1049) targeting adult subjects whose asthma was poorly controlled by high dose ICS/LABA. 
In that study, tralokinumab at a fixed dose of 300 mg SC every other week produced 
improvements in multiple metrics of asthma control, including the AAER, lung function, 
Asthma Control Questionnaire-6 (ACQ-6) scores, and symptoms, in a subpopulation who 
demonstrated reversibility of FEV1 upon study entry.
Approximately 520 subjects with asthma have so far been exposed to tralokinumab at various 
doses and for different periods of time. The 1 year long phase 2b study has contributed 301 of 
these subjects with 140 of them receiving 300 mg every other week. In all studies conducted 
so far, tralokinumab has been well tolerated, and no safety concerns have been identified. 
However, because it is believed that the Th2 response may be of importance in the defense 
against helminthic parasitic infections, a theoretical risk for such infestations exists. IL-13 
may also play a role in regulating tumours (Hallett et al 2012), and although evidence for this 
is scarce and inconclusive, this theoretical risk needs to be considered. In conjunction with the 

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Edition Number 4.0
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performance of routine pharmacovigilance activities risk minimization measures therefore 
include the exclusion of subjects with untreated parasitic infection and active or recent 
malignancy. 
As with all biologics therapies, anti-drug antibodies (ADA), including neutralizing antibodies 
(nAb), may develop. Development of ADA to tralokinumab has been rare in the phase 1 and 2 
studies conducted thus far (<1% overall). Theoretical risks due to development of ADA 
include decreased drug efficacy and hypersensitivity reactions (eg, anaphylaxis or immune 
complex disease) and observation following administration of tralokinumab is therefore 
mandated.
Pharmacokinetic modelling suggests that exposure to tralokinumab is slightly higher in 
adolescents (12-17 years of age) than that in adults; however, considering the overall 
variability of tralokinumab PK, and the absence of safety findings at doses at or above 300 mg 
every other week in the phase 2 studies, dose adjustment is not considered to be required for 
subjects in this age group. 
In summary, the efficacy and safety data obtained to date support the continued clinical 
development of tralokinumab in adult and adolescent subjects with uncontrolled asthma
A detailed assessment of the risk/benefit of tralokinumab in subjects with asthma is given in 
the Investigator’s brochure (IB).
1.4
Study Design 
This is a randomized, double-blind, parallel group, placebo-controlled study designed to 
evaluate the efficacy and safety of a fixed 300 mg dose of tralokinumab administered 
subcutaneously every 2 weeks in adult and adolescent subjects with OCS dependent asthma.
Approximately 120 subjects will be randomized to tralokinumab or placebo (1:1 ratio) 
globally from about 75 centers.  All subjects will be stratified at randomization by age group 
(adults versus adolescents). Adult subjects will also be stratified at randomization by the 
baseline oral corticosteroid dose (≤ 10 mg versus > 10 mg prednisone or prednisolone).
Subjects will be administered 300 mg tralokinumab (2 x 150mg, 1mL injections) or placebo (2 
x 1mL injections) every 2 weeks using pre-filled syringes over a 40-week treatment period.
After the initial enrolment (Visit 1) and confirmation of entry criteria subjects will, depending 
on their recent asthma and OCS medication history, enter either:
-
a 2-week run-in period (if there has been documented failure of OCS dose reduction 
within 6 months prior to Visit 1 and after discussion with the sponsor study physician) 
(see section 4.1.1 and 4.1.2), or
-
a 2-week run-in period plus an 8-week optimization period to establish a minimum 
effective dose of the prescribed OCS (established by dose titration every two weeks).  

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The criteria for the adjustment of the OCS dose are noted in section 5.1.2.
Once subjects have completed the run-in period or run-in/optimization period, (reached their 
minimum effective dose of OCS and have remained stable on this dose for 2 weeks), they will 
be randomized in a 1:1 ratio to receive tralokinumab or placebo over a 40-week treatment 
period. 
The total treatment period of 40 weeks consists of three phases: an initial 12 week induction 
phase needed to ensure maximal effect on FEV1; a 20 week OCS dose reduction phase to 
reach the lowest possible dose based on the titration schedule (Table 4) and a maintenance 
phase to demonstrate that asthma control is maintained after achieving the lowest OCS dose.
The details of the three phases are listed below:
!
Induction phase (12 weeks) – from week 0 up to week 12 where subjects should remain 
on their optimized OCS dose 
!
OCS reduction phase (20 weeks) – from week 12 up to week 32, OCS dose reduction can 
be started at week 12 with the possibility of dose titration every 4 weeks.
!
Maintenance phase (8 weeks) – after the week 32 visit to week 40, subjects should remain 
on the OCS dose reached at week 32 or remain on complete OCS elimination. 
The last dose of tralokinumab or placebo will be given at week 38 with end of treatment visit 
at week 40.
Post-treatment safety follow up visits will be performed at Week 44 and Week 54.
Subjects will be maintained on their currently prescribed ICS/LABA therapy and any 
additional asthma controller medications, without changes, from enrollment throughout the 
run-in/optimization and treatment periods.
An independent Adjudication Committee, blinded to the treatment of the subjects, will 
evaluate cases of ER or urgent care visits and hospitalizations, as well as all deaths, to 
determine whether they are due to asthma or not.  For completeness, the adjudication 
committee will also be tasked with reviewing cardiovascular, cerebrovascular and malignant 
adverse events occurring after randomisation.  An Independent Data and Safety Monitoring 
Board (DSMB) will safeguard the interest of adolescent subjects by assessing the safety of the 
intervention. The DSMB will also have access to study data from adults.

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Figure 1
Study flow chart (subjects with documented failure of OCS reduction within 6 months prior to Visit 1)
Randomization 
1:1
Visits 27,
28
40-week, double-blind, randomized, treatment period
    
Tralokinumab 300mg, SC, every 2 weeks (n=60)
    
Induction Phase
Weeks 0 up to 12
Visit 26
Placebo, SC, every 2 weeks (n=60)
    
OCS Dose Reduction 
Phase
Weeks 12 up to 32
    
Maintenance Phase
Weeks 32-40
Enrolment/
Run-in
Week –2
    
Week 0
Visit 6
    
End of 
Treatment
    
Follow-up
Weeks 44,54
Visit 1
Enrolment/
Run-in

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Edition Number 4.0
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Figure 2
Study flow chart (subjects undergoing dose optimization)
Visit 1            
Visit 2-Visit 5*
Visits 27,
28
40-week, double-blind, randomized, treatment period
    
Enrolment/Run-in/Optimization
Tralokinumab 300mg, SC, every 2 weeks (n=60)
    
Induction Phase
Weeks 0 up to 12
Visit 26
Placebo, SC, every 2 weeks (n=60)
    
OCS Dose Reduction 
Phase
Weeks 12 up to 32
    
Maintenance Phase
Weeks 32-40
    
Optimization
Weeks –8 to 0
Enrolment/
Run-in
Week –10 
    
Week 0
Visit 6
    
End of 
Treatment
    
Follow-up
Weeks 44,54
Randomization 
1:1
*Visit 2 –Visit 5 to be completed for 
subjects that do not have a documented 
failure of OCS dose reduction within 6
months prior to Visit 1.

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2.
STUDY OBJECTIVES 
2.1
Primary objective
Primary Objective:
Outcome Measures:
To evaluate the effect of tralokinumab 
compared to placebo in reducing the 
prescribed, OCS maintenance dose in adult 
and adolescent subjects with asthma 
requiring chronic treatment with 
maintenance OCS in addition to 
ICS/LABA
Primary outcome variable: Percent change 
from baseline in the daily, average, OCS dose at 
week 40 post randomization while not losing  
asthma control
Primary outcome measure: Percent difference 
vs. placebo at Week 40 post randomization
2.2
Secondary objectives
Secondary Objectives:
Outcome Measures:
To evaluate the effect of tralokinumab 
compared to placebo on the proportion of 
subjects with the prescribed, OCS 
maintenance dose ≤5 mg in adult and 
adolescent subjects with asthma requiring 
chronic treatment with maintenance OCS
in addition to ICS/LABA
Difference vs. placebo in the proportion of 
subjects with final daily average OCS dose ≤5 
mg at Week 40 post randomization
To evaluate the effect of tralokinumab 
compared to placebo on the proportion of 
subjects with at least 50% reduction in 
their prescribed, OCS maintenance dose in 
adult and adolescent subjects with asthma 
requiring chronic treatment with 
maintenance OCS in addition to 
ICS/LABA
Difference vs. placebo in the proportion of 
subjects with ≥50% reduction in average daily 
OCS dose at Week 40 post randomization

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2.3
Safety objectives
Safety Objective:
Outcome Measures:
To evaluate the safety and tolerability of 
tralokinumab
!
AE/SAEs
!
Vital signs
!
dECG
!
Clinical chemistry/haematology/urinalysis
!
Physical examinations
2.4
Exploratory objectives  
Exploratory Objectives:
Outcome Measures:
To evaluate the effect of tralokinumab 
versus placebo in overall OCS exposure
Overall OCS exposure measured by the area 
under the dose curve
To evaluate the effect of tralokinumab 
versus placebo in the proportion of 
subjects that have decreased their daily 
average prescribed, OCS dose
Change from baseline daily average oral 
corticosteroid dose classified as:
1. 100% reduction (no OCS)
2. ≥ 90% to < 100% reduction
3. ≥ 75% to < 90% reduction
4. ≥ 50% to < 75% reduction
5.
> 0% to < 50% reduction
6. no change in average OCS dose
7. increased average OCS dose
To evaluate the effect of tralokinumab 
compared with placebo on asthma 
exacerbations.
Outcome variable: The AAER up to Week 40.    
Outcome measure: Asthma exacerbation rate 
reduction
To evaluate the effect of tralokinumab 
compared with placebo on lung function 
Outcome variable: Percent change from 
baseline in pre-bronchodilator FEV1 , Forced 
Vital Capacity (FVC) and Forced Expiratory 
Flow (FEF) 25-75%
Outcome measure: Percent difference vs. 
placebo at Week 12 and 40

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To evaluate the effect of tralokinumab 
compared with placebo on asthma 
symptoms and other asthma control 
metrics
Outcome variables: 
-
Change from baseline in bi-weekly mean 
daily asthma symptom score (combined 
daytime and night-time score as captured 
in the Asthma Daily Diary). 
-
Change from baseline in rescue 
medication use 
-
Change from baseline in home peak 
expiratory flow (morning and evening) 
-
Change from baseline in the number of 
night-time awakening due to asthma 
-
Change from baseline in ACQ-6
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
asthma specific health-related quality of 
life
Outcome variable: Change from baseline in 
Standardised AQLQ(S) + 12
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
health related quality of life.
Outcome variable: EQ-5D-5L
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40
To evaluate the effect of tralokinumab 
compared with placebo with regards to 
HRU and productivity loss due to asthma
Outcome variables:
!
Asthma specific resource utilization (e.g., 
unscheduled physician visits, unscheduled 
phone calls to physicians, use of other 
asthma medications)
!
WPAI+CIQ scores
Outcome measure: Mean difference vs. placebo 
at Week 12 and Week 40

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To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab
Outcome variables:
!
PK parameters: Ctrough at steady-state
!
Immunogenicity outcome variables: 
incidence rate of positive ADA and 
characterization of their neutralizing 
potential
To evaluate the change from baseline of   
biomarkers that may be associated with up-
regulation of IL-13
To evaluate the relationship between 
baseline biomarkers and the effect of 
tralokinumab on OCS dose reduction and 
clinical efficacy
To evaluate the impact of OCS
optimization on biomarkers
Biomarkers will include: 
!
Periostin
!
DPP-4
!
Blood eosinophils 
!
Total serum IgE
!
FENO
Other specific blood biomarkers may also be 
analyzed.
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 must fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures for subjects 
who are at, or over the age of majority (as per local law). For subjects less than the 
age of majority, in addition to the subject providing informed assent, the subject’s 
legal guardian must also provide their informed consent.
2.
Female or male, ages 12 to 75 years, inclusively at time of enrolment (Visit 1).  For 
those countries where local regulations permit enrolment of adults only, subject 
recruitment will be restricted to those who are ≥18 years.

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3.
Women of childbearing potential (WOCBP) (after menarche) and all adolescent 
females must use a highly effective form of birth control (confirmed by the 
Investigator). Highly effective forms of birth control includes: true sexual 
abstinence, a vasectomised sexual partner, Implanon® , female sterilization by tubal 
occlusion, any effective intrauterine device/system (IUD/IUS), Depo-Provera™ 
injections, oral contraceptive, and Evra Patch ™ or Nuvaring™. WOCBP must 
agree to use highly effective method of birth control, as defined above, from 
enrolment (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).
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 medium-to-high dose ICS for at least 6 of the 12 months prior to 
enrolment (Visit 1). In addition, subjects must have used physician prescribed ICS 
(at a total daily dose ≥ 500μg fluticasone propionate via dry powder inhaler or 
equivalent delivered dose) that has been taken at a stable dose for at least 3 months 
prior to enrolment (Visit 1).
6.
Documented treatment with ICS at a total daily dose corresponding to ≥500μg 
fluticasone propionate dry powder formulation equivalents and a LABA for at least
3 months prior to Visit 1. The ICS and LABA can be parts of a combination 
product, or given by separate inhalers. 
∀
In order to aid the assessment, ICS equivalents for high-dose and medium-
dose fluticasone propionate dry powder, are presented in Appendix E. The 
Investigator will assess the subject’s total daily ICS dose and determine that 
it corresponds to ≥500μg fluticasone propionate dry powder formulation 

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equivalents. If the subject is on two or more different types of ICS, these 
can form parts of an addition, and the sum, however approximate, will be 
assessed.
7.
Subjects must have received OCS for the treatment of asthma for 6 months prior to 
Visit 1 and on a stable OCS dose of between ≥ 7.5 to ≤ 30mg (prednisone or 
prednisolone equivalent) daily or daily equivalent for at least one month prior to 
enrolment (Visit 1).
∀
Subjects with a documented failure of OCS dose reduction within 6 
months prior to Visit 1 can omit Visits 2 to 5 (after discussion with the 
sponsor study physician) and complete a shorter 2 week run-in prior to 
Visit 6 (randomization visit)
∀
Failed attempts at OCS dose reduction are those that resulted in a clinical 
deterioration or reduced lung function attributed to asthma, demonstrated 
by documented occurrence of at least one of the following: 
o
Pre-BD FEV1 < 80% of personal baseline
o
Morning peak expiratory flow (PEF) < 80% of personal baseline
o
Night time awakenings increase of > 50% of mean personal 
baseline
o
Rescue medication use, for example salbutamol > 4 puffs/day 
above mean personal baseline
o
Requirement for an OCS burst (large temporary increase) to treat 
an asthma exacerbation provoked by steroid reduction
Subjects without a documented failure of OCS dose reduction within the previous 6 
months must complete the 2-week run-in period plus the 8-week dose optimization 
period prior to Visit 6 (randomization visit).  See section 4.1.2 for details.
8.
Additional maintenance asthma controller medications are allowed according to 
standard practice of care. These medications must be stable for 3 months prior to 
Visit 1. Furthermore, after randomization, the subject's background maintenance 
medication for asthma shall remain unchanged throughout the study.
9.
At enrolment (Visit 1) the subject must have a pre-BD FEV1 of <80% (<90% for 
patients 12 to 17 years of age) of their predicted normal value (PNV). If this 
criterion is not met at Visit 1, the criterion must be met at Visit 2 or Visit 6 (if a 
subject is not required to undergo dose optimization). Prior to the lung function 
measurement, the subject should withhold theophylline and their BD for the effect 
duration specific to the BD (see 5.1.4 and Appendix G).

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10.
A post-BD reversibility in FEV1 of ≥12% at enrolment (Visit 1) or documented 
reversibility within 6 months prior to Visit 1 with available source documentation 
and after discussion with the sponsor study physician. If there is no evidence of a 
documented reversibility within 6 months prior to Visit 1 or this criterion is not met 
at Visit 1, the criterion must be met at Visit 2 or Visit 6 (if a subject is not required 
to undergo dose optimization). Prior to the lung function measurement, the subject 
should withhold theophylline and their BD for the effect duration specific to the BD 
(see 5.1.4 and Appendix G).
Prior to randomization at Visit 6, subjects should fulfil the following inclusion criteria:
11.
For WOCBP (including all adolescents) only: have a negative urine pregnancy test 
prior to administration of the IP.
12.
No requirement for a change in the subjects ICS/LABA, other asthma controller 
medications and/or the requirement to add asthma controller medications during the 
run-in or run-in/optimization periods.
13.
For all subjects (those proceeding directly to run-in and those undergoing dose 
optimization), the optimized OCS dose reached at least two weeks prior to 
randomization.
14.
Minimum 70% compliance with OCS use.
∀
For example, 10 out of the 14 days between each visit in the run-in/optimization 
periods, prior to randomization as reported by the subject in the eDiary.
15.
Ability to perform acceptable inhaler, peak flow meter, and spirometry techniques.
16.
Minimum 70% compliance with both the usual asthma controller (ie ICS/LABA and 
any other asthma controller medications).
∀
For example, 10 out of the 14 days between each visit in the run-in/optimization 
periods, prior to randomization as reported by the subject in the eDiary.
17.
Minimum 70% compliance with the eDiary assessment schedule.
∀
For example, 10 out of the 14 days between each visit in the run-
in/optimization periods, prior to randomization as reported by the subject in the 
eDiary.
3.2
Exclusion criteria
Subjects must not enter the study if any of the following exclusion criteria are fulfilled:
1.
Clinically important pulmonary disease other than asthma (eg, active lung infection, 
COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation 

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syndrome associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and 
primary ciliary dyskinesia) or ever been diagnosed with pulmonary or systemic 
disease, other than asthma, that are associated with elevated peripheral eosinophil 
counts (eg, allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss 
syndrome, hypereosinophilic syndrome).
2.
Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, 
haematological, psychiatric, or major physical impairment that is 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.
4.
History of anaphylaxis following any biologic therapy.
5.
A helminth parasitic infection diagnosed within 6 months prior to the date informed 
consent or assent obtained 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 the 
date informed consent or assent is obtained or during the run-in period. 
7.
Tuberculosis requiring treatment within the 12 months prior to enrolment (Visit 1).
8.
Any clinically significant abnormal findings in physical examination, vital signs, 
dECG, haematology, clinical chemistry, or urinalysis during the run-in period, 
which in the opinion of the Investigator, may put the subject at risk because of 
his/her participation in the study, or may influence the results of the study, or the 
subject’s ability to complete entire duration of the study.
9.
History of chronic alcohol or drug abuse within 12 months of the enrolment visit 
(Visit 1), or a condition associated with poor compliance as judged by the 
Investigator.
10.
Positive hepatitis B surface antigen or hepatitis C virus antibody serology. Subjects 
with a history of hepatitis B vaccination without a history of hepatitis B are allowed 
to be enrolled. 

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Edition Number 4.0
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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 the date informed consent was obtained.
∀
Subjects who have had other malignancies provided that the subject is in 
remission and curative therapy was completed at least 5 years prior to the date 
informed consent was obtained.
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 the date informed consent or assent is 
obtained. Chronic maintenance OCS for the treatment of asthma is allowed.
15.
Clinically significant asthma exacerbation, in the opinion of the Investigator, 
including those requiring use of systemic corticosteroids or increase in the 
maintenance dose of OCS within 30 days prior to the date of informed consent or 
during the enrolment/run-in or last 2 weeks of optimization period.
16.
Asthma control reached at an OCS dose of ≤5 mg during the run-in/OCS 
optimization period (Visit 2 to Visit 6, for subjects undergoing dose optimization)
17.
Qualifies for 3 consecutive dose reductions at Visits 2-4 and continues to meet OCS 
dose reduction criteria at Visit 5 (for subjects undergoing dose optimization).
18.
Receipt of immunoglobulin or blood products within 30 days prior to the date 
informed consent or assent is obtained.
19.
Receipt of any marketed or investigational biologic agent (eg. omalizumab) within 4 
months or 5 half-lives prior to the date of randomization, whichever is longer.
20.
Receipt of live attenuated vaccines within 30 days prior to the date of randomization 
and during the treatment and the follow-up period.

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∀
Receipt of inactive/killed vaccinations (eg, inactive influenza) are allowed, 
provided they are not administered within 5 days before/after any study visit.
21.
Receipt of any investigational non-biologic agent within 30 days or 5 half lives prior 
to informed consent or assent being obtained, 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 the date of informed consent. 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 (eg,
propranolol).
25.
Current use of five-lipoxygenase inhibitors (eg, 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.
34.
Individuals who are legally institutionalized.
For procedures for withdrawal of incorrectly enrolled subjects see Section 3.4.

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3.3
Subject enrolment and randomization
Investigator(s) should keep a record (ie, a subject screening log) of subjects who have been 
pre-screened/screened. The pre-screening/screening log will be evaluated periodically by 
AstraZeneca and/or its delegates during routine monitoring visits.
The Investigator(s) will:
1.
Obtain signed informed consent or assent from the potential subject, or their 
guardian/legal representative, before any study specific procedures are performed.
2.
Assign the potential subject a unique enrolment number (which begins with an ‘E’) 
via the Interactive Web Response System/ Interactive Voice Response System 
(IWRS/IVRS) at Visit 1.
3.
Determine subject eligibility. See Section 3.1and 3.2.
4.
Assign the eligible subject unique randomization code IWRS/IVRS at Visit 6.
Subjects will be allocated to receive tralokinumab or placebo in a 1:1 ratio (ie 60 subjects on 
tralokinumab versus 60 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 
randomized or receive study medication.  There can be no exceptions to this rule.  Subjects 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the subject from 
treatment, with a consideration whether or not there is a safety concern. The AstraZeneca 
study physician must ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially in each stratum as subjects become 
eligible for randomization.

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Edition Number 4.0
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The randomization code will be assigned from a randomization list prepared by an internal 
AstraZeneca computerized system (Grand).  All subjects will be stratified at randomization by 
age group (adults versus adolescents). Adult subjects will also be stratified at randomization 
by the baseline oral corticosteroid dose (≤ 10 mg versus > 10 mg prednisone or prednisolone).
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 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 CRO handling data, will have 
access to the randomization scheme during the conduct of the study, with the exception of the 
Supply Chain Study Management department and the Patient Safety department at 
AstraZeneca and personnel at the bioanalytical lab performing the PK sample analysis.

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A DSMB will review the safety data and will assess the safety of the interventions for 
adolescents. The DSMB will have access to the individual treatment codes and will be able to 
merge these with the collected study data while the study is ongoing (see Section 6.8.1), if and 
as required. The personnel involved in the clinical study at AstraZeneca will remain blinded to 
these analyses and will have no knowledge of the results presented to the DSMB.
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or pharmacists at the study sites from the 
IVRS/IWRS. The instructions for unblinding will be described in the IVRS/IWRS user 
manual that will be provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment 
given to subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual subject have been made 
and documented.
3.8
Restrictions during and after the study
Fertile and sexually active female subjects (including adolescent females) should use highly 
effective contraceptive methods throughout the study and at least for 16 weeks (5 half-lives) 
after last administration of the IP. 
Subjects must abstain from donating blood or plasma from the time of informed consent or 
assent and up to 16 weeks (5 half-lives) after last dose of IP.
3.9
Discontinuation of investigational product
At any time, subjects are free to discontinue IP or withdraw from the study (ie, IP and 
assessments – see Section 3.10), without prejudice to further treatment.  A subject that decides 
to discontinue the IP will always be asked about the reason(s) for their decision to withdraw
and the presence of any AEs.  If possible, they will be seen and assessed by an Investigator(s).  
Adverse events will be followed up (as described in Section 6). The enrolment/randomization 
code of the withdrawn subject cannot be reused.
3.9.1
Procedures for discontinuation of a subject from investigational product 
Subjects will be discontinued from IP in the following situations:

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1. Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment
2. The subject experiences an AE that, in the opinion of the Investigator, contraindicates 
further dosing
3. The development of any risk to the subject as judged by the Investigator or AstraZeneca
4. Severe non-compliance with the study protocol
5. Pregnancy 
6. Lost to follow-up1
7. Development of any study specific criteria for discontinuation, including:
a) An anaphylactic reaction to the IP requiring administration of epinephrine
b) A helminth parasitic infestation requiring hospitalization
c) An asthma-related event requiring intubation
d) Any malignancy
8. Development of one or more of the following:
a) Confirmed ALT or AST increase of ≥8 x ULN
b) Confirmed ALT or AST increase of ≥5 x ULN for more than 2 weeks
c) Confirmed ALT or AST increase of ≥3 x ULN and total bilirubin of ≥2 x ULN 
d) ALT or AST of ≥3 x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥5%)
Subjects who discontinue IP or the study will always be asked about the reason(s) for 
discontinuation and the presence of any AEs. The Principal Investigator will perform the best 
possible observation(s), test(s) and evaluation(s) as well as give appropriate medication and all 
possible measures for the safety of the subject. They will also immediately inform 
AstraZeneca of the withdrawal. Adverse events will be followed up (see Section 6) and any 
questionnaires (eg, for patient reported outcomes) are to be completed.
Discontinuation of IP does not necessarily mean discontinuation of follow-up or termination 
of study participation. Compliant subjects who are discontinued from the IP should be 
                                                
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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encouraged to continue to undergo all study related visits/procedures for the full 40 -week 
study period in order to support the final efficacy and safety analysis for tralokinumab (see 
section 8). The reason for premature discontinuation of IP will be documented in the source 
documentation and recorded in the electronic case report form (eCRF).
It is essential to collect as much data as possible for all subjects throughout the study and 
especially all potential endpoint data. Complete withdrawal from the study (ie, withdrawal of 
consent) has a direct negative impact on the potential validity of all study data and should be 
avoided wherever possible.
Subjects who prematurely discontinue IP should return to the study site and complete 
procedures described for the IP Discontinuation (IPD) visit (see Table 2). 
At the IPD visit, the subject will be given three options as to how they will be followed up as 
follows:
1.
Ideally the subject should return for all regular clinic visits and perform all 
scheduled assessments until he/she completes a total of 40 weeks in the study, or
2.
The subject will be offered to be followed up on a monthly basis via telephone calls 
while continuing eDiary completion, until the subject completes 40 weeks in the 
study (no further procedures will be performed) or,
3.
If the subject cannot comply or does not wish to comply with the options above, the 
Investigator will only contact the subject at 40 weeks post randomization. No study 
assessments will be performed prior to this contact.
The key elements to be collected at these follow up visits or telephone contacts for options 2 
and 3 are AEs/SAEs, changes in concomitant medications (such as OCS dose), and asthma 
exacerbation information.  For option 1, all procedures will be done at each visit as indicated 
in Table 2.
The subject’s decision needs to be documented in the eCRF and the specific section in the 
ICF/assent form addendum needs to be signed by the subject.
Should the subject choose option 3 above, they will complete the IPD visit immediately and 
then a follow up telephone call at week 40.  If the subject chooses either option 1 or 2, they 
will complete the IP Discontinuation visit immediately and then the EOT visit at week 40.  
The EOT visit will be completed immediately in the case of early withdrawal from option 1 or 
2.
Subjects who initially chose options 1 or 2 and subsequently cannot or do not wish to comply 
with the requirements of the chosen option, can choose to continue with a less invasive option 

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(ie: Subject initially choosing option 1 can continue with 2 or 3, subjects initially choosing 
option 2 can continue with 3).
Subjects who do not wish to have any follow up contact at all, will be discontinued from the 
study. All discontinued subjects must return the electronic patient reported outcome (ePRO)
and electronic PEF devices at the EOT visit.
Completion, or early termination of IP treatment, will be registered via the IWRS/IVRS for 
each subject.
For subjects who wish to withdraw from the study completely, refer to Section 3.10.2.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are subjects who do not fulfil the eligibility criteria for the study, and therefore 
must not be randomized.  These subjects should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (ie, subject does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures, and not
randomized subjects.
3.10.2
Withdrawal of the informed consent or assent
Subjects are free to withdraw from the study at any time (ie, from receiving IP and/or having 
assessments performed), without prejudice to further treatment.
A subject who withdraws their consent or assent will always be asked about the reason(s) for 
their decision to withdrawal, and the presence of any AE.  The Investigator will follow up 
AEs outside of the clinical study. The subject must return the ePRO and ePEF devices.  
If a subject withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn subjects will not be replaced. 
If the subject only withdraws consent for the retention of blood samples for future exploratory 
use (eg, study of markers of asthma, identifying potential new drug targets for asthma, or for 
assay development purposes), the subject will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF as well as in the Informed Consent Form (ICF) or assent form. The 
ICF or assent form must be re-signed and dated by both the subject and the Investigator.

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Edition Number 4.0
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4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study Plan – Enrolment/Run-in/OCS optimization period
*subjects with a documented failure of OCS reduction within 6 months prior to Visit 1 do not need to enter the 8 week OCS 
optimization period
Assessment/ activity
Enrolment/
Run-in
OCS optimization period
V1a
V2
V3 
V4 
V5 
(w–10)
(w–8)
(w–6)
(w–4)
(w–2)
Visit window (days)
N/A
±3
±3
±3
–3
Informed consent
X
Inclusion/exclusion criteria
X
X
X
X
X
Demographics
X
Medical/Surgical and asthma history
X
Complete physical examination
X
Brief physical examination
X
X
X
X
Weight, Height
X
Vital Signs
X
X
X
X
X

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Assessment/ activity
Enrolment/
Run-in
OCS optimization period
V1a
V2
V3 
V4 
V5 
(w–10)
(w–8)
(w–6)
(w–4)
(w–2)
Visit window (days)
N/A
±3
±3
±3
–3
dECG
X
Serum chemistry 
X
Haematology 
X
Serum Biomarkers
X
FENO
X
Urinalysis (dipstick)
X
Serology (hepatitis B,C; HIV-1; HIV-2)
X
Serum pregnancy test
X
FSHb
X
Dispense PEF meter and eDiary
X
PEF adherence check
X
X
X
X
Asthma Daily Diary adherence check 
X
X
X
X
ACQ-6 at the site
X
ACQ-6 adherence check
X
X
X
X
AQLQ (S) +12 at the site
X

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
45 (130)
Assessment/ activity
Enrolment/
Run-in
OCS optimization period
V1a
V2
V3 
V4 
V5 
(w–10)
(w–8)
(w–6)
(w–4)
(w–2)
Visit window (days)
N/A
±3
±3
±3
–3
AQLQ (S) +12 adherence check 
X
X
X
X
Healthcare resource utilization
X
Pre-BD spirometry
X
X
X
X
X
Run in reversibility (Post-BD 
spirometry) c
X
X
Assessment of asthma exacerbations
X
X
X
X
OCS switch to prednisone or 
prednisolone if required
X
OCS dose reduction 
Xe
X
X
OCS dose increase, if indicated d
X
Adverse events
X
X
X
X
X
Concomitant medication
X
X
X
X
X
a
Visit 1 can be performed over a period of 3-working days, with the exception of documentation of informed consent and assent (if applicable), which can be completed 
up to 30 days prior to Visit 1. For subjects not undergoing dose optimization (Visit 2-Visit 5), the next visit after Visit 1, will be Visit 6 (to be scheduled 14 up to 17 days 
after Visit 1).
b
FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 month
c
If there is no evidence of documented reversibility within 6 months prior to Visit 1, the reversibility criterion must be met at Visit 1 or Visit 2 or Visit 6 (for subjects not 
required to undergo dose optimization). For reversibility assessment at Visit 1 (and Visit 2 or 6, if required) the full procedure as defined in section 5.1.4.1 should be 

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
46 (130)
followed until the subject either meets FEV1 reversibility requirement (≥12% and ≥200 mL) or completes all steps.  For patients with historical reversibility or once the 
reversibility criterion is met, only step 1 of the reversibility assessment (5.1.4.1) is required.  
The Visit 2 reversibility assessment (Post-BD spirometry) will only be performed if the run-in reversibility criterion is not met at Visit 1 or if there is no documented 
history of reversibility.
d
If the subject fails to meet titration criteria at Visits 3-4, the OCS dose should be returned to one level higher and Visit 5 should be activated on the same day
e
Visit where OCS dose titration will not be based on the protocol captured set of baseline data and details are included in Section 4.1.2
Table 2
Study plan – Treatment and follow-up period 
Assessment/ 
activity
Induction phase
Reduction Phase
Maintenance Phase
EOT
FU
FU
IPD
UNSg
V6 
V7 
V8
V9
V10
V11
V12 
V13
V14
V15 
V16
V17
V18 
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28 
(W 0)
(W2)
(W4)
(W 6)
(W8)
(W10)
(W 12)
(W 14)
(W16)
(W18)
(W 20)
(W 22)
(W24)
(W26)
(W 28)
(W30)
(W32)
(W 34)
(W 36)
(W 38)
(W 40)
(W 44)
(W 54)
Visit windowa (days)
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
N/A
N/A
Inclusion/
exclusion criteria
X
Complete physical 
examination
X
X
X
X

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
47 (130)
Assessment/ 
activity
Induction phase
Reduction Phase
Maintenance Phase
EOT
FU
FU
IPD
UNSg
V6 
V7 
V8
V9
V10
V11
V12 
V13
V14
V15 
V16
V17
V18 
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28 
(W 0)
(W2)
(W4)
(W 6)
(W8)
(W10)
(W 12)
(W 14)
(W16)
(W18)
(W 20)
(W 22)
(W24)
(W26)
(W 28)
(W30)
(W32)
(W 34)
(W 36)
(W 38)
(W 40)
(W 44)
(W 54)
Visit windowa (days)
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
N/A
N/A
Brief physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
Height
Xh
Xh
Vital Signsb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
dECG 
X
X
X
Serum chemistry
X
X
X
X
X
X
Haematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (dipstick)
X
X
X
X
X
Urine pregnancy 
test (dipstick)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Total IgE
X
X
X
Phadiatop
X

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
48 (130)
Assessment/ 
activity
Induction phase
Reduction Phase
Maintenance Phase
EOT
FU
FU
IPD
UNSg
V6 
V7 
V8
V9
V10
V11
V12 
V13
V14
V15 
V16
V17
V18 
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28 
(W 0)
(W2)
(W4)
(W 6)
(W8)
(W10)
(W 12)
(W 14)
(W16)
(W18)
(W 20)
(W 22)
(W24)
(W26)
(W 28)
(W30)
(W32)
(W 34)
(W 36)
(W 38)
(W 40)
(W 44)
(W 54)
Visit windowa (days)
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
N/A
N/A
FENO
X
X
X
X
X
X
PK
X
X
X
X
X
X
X
ADA/nAB
X
X
X
X
Serum biomarkers
X
X
X
X
X
X
X
X
PEF adherence 
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Asthma Daily Diary 
adherence check 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ACQ-6 at the sited
X
X
X
ACQ-6 adherence 
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AQLQ (S) +12 , 
WPAI+CIQ, EQ-
5D-5L at the sitee
X
X
X

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
49 (130)
Assessment/ 
activity
Induction phase
Reduction Phase
Maintenance Phase
EOT
FU
FU
IPD
UNSg
V6 
V7 
V8
V9
V10
V11
V12 
V13
V14
V15 
V16
V17
V18 
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28 
(W 0)
(W2)
(W4)
(W 6)
(W8)
(W10)
(W 12)
(W 14)
(W16)
(W18)
(W 20)
(W 22)
(W24)
(W26)
(W 28)
(W30)
(W32)
(W 34)
(W 36)
(W 38)
(W 40)
(W 44)
(W 54)
Visit windowa (days)
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
N/A
N/A
AQLQ (S) +12, 
WPAI+CIQ, EQ-
5D-5L adherence 
check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
asthma 
exacerbations 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
OCS dose titration
X
X
X
X
X
X i
Pre-BD spirometryk
X
X
X
X
X
X
X
X
X
X
X
Post-BD spirometryj
X
X
X
X
Health care resource 
utilization 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
50 (130)
Assessment/ 
activity
Induction phase
Reduction Phase
Maintenance Phase
EOT
FU
FU
IPD
UNSg
V6 
V7 
V8
V9
V10
V11
V12 
V13
V14
V15 
V16
V17
V18 
V19 
V20
V21
V22
V23
V24
V25
V26
V27
V28 
(W 0)
(W2)
(W4)
(W 6)
(W8)
(W10)
(W 12)
(W 14)
(W16)
(W18)
(W 20)
(W 22)
(W24)
(W26)
(W 28)
(W30)
(W32)
(W 34)
(W 36)
(W 38)
(W 40)
(W 44)
(W 54)
Visit windowa (days)
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
N/A
N/A
Randomization
X
Administration of 
IPf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a
All visits are to be scheduled from the date of randomization but not from the date of previous visit 
b
Vital signs will be taken pre-dose prior to administration of IP. Subjects will be observed 2 hours post treatment for Visits 6, 7, 8 and 9.  For all other visits where IP is 
administered, subjects will be observed for a minimum of 1 hour. 
c
For WOCBP and adolescent females, urine pregnancy test (dipstick) to be done at centre at each treatment visit prior to IP administration.
d
ACQ-6 performed at the site unless completed at home the day prior.
e
ePROs performed at the site unless completed at home the day prior.
f       In case of anaphylaxis additional samples will be taken (see Section 6.7)
g
Unscheduled visits may be initiated as needed, and additional assessments performed at these visits. At unscheduled visits for assessing an asthma exacerbation, at a 
minimum, these assessments need to be performed. Other unscheduled visits may be initiated as needed, and assessments performed as per investigator’s judgement.
h
Height will be measured for adolescent subjects only.

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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i
Uptitration only
j
On Visit 6 (if reversibility criterion has already been met at Visit 1 or Visit 2 or for patients with historical reversibility), Visit 12, Visit 26 and IPD Visit: Only step 1 of  
the reversibility assessment (Section 5.1.4.1) is required. 
k        The investigator can consider to perform a pre-BD spirometry assessment at visits where this is not required.

Clinical Study Protocol
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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4.1
Enrolment and run-in/optimization period
4.1.1
Run-in period (Visit 1 – Visit 2)
Each potential subject who is at, or over the age of majority (as per local law) will provide 
informed consent prior to the start of any study specific procedures and undergo assessments 
applicable for this visit (see Table 1).
For subjects less than the age of majority, in addition to the subject providing informed assent, 
the subject’s legal guardian must also provide their informed consent.
With the exception of documentation of informed consent and assent (if applicable), which 
can be completed up to 30 days prior to Visit 1, all other Visit 1 procedures should be 
completed within a 1 to 3-working day window.  The 3-day window is to enable subjects to 
return if necessary for the spirometry assessments on a day when they have had their 
bronchodilator medications withheld in accordance with the spirometry instructions (see 
section 5.1.4). The registration of the subject’s enrollment 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. The baseline for the 
ePRO parameters (OCS optimization period) will be established from Visit 1 to Visit 2.
Spirometry will also be performed at Visit 1. Subjects must have a pre-BD FEV1 value <80% 
of their PNV (<90% for subjects 12 to 17 years of age). Should this criterion not be met or 
cannot be performed at Visit 1, subjects must fulfill it at Visit 2 or Visit 6 (if a subject is not 
required to undergo dose optimization) in order to proceed in the study (as per Section 3.1, 
criterion 9). 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) or documented reversibility within 6 months prior to Visit 1 with available source 
documentation. The use of the historical reversibility to meet this criterion must be reviewed 
with the sponsor study physician prior to the run-in/optimization period. If there is no 
evidence of documented reversibility within 6 months prior to Visit 1 or this criterion is not 
met at Visit 1, the criterion must be met at Visit 2 or Visit 6 (if subject is not required to 
undergo dose optimization), see section 5.1.4.1.  Visit 2 post-BD spirometry will only be 
performed if the run-in reversibility criterion is not met at Visit 1 or if there is no documented 
history of reversibility.
Other study assessments and procedures to be performed at this visit include the recording of
the subject’s demographics, a complete physical examination (including height and weight),
vital signs, a dECG, medical/surgical history and concomitant medications, collection of 
blood samples for haematology/clinical chemistry, serology, collection of a urine sample for 
dipstick and urinalysis (if applicable), and a pregnancy test for WOCBP.

Clinical Study Protocol
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Edition Number 4.0
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A record of physician-diagnosed asthma, ICS/LABA use, use of other asthma controllers
is required source documentation. A subject’s verbal history suggestive of asthma, but without 
supporting documentation is not sufficient to satisfy inclusion criteria 5 and 6.
Current, regular use of an ICS and LABA for at least 3 months prior to enrolment (Visit 1)
and OCS use for at least 6 continuous months prior to enrolment (Visit 1) must be 
documented in the source.
The ICS and LABA may have been administered as either a fixed dose or as 2 separate 
inhalers, and consistent with dose limits set by inclusion criterion 6. Stable dose of OCS must 
have been maintained for at least 1 month prior to Visit 1. This documentation may be in the 
form of a recent, active medication list as per a healthcare professional(HCP) note, or filled 
prescription.
Subjects with documented failure of OCS reduction
Subjects with documented failure of OCS reduction within 6 months prior to Visit 1 do not 
need to enter the 8 week optimization period. These subjects will complete the 2 week run-in 
period prior to randomization (after discussion with the study sponsor physician) and proceed 
directly to Visit 6. Failed attempts at OCS dose reduction are those, which resulted in 
documented clinical deterioration or reduced lung function attributed to asthma, demonstrated 
by documented occurrence of at least one of the following:
!
Pre-BD FEV1 < 80% of personal baseline
!
Morning PEF < 80% of personal baseline
!
Night time awakenings increase of > 50% of mean personal baseline
!
Rescue medication use, for example salbutamol > 4 puffs/day above mean personal 
baseline
!
Requirement for an OCS burst (large temporary increase) to treat an asthma exacerbation 
provoked by steroid reduction
After confirmation of initial entry criteria the subject will be supplied with an electronic 
handheld spirometer (peak flow meter) to monitor home lung function, and an ePRO device to 
record asthma symptoms and complete relevant questionnaires (see Section 5.2.2 for further 
details).
Subjects will continue on their current ICS/LABA and other maintenance asthma controller 
medications (if applicable) with no changes.

Clinical Study Protocol
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Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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At the enrolment visit, subjects who are not currently using prednisone or prednisolone as 
their maintenance corticosteroid will be switched to the corresponding 
prednisone/prednisolone equivalent dose given as a daily dose.
4.1.2
OCS Optimization period (Visit 2 – Visit 5)
For those subjects who have not had a documented failure at OCS reduction, they will enter an 
OCS optimization period that will be a maximum of 8 weeks in duration (from Visit 2, Week -
8 to Visit 6, Week 0). 
The subjects should remain on their current ICS/LABA treatment and other maintenance 
asthma controller medications (if applicable) with no changes throughout this period. 
Assessments applicable for the period are listed in Table 1.
During the OCS optimization period, a subject’s OCS dose will be titrated down (see Section 
5.1.2) to ensure the subject is taking the minimum effective OCS dose without losing asthma 
control.
The OCS dose titration must be initiated at Visit 2. The Investigator should follow the titration 
schedule listed in Table 3. Visit 2 is the only titration visit that will not be based upon a 
protocol-captured set of baseline data, because the first baseline data capture period is not yet 
complete. Visit 2 spirometry and data captured in the electronic diary compared with a historic 
baseline from the past 6 months can be used for the Investigators who would want to initiate 
the titration at this visit. Subjects who are judged not to be candidates for OCS dose reduction
at Visit 2, based upon asthma symptoms or other clinical reasons in the opinion of the 
Investigator, should be screen-failed.
From Visit 3 onwards, the dose of the OCS may be reduced only if all criteria listed in Section 
5.1.2 are met. The reductions can occur at 2-week intervals according to the titration schedule 
(see Table 3). The optimized dose of OCS is defined as a lowest dose of OCS at which the 
subject meets criteria listed in section 5.1.2. In cases when the subject is optimized on their 
OCS dose prior to Visit 5 (Week-2), he/she should be maintained at the optimized dose of 
OCS for at least 2 weeks and then can be randomized. If the subject fails to meet the OCS 
dose titration criteria at Visits 3-4, the OCS dose should be returned to one level higher and 
Visit 5 should be activated on the same day. The optimized dose reached during the OCS 
optimization period becomes the subject’s baseline OCS dose for analysis purposes.
If a subject does not meet the down titration criteria, the OCS dose should be returned to the 
previous effective dose (i.e., the higher dose level prior to the titration criterion not being 
met), which will be considered the minimal effective dose and should be maintained on that 
OCS dose until randomization (Visit 6).
If a subject experiences an asthma exacerbation during this period, a temporary increase of 
systemic steroids (bolus/burst dosing) will be performed; when clinically indicated, the 
systemic corticosteroid dose used in the burst will be tapered down over 7 to 10 days to a dose 
above the pre-burst dose. That is the subject should be placed on an OCS dose one step higher 

Clinical Study Protocol
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Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
55 (130)
(or two in the judgement of the investigator) than the dose they were on when the 
exacerbation occurred. In that instance the subject must maintain the optimal dose for the 
protocol required 2 weeks prior to randomization.
Subjects who are considered by Investigators not to be candidates for OCS dose reduction, 
based upon asthma symptoms or other clinical reasons should be screen-failed.
If a subject reaches asthma control at an OCS dose of ≤5 mg during this phase, the subject will 
be a screen failure and will not be randomized. 
If the subject does not reach the optimized dose of the OCS by the end of the run-
in/optimization period the subject should be screen failed and cannot be randomized.
Subjects whose compliance with the electronic diary is <70% will be given the option, one 
time during screening, to reschedule a study visit (with the exception of Visit 6) within 72 
hours.
4.1.3
Re-screening
Subjects who experience an asthma exacerbation within 30 days prior to ICF date, during the 
run-in period or optimization period whereby a subject has not maintained the optimal dose 
for the protocol required  2 weeks prior to randomization should be screen failed (the 
optimization period will not be extended).  They may be re-screened no sooner than 30 days 
after their last dose of systemic steroids.
Subjects with respiratory infections requiring antibiotics or antiviral medication within 30 
days prior to the date informed consent is obtained or during the screening/run-in period may 
also be re-screened.
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), or assent form, and after all Visit 1
assessments have been performed as listed in Table 1 (with the exception of testing for HIV1 
and HIV2, hepatitis B and C, and FSH). 
Re-enrolment is only allowed once for any subject. 
Re-screening of a subject for any other reason will be allowed only upon approval of the 
AstraZeneca Study Physician. A documented approval for re-screening should be filed in the 
Investigator Study File (ISF). 

Clinical Study Protocol
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Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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4.2
Randomized treatment period (Visit 6 – Visit 26)
The randomized treatment period is divided into 3 phases: induction phase (Section 4.2.1), 
reduction phase (Section 4.2.2), and maintenance phase (Section 4.2.3).
Inclusion criteria at randomization will be confirmed at Visit 6. Before randomization the
subject’s compliance with usual asthma medications, OCS, and ePRO completion must be 
confirmed (see Section 3.1 , inclusion criteria 14, 16, 17).
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 
dose of the IP will be administered at Visit 6 after the subject’s randomization via 
IVRS/IWRS.
Following randomization the subject will receive double-blind treatment for 40 weeks, with 
the last dose of tralokinumab /placebo administered at Visit 25 (Week 38).
If worsening of symptoms occurs, the OCS dose may be increased to the next dose increment. 
If a subject experiences an asthma exacerbation, a temporary increase of systemic steroids 
(bolus/burst dosing) will be performed; when clinically indicated, the systemic corticosteroid 
dose used in the burst will be tapered down over 7 to 10 days to a dose above the pre-burst 
dose.
4.2.1
Induction Phase
The induction phase will start at Week 0 (Visit 6) and will continue through Week 12 (Visit 
12) in which subjects will remain on all of their regular asthma controller medications. 
Subjects will continue with the OCS dose that was achieved during OCS optimization unless 
an exacerbation occurs.
4.2.2
Reduction Phase
The OCS reduction period will start at week 12 (Visit 12) and will be completed at Week 32 
(Visit 22). The first reduction of the OCS dose should occur at the Week 12 (Visit 12). The 
OCS reduction at Visit 12 is the only down-titration during the reduction phase that will not 
be based upon a protocol-captured set of baseline data. Subsequent OCS dose reductions can 
occur at 4-week intervals according to the titration schedule of OCS dose reductions presented 
in Table 4. These subsequent OCS reductions will only take place if all criteria listed in 
Section 5.1.2 are met. The presence of an asthma exacerbation, changes in symptoms, and 
rescue medication use will be assessed. Subjects who experience an asthma exacerbation 
requiring evaluation in an urgent care centre, in ED, hospitalization, or temporary increase of 
systemic steroids (bolus/burst dosing), in the judgment of the Investigator should be returned 
to the previous effective OCS dose (i.e., the higher dose level prior to the titration criterion not 
being met) after they have returned to their baseline level of asthma control that is established
prior to the randomization visit. Further dose reductions can be considered in the opinion of 
the PI (further reductions will follow the scheduled titration, see Table 4).

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Note: OCS dose reduction may take place only when criteria for OCS dose reduction are met 
(not applicable for Visit 12; see section 5.1.2).
4.2.3
Maintenance Phase
The maintenance phase is 8 weeks after Week 32 (Visit 22). During this phase, subjects 
should be maintained on the stable dose of OCS achieved during the reduction phase unless an 
exacerbation occurs. If the requirement for OCS was eliminated then the subject will be 
maintained without any OCS.
4.3
Follow-up period
Subjects will have follow-up visits at Weeks 44 and 54 respectively. Subjects will be 
requested to return to the study centre for the follow-up assessments. During these visits 
subjects will be assessed for any ongoing safety issues and any potential prospective AEs, 
serum biomarker, PK and immunogenicity samples will be collected (see Table 2).
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 is 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 completion of the study.
5.1
Efficacy assessments
5.1.1
Assessment of OCS dose
During the run-in/OCS optimization period the minimum OCS dose while not losing asthma 
control will be reached for subjects that have undergone dose optimization. The optimized 
dose will be considered as the baseline OCS dose.
The baseline dose will be the dose at randomization, regardless of whether or not the subject 
has undergone dose optimization.
The baseline OCS dose should be maintained at the same level from Visit 6 up to Visit 12 
(induction phase).
If the dose reduction criteria are met (see Section 5.1.2), the dose reduction of the OCS will 
commence at Visit 12 and will continue at 4-weekly intervals until Visit 22 in accordance with 
the OCS dose titration schedule provided in Table 4 (reduction phase). During the reduction 

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phase a minimum stable OCS dose, or complete elimination of requirement for OCS, while 
maintaining asthma control, will be reached for each subject.
If a subject does not meet the titration criteria, the OCS dose should be returned to the 
previous effective dose (i.e., the higher dose level prior to the titration criterion not being met) 
and should be maintained on that OCS dose until EOT (Visit 26).
No adjustments should be made to the OCS dose after Visit 22 (the subject will enter the 
maintenance period).
The OCS dose changes will be documented in the source documentation and recorded in the 
appropriate eCRF form.
Subjects should complete the Asthma Daily Diary twice daily for at least 70% of the days 
before Visit 6 and the OCS reduction phase (Visit 12 to Visit 22) based on the Asthma Daily 
Diary for OCS dose titration. If the compliance falls under 70% during the treatment period 
(Visit 6 – Visit 22), OCS dose reduction may still be performed at the Investigator’s discretion 
according to the protocol-specified titration criteria.
5.1.2
OCS dose titration
The OCS dose titration will follow the same approach for those subjects who have not had a 
documented failure at OCS reduction and enter the optimization phase (Visit 2 to Visit 6) and 
all subjects following the induction phase (Visit 12 to Visit 20).  
For those entering the OCS dose optimization period, dose titration begins at Visit 2 (see 
Section 4.1.2).   
For the optimization period, the baseline will be the mean of measures (morning PEFs, SABA 
use, night time awakenings, and total asthma symptom score) collected on each day between 
Visit 1 and Visit 2. 
The dose titration during the treatment period will begin at Visit 12 and ends at Visit 20. Dose 
reduction begins at Visit 12 and it is the only titration visit during reduction phase that will not 
be based upon a protocol-captured set of baseline data. For all subjects entering the dose 
reduction phase, the baseline values will be the mean of measures (morning PEFs, SABA use, 
night time awakenings, and total asthma symptom score) collected on each day of the last two 
weeks prior to randomization regardless of whether they went through the OCS optimization 
period or not. For FEV1, all efficacy assessments are relative to the pre-dose baseline obtained 
at randomization (Visit 6).
Subjects who meet all of the following criteria are eligible for OCS dose titration (dose 
reduction):
!
Pre-BD FEV1 ≥ 80% of baseline FEV1 at the clinic visit

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!
Mean of the morning PEF measures during 14 days prior to visit ≥80% of baseline mean 
morning PEF measure
!
Not more than or equal to 50% increase compared to baseline in the proportion of nights 
with awakenings in the 14 days period prior to the visit
!
Mean rescue medication use not more than 4 puffs/day above the baseline mean or 12 
puffs/day overall in the 14 days period prior to the visit
!
No asthma exacerbation requiring a burst of systemic corticosteroids since the previous
visit 
!
Investigator judges subject’s asthma control to be sufficient to allow OCS dose reduction
When a subject doesn’t meet the above criteria, further reduction of the OCS dose will be 
stopped for the duration of the study and the subject will be returned to the dose one level 
higher.
For subject safety those that started on a higher dose of OCS will not be allowed to reduce 
their OCS dose to 0 during the OCS reduction phase. This is to protect the subject from 
potentially experiencing adrenal crisis. Throughout the reduction phase subjects should be 
monitored for the signs and symptoms of adrenal insufficiency. A minimum maintenance 
OCS dose will be required for subjects whose dose at Visit 6 is 15 – 30 mg/day (see Table 4
for the minimum dose that can be reached).
If, in the opinion of the Investigator, additional OCS dose reductions are not clinically 
indicated (due to disease factors that may affect subject safety), titration may be stopped.  The 
subject should be returned to a dose one level higher (unless a temporary bolus/burst of steroid 
is warranted). Further dose reductions can be considered in the opinion of the PI (further 
reductions will follow the scheduled titration, see Table 4).
The titration schedule of OCS dose reductions is presented in Table 3 and Table 4.

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Table 3
OCS dose titration schedule during the optimization period (V2 – V4)
Regimen
Starting dose of OCS (mg/day)
at each visit of optimization 
period
Reduction by a
Daily regimen
12.5-30
5.0
7.5-10
2.5
a During the Run-in/optimization period the reductions should occur at 2-week intervals.
Table 4
OCS dose titration schedule recommended during the reduction phase 
(V12-V20) a,b
Optimized 
dose at V6
W0
Visit 12
W12
Visit 14
W16
Visit 16
W20
Visit 18
W24
Visit 20
W28
30
25
20
15
10
7.5
27.5
22.5
17.5
12.5
7.5
5
25
20
15
10
7.5
5
22.5
17.5
12.5
7.5
5
2.5
20
15
10
7.5
5
2.5
17.5
12.5
7.5
5
2.5
1.25
15
10
7.5
5
2.5
1.25
12.5
7.5
5
2.5
1.25
0
10
7.5
5
2.5
1.25
0
7.5
5
2.5
1.25
0
0
a – All doses expressed in mg/day
b- Titration schedule should be followed when the titration criteria are met at every titration visit (not applicable 
for Visit 12, see Section 4.2.2). A daily dose of 1.25 mg may be administered as 2.5 mg every other day.

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5.1.3
Assessment of asthma exacerbations
The treatment, including changes in the OCS dose and duration and the use of additional, 
potentially emergent therapies is at the discretion of the treating physician. 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

Discontinuation due to an exacerbation after Visit 6 is not mandatory. Subjects 
who experience an exacerbation during the run-in period should be screen failed 
and may be considered for re-screening. Those who experience an exacerbation 
after randomization may remain on the investigative product at the PI’s discretion. 
After the bolus/burst is complete, in the judgment of the PI, the subject may be 
returned to the higher OCS dose than the dose that preceded their exacerbation.
Further dose reductions can be considered in the opinion of the PI (further 
reductions will follow the scheduled titration, see Table 4).

Up titration of OCS dose during optimization to one level higher is not considered 
an exacerbation 
∀An emergency room or urgent care visit (defined as evaluation and treatment for <24 hours 
in an emergency department or urgent care center) 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 patient (patient-driven) or related to an 
Asthma Daily Diary alert (diary-driven).
For those subjects entering the optimization period, the baseline for OCS reduction will be the 
mean of measures collected each day between Visit 1 and Visit 2.
For the dose reduction phase, the baseline will be the mean of measures collected 14 days 
prior to Visit 6. For those entering the run-in period only the 14 days between Visits 1 and 6 
will be used for baseline calculations. For those entering the run-in/optimization period the 14 
day period between Visits 5 and 6 will be used for baseline calculations.  
The ePRO device will be programmed to alert both the patient and study centre when certain 
pre-specified worsening thresholds are crossed including:

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∀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
∀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.
The subject may remain in the study after an exacerbation and continue to receive IP if the 
Investigator judges that it is medically appropriate for the subject to do so.
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 (eg, 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 
exacerbation must be recorded in the appropriate module of the eCRF.
5.1.4
Spirometry
General requirements
Pulmonary function will be measured by spirometry at the study site using equipment 
provided by a central vendor. Spirometry will be performed by the Investigator or authorized 
delegate according to American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines (Miller et al 2005).
The vendor providing central spirometry services will be responsible for assuring that the 
spirometer used by each site meets ATS/ERS recommendations, and that the study site 
personnel who will be performing the testing are properly certified. Spirometry calibration 
will be detailed in a separate spirometry procedures manual.

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Time of day for scheduled site visit spirometry
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomization spirometry was performed. For example, if the randomization 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM.
Important! Subjects should be instructed not to use their maintenance twice daily LABA 
or ICS/LABA combination within 12 hours of the scheduled site visit spirometry, as this 
will affect the pre-BD FEV1 value; they may be taken subsequently, at the site. For 
theophylline and once daily bronchodilators a 48 hour washout period is required. For the 
same reason subjects should not use their rescue SABA medication within 6 hours 
scheduled spirometry. This restriction is particularly critical for efficacy measures taken 
during the treatment period, but should also facilitate meeting the run-in FEV1 and 
reversibility eligibility criteria. 
Options for handling subjects who have inadvertently taken their asthma medication within 
the restricted window are described in section 7.7.2.
Spirometry technique
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Subjects should avoid eating a large meal for at least 2 hours prior
to spirometry measurements at the site. All spirometry manoeuvres (irrespective of whether to 
obtain values for FEV1, FVC, FEF25-75%) should be performed with the subject seated in an 
upright position. If this is not comfortable for the subject, standing is permitted. The same 
position should be used by the subject for each forced expiratory manoeuvre from enrolment
throughout the study. The head must not be tilted during manoeuvres and the thorax should be 
able to move freely; hence tight clothing should be loosened. A nose-clip should be used for 
the manoeuvre. Mouthpieces of the same dimension and shape should be used by the subject 
from enrolment throughout the study.
The Spirometry manoeuvre consist of three phases; The first is maximal inspiration, the 
second a ”blast” of exhalation (to obtain the FEV1 value) and the last continued complete 
exhalation to the end of test. The subject should inhale rapidly and completely from functional 
residual capacity. It is Important that the preceding inspiration is fast and any pause at full 
inspiration be minimal (i.e. only for 1–2 s). The subject should be prompted to ‘‘blast,’’ not 
just ‘‘blow,’’ and he/she should be encouraged to fully exhale until end of test criteria are met. 
If the patient feels ‘‘dizzy’’, the manoeuvre should be stopped, since syncope could follow 
due to prolonged interruption of venous return to the thorax. Manoeuvres that do not meet the 
end of test criteria should not be used to satisfy the requirement of three acceptable 
manoeuvres. However, early termination, by itself, is not a reason to eliminate all the results 
from such a manoeuvre from further consideration. Please note that Information such as the 
FEV1 may be useful (depending on the length of exhalation) and can be reported from these 
early terminated manoeuvres.

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To allow recording of the FVC value it is important that the whole manouvre lasts for at least 
6 seconds. Ensure that none of the following has occurred: coughing during the first second, 
glottis closure, leak or obstruction of the mouthpiece (by the tongue).
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
spirometry session. There should be at least 3 efforts that meet the ATS/ERS acceptability 
criteria with the highest value and second highest value for FEV1 and FVC meeting the 
ATS/ERS reproducibility criteria. The largest FVC and the largest FEV1 should be recorded 
after examining the data from all of the usable curves, even if they do not come from the same 
curve. If the criteria for acceptability and reproducibility are not met with the first 3 expiratory 
efforts, then additional attempts are required up to a maximum of 8. If the reproducibility 
criterion is not fulfilled after the maximum number of manoeuvres has been performed, the 
highest of the FEV1 and FVC value that is deemed acceptable should be selected.
The mean forced expiratory flow between 25% and 75% of the FVC (FEF25–75%) is taken from 
the blow with the largest sum of FEV1 and FVC. The FEF25–75% must be measured with an 
accuracy of at least +5% of reading or +0.2 L whichever is greater. It is highly dependent on 
the validity of the FVC measurement and the level of expiratory effort.
The absolute measurement (for FEV1), and the percentage of PNV (Quanjer et al 2012) will 
be recorded. 
Order of administration of usual asthma controller medication and IP relative to
scheduled pre-and post-BD spirograms.
On visits when spirometry is performed the subject´s usual asthma controller medication 
should be withheld until the whole procedure for spirometry has been completed; usual
asthma controller may be given after final post-BD spirograms.  IP dosing should also be 
withheld until pre-BD spirometry has been completed.  
Record keeping
A signed and dated copy of the pre- and post- BD printout must be kept at the study site for 
source data verification. The printout must be marked with the study code, subject enrolment 
code, date and time of measurement, and visit number.
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the subjects 
PNV values and are pre-programmed into the spirometer (Quanjer et al 2012). 
FEV1, expressed as percent of the PNV, will be calculated as follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100

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5.1.4.1
Reversibility test and post-BD FEV1 efficacy assessment
Complete the initial (pre-BD) FEV1 measurement (Section 5.1.4) before commencing the 
post-BD assessment.  
It is important that the subject has withheld each of their theophylline and BD medications for 
the minimum period of time specified in Section 7.7.2 and Appendix G.  If at Visit 1, Visit 2, 
if applicable, or Visit 6 the subject has not adhered to this restriction the reversibility 
assessment should be re-scheduled within the next 7 days; other assessments for the visit can 
be completed as planned.  
Albuterol 90μg metered dose or Salbutamol 100μg metered dose will be used in the 
reversibility assessment.  Up to 8 doses may be administered at Visit 1, Visit 2 and 6 for run-
in reversibility, and up to 4 doses at the other visits (Visits 12, 26 and IPD).  Up to 4 doses 
will be administered at Visit 1 for subjects with the historical reversibility and Visit 6 if the 
reversibility criterion has been met at Visit 1 or for subjects with the historical reversibility.  If 
there is any concern about the effect on the subject’s heart rate, tremor or any other safety 
parameter during the assessment fewer doses can be administered; the reason should be noted 
in the subject’s medical records.
A spacer device should be used for administration of the SABA; nebulizers should not be 
used.  The same bronchodilator and type of device should be used at each visit where 
reversibility is assessed. 
Step 1: FEV1 measurement after 4 SABA inhalations  
For administration of albuterol/salbutamol, the subject will:
i.
Perform a gentle, complete expiration 
ii.
Inhale Dose 1 of the SABA to TLC and hold their breath for 5-10 seconds before 
the subject exhales.
iii.
Rest for approximately 30 seconds before the next dose
iv.
Repeat this for Dose 2, Dose 3 and Dose 4, resting for a further 15 – 20 minutes 
after Dose 4.  
After resting for 15 – 20 minutes FEV1 is measured following the technique described in 
Section 5.1.4.
Visit 1, Visit 2 and Visit 6:  if the inclusion criterion for reversibility is met (≥12% and ≥200 
mL) or at Visit 1 for the subjects with the historical reversibility, this is the end of the 
reversibility assessment/post-BD FEV1 assessment.  If it is not met the subject proceeds to 
Step 2.
Visit 12, Visit 26 and IPD Visit:  this is the end of the post-BD FEV1 assessment.  

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Step 2: FEV1 measurement following a further 2 (total of 6) SABA inhalations (Only at 
Visit 1, Visit 2 and Visit 6, if assessed)
The subject will repeat the SABA inhalation procedures for Dose 5 and Dose 6.  (See Step 1 
above for instructions.)
After resting for the 15 – 20 minutes FEV1 will be measured following the technique 
described in Section 5.1.4
This is the end of the reversibility assessment if either of the following occurs: 
o
the inclusion criterion for reversibility is met (≥12% and ≥200 mL) or 
o
the incremental change in FEV1 between Step 1 and 2 is ≤5% and the inclusion 
criterion is not met 
Subjects proceed to Step 3 if the incremental change in FEV1 between Step 1 and Step 2 is 
>5% and if the criterion for reversibility has not yet been met.
Step 3: FEV1 measurement following a further 2 (total of 8) SABA inhalations (Only at 
Visit 1, Visit 2, and Visit 6 if assessed)
The subject will repeat the inhalation procedures for Dose 7 and Dose 8, resting for 15 – 20 
minutes after Dose 8. (See Step 1 above for instructions.) 
After resting for the 15 – 20 minutes FEV1 will be measured following the technique 
described in Section 5.1.4. The reversibility assessment is now complete.
For subjects who need to perform step 2 and/or step 3 of the reversibility testing at Visit 
6, the baseline value for the post-BD outcome variable in FEV1 will be derived from the 
value obtained after step 1.
5.1.5
Home PEF testing
An electronic, hand-held spirometer (peak flow meter) will be provided to the subject at Visit 
1.
Home PEF testing will be performed by the subject in the morning upon awakening (and prior 
to taking their AM asthma controller) and in the evening at bedtime (and prior to taking their 
PM asthma controller). Recording of home PEF should start from the evening of Visit 1 until 
the morning of Visit 26 (Week 40) using an ePEF meter device. When possible, ambulatory 
lung function measurements should be taken at least 6 hours after the last dose of SABA 
rescue medication.
Subjects should perform 3 successive peak flow manoeuvres while sitting or standing, but in 
the same position at every testing; the highest of the 3 values will be captured for the morning 
and for the evening manoeuvres.

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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 and Table 2 (or at the EOT visit if prematurely 
discontinued from the study).
5.1.6
Safety assessments
5.1.6.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at visits in accordance with the schedule outlined in Table 1 and Table 2.  
Haematology and clinical chemistry samples should be collected at unscheduled visits for 
assessing an asthma exacerbation, at a minimum. Other unscheduled visits may be initiated as 
needed, and assessments performed as per investigator’s judgement. For dosing visits, all 
samples will be taken prior to the administration of IP.
Detailed schedules of the chemistry, haematology, and urinalysis tests are presented in Table 
5, Table 6, Table 7, and Table 8, respectively.

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Table 5
List of safety laboratory tests
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum)
B-Haemoglobin 
S-Alkaline phosphatase (ALP)
B-Leukocyte count
S-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen
B-Mean corpuscular volume
S-Calcium, total
B-Red blood cell (RBC) count
S-Carbon dioxide (CO2)
S-Chloride
S-Creatinine
S-Creatinine kinase
Urinalysis
U-Nitrite,Bilirubin, Glucose, Blood, Protein, 
Ketones (dipstick)
Urine microscopy and urine casts (as required)
S-CRP
Urine culture ( as required)
S-Gamma-glutamyl transpeptidase (GGT)
S-Glucose
S-Phosphorus
S-Potassium
S-Sodium
S-Total cholesterol
S-Uric acid
Table 6
Clinical chemistry tests schedule 
Visit
V1
V6
(Rand)
V12
V22
V26
IPD
Week
-10
0
12
32
40
(EOT)
ALP
X
X
X
X
X
X
ALT
X
X
X
X
X
X
AST
X
X
X
X
X
X
BUN
X
X
X
X
X
X
Calcium, total
X
X
X

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Visit
V1
V6
(Rand)
V12
V22
V26
IPD
Week
-10
0
12
32
40
(EOT)
Chloride
X
X
X
CO2
X
X
X
Creatinine
X
X
X
X
X
X
Creatinine kinase
X
CRP
X
GGT
X
X
X
X
X
X
Glucose 
X
X
X
Phosphorus
X
X
X
Potassium
X
X
X
Sodium
X
X
X
Total bilirubin
X
X
X
X
X
X
Total cholesterol
X
X
X
Uric acid
X
X
X

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Table 7
Haematology/Haemostasis (whole blood) schedule
VISIT
V1
V6
(Rand)
V7
V8
V10
V12
V14
V16
V18
V20
V22
V24
V26
V27
V28
IPD
Week
-10
0
2
4
8
12
16
20
24
28
32
36
40
44
54
B-Haemoglobin 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Leukocyte count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Leukocyte 
differential count 
(absolute count)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Platelet count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Hematocrit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Mean 
corpuscular 
volume
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
B-Red blood cell 
count
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 8
Urinalysis schedule 
VISIT
V1
V6
(Rand)
V12
V22
V26
IPD
Week
-10
0
12
32
40 
(EOT)
U-Nitrite,Bilirubin, Glucose, 
Blood, Protein, Ketones 
(dipstick)
X
X
X
X
X
X
Urine microscopy and urine 
casts (as required)*
Urine culture (as required)*
* Urine samples will be collected and sent for analysis at the central lab only when a positive 
dipstick result for any parameter is observed.
The total volume of blood that will be collected from each subject during the study is 
presented in Table 9.
Table 9
Volume of blood to be drawn from each subject
Assessment3
Sample volume 
(mL)
No. of samples
Total volume2
(mL)
Safety
Clinical chemistry
2.5
5
12.5
Haematology
2
15
30
FSH, β-HCG1
1
1
1
Serology
7.5
1
7.5
IgE
2.5
2
5.0
Phadiatop
2.5
1
2.5
Serum Biomarkers
16
8
128
ADA/nAb
3.5
4
14
PK
3.5
6
21
Total
221.5
1         Female subjects only
2        The number of samples may be changed due to additional sampling at IPD, 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 Tables 1 and 2
                                                

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Blood samples for determination of haematology/haemostasis and clinical chemistry will be 
performed at a central laboratory. For information on methods of collection, assessment, 
labeling, 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 or 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.
5.1.6.2
Pregnancy Test
The following tests are applicable to female subjects only, and will be conducted in 
accordance with the schedule provided in Table 1 and Table 2.
− Serum β-human chorionic gonadotropin (ß-HCG) – the test done at enrolment (Visit 
1) only, for WOCBP and adolescent females (analyzed at central laboratory)
− FSH – the test done at enrolment (Visit 1) only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrheic for 12 months
or more
− Urine HCG – the test will be performed at the study site for WOCBP and adolescent 
females at each treatment visit before IP administration using a dipstick. Positive urine 
test result must be confirmed with serum β-HCG.
5.1.7
Physical examination
Physical examinations (complete and brief) will be performed in accordance with schedule 
provided in Table 1 and Table 2.
Any new finding(s) or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE as described in section 6.1.
5.1.7.1
Complete physical examination
The complete physical examination will include an assessment of the following: general
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes,
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and
neurological systems.

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5.1.7.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system. For the brief physical examination only, 
information on whether the assessment was performed or not will be recorded.
5.1.8
dECG
All ECG assessments must be performed using a digital electrocardiogram (dECG) device.  
Digital ECGs will be performed in accordance with schedule provided in Table 1 and Table 2.
Digital ECG assessments will be performed prior to blood drawing, spirometry, IP 
administration and BD administration.
For all subjects, the printouts of the dECG will be collected and signed, dated and stored at the 
study site along with a signed and dated photocopy of each printout (ie, if the printout is not 
on archive-quality paper).
5.1.8.1
Resting 12-lead dECG
A 12-lead dECG will be taken in supine position, after the subject has been resting for at least 
5 minutes. The assessment should be performed before interventions with the subject (eg,
spirometry and administration of asthma-related medications and IP).
A standard dECG with a recommended paper speed of 50 mm/second covering at least 6 
sequential beats will be used. The Investigator or authorized delegate will be responsible for 
the overall interpretation and determination of clinical significance of any potential dECG 
findings. In case of discrepancy between the Investigator’s interpretation and that provided by 
the dECG machine (if applicable), the Investigator’s interpretation takes precedence and 
should be noted on the printout and recorded in the eCRF. Two identical copies of the dECG 
will be produced and quality checked and kept in case of further need for re-evaluation.
It is highly recommended that the same machine be used for all dECG assessments throughout 
the subject’s participation in the study.
dECG data and evaluation will be performed by the site Investigator and recorded in the 
eCRF.
5.1.9
Vital signs
Vital signs (i.e., pulse, blood pressure, respiration rate and body temperature) will be obtained 
in accordance with the schedule provided in Table 1 and Table 2. Vital signs will be taken 
prior to blood drawing, IP administration, and, if possible, usual asthma controller medication. 
At Visits 6 through 9, 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.

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Vital signs should also be taken prior to BD administration, if applicable for that visit.
Pulse, blood pressure and respiration rate
Pulse rate and blood pressure should be measured after the subject has been resting for at least 
5 minutes. The measurement will be taken in sitting position. Pulse rate will be obtained 
before blood pressure.
Respiration rate will be obtained after subject has been resting for at least 5 minutes, by 
counting number of breaths (ie, how many times the chest rises) for one minute.
Body temperature
Body temperature will be measured in degrees Celsius prior to IP administration, in 
accordance with local standards.
5.1.10
Other safety assessments
5.1.10.1
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be 
assessed at enrolment (Visit 1) only.  All testing for these will be performed at a central 
laboratory.
Instructions for sample collection, processing, storage, and shipment will be provided in a
separate laboratory manual provided to the sites.
5.1.10.2
Infections
Subjects experiencing 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. 
5.2
Other assessments
5.2.1
Weight and height
Weight and height will be measured in accordance with the schedule provided in Table 1 and 
Table 2.
Height will be measured at enrolment (Visit 1) for all subjects and at Visit 26 (EOT) and IPD 
visit for adolescents only.
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.

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5.2.2
Patient reported outcomes
Patient reported outcomes data will be captured using an ePRO. The device will be paired 
with a handheld spirometer (peak flow meter) for measuring at-home PEF testing (as outlined 
in section 5.1.5). Subjects will be trained on at-home use of the ePRO and handheld 
spirometer at Visit 1. Training will include explanation of device functionality and proper use 
of the spirometer. The subject will be asked to use both devices as part of the training and will 
be asked to verify completion of training on the ePRO device. Subjects will be provided with 
information on device use and issue resolution (eg, helpdesk numbers) to conclude the 
training. The site staff will set assessment reminder alarms on the device and the subject will 
complete the ACQ-6 at Visit 1. At-home PRO assessment will start the evening of Visit 1. 
Subjects will be asked to bring the device back at each study visit. At Visit 6 subjects will 
complete non-daily PROs on the device to start the visit for the baseline assessments at the 
site. Following Visit 6, all PRO data will be collected at home until Visit 26. Additional 
details concerning the assessments can be found in the subsequent sections (see sections 
5.2.2.1 to 5.2.2.5).
5.2.2.1
Asthma Daily Diary
The Asthma Daily Diary will be completed each day from the evening of Visit 1 to the 
morning of Visit 26. The Asthma Daily Diary will include the following daily recordings: 
morning and evening home PEF data (obtained from the home peak flow meter), asthma 
symptoms, inhalations of rescue medication, nights with awakenings due to asthma 
symptoms, maintenance medication compliance. There will be triggers in the ePRO device to 
alert the subjects to signs of worsening of asthma and to contact their physician, please refer to 
section 5.1.1.
The subject should contact the 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 and Table 2.
Home PEF measurement
Details regarding home PEF measurement please refer to section 5.1.5.
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 26.
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.

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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 (ie, in the morning and 
evening) beginning the evening of Visit 1 until the morning of Visit 26. 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 
26, 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 and OCS compliance will be captured daily from the evening of Visit 
1 until the morning of Visit 26. Maintenance medication (non-OCS) will be recorded in the 
Asthma Daily Diary once daily in the morning. The maintenance medication question will ask 
about compliance with regularly scheduled asthma medications taken “yesterday”. The 
response options will be: “Yes, I took all doses as scheduled”; “No, I did not take any of the 
doses scheduled”; and “I took some but not all scheduled doses”. The question will instruct 
respondents to not consider their rescue medication or OCS when answering. During device 
training, sites will instruct subjects that they should only consider their non-OCS controller 
medication when answering this question. Compliance with OCS will be captured via a 
separate question in the evening diary.  The OCS compliance question will have the following 
response options: “yes”, “no, dose was missed”, not scheduled today” or “not applicable, dose 
reduced to 0”.
5.2.2.2
Asthma Control Questionnaire (ACQ-6)
The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time 
waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and short-
acting β2-agonist use) omitting the FEV1 measurement from the original ACQ score.
Subjects will be asked to recall how their asthma has been during the previous week by 
responding to 1 question regarding their BD use, and 5 questions pertaining to their asthma 
symptoms.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 
indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled 
asthma, and a score >1.5 indicates uncontrolled asthma (Juniper et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful.

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The questionnaire will be completed using the ePRO device.
An initial screening ACQ-6 will be taken at Visit 1 at the study site, then every 14 days (± 1 
day) throughout the enrolment (Visit 1), run-in/optimization period. Subjects will then 
complete the ACQ-6 at Visit 6, and once randomized, subjects will be asked to complete 
ACQ-6 once every 14 days (± 1 day) throughout the treatment period, until the EOT visit 
where the ACQ-6 will be completed at the site.
The Investigator/authorized delegate will check the subject’s adherence to the ACQ-6 at each 
visit as shown in Table 1 and Table 2.
5.2.2.3
Standardised Asthma Quality of Life Questionnaire for 12 Years and Older 
(AQLQ(S)+12)
The AQLQ(S)+12 is a questionnaire that measures health related quality of life , developed 
for asthma subjects ages 12 and above.
The questionnaire comprises 4 separate domains (ie, asthma symptoms, activity limitations, 
emotional function, and environmental stimuli).
Subjects will be asked to recall their experiences during the previous 2 weeks and to score 
each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe 
impairment). The overall score will be calculated as the mean response to all questions. The 4 
individual domain scores (symptoms, activity limitations, emotional function, and 
environmental stimuli) are the means of the responses to the questions in each of the domains. 
Individual improvement in both the overall score and individual domain scores of 0.5 has been 
identified as a minimally important change. The questionnaire will be completed using the 
subject’s ePRO device.
The AQLQ(S)+12 will be first completed by the subject at the site at Visit 1, then every 14 
days (± 1 day) throughout the enrolment (Visit 1), run-in/optimization period. Subjects will 
then complete the AQLQ(S)+12 at Visit 6, and once randomized, subjects will be asked to 
complete AQLQ(S)+12 once every 28 days (± 1 day) throughout the treatment period, until 
the EOT visit where this will be completed at the site.
The Investigator/authorized delegate will check the subject’s adherence to AQLQ(S)+12 at 
each visit as shown in Table 1 and Table 2.
5.2.2.4
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ)
The WPAI+CIQ consists of questions about how asthma and asthma related issues impact
a subject’s ability to work, attend classes, and perform regular daily activities. The 
questionnaire relates to the subject’s experience over the previous 7 days. The WPAI+CIQ 
will be used to measure self-reported productivity loss. The questionnaire will be completed 
using the subject’s ePRO device.

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The WPAI+CIQ will be first completed at Visit 6 (Week 0), then every 2 weeks (±1 day) at 
home throughout the 40 week treatment period.
The Investigator/authorized delegate will check subject’s adherence to WPAI+CIQ at each 
visit as shown in Table 2.
5.2.2.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.
The subject will be asked to indicate his/her current health state by selecting the most
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state
The EQ-5D-5L will be completed weekly (+1 day) starting from Visit 6 (Week 0) throughout
Week 40 (Visit 26) using the ePRO device.
The Investigator/authorized delegate will check subject’s adherence to EQ-5D-5L at each visit 
as shown in Table 2.
5.2.2.6
Health care resource utilization
Broad-based health care utilization due to asthma-related event information will be collected 
by the Investigator/authorized delegate (as shown in Table 1 and Table 2) and recorded in the 
appropriate eCRF module.
At Visit 1, Healthcare Resource Utilization (HRU) information will be collected with a ‘one 
year’ recall period. All the subsequent visits will collect HRU information with a recall period 
of ‘since the last scheduled visit’.
Note: cases of hospitalization must also be reported as an SAE (as described in sections 6.2
and 6.4). 
5.3
Pharmacokinetics and Immunogenicity
5.3.1
Collection of samples
Blood samples for determination of tralokinumab in serum will be collected pre-dose at the 
times presented in Table 1 and Table 2. It is important that date and time of each SC injection 
and sample collection be recorded for each subject. 
Instructions for sample collection, labeling, 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 9.
5.3.2
Determination of drug concentration
Samples for determination of tralokinumab concentration in serum will be analyzed by a 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method. Details of the 
analytical method used will be described in a bioanalytical report. The PK samples will be 
retained for future use at AstraZeneca, or designee, for a maximum of 15 years following the 
date of Last Subject Last Visit. 
A summary of PK analysis results will be reported in the CSR; details of the PK analysis will 
be reported separately in a bioanalytical report.
5.3.3
Storage and destruction of pharmacokinetic samples
Pharmacokinetic samples may be disposed of or destroyed and anonymized by pooling. 
Additional analyses may be conducted on the anonymized, pooled pharmacokinetic samples 
to further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples.  The results from the evaluation will not be reported in the Clinical Study 
Report but separately in a Bioanalytical Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in 
this case, residual back-up PK samples will be shipped to the AstraZeneca Biobank; see 
details in the Laboratory Manual).
5.3.4
Immunogenicity 
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and
shipment will be provided in a separate laboratory manual provided to the sites.
Samples used for immunogenicity analyses will be retained at AstraZeneca or designee for a 
maximum of 15 years following the Last Subject’s Last Visit.  A summary of the analysis will 
be presented in the CSR. Details of the analytical method used will be described in a 
bioanalytical report.
Anti-tralokinumab antibodies
The pre-dose serum samples to measure presence of ADA will be collected according to the
schedule of study procedures (see Table 2).
The presence or absence of ADA will be determined in the serum samples using a validated
bioanalytical method. A tiered testing scheme will be employed, with the first step being 
screening. Samples found positive in the screening step will be tested in the confirmatory step. 

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Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titer 
determination and will be analyzed for the presence of nAb. 
Neutralizing antibodies
Neutralizing antibodies will be assessed as per Table 2 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.
5.3.5
Total IgE 
Testing for total IgE will be performed at Visits 6 and 26 (Weeks 0 and 40, respectively).  
Instructions for sample collection, processing, storage, and shipment will be provided in a
separate laboratory manual provided to the sites.
5.3.6
Phadiatop (Allergy Screen)
Testing for phadiatop (allergy screening test) will be performed at Visit 6 (Week 0).  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.
5.4
Pharmacodynamics
5.4.1
Serum biomarkers
Blood (serum) samples will be collected pre-dose according to the schedule in Table 1 and
Table 2 to evaluate the pharmacology of tralokinumab, including but not limited to, periostin 
and DPP4. Instructions for sample collection, processing, storage, and shipment will be 
provided in a separate laboratory manual provided to the sites. AstraZeneca or a designee will 
retain serum biomarker samples for investigation of the pharmacology of tralokinumab for a 
maximum of 15 years following the last subject’s last visit. 
The results from the investigation of such samples may not be reported in the CSR but in 
separate reports and in scientific publications as appropriate.
5.4.2
Level of fractional exhaled nitric oxide
Method of assessment
Fractional exhaled nitric oxide (FENO) measurements will be performed at Visits 1, 6, 8, 10, 
12, 18, 22, 26 (see Table 1 and Table 2). Subjects should not use their rescue SABA 
medication (eg, albuterol/salbutamol) within 6 hours of the measurement. Inhaled BDs, 

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including ICS/LABA combinations should be withheld for the effect duration specific to the
BD (see Appendix G) prior to all visits.  If not, the visit must be rescheduled.
Measurements will not be performed until 2 weeks after a respiratory infection. Subjects will 
be asked whether they have had a respiratory infection in the 2 weeks prior to measurement, 
which will be recorded as “Yes or No” in the eCRF. Measurement of (FENO) will be 
performed prior to the spirometry measurements.
FENO will be measured using an electrochemical sensor. Information concerning the 
specifications and use of the analyzer will be provided in a separate instruction manual.
The standard single exhalation technique recommended by the ATS will be followed (Dweik 
et al 2011). 
Signed and dated printouts from the measurements will be kept in the ISF for Source Data 
Verification (SDV). Printouts will be marked with the study code, subject enrolment/ 
randomization code, date, time of measurement, visit number and subject initials. If a printout 
cannot be printed, the mean value of the measurements will be recorded in the subject’s 
medical records for SDV.
The vendor supplying the chemiluminescence analyzer to participating sites will be 
responsible for ensuring that the equipment and procedures for the measurement of FENO are 
validated prior to the start of the study.
5.5
Pharmacogenetics (Not Applicable)
5.6
Biomarker analysis 
The subject’s consent or assent to the use of donated biological samples for non-exploratory 
analysis purposes is mandatory.    
Biological samples (ie, blood, plasma, serum) will be collected and may be analyzed for 
exploratory biomarkers to assess correlations with disease activity, effects of study drug, 
clinical outcomes and toxicity.
5.6.1
Storage, re-use and destruction of biological samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the Clinical Study Report itself or as an addendum, or separately in a 
scientific report or publication. The results of this biomarker research may be pooled with 
biomarker data from other studies with the study drug to generate hypotheses to be tested in 
future research.

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

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The laboratory(ies) holding the samples is/are informed about the withdrawn consent or assent 
immediately, and that samples are disposed of/destroyed, the action documented, and the 
signed document returned to the study site
The subject and AstraZeneca are informed about the sample disposal.
AstraZeneca will ensure that the central laboratory(ies) holding the samples is/are informed 
about the withdrawn consent or assent immediately, the samples are disposed of/destroyed, 
and that the action is documented and provided to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal 
results of an investigation (eg, laboratory findings, electrocardiogram).  In clinical studies, an 
AE can include an undesirable medical condition occurring at any time, including run-in or 
washout periods, even if no study treatment has been administered.
The term AE is used to include both serious and non-serious AEs.
6.2
Definitions of serious adverse event
An SAE is an AE occurring during any study period (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the subject or may require medical 
intervention to prevent one of the outcomes listed above.

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For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events, including SAEs will be collected from the time the subject signs the informed 
consent or assent form, throughout the treatment period and the follow-up periods (ie, Visit 
28, Week 54).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at any follow up visit in the study will be followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF. 
AstraZeneca retains the right to request additional information for any subject with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Adverse event variables 
The following variables will be collected in the eCRF for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity* of the AE
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product (yes or no)
!
Action taken with regard to IP
!
AE caused subject’s withdrawal from study (yes or no)
!
Outcome
*Intensity rating scale:
1 mild (awareness of sign or symptom, but easily tolerated)
2 moderate (discomfort sufficient to cause interference with normal activities) 
3 severe (incapacitating, with inability to perform normal activities)
In addition, the following variables (if applicable) will be collected in the eCRF for SAEs:
!
Date AE met criteria of serious

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!
Date Investigator became aware of the SAE
!
AE is serious due to
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Description of the AE
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity, whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Assessment of causality
The Investigator will assess causal relationship between the IP and each Adverse Event, and
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is provided in Appendix B to the 
Clinical Study Protocol.
6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you/your child had any health problems since the previous 
visit/you were last asked’, or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 

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signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
will use the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
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:
!
the sign or symptom is serious according to definitions, see Section 6.2,
!
the subject discontinues the study due to the sign or symptom, and/or
!
the sign or symptom is new to the subject or not consistent with the subject’s pre-existing 
asthma history (defined as within 1 year of Visit 1) as judged by the Investigator.
Asthma exacerbations should not be recorded as AEs, unless it fulfils any of the above 
criteria.  All asthma exacerbations should be recorded in the exacerbation eCRF as per Section 
5.1.3.

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If a subject discontinues IP due to a study specific discontinuation criterion, this should 
always be recorded as ’Development of study specific withdrawal’ on the termination form in 
the eCRF. In addition, the Investigator must assess whether the asthma deterioration should 
also be reported as an AE leading to discontinuation of IP (DAE)/AE leading to withdrawal 
from study on the AE form.
6.4
Reporting of serious adverse events
All SAEs must be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the course of the study, Investigators or other site personnel must 
inform the appropriate AstraZeneca representatives within one day (ie, immediately) but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Subject Safety data entry site within 
1 calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs, where important or relevant information is missing, active 
follow-up will be undertaken immediately.  Investigators or other site personnel must inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day (ie, immediately) but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert will be sent to the designated AstraZeneca representative(s).
If the WBDC system is not available, then the Investigator or other study site personnel
reports a SAE to the appropriate AstraZeneca representative(s) by telephone.
The AstraZeneca representative(s) will advise the Investigator/study site personnel how to 
proceed.
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca IP.
6.5
Overdose
An overdose with associated AEs is to be recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF, as well as in the Overdose eCRF module.
An overdose without associated symptoms is only to be reported on the Overdose eCRF 
module.

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If an overdose with the AstraZeneca study drug occurs during the course of the study, the 
Investigator, or other site personnel, must inform appropriate AstraZeneca representative(s) 
immediately, and no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Subject Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4.  
For other overdoses, reporting must occur within 30 days.
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
6.6.1
Maternal exposure
If a subject becomes pregnant during the course of the study IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the subject 
was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
will inform the appropriate AstraZeneca representatives within 1 day (ie, immediately) but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Subject Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy module in the eCRF will be used to report the pregnancy and the pregnancy 
outcome module will be used to report the outcome of the pregnancy.
6.6.2
Paternal Exposure
There is no restriction on fathering children or donating sperm during the study.
6.7
Management of IP related toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions must be immediately available 

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when IP is being administered.  Study site personnel must be trained to recognize and treat 
anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are provided in 
Appendix F.
Anaphylaxis will be defined as serious reaction that is rapid in onset and may cause death
(Sampson et al 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin,
mucosal tissue or both and at least one of the following: a) respiratory compromise; or
b) reduced blood pressure or symptoms of end-organ dysfunction
2.
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms
3.
Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (ie, vital signs and lung function) prior to IP 
administration.  At Visits 6 through 9, subjects should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, subjects will be observed for a minimum of 1 hour after IP 
administration for any such reaction.
In order to help understand the potential drug-relatedness of any acute reaction, a blood
sample should be drawn during the event for additional ADA testing (if not already scheduled
for this visit). If an anaphylactic reaction occurs, a blood sample will be drawn from the 
subject as soon as possible after the event, at 60 minutes ± 30 minutes after the event, and at 
discharge for analysis of serum tryptase.  The sample will be tested at the local lab or central 
laboratory where applicable.
6.8
Study governance and oversight
6.8.1
Independent Adjudication Committee
Tralokinumab is being developed for the treatment of severe asthma. There is considerable 
variation in the severity of subjects who seek ER or urgent care, and in the clinical thresholds 
used to determine the need for hospitalization.
An independent adjudication committee, blinded to the treatment of the subjects, will evaluate 
cases of ER or urgent care visits and hospitalizations, as well as all deaths, that occur during 
the course of the study to confirm that any such event is due to a worsening of asthma. For 
completeness, the adjudication committee will also be tasked with reviewing cardiovascular, 
cerebrovascular and malignant adverse events occurring after randomization.  The committee 
will include specialists in pulmonology, cardiology, neurology and oncology and will operate 
in accordance with dedicated Adjudication Committee Charter/Manual of Operations.

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6.8.2
Data and safety monitoring board
An external DSMB will monitor and protect the safety of adolescent subjects throughout the 
double blind treatment period of the study. The DSMB members will be selected for their 
expertise. The voting members of the DSMB will be comprised of external individuals 
including the DSMB chair. To minimize the potential introduction of bias, DSMB members 
will not have direct contact with the study site personnel or subjects. 
The DSMB will review safety data on a regular basis as set out in the DSMB charter. The data 
for review will be outlined in the DSMB charter The DSMB will have access to individual 
treatment codes and will be able to merge these with the collected study data while the study 
is ongoing. For reference, the DSMB will also have access to study data from adults. Subject 
enrollment will continue during DSMB review of safety data.
The DSMB will operate in accordance with the dedicated DSMB Charter/Manual of 
Operations and will be agreed to in advance by the DSMB members.
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
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, colourless
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 
10.

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Table 10
Identity of investigational product
Investigational 
product
Concentration and 
Formulation 
Dosage form and 
strength
Manufacturer
Tralokinumab
Formulated at a 
nominal concentration 
of 150 mg/mL in 
50mM sodium 
acetate/acetic acid 
buffer, 85mM sodium 
chloride, 0.01% (w/v) 
PS-80 pH 5.5 solution.
150 mg/mL solution 
for injection in an 
accessorized pre-filled 
syringe, 1.0 mL fill 
volume.
MedImmune
Placebo
Placebo contains the 
same excipients, in the 
same concentration 
only lacking 
tralokinumab
Placebo solution for 
injection in an 
accessorized pre-filled 
syringe, 1.0 mL fill 
volume.
MedImmune
The accessorized 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. 
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 2.
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 

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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 3. 

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Figure 3
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.
After IP administration
Subjects will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration.  At Visits 6 through 9, subjects should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions with vital signs taken
every 30 minutes or until stable, whichever is later. For the remaining visits involving IP 
administration, subjects will be observed for a minimum of 1 hour after IP administration for 
any such reaction with vital signs taken every 30 minutes or until stable, whichever is later.
Conditions requiring IP administration rescheduling
If any of the following should occur, the Investigator should reschedule the visit and
IP should not be administered until the rescheduled visit:
-
The subject has an intercurrent illness, that in the opinion of the
Investigator may compromise the safety of the subject in the study
(eg, viral illnesses)
-
The subject, in the opinion of the Investigator, is experiencing an acute or 
emerging asthma exacerbation
-
The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to IP 
administration

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7.3
Labelling
Labelling of the IP will be carried out by AstraZeneca or designee in accordance with Annex 
13 and current GMP and regulatory requirements of each country participating in the study.  
The labels will be translated into local languages where applicable and required by local 
regulations.
7.4
Storage
Tralokinumab/placebo is to be stored at the study site in a secured facility with limited
access and controlled temperature. The temperature should be monitored on daily basis and
documented in the temperature monitoring log.
The IP must be kept in the original outer container and under conditions specified on the label.
In the following cases:
-
Temperature excursion upon receipt or during storage at the study site
-
Damaged kit upon receipt, or
-
Damaged syringe/cartridge,
site staff should not use the affected IP, and should immediately contact their AstraZeneca 
representative for further guidance. Damaged IP should be documented via IWRS/IVRS 
(please refer to the IWRS/IVRS manual for further details).
7.5
Compliance
The date and time of all IP administrations, as well as any missed doses, should be recorded in 
the appropriate section of the eCRF.
7.6
Accountability
The study drugs provided for this study will be used only as directed in the protocol. 
It is the Investigator’s responsibility to ensure that a procedure is established and maintained 
for the operation of the unblinded study drugs, this includes but is not limited to:
∀
The study drugs are administrated only by a qualified, unblinded health professional 
named in the delegation of responsibility log.
∀
An unblinded health professional will account for all study drugs dispensed to the 
subjects.
An unblinded health professional, if applicable, or the blinded AstraZeneca monitor will 
account for all study drugs received at the site, unused study drugs and for appropriate 
destruction. Certificates of delivery and destruction should be signed.
In case of malfunctioning APFS, the centre should contact the unblinded AstraZeneca monitor 
to initiate a product complaint process according to applicable guidelines.

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7.7
Concomitant and other treatments 
7.7.1
Concomitant medications
Information about any treatment in the 3 months prior to the date of the 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 Electronic 
Case Report Form (eCRF).
Note: to satisfy inclusion criteria 6 and 7, the history of continuous treatment with high-dose 
ICS/LABA for at least 3 months prior to Visit 1 and use of OCS for at least 6 months prior to 
Visit 1 should be documented in source and recorded in the eCRF.
Oral corticosteroids
For eligibility purposes all subjects are required to be treated with OCS for at least 6 months 
prior to Visit 1 and be on the stable maintenance dose for at least 1 month prior to Visit 1.
The dose of OCS will be titrated down during optimization and reduction periods of the study 
(OCS optimization and Reduction periods, for details see Section 5.1.2).
Subjects who have one or more documented OCS reduction failures as outlined in section 3.1
which define the optimized dose prior to Visit 1 are not required to proceed through the pre-
randomization optimization period.
OCS 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.
Maintenance of asthma controller medication 
All subjects are required to be treated with a stable dose of ICS corresponding to ≥500 μg 
fluticasone propionate dry powder formulation equivalents (as outlined in Appendix E) and 
LABA for at least 3 months prior to Visit 1 and during the treatment period. Subjects may also 
receive other physician prescribed asthma controller medications.
The aim of this study is to establish the treatment effect of tralokinumab as an add-on 
treatment and therefore the maintenance asthma controller therapy should be maintained at a 
stable dose from Visit 1 until the end of the treatment period, in order to prevent any 
independent confounding of the anticipated treatment effect of tralokinumab. 
Changes to the subject’s maintenance asthma controller medication regimen are 
discouraged during the treatment period, unless judged medically necessary by the 
Investigator. Ideally, such changes should be discussed with the AstraZeneca Study Team 
Physician, prior to any change being made. 
All changes in the subject’s maintenance medication should be documented in source along 
with rational for change and recorded in eCRF.

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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.
Please note that subjects on maintenance treatment with theophylline should have 
documented blood concentration levels within therapeutic range. If this is not documented
before signing the informed consent, it can be obtained after informed consent has been given or
as part of the Visit 1 procedures. The sample can be analysed at the central or local lab as
applicable.
Rescue medication 
Salbutamol, albuterol, or levalbuterol will be used as rescue medication during the study in the 
event of a worsening of asthma symptoms. As with the maintenance ICS/LABA, rescue 
medication is not regarded as an IP, but will be provided/reimbursed by AstraZeneca 
according to local regulations, in order to ensure access to essential rescue therapy.
7.7.2
Restrictions during and after the study
7.7.2.1
Asthma medication restrictions
Use of short-acting β2-agonists (SABA)
Regularly scheduled SABA use in the absence of any asthma symptoms is discouraged from 
enrolment (Visit 1) and throughout the study duration.
Prophylactic use of SABA (eg, 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 (ie, 
rescue use) and will be recorded in the Asthma Daily Diary as number of inhalations.
Rescue use of SABA administered via jet or ultrasonic nebulization is allowed.  Occasions 
where SABA was administered via nebulization will be recorded separately from metered 
dose inhaler inhalations in the Asthma Daily Diary.  
Use of short acting anticholinergics 
The use of short acting anticholinergics (eg, ipratropium) as a rescue treatment for worsening 
asthma symptoms outside of managing an asthma exacerbation event is not allowed from 
enrollment and throughout the study duration.
Use of long-acting β2-agonists (LABA) as a reliever
The use of LABA as a reliever (eg, Symbicort maintenance and reliever treatment) is not 
allowed from enrollment and throughout the study duration.

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Use of once daily bronchodilators and theophylline
Use of theophylline and once daily BDs is allowed at the discretion of the Investigator. These 
drugs should have been used at a stable dose for at least 3 months before Visit 1. A 48 hour 
minimum washout period for theophylline or once daily BDs is required before spirometry.
Should the subject be taking theophylline or once daily BD in the evening, it is advised that 
the Investigator ask the subject to reschedule their theophylline or BD regimen to morning 
use, if there are no medical reasons to prevent this change.
It is important that a true pre-BD (ie, trough) FEV1 reading obtained in order to maintain the 
integrity of planned efficacy analyses around lung function improvement. Therefore, 
subjects will be asked to withhold from taking their usual regular BD medications and 
reliever SABA.  The subject’s usual asthma controller medications may be administered, 
following completion of the pre-BD spirometry. The suggested order of administration of the 
subject’s usual asthma controller, per protocol SABA (on visits where post-BD spirometry is 
assessed), and IP administration relative to scheduled pre and post-BD spirometry is given in 
section 5.1.4., for eligibility assessment (see Section 3.1, inclusion criteria 9 and 10).  In case 
the subject does not meet the reversibility eligibility criteria, and a second re-test is done (not 
earlier than next calendar day and not later than 7 calendar days after the failed attempt), 
ICS/LABA medications can be withheld for 24 hours.  In addition, SABA should not be used 
within 6 hours of these spirometry assessments.  The subject’s usual asthma medications may 
be administered following completion of the screening lung function procedures.
If the subject has taken their usual ICS/LABA and/or any other BD without the appropriate 
washout period before a site visit, the Investigator/authorized delegate should remind the 
subject of the importance of withholding their BD for an appropriate time and reschedule the 
visit for another day, within the allowed window. 
If the subject has taken rescue SABA within 6 hours of the planned site visit spirometry they 
should ideally 1) remain at the site until such time that the 6 hour window has been reached or 
2) return on another day, within the visit window. 
Asthma medication restrictions prior to home PEF testing 
Subjects should avoid taking their morning asthma controller medication prior to the morning 
home PEF testing, and should conduct the evening home lung function testing before taking 
evening asthma controller medication. When possible, home PEF testing, should be taken at 
least 6 hours after the last dose of SABA reliever medication
Asthma medication restrictions on unscheduled visits
Asthma medication restrictions on unscheduled visits may not be feasible, and may be applied 
at the discretion of the Investigator. Timing of recent controller and reliever SABA use 
relative to the unscheduled spirometry should be noted in the record.
Asthma medication restrictions at site visits with scheduled dECG assessment

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Subjects should be instructed not to take their usual asthma controller medication prior to 
scheduled dECG assessment. Use of SABA should be avoided within 6 hours prior to the 
dECG assessment, use of twice daily LABA for 12-24 hours and theophylline or once daily 
BD for 48 hours.
The medication restriction is waived for the enrolment dECG at Visit 1.
7.7.2.2
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 is not allowed (other than prior, stable OCS for the 
maintenance treatment of asthma).
∀
Receipt of live attenuated vaccines within 30 days prior to randomization and during the 
study, including the follow up period, is not allowed. Inactive/killed vaccines (eg, inactive 
influenza vaccine) are allowed provided they are not administered within 5 days 
before/after any dosing visit.
∀
Subject should not receive allergen immunotherapy injection on the same day as the IP 
administration
∀
Subjects should not take any other excluded medications:
!
Oral or ophthalmic non-selective β-adrenergic antagonist (eg, propranolol)
A table with medication-related restrictions is presented in Appendix G.
7.7.2.3
Bronchial Thermoplasty
Subjects should not undergo bronchial thermoplasty during the entire study.
7.7.3
Other treatments
Other treatments which is considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the Investigator.  If any such treatment includes medications other 
than those described above, these medications are to be recorded in the appropriate section of 
the eCRF.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations
The primary objective of this study is to show efficacy of tralokinumab vs. placebo with 
regards to reduction in the prescribed, daily, average, OCS maintenance dose. The primary 

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outcome variable is percent change from baseline in the daily OCS dose (primary) after 8
weeks of maintenance treatment following OCS dose reduction. Other outcome variables 
related to the reduction of the OCS maintenance dose are considered supportive to the primary 
variable.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject 
randomized and any subsequent amendments will be documented, with final amendments 
completed prior to unblinding of the data. Analyses will be performed by AstraZeneca or its 
representatives. 
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified.
8.2
Sample size estimate
For sample size estimation purposes, the targeted difference in the percentage reduction of the 
OCS dose between the active and placebo is 50% (for example if the final OCS reduction 
from baseline in tralokinumab group is 75% and the final OCS reduction from baseline in the 
placebo group is 25%). Based on previous studies of OCS reduction an estimate of 80% was 
used for the standard deviation. Assuming a Type I error rate of 5% and at least 90% power, 
the sample size required is at least 55 subjects per treatment group.
8.3
Definitions of analysis sets
All efficacy analyses will be performed using an ITT approach based on the full analysis set. 
For consistency, demographic and baseline characteristics will be presented using the full 
analysis set. Safety objectives will be analyzed based on the Safety population.
All subjects analysis set (All subjects): This analysis set comprises all subjects screened for 
the study and will be used for the reporting of disposition and screening failures.
8.3.1
Efficacy analysis set
Full analysis set: All subjects randomized and receiving any IP will be included in the full 
analysis set, irrespective of their protocol adherence and continued participation in the study. 
Subjects will be analyzed according to their randomized treatment, irrespective of whether or 
not they have prematurely discontinued. For subjects who withdraw consent or assent to 
participate in the study all data will be included up to the date of their study termination.
8.3.2
Safety analysis set
Safety analysis set (Safety): All subjects who received any IP will be included in the safety 
analysis set. Subjects will be classified according to the treatment they actually received. A 
subject who has on one, or several occasions, received active treatment will be classified as 
active. All safety summaries will be based on this analysis set.

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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
General Definitions
8.4.1.1
Definition of baseline and subject baseline variables
The baseline OCS dose for the primary and secondary variables related to OCS reduction 
during the reduction and maintenance periods (Week 12 and onwards) is defined as the 
prescribed, daily, average dose prior to randomization (Visit 6)
For FEV1 variables the measurement recorded at the randomization visit (Visit 6) will be used 
as baseline. If the Visit 6 measurement is missing, the last non-missing value before Visit 6 
will be used as baseline instead. For post-BD FEV1, the measurement after the first BD 
administration will be used as baseline.
The baseline for ACQ-6, AQLQ(s)+12, WPAI-CIQ, and EQ-5D-5L will be captured on the 
ePRO device at Visit 6. Baseline for Asthma Daily Diary variables will be the bi-weekly mean 
for data collected between study day -14 and -1 (ie 14 to 1 day before Visit 6). 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 6).
Absolute change from baseline outcome variables is computed as (post-randomization value –
baseline value). 
Percent change from baseline is computed as (post-randomization value – baseline value) / 
baseline value) × 100%. If either the post-randomization value or the baseline value is 
missing, then the absolute or percent change from baseline value will also be set to missing.
8.4.1.2
Visit and period windows
For the exacerbation-related analyses no windows will be applied. 
For non daily patient reported questionnaires collected in the ePRO, the variables will be 
summarized based on the protocol scheduled Days with ± 3-day window. 

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For the other questionnaires, the window is the same as the protocol-defined visit windows. 
For local laboratory data, and all vital signs, the visit recorded in the WBDC system will be 
used. 
For the central laboratory results and other endpoints that present visit-based data, the 
variables will be summarized based on the scheduled days with adjusted analysis-defined visit 
windows. 
A more detailed definition of visit and period windows will be provided in the statistical 
analysis plan.
8.4.2
Calculation or derivation of efficacy variables
8.4.2.1
Percentage reduction from baseline in prescribed oral corticosteroid dose
The primary variable is the percentage reduction from baseline in the final prescribed, OCS 
dose, defined as:
{(Baseline dose–final dose)/baseline dose}*100%
From week 32 - 40, the subjects should be on a maintenance dose of OCS and no reduction 
will be attempted. If a subject’s asthma deteriorates during that time to the point that the 
subject requires an increase in the daily dose of OCS, that increased dose will be recorded in 
the CRF and deemed as the subject’s final dose for analysis purposes, even if the increased 
dose is only taken after the 40 week treatment period.
If a subject discontinues from the study during the dose reduction period, the subject’s final 
dose will be defined as the higher dose level from one step back in the titration schedule. For 
example, suppose a subject had completed a previous dose reduction period while receiving 
10mg daily and was now in a subsequent dose reduction period receiving 5mg daily but 
withdrew before completing that period. In this case, the subject’s final dose level would be 
defined as 10mg daily because the subject had not completed the period in which 5mg was 
used. In the event that a subject withdraws as a result of an asthma exacerbation, the OCS 
dose prior to the systemic steroid burst will be the final dose. 
If a subject has prematurely discontinued IP, agreed to modified follow-up (Section 3.9.1) and 
data is not sufficient to verify asthma control then the subject’s final dose will be defined as 
the higher dose level from one step back in the titration schedule compared to the last reported 
dose level when asthma control could be verified.
Also, should a subject be placed on an every other day regimen of OCS, their final dose will 
be defined as the average daily dose. For example, if a subject is placed on a regimen of 
2.5mg every other day, their final dose is defined as 1.25mg/day.
The impact of different imputation strategies for the final OCS dose will be explored.

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8.4.2.2
The proportion of subjects with average final prescribed OCS dose ≤5.0 mg 
daily
For each treatment group, the number of subjects with average final OCS dose ≤5.0 mg daily 
will be calculated. The proportion of such subjects will be calculated for each treatment group 
as:
Number of subjects with average final OCS dose ≤ 5 mg daily at final visit / number of 
subjects in treatment group
Final OCS is defined as in 8.4.2.1.
8.4.2.3
Proportion of subjects with ≥50% reduction from baseline in the prescribed 
oral corticosteroid dose 
For an individual subject, if the calculation in section 8.4.2.1 results in a value of 50% or 
greater, that subject will be classified as having at least a 50% reduction in daily OCS dose. 
The proportion of such subjects will be calculated for each treatment group as:
Number of subjects with ≥50% reduction at final visit/number of subjects in treatment group
8.4.2.4
Area under the prescribed oral corticosteroid dose curve
Area under the OCS dose curve will be calculated using the time period from baseline to week 
40. If a subject is discontinued from the study, the final dose as defined in 8.4.2.1 will be used 
for the time from discontinuation to week 40.
8.4.2.5
Proportion of subjects in different categories of reduction from baseline in oral 
prescribed corticosteroid dose
The percent reduction defined in Section 8.4.2.1 will be categorized into the following 
categories:
∀
100% reduction (no OCS)
∀
≥ 90% to < 100% reduction
∀
≥ 75% to < 90% reduction
∀
≥ 50% to < 75% reduction
∀
> 0 to < 50% reduction
∀
no change in average OCS dose
∀
increased average OCS dose
The proportion of subjects in each category will be calculated for each treatment group as:
Number of subjects in each category / number of subjects in treatment group

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8.4.2.6
Proportion of subjects with ≥25% reduction from baseline and with average 
final OCS dose ≤5.0 mg daily
For an individual subject, if the calculation in section 8.4.2.1 results in a value of 25% or 
greater and if the average final OCS dose ≤5.0 mg daily, that subject will be classified 
accordingly. The proportion of such subjects will be calculated for each treatment group as:
Number of subjects with ≥25% reduction from baseline and average final OCS dose ≤5.0 mg 
daily / number of subjects in treatment group
Final OCS dose is defined as in 8.4.2.1.
8.4.2.7
Proportion of subjects with ≤5.0 mg reduction from baseline in oral 
corticosteroid dose 
For each treatment group, the number of subjects with change in average daily OCS dose ≤5.0 
mg will be calculated. The proportion of such subjects will be calculated for each treatment 
group as:
Number of subjects with ≤5.0mg reduction at final visit / number of subjects in treatment 
group
Final OCS dose is defined as in 8.4.2.1.
8.4.2.8
Exacerbation rate
In the statistical analysis, the number of asthma exacerbations experienced by a subject during 
the 40-week double-blind treatment period will be used as response variable, and the 
logarithm of the subject’s corresponding follow-up time will be used as an offset in the 
analysis to adjust for subjects having different exposure times during which the events occur. 
Asthma exacerbation is defined in Section 5.1.3.
In order to calculate the number of exacerbations experienced by a subject during the 40-week 
treatment period the following rule will be applied: 
∀
The start of an exacerbation is defined as the start date of systemic corticosteroids, 
ER or urgent care visits requiring systemic steroids or hospital admissions due to 
asthma, whichever occurs earlier. The end date is defined as the last day of 
systemic corticosteroids or ER or urgent care visit or hospital discharge, whichever 
occurs later.
Additional systemic corticosteroid treatments, ER or urgent care visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled. 
Maximum follow-up time for a subject is approximately 40 weeks; defined as the time from 
randomization to the date of Visit 26. For a subject lost to follow-up, this will be defined as 

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the time from randomization to the time point after which an exacerbation could not be 
assessed. 
For the production of summary statistics, the annual asthma exacerbation rate per subject is 
calculated, and standardized per a 52-week period according to the formula described below.
Annual Exacerbation Rate = No. of Exacerbations*365.25 / (Follow-up date – Visit 6 date + 
1).
8.4.2.9
Time to first exacerbation
Time from randomization to the first asthma exacerbation is calculated as follows:
Start Date of first asthma exacerbation − Date of Randomization + 1.
The time to first asthma exacerbation for subjects who do not experience an asthma 
exacerbation during the treatment period will be censored at the date of their last visit for the 
40-week double-blind treatment period, or at the time point after which an exacerbation could 
not be assessed.
8.4.2.10
Proportion of subjects with ≥ 1 asthma exacerbation during 40 weeks of 
treatment
The proportion of subjects with ≥ 1 asthma exacerbation during the 40 weeks of treatment will 
be a supportive variable. The variable will categorize each subject as having at least one 
asthma exacerbation or not (yes/no).
8.4.2.11
Annualised asthma exacerbation rate associated with an ER or urgent care 
visit or a hospitalization
The number of asthma exacerbations that are associated with an ER or urgent care visit or a 
hospitalization experienced by a subject during the 40-week treatment period will be derived 
according to the following rule:
The start date of an asthma-related ER or urgent care visit or hospitalizations is the start date 
of the ER visit or urgent care or hospitalization.
The cessation date of an asthma-related ER or urgent care visit or hospitalization is the stop 
date of the ER visit or urgent care or hospitalization.
In the statistical analysis, the number of asthma exacerbations that are associated with an ER 
or urgent care visit or a hospitalization experienced by a subject during the 40-week double-
blind treatment period will be used as response variable, and the logarithm of the subject’s 
corresponding follow-up time will be used as an offset in the analysis to adjust for subjects 
having different exposure times during which the events occur.
Maximum follow-up time is approximately 40 weeks, and the follow-up time is derived as 
described in Section 8.4.2.5

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Additionally, for the production of descriptive statistics, the annualised rate of asthma-related 
ER or urgent care visits and hospitalizations will be calculated using the same methodology as 
the annualised rate of exacerbations described in Section 8.4.2.5.
8.4.2.12
Lung Function Variables
FEV1, FVC and FEF25-75% variables will be calculated based on the pre BD and the post BD 
measurements. 
Percent change and absolute change from baseline (supportive variable) will be calculated as 
described in 8.4.1.1.
8.4.2.13
Diary Based Variables
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 8.4.2.1.
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 
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 change from baseline in biweekly mean daily asthma symptom 
total score. 
Rescue Medication Use
The number of rescue medication inhalations and nebulizer treatments taken will be recorded 
by the subject in the Asthma Daily Diary twice daily.
The number of inhalations of rescue medication captured in the eDiary each day will be 
calculated per subject. If a subject is missing a value for either morning or evening rescue 
medication on a given day, then the total rescue medication use for that day will be set to 
missing.

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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 percentage 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.
8.4.2.14
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
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:

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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
8.4.2.15
Asthma Quality of Life Questionnaire for 12 Years and Older
Using the AQLQ(S)+12 questionnaire, subjects are asked to recall their experiences during the 
previous 2 weeks and to score each of the 32 questions on a 7-point scale ranging from 7 (no 
impairment) to 1 (severe impairment).
The overall score is calculated as the mean response to all questions. The 4 individual domain 
scores (4 domains assessing 1) symptoms, 2) activity limitations, 3) emotional function, and 
4) environmental stimuli) are the means of the responses to the questions in each of the 
domains. 
The main outcome variable for the AQLQ(S)+12 will be the change in mean overall score 
from baseline to each of the post-randomization periods. The change from baseline will be 
derived as post-randomization score minus baseline score, there will be no imputation for 
missing values.
Other variables based on AQLQ(S) +12 to be reported include:
∀
AQLQ(S) +12 -responder (Yes=1/No=0)
o
Responder: Change from baseline AQLQ(S) +12 score ≥  0.5
o
Non-responder :  Change from baseline AQLQ(S) +12 score < 0.5
∀
AQLQ(S) +12 -responder (improved/No Change / Deterioration)
o
Improvement: Change from baseline AQLQ(S) +12 score ≥  0.5
o
No change: -0.5 < Change from baseline AQLQ(S) +12 score < 0.5
o
Deterioration:  Change from baseline AQLQ(S) +12 score  ≤ -0.5
∀
Change in mean domain score from baseline to each of the post-randomization periods
8.4.2.16
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, 
moderate problems, severe problems, and extreme problems) that reflect increasing levels of 
difficulty.
The subject will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual 
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state.
The change from baseline in visual analogue scale will be calculated by visit as described in 
8.4.1.1.

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8.4.2.17
Health care resource utilization
Broad-based health care utilization event information will be collected by the 
Investigator/authorized delegate at each visit as specified in the protocol and recorded in the 
appropriate eCRF module. Examples include aspects such as unscheduled physician visits or 
telephone calls or ambulance transport.
8.4.2.18
The Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions (WPAI+CIQ)
The WPAI+CIQ questionnaire is a 10-item questionnaire that assesses productivity and 
activity impairment over the previous week.
There are a maximum of 10 questions and a minimum of 3 questions that will be completed 
by subjects as follows:
1. Currently employed (yes/no)
2. Hours missed work due to health problems
3. Hours missed work due to other reasons
4. Hours actually worked
5. Degree health affected productivity while working (0-10 scale, with 0 meaning no 
effect)
6. Attends class in an academic setting (yes/no)
7. Hours missed class due to health problems
8. Hours actually attended class
9. Degree health affected productivity while attending class (0-10 scale, with 0 meaning 
no effect)
10. Degree health affected regular activities (other than work or class) (0-10 scale, with 0 
meaning no effect)
If the answer to question 1 is ‘No, not currently employed’, then the subject should skip to 
question 6. If the answer to question 6 is ‘No, not currently attending class’, then the subject 
should skip to question 10.
The WPAI+CIQ provide 4 scores: 
∀
Absenteeism (work or class time missed),
∀
Presenteeism (impairment at work or class/reduced on-the-job effectiveness), 
∀
Work productivity loss (overall work or class impairment/absenteeism plus 
presenteeism) 
∀
Activity impairment. 
WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers 
indicating greater impairment and less productivity.

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For the work related questions, the following calculations should be used to create the 
outcomes of interest:
∀
Absenteeism = Q2/(Q2+Q4)
∀
Presenteeism = Q5/10
∀
Work Productivity Loss = Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]
∀
Activity Impairment = Q10/10
The class related questions will be used in a similar manner.
8.4.3
Calculation or derivation of safety variable(s)
The following safety data will be collected: vital signs, physical examination, 12-lead dECG, 
hematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline (Visit 6) to each post-baseline time point where scheduled assessments 
were made will be calculated for relevant measurements. 
8.4.3.1
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 ≤week 54; 
this is only applicable for subjects that are treated the entire treatment 
period)
o
(onset date > the last day of study treatment + 2 weeks and ≤the last 
day of study treatment + 14 weeks; this is only applicable for subjects 
that prematurely discontinued treatment)
∀
AEs occurring post-treatment (onset date > the last day of study treatment + 
14 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 

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partial onset date or the stop date indicates otherwise, this will be considered an on treatment 
AE.
8.4.3.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations due to AEs. 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR.
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
8.4.3.3
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 5, Table 6, Table 7 and Table 8 in Section 
5.1.6.1, will be collected. Laboratory data will be reported in SI units.
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent scheduled assessment will be calculated. Baseline will be defined as the last 
available value measured prior to the first dose of randomized treatment. The change from 
baseline will be defined as the treatment period value minus the baseline period value. There 
will be no imputation for missing values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The AstraZeneca extended 
reference ranges will be used for laboratory variables (where they exist). All values (absolute 
and change) falling outside the reference ranges will be flagged.
Urinalysis data will be categorised as negative (0), trace or positive (+) at each time-point. 
For the purposes of haematology, clinical chemistry and urinalysis shift tables, baseline will 
be defined as the latest non-missing assessment prior to first dose, and on-treatment will be 
defined as the latest non-missing assessment whilst the subject is ongoing on treatment.
For the liver function tests: AST, ALT, ALP, GGT and total bilirubin, the multiple of the 
AstraZeneca ULN (not extended) range will be calculated for each data point.
Multiple = Value / ULN
ie, 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:

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∀
AST ≥ 3x ULN
∀
ALT ≥3x ULN
∀
TBL ≥ 2xULN
8.4.3.4
dECGs
Twelve-lead dECG measurements will be recorded in accordance with the protocol, with the 
baseline visit being defined as Visit 1.
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant.
8.4.3.5
Physical Examination
Complete and brief physical examinations will be performed at time points specified in Table 1
and Table 2. What is included in the assessment will be dependent on whether the examination 
is complete or brief, as described in Section 5.1.7. For the brief physical examination, only 
information on whether the assessment was performed or not will be recorded.
Each component of the baseline visit (i.e., Visit 6) complete physical examination will be 
recorded as normal or abnormal. Each component of the follow-up complete physical 
examinations will be recorded as normal, same as baseline, or new/aggravated.
Any new finding(s), or aggravated existing finding(s) after Visit 1, judged as clinically 
significant by the Investigator, will be reported as an AE, as described in Section 6.1.
8.4.3.6
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
and Table 2.
Changes in vital signs variables between baseline and each subsequent scheduled assessment 
will be calculated. Baseline will be defined as the last value prior to the first dose of 
randomized treatment. The change from baseline will be defined as the treatment period value 
minus the baseline period value. There will be no imputation for missing values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). All values (absolute and 
change) falling outside the reference ranges will be flagged.
Body mass index (BMI) will be calculated from the height (in meters) and weight (in 
kilograms) as follows: 
BMI = kg/m2

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8.4.4
Calculations or derivation of Pharmacokinetic and Immunogenicity variables
Blood samples (processed to serum) for pharmacokinetic and immunogenicity assessments 
will be collected from all subjects at baseline prior to first tralokinumab administration at Visit 
6, at multiple time points before tralokinumab administrations during the treatment period, 
and at selected time points in the follow-up period of the study. ADA assessments will be 
conducted utilizing a tiered approach (screen, confirm, titer). These validated methods are 
conducted using a bridging assay format and statistically determined floating screening assay 
cut point factor and confirmatory assay cut point. The minimal sample dilution is 1:13. Titer 
values are reported as the reciprocal of the highest dilution that yields a value above the cut 
point. Samples from pre-defined study time points that confirm positive for ADA will also be 
tested for nAb activity. Both ADA and nAb will be summarized using descriptive statistics as 
described in Section 8.5.10.
Pharmacokinetics and immunogenicity of tralokinumab:
Tralokinumab serum concentrations will be tabulated by time along with descriptive statistics.  
Population PK modelling may also be performed to better characterize the PK of 
tralokinumab, but will be reported separately from the CSR. 
The incidence rate of ADA to tralokinumab will be reported by tralokinumab treatment group. 
If possible and if relevant, the impact of ADA occurrence on the PK and PD and safety will be 
summarized in the CSR.
8.5
Methods for statistical analyses
The main focus for the statistical analyses is to compare tralokinumab to placebo in with 
regards to primary, secondary, and safety objectives.
The analysis of the study endpoints will include all data captured during the 40-week double-
blind treatment period. This includes data regardless of whether study treatment was 
prematurely discontinued or delayed, and/or irrespective of protocol adherence, unless the 
subject withdraws consent or assent to study participation. The statistical analyses will 
compare tralokinumab to placebo.
Summary data will be presented in tabular format by treatment. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous variables 
for parametric data will be summarized by descriptive statistics including N, mean, SD,   
median, and range. Variables will be summarized by visit, if applicable. All data will be listed. 
Data listings will be sorted by treatment, subject number. 
All hypothesis testing will be reported using 2-sided tests. P-values will be rounded to 3 
decimal places.
8.5.1
Testing strategy for primary and key secondary objectives
To account for multiplicity when testing the primary and secondary endpoints, a hierarchical 
testing strategy will be used for primary and secondary outcomes:

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The difference in the proportion of subjects with final OCS dose ≤5 mg will only be tested if 
the p-value for the test of difference in percentage reduction in OCS is less than 0.05.
The difference in the proportion of subjects with ≥50% reduction will only be tested if both p-
values for the tests of difference in percentage reduction in OCS and difference in the 
proportion of subjects with final OCS dose ≤5 are less than 0.05.
No adjustments will be made for tests of safety or exploratory efficacy variables.  Any results 
reported for these variables will be considered nominal (ie, unadjusted).
8.5.2
Sensitivity analyses
The interpretation data post-discontinuation of treatment is likely to be confounded by 
reduced quality of objective confirmation of deterioration, and by the use of subsequent 
therapies. Sensitivity analyses for the primary endpoint will be carried out to explore the 
impact of this, e.g. exclusion of data post-discontinuation of treatment or exclusion of data.
Also sensitivity analyses for the primary, secondary and supportive endpoints based on 
different missing data mechanism assumptions including those expected to be more 
conservative such as missing not at random will be used to explore the robustness of any 
treatment effect, including multiple imputation approaches.
Full details of the sensitivity analyses will be pre-specified in SAP and documented prior to 
database lock of the studies.
8.5.3
Subject disposition, demography data and subjects characteristics
Subject disposition will be summarized using the all subjects analysis set. 
The number of enrolled subjects will be summarized. The number and percentage of subjects 
within each treatment group will be presented by the following categories; randomized, not 
randomized (and reason), received study treatment, didn’t receive study treatment (and 
reason), completed treatment, discontinued treatment (and reason), completed study, and 
discontinued study (including reason).
Demographic data such as age, gender, and race will be summarized by treatment group for 
the full analysis set.
Various baseline characteristics will also be summarized by treatment for the full analysis set. 
These include medical, surgical and respiratory disease histories, weight, height and BMI, 
smoking status, history of allergy, OCS dose at baseline, FEV1 (pre and post-BD) at baseline, 
asthma duration, age at onset of asthma, asthma medications, the number of asthma 
exacerbations in the previous 12 months, and the number of asthma exacerbations requiring 
hospitalizations in the previous 12 months.
Medical and surgical histories will be summarized by MedDRA Preferred Term (PT) within 
the System Organ Class (SOC) level of MedDRA.

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The number and percentage of subjects who take concomitant medications, and those who 
take disallowed concomitant medications during the study, will be presented by treatment 
group. Concomitant medications will be classified according to the AstraZeneca Drug 
Dictionary. The summary tables will present data by generic term using Anatomical 
Therapeutic Chemical (ATC) classification system codes.
8.5.4
Exposure
Exposure to IP will be summarized by treatment group, for the safety analysis set.
8.5.5
Violations and deviations
Only important protocol deviations will be listed and tabulated in the CSR. Protocol 
deviations that may greatly impact the completeness, accuracy, and/or reliability of the study 
data or that may significantly affect a subject’s rights, safety, or well-being include:
•
Subjects who do not meet the inclusion criteria
•
Subjects who do not meet the randomization criteria
•
Subjects who meet any of the exclusion criteria
•
Subjects who use one or more disallowed medication (for any reason, unless otherwise
specified) during the 40-week double-blind treatment period 
•
Subjects who received the incorrect study treatment or study dose at any time during 
the 40-week double-blind treatment period
•
Subjects who developed withdrawal criteria during the study but were not withdrawn
8.5.6
Analysis of the primary variable
The primary efficacy variable is the percentage reduction from baseline in the subject’s 
prescribed, OCS dose. 
The null hypothesis is that the percentage reduction in OCS dose on tralokinumab is equal to 
the percentage reduction in OCS dose on placebo.  The alternative hypothesis is that the 
percentage reduction in OCS dose on tralokinumab is not equal to the percentage reduction in
OCS dose on placebo, ie:
H0: difference in % reduction OCS dose (tralokinumab vs. Placebo)=0
Ha: difference in % reduction OCS dose (tralokinumab vs. Placebo)≠0
The percentage reduction in OCS dose in tralokinumab treatment group will be compared to 
the percentage reduction in OCS dose in the placebo group using an analysis of covariance 
(ANCOVA) model.

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The response variable in the model is the percentage reduction in OCS dose from baseline to 2 
weeks after the final dose that the subject is receiving (Week 40, Visit 26). The model will 
include covariates of treatment group, age group and baseline OCS dose.
The estimated treatment effect (ie, difference in mean percentage reduction of tralokinumab 
versus placebo), corresponding 95% confidence interval (CI), and two-sided p-value for the 
difference will be presented.  In addition, the percentage reduction in OCS and the 
corresponding 95% CI within each treatment group will be presented.
Due to the discrete nature of data, blinded data will be used to assess whether an analysis of 
covariance model is robust against the departure from the assumption of normal data.  Any 
changes of the primary analysis based on this assessment will be documented in the SAP.
8.5.7
Analysis of secondary variable(s)
8.5.7.1
The proportion of subjects with average final prescribed OCS dose ≤5.0 mg 
daily
The proportion in the tralokinumab group will be compared with the proportion in the placebo 
group using a Cochran–Mantel–Haenszel test controlling for age group and baseline OCS 
dose.
The results of the analyses will be presented as difference in the proportion of subjects 
reaching ≤5mg daily, together with associated 95% CI and 2-sided p-value. The number and 
percentage of subjects reaching ≤5mg daily will also be summarized by randomized 
treatment.
8.5.7.2
Proportion of subjects with ≥50% reduction from baseline in prescribed oral 
corticosteroid dose 
The proportion of subjects with ≥50% will be summarized and analyzed using the approach 
defined for the proportion of subjects with average final prescribed OCS dose ≤5.0 mg daily, 
as described in Section 8.5.7.1.
8.5.8
Analysis of supportive and exploratory variables
8.5.8.1
Area under the in prescribed oral corticosteroid dose curve 
The area under the OCS dose curve will be addressed as a supportive variable to the primary 
objective will be summarized and analyzed using the ANCOVA approach defined for the 
primary variable, as described in Section 8.5.6.
8.5.8.2
Proportion of subjects in different categories of reduction from baseline in oral 
corticosteroid dose
To support the primary analysis the reduction in baseline OCS will be evaluated descriptively 
using the categorical variable defined in Section 8.4.2.5.
The results of the analyses will be presented as differences versus placebo in the proportion of 
subjects in each group, together with the associated 95% CI.

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8.5.8.3
Proportion of subjects with ≥25% reduction from baseline and with average 
final prescribed OCS dose ≤5.0 mg daily
Proportion of subjects with ≥25% reduction from baseline and with average final OCS dose 
≤5.0 mg daily with be addressed as a supportive variable to the secondary objectives and will 
be summarized and analyzed using the approach defined for the proportion of subjects with 
average final prescribed OCS dose ≤5.0 mg daily, as described in Section 8.5.7.1.
8.5.8.4
Proportion of subjects with ≤5.0 mg reduction from baseline in oral 
corticosteroid dose 
The proportion of subjects with ≤5.0 mg reduction from baseline in average daily oral 
corticosteroid dose will be addressed as a supportive variable to the secondary objectives and 
will be summarized and analyzed using the approach defined for the proportion of subjects 
with average final prescribed OCS dose ≤5.0 mg daily, as described in Section 8.5.7.1.
8.5.8.5
Exacerbation rate
The AAER in the tralokinumab group will be compared to that seen in the placebo group 
using a negative binomial model. The response variable in the model will be the number of 
asthma exacerbations experienced by a subject, over the 40-week double-blind treatment 
period. Covariates and factors included in the model will include at least treatment and the 
stratifying variables. The logarithm of the subject’s corresponding follow-up time will be used 
as an offset variable in the model to adjust for subjects having different exposure times during 
which the events occur.
The standard parameterization approach (NB2) of the Negative Binomial model will be 
applied (Hilbe 2011).
The estimated treatment effect (ie, the rate ratio of tralokinumab versus placebo) and
corresponding 95% confidence interval (CI), and for the rate ratio will be presented. In 
addition, the AAER and the corresponding 95% CI within each treatment group will be 
presented.
The individual exacerbation criteria (ER or urgent care visits due to asthma that required 
systemic corticosteroids, hospitalization due to asthma, or use of systemic corticosteroids) will 
also be summarized descriptively.
8.5.8.6
Other endpoint associated with asthma exacerbations
The proportion of subjects with ≥1 asthma exacerbation will be summarized and analyzed
using the approach defined for proportion of subjects with ≥50% reduction, as described in 
Section 8.5.7.2.

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Time to first asthma exacerbation
Time to first asthma exacerbation will be analyzed to explore the extent to which treatment 
with tralokinumab delays the time to first exacerbation compared with placebo. A Cox 
proportional hazard model will be fitted to data with including treatment and at least 
stratifying variables as covariates.
Results of the analysis will be summarized as hazard ratios and 95% confidence intervals.
Time to first asthma exacerbation will be displayed graphically using a Kaplan-Meier plot. 
The median time to event will be summarized by randomized treatment, if there is sufficient 
uncensored data available to calculate these median values. 
8.5.8.7
Emergency room or urgent care visits and hospitalizations due to asthma
Annual rate of asthma exacerbations that are associated with an ER or urgent care visit or a 
hospitalization will be analyzed using a similar negative binomial model as outlined for the 
efficacy variable in Section 8.5.8.5.
8.5.8.8
Lung Function
The percent change from baseline in pre-BD FEV1, FVC and FEF25-75% at Week 12 and 40 
will be compared between tralokinumab and placebo using a repeated measures analysis on all 
subjects with a baseline measurement in the full analysis set. 
The dependent variables will be the percent change from baseline in each lung function 
variable at post-baseline protocol-specified visits (up to the EOT visit). Treatment group and 
the variables used in the stratified randomization will be included as independent variables. 
Visit will be fitted as a categorical variable, and the variance-covariance matrix will be 
assumed to be unstructured. If the procedure does not converge then a compound symmetric 
variance-covariance matrix will be used instead. The model is:
Percent change in lung function variable= Treatment group + stratifying variables + visit + 
treatment*visit
Results will be presented in terms of LSMEANS, treatment differences in LSMEANS and
95% confidence intervals. 
8.5.8.9
Asthma symptoms
The change from baseline in asthma symptom total score, daytime score, and night-time score 
at Week 12 and 40 will each be summarized and analyzed using the repeated measurement 
approach defined for change from baseline in pre-BD FEV1, as described in Section 8.5.8.8. 
Included in the model will also be the baseline mean daily asthma symptom score.

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8.5.8.10
Asthma symptom, general health-related quality of life and asthma control
Rescue medication use
Total rescue medication use (average puffs/day) will be summarized and analyzed using a 
similar model as for the change from baseline in pre-BD FEV1, as described in Section 
8.5.8.8.
Home PEF (morning and evening)
Change from baseline in morning and evening PEF at Week 40 will each be summarized and 
analyzed using the same approach as for the change from baseline in pre dose/pre-BD FEV1, 
as described in Section 8.5.8.8.
Nights with awakening due to asthma
The percentage of nights with awakening due to asthma and requiring rescue medication will 
be summarized and analyzed in the same way as rescue medication use, described above.
8.5.8.11
ACQ-6 defined asthma control
Change in mean score from baseline for ACQ-6 will be summarized and analyzed using the 
repeated measurement approach defined for change from baseline in pre-dose/pre-BD FEV1, 
as described in Section 8.5.8.8. Included in the model will also be the baseline ACQ-6 mean 
score.
Responder variables ACQ-6 (yes/no) at Week 12 and Week 40 will be analyzed using a 
logistic regression model with covariates of at least treatment, stratifying variables, and 
baseline value.
The number and percentage of subjects achieving mean ACQ-6 ≤ 0.75, 0.75 < mean ACQ-6 
<1.5 and mean ACQ-6 of ≥ 1.5 at EOT will be summarized by treatment. Additionally, the 
number and percentage of subjects achieving an improvement, no change, or deterioration as 
per Section 8.4.2.14, ACQ-6 will also be summarized by treatment. 
Supportive outcome measure: change from baseline to overall post-baseline mean of ACQ-
6.
8.5.8.12
Asthma specific health-related quality of life
The change in mean score from baseline for AQLQ(S)+12 at Week 12 and 40 will be 
summarized and analyzed using the repeated measurement approach defined for change from 
baseline in pre-dose/pre-BD FEV1, as described in Section 8.5.8.8. Included in the model will 
also be the baseline AQLQ(s)+12 total score.
Responder variables AQLQ(S)+12 (yes/no) at Week 12 and 40 will be analyzed using a 
logistic regression model with covariates of at least treatment, stratifying variables, and 
baseline value.

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The number and percentage of subjects with AQLQ(s)+12 total score changes ≥ 0.5 will be 
summarized by treatment. Additionally, the number and percentage of subjects achieving an 
improvement, no change, or deterioration will be summarized by treatment as per Section 
8.4.2.5.
Supportive outcome measure: change from baseline to overall post-baseline mean of 
AQLQ(S)+12.
8.5.8.13
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The EQ-5D-5L responses from each dimension and the visual analogue scale (VAS) will be 
summarized by treatment group and period. Shift tables will be produced for each dimension, 
and the change from baseline in VAS will be summarized with descriptive statistics by visit.
8.5.8.14
Health care resource utilization and productivity loss due to asthma
WPAI-CIQ
The WPAI+CIQ data will be summarized by treatment, including the 4 types of scores: 
absenteeism, presenteeism, work/class productivity loss, and activity impairment described. 
The number and percentage of subjects with asthma specific resource utilization (defined in 
Section 8.4.2.18) will be presented by treatment group.
8.5.9
Safety and tolerability
All safety variables will be summarized using the safety analysis set and data presented 
according to treatment received.
8.5.9.1
Adverse events
AEs will be summarized separately for the treatment and follow-up periods, as defined in 
Section 6.3. AEs occurring during the run-in period, or occurring post-treatment (as per the 
definition above) will be listed, but not summarized.
An overall summary table will be produced showing the number and percentage of subjects 
with at least 1 AE in any of the following categories; AEs, SAEs, deaths due to AE, 
discontinuation if IP due to AEs (DAEs), and other significant adverse events (OAEs). The 
total number of AEs in the different AE categories in terms of AE counts will also be 
presented (ie, accounting for multiple occurrences of the same event in a subject).
AEs will be summarized by SOC and PT assigned to the event using MedDRA. For each PT, 
the number and percentage of subjects reporting at least one occurrence will be presented ie, 
for a subject multiple occurrences of an AE will only be counted once.
AEs (by PT) will be summarized by causality and maximum intensity. If a subject reports 
multiple occurrences of the same AE, the maximum intensity will be taken as the highest 
recorded maximum intensity (the order being mild, moderate, and severe). SAEs, OAEs, 
DAEs, and deaths will also be summarized in separate tables.

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The rate of AEs per person-years at risk, calculated as (number of subjects reporting 
AE)/(total time at risk of AE), will also be reported. Rates will typically be expressed in terms 
of events per 100 subject-years.
Separate listings of subjects with AEs, SAEs, death due to AE, or discontinuations due to AEs 
will be presented.
8.5.9.2
Laboratory data
All continuous laboratory parameters will be summarized by absolute value at each visit by 
treatment group, together with the corresponding changes from baseline, in both primary 
populations. The summary statistics presented will be the minimum, 1st quartile, median, 3rd 
quartile, maximum, mean and SD. Mean changes from baseline over time will also be plotted 
by treatment group.
AstraZeneca defined extended reference ranges will be used for the identification of 
individual clinically important abnormalities, and a shift table will be produced for each 
laboratory parameter to display low, normal, high, and missing values. The shift tables will 
present baseline and maximum/minimum on-treatment value, as applicable for each 
parameter.
Shift plots showing each individual subject’s laboratory value at baseline and at 
maximum/minimum will be produced for each continuous laboratory variable. If any 
laboratory variables show any unusual features (high or low values or a general shift in the 
data points) at other time points then shift plots of these data may be produced. A diagonal 
line indicating no change, and horizontal and vertical reference lines indicating the limits of 
the AstraZeneca defined reference ranges will also be displayed on the shift plots.
Data for subjects who have treatment-emergent changes outside the predefined criteria will be 
presented. This data presentation will include all visits for this subset of subjects.
The frequency of changes with respect to normal ranges between baseline and each post-
treatment time point will be tabulated. Frequencies of clinically noteworthy values (using 
AstraZeneca defined reference ranges) occurring during the clinical study will also be given.
In order to identify potential Hy’s Law cases, maximum post baseline total bilirubin will be 
plotted against maximum post baseline ALT, expressed as multiples of ULN. This plot will be 
repeated to show maximum post baseline total bilirubin against maximum post baseline AST, 
expressed as multiples of ULN. These plots will be produced on a log scale and reference 
lines will be included at 2xULN for total bilirubin and at 3xULN for ALT/AST. 
For all subjects who meet the biochemical criteria for Hy’s law (potential Hy’s Law), a 
Subject Safety Narrative will be produced, and the relevant laboratory parameters will be 
tabulated showing all visits for these subjects. Subjects with elevated ALT or AST, and 
elevated total bilirubin, at any time may be explored further graphically using individual 
subject profile plots.

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For urinalysis data, a shift table will be generated to present changes from baseline to EOT. 
The number of subjects with treatment-emergent changes will also be summarized. Here, 
treatment-emergent changes are defined as None/Trace at baseline to Positive, at any visit 
after baseline.
Any data outside the AstraZeneca normal and extended reference ranges will be explicitly 
noted on the listings that are produced.
8.5.9.3
dECGs
The Investigator’s assessment of the 12-lead dECG (normal or abnormal) will be listed for all 
subjects, along with detailing whether any abnormalities were clinically significant or not.
The number and percentage of subjects with clinically significant abnormal dECGs will be 
summarized by treatment group and visit.
8.5.9.4
Physical Examination
Shift tables (normal, abnormal) of baseline versus EOT will be generated, presenting the 
assessment for each component of the complete physical examination separately.
Listings of abnormal results will be produced.
8.5.9.5
Vital Signs
Vital signs data will be presented in the same way as described in Section 8.4.3.3 for the 
clinical laboratory data, and will be presented using AstraZeneca defined reference ranges, 
and clinically important change criteria.
All recorded vital signs data will be listed.
8.5.9.6
Analysis of Immunogenicity variables
ADA status (positive vs. negative) at each visit will be summarized by treatment group. 
Descriptive statistics including number of subjects, mean, standard deviation, median, and 
range of the actual ADA titers by treatment group and visit, where possible, will be provided. 
The ADA status across the study for each subject (positive vs. negative) will also be 
classified and summarized by treatment group. The association of ADA status across the 
study (positive vs. negative) with AEs/SAEs may be evaluated. In addition, the association of 
ADA titers (≥median titer in positive subjects vs. < median titer) with AE/SAEs may be 
evaluated for ADA-positive treated subjects only. A subject will be considered as positive if
he/she has positive ADA for any visit during the study. Otherwise, the subject will be
considered as ADA negative. The associations between ADA and AE/SAEs may be 
summarized for positive. The ADA-positive subjects may also be divided into persistent 
positive versus transient positive. A subject will be considered as persistent positive if he/she 
has positive ADAs for at least two consecutive visits. Otherwise, the subject will be 
considered as transient ADA positive. The associations between ADA and AE/SAEs may be 
summarized for both persistent positive subjects versus transient positives subjects.

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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.
For ADA, all subjects with titer information will be shown in the data listing.
8.5.10
Analysis of pharmacokinetics
All analyses of pharmacokinetics variables will be based on the PK data set. All analyses on 
immunogenicity variables will be based on the safety analysis set.
Due to the limited sampling schedule, the PK assessment will be primarily based on the 
observed steady-state serum trough (predose) concentrations, Ctrough. Empirical evaluation of 
potential impact of demographic covariates and ADA on Ctrough will be conducted.   
The PK data will be merged with those from other clinical studies for a population-based 
meta-analysis. Results of the meta-analysis will be presented in a separate pharmacometrics 
report outside of the CSR.
8.5.11
Interim analysis
No interim analysis is planned for this study.
8.5.12
Exploratory analysis
The analysis of exploratory objectives will be specified in the statistical analysis plan.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site personnel
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational site staff, and also train them on any study specific procedures, the WBDC and 
IVR/IWR systems, ePRO and ePEF devices, spirometers, and any other system(s) that may be 
utilised in the study.
The Principal Investigator will ensure that appropriate training relevant to the study is 
provided to all of these staff, and that any new information relevant to the performance of this 
study is forwarded to the staff involved.
The Principal Investigator will ensure that a record of all individuals involved in the study 
(medical, nursing and other staff) is maintained.

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

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Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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The study is expected to start in Q1, 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 tracked in the system’s audit trail. All data will be Source 
Data Verified (SDV) by an AstraZeneca site monitor (or representative), reviewed /queried 
and updated as needed. 
Data queries will be raised for inconsistent, impossible, or missing data, and must be resolved 
in a timely manner. Clean file occurs when all data have been declared clean and signed off by 
all Investigators. Data will be frozen and then locked to prevent further data entry/editing. 
Any treatment revealing data may thereafter be added and the final database will be locked. A 
copy of the eCRFs will be provided to and archived at the study site when the study has been 
locked.
Data collected through third party sources will be obtained and reconciled against study data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA.  Medications will be classified according to the AstraZeneca 
Drug Dictionary.  All coding will be performed by the Medical Coding Team at the 
AstraZeneca Data Management Centre. 
Serious Adverse Event (SAE) Reconciliation
SAE reconciliation reports will be produced and reconciled with the Subject Safety database 
and/or the investigational site. 
Data associated with human biological samples

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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 (eg, ePRO diary, IVRS/IWRS, etc) 
will be tested/validated as necessary. External data reconciliation will be done with the 
clinical database as applicable.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AstraZeneca policy on Bioethics and 
Human Biological Samples.
10.2
Subject data protection
The Informed Consent or assent Form(s) will incorporate (or, in some cases, be accompanied 
by a separate document incorporating) wording that complies with relevant data protection 
and privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee (EC)/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the subject’s ICF (and assent form for subjects under 
the age of majority), and any other written information and/or materials to be provided to a 
subject.  The Investigator will ensure the distribution of these documents to the applicable 
EC/IRB, and to the study site staff.
The opinion of the EC/IRB should be given in writing. The Investigator should submit the 
written approval to AstraZeneca before enrolment of any subject into the study. 
The EC/IRB should approve all advertising used to recruit subjects for the study.
AstraZeneca should approve any modifications to the ICF (and/or assent form for subjects 
under the age of majority) that are needed to meet local requirements.
If required by local regulations, the protocol should be re-approved by the EC/IRB annually.

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Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF (and assent form for subjects under the age of majority), should be 
approved by the national regulatory authority or a notification to the national regulatory 
authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, ECs/IRBs and Principal Investigators with 
safety updates/reports according to local requirements.
Each Principal Investigator is responsible for providing the EC/IRB with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the IP.  
AstraZeneca will provide this information to the Principal Investigator so that he/she can meet 
these reporting requirements.
10.4
Informed consent and assent
The Principal Investigator(s) at each site will:
Ensure each subject is given full and adequate oral and written information about the nature, 
purpose, possible risk and benefit of the study
Ensure each subject is notified that they are free to discontinue from the study at any time
Ensure that each subject is given the opportunity to ask questions and allowed time to consider 
the information provided
Ensure each subject provides signed and dated informed consent (and assent form for subjects 
under the age of majority) before conducting any procedure specifically for the study
Ensure the original, signed ICFs (and assent form for subjects under the age of majority) are 
stored in the Investigator’s Study File
Ensure copies of the signed ICFs (and assent form for subjects under the age of majority) are 
given to the subject
Ensure that any incentives for subjects who participate in the study as well as any provisions 
for subjects harmed as a consequence of study participation are described in the informed 
consent or assent form that is approved by an Ethics Committee.
10.5
Changes to the protocol and informed consent or assent forms
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, and AstraZeneca.

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If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant EC/IRB and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed
for revised protocols.
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to ECs/IRB, see Section 10.3.
If a protocol amendment requires a change to a site’s ICF (and/or assent form for subjects 
under the age of majority), AstraZeneca and the site’s EC/IRB are to approve the revised ICF 
(and/or assent form for subjects under the age of majority) before the revised form(s) is/are 
used. 
If local regulations require, any administrative change will be communicated to or approved 
by each EC/IRB.
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an EC/IRB may perform 
audits or inspections at the site, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded,
analyzed, and accurately reported according to the protocol, GCP, 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 
Accordini et al 2006
Accordini S, Bugiani M, Arossa W, Gerzeli S, Marinoni A, Olivieri M, et al. Poor control 
increases the economic cost of asthma. A multicentre population-based study. Int Arch 
Allergy Immunol. 2006;141(2):189-98. Epub 2006 Aug 4.
Bateman et al 2010
Bateman ED, Reddel HK, Eriksson G, Peterson S, O’stlund O, Sears MR, Jenkins C, MD, 
Humbert M, Buhl R, Harrison TW, Quirce S,  and. O’Byrne PM. Overall asthma control: The 
relationship between current control and future risk. American Academy of Allergy, Asthma 
& Immunology doi:10.1016/j.jaci.2009.11.033. 2010; 125(3); 600-08.
Dweik et al 2011
Dweik RA et al. An official ATS clinical practical guideline: Interpretation of exhaled nitric 
oxide levels (FENO) for clinical applications. Am. J. Respir. Crit. Care Med. 2011;184:602-
615.
GINA 2014
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA) May 2014. Available from: URL: http://www.ginasthma.org.
Grunstein et al 2002
Grunstein MM, Hakonarson H, Leiter J, Chen M, Whelan R, Grunstein JS, Chuang S.IL-13-
dependent autocrine signaling mediates altered responsiveness of IgE sensitized airway 
smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2002;282:L520-8.
Hallett et al 2012
Hallett MA, Venmar KT, Fingleton B. Cytokine stimulation of epithelial cancer cells: the 
similar and divergent functions of IL-4 and IL-13. Cancer Res. 2012 Dec 15;72(24):6338-43. 
Epub 2012 Dec 7.
Hershey 2003
Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin 
Immunol. 2003;111(4):677-90.
Hilbe 2011
Hilbe J. M. (2011) “Negative Binomial Regression” Cambridge University Press ISBN: 978-
0521-19815-8.
Juniper et al 2006
Juniper EF, Bousquet J, Abetz L, Bateman ED. Identifying ‘well-controlled’ and ‘not well-
controlled’ asthma using the Asthma Control Questionnaire. Respir Med 2006; 100: 616- 621.

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Study Code D2210C00013
Edition Number 4.0
Date 22 February 2016
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Keene et al 2007
Keene ON, Jones MRK, Lane PW, et al. Analysis of exacerbation rates in asthma and chronic 
obstructive pulmonary disease: example from the TRISTAN study. Pharm Stat 2007;6:89–97.
Lieberman et al 2010
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, et al. The 
diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin 
Immunol. 2010 Sep;126(3):477-80.e1-42.
Miller et al 2005
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas 
D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of 
spirometry. Eur Respir J. 2005 Aug;26(2):319-38.
Piper et al 2013
Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-
controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41(2):330-
8.
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, Enright PL, Hankinson JL, 
Zheng J, Stocks J and the ERS Global Lung Function Initiative. Multi ethnic reference values 
for spirometry for the 3-95 year age range: the global lung function 2012 equations. Report of 
the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung 
Function Reference Values. 2012 Jun, as doi: 10.1183/09031936.00080312.
Reddel et al 2009
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al on behalf of 
the American Thoracic Society/European Respiratory Society Task Force on Asthma Control 
and Exacerbations. An Official American Thoracic Society/European Respiratory Society
Statement: Asthma Control and Exacerbations: Standardizing Endpoints for Clinical Asthma 
Trials and Clinical Practice. Am. J. Respir. Crit. Care Med. 2009;180:59-99.
Saha et al 2008
Saha S, Berry M, MD, Parker D, Siddiqui S, Morgan A, May R, Monk P, Bradding P, 
Wardlaw A, Pavord I, Brightling C. Increased sputum and bronchial biopsy IL-13 expression 
in severe asthma. J Allergy Clin Immunol. 2008 March ; 121(3): 685–691
Sampson et al 2006
H.A. Sampson, A. Munoz-Furlong, R.L. Campbell, N.F. Adkinson Jr., S.A. Bock, A. Branum 
et al. Second symposium on the definition and management of anaphylaxis: summary report: 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol, 117 (2006), pp. 391–397.

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Sorkness et al 2008
Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, 
Erzurum SC, Gaston BM, Israel E, Jarjour NN, Moore WC, Peters SP, Teague WG, Wenzel 
SE. Lung function in adults with stable but severe asthma: air trapping and incomplete 
reversal of obstruction with bronchodilation. J Appl Physiol 104: 394–403, 2008.
Siddiqui et al 2009
Siddiqui S, Cruse G, Mckenna S, Monteiro W, Mistry V, Wardlaw A, Brightling C. IL-13 
expression by blood T cells and not eosinophils is increased in asthma compared to non-
asthmatic eosinophilic bronchitis. BMC Pulmonary Medicine 2009, 9:34: 1-7
Wardlaw et al 1988 
Wardlaw AJ, Dunnette S, Gleich GJ, Collins JV, Kay AB. Eosinophils and mast cells in 
bronchoalveolar lavage in subjects with mild asthma. Relationship to bronchial 
hyperreactivity. Am Rev Respir Dis. 1988; 137:62-9.
Wenzel 2012
Wenzel S E. Asthma phenotypes: the evolution from clinical to molecular approaches. 2012 
May 4, 18(5):716-25.
Wills-Karp et al 1998
Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, et al. Interleukin-13: 
central mediator of allergic asthma. Science. 1998;282(5397):2258-61.

Clinical Study Protocol Appendix B
Drug Substance
Tralokinumab
Study Code
D2210C00013
Edition Number
1.0
Date
7 October 2014
Appendix B
Additional Safety Information

Clinical Study Protocol Appendix B
Drug Substance Tralokinumab
Study Code D2210C00013
Edition Number 1.0
Date 7 October 2014
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
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A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug.  Has the 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
D2210C00013
Edition Number
1.0
Date
7 October 2014
Appendix C
International Airline Transportation Association (IATA) 6.2 Guidance 
Document

Clinical Study Protocol Appendix C
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Study Code D2210C00013
Edition Number 1.0
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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
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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
D2210C00013
Edition Number
1.0
Date
7 October 2014
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 D2210C00013
Edition Number 1.0
Date 7 October 2014
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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...............6
6.
REFERENCES ........................................................................................................7

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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).

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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, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the
elevations in transaminases and TBL must occur.
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)

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The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the patient meets PHL criteria (see 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 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

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Study Code D2210C00013
Edition Number 1.0
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5.
REVIEW AND ASSESSMENT OF POTENTIAL HY’S LAW 
CASES
The instructions in this Section should be followed for all cases where PHL criteria are met.
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 D2210C00013
Edition Number 1.0
Date 7 October 2014
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 D2210C00013
Edition Number 1.0
Date 7 October 2014
1(1)
Clinical Study Protocol Appendix E
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00013
Edition Number
1.0
Date
7 October 2014
Appendix E
Maintenance Therapy Equivalence Table
Estimated daily doses for inhaled corticosteroids.
Asthma Therapy 
Total Daily Dose (μg/day) 
Inhaled Corticosteroid
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 fuorate
100
200
Fluticasone propionate 
>250 - 500
>500 - 1000
Fluticasone propionate HFA
>364 - 440
>440
Budesonide
Budesonide, if as delivered dose (eg 
Symbicort)
>400 to 800
>320 to 640
>800 - 1600
>640 - 1280
Mometasone furoate 
≥400
≥800
                                                
1 The acceptable medium ICS dose for this study is bolded.

Clinical Study Protocol Appendix F
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00013
Edition Number
1.0
Date
7 October 2014
Appendix F
Anaphylaxis: definition criteria, signs and symptoms, and management

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 1.0
Date 7 October 2014
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 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 D2210C00013
Edition Number 1.0
Date 7 October 2014
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 D2210C00013
Edition Number 1.0
Date 7 October 2014
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.
(d)
Consider systemic corticosteroids.

Clinical Study Protocol Appendix F
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 1.0
Date 7 October 2014
5(5)
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for patient taking b-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.

Clinical Study Protocol Appendix G
Drug Substance
Tralokinumab (CAT-354)
Study Code
D2210C00013
Edition Number
3.0
Date
22 February 2016
Appendix G
Restricted and prohibited medications

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 3.0
Date 22 February 2016
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 spirometry, ECG 
and home lung function assessments 
(to be administered once assessments 
are completed)
Subjects should be instructed not to 
use their twice daily bronchodilator 
within 12 hours of the scheduled site 
visit spirometry. For once daily 
bronchodilators a 48 hour washout 
period is required. 
Subjects will not need to washout of 
their asthma medications for 
unscheduled visits due to asthma 
worsening.
Short acting beta-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 site visit 
spirometry, ECG and home lung 
function assessments with the 

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 3.0
Date 22 February 2016
3(5)
exception of any unscheduled visits 
due to asthma worsening, ECG and 
home lung function assessments.
Additional Maintenance 
Controllers
Allowed with 
restriction
Stable dose for 3 months 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 theophylline and additional once 
daily bronchodilators within 48 hours
of the scheduled site visit spirometry 
at site visits 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.
Long-acting beta-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 the date 
of randomization; during treatment -

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 3.0
Date 22 February 2016
4(5)
Medication
Prohibited/restricted
Details
and follow-up period.
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 (other 
than prior, stable OCS for the 
maintenance treatment of 
asthma)
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 
Last Dose
Blood products or 
immunoglobulin therapy
Prohibited
Not allowed 30 days prior to date of 
ICF; 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 the date 
of randomization; 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 
approved drug)
Prohibited
Not allowed 30 Days or 5 Half Lives 
(whichever is longer) prior to Visit 1; 
during treatment period
Allergen Immunotherapy
Restricted
Allowed if on stable therapy for at 
least 30 days prior to date of ICF; no 
anticipated changed during treatment 
period
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 
Prohibited
Patients currently using any oral or 
ophthalmic non-selective β-adrenergic 
antagonist at the time of enrolment are 

Clinical Study Protocol Appendix G
Drug Substance Tralokinumab (CAT-354)
Study Code D2210C00013
Edition Number 3.0
Date 22 February 2016
5(5)
Medication
Prohibited/restricted
Details
antagonist (e.g. propranolol)
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