A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety of Tralokinumab in Japanese Adults and Adolescents With Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist
Phase: PHASE3
Conditions: Inadequately Controlled Asthma
Sponsor: AstraZeneca

 
 
 
Clinical Study Protocol 
 
Drug Substance 
Tralokinumab (CAT-354) 
Study Code 
D2210C00029 
Version 
2.0 
 
Date 
15 June 2017 
 
 
 
A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety of 
Tralokinumab in Japanese Adults and Adolescents with Asthma 
Inadequately Controlled on Inhaled Corticosteroid plus Long-Acting β2- 
Agonist 
 
 
 
 
Sponsor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Redacted
Redacted
Redacted
Redacte
Redacted
Redacted

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
2 (101) 
 
 
 
 
 
VERSION HISTORY 
 
Version 1.0, 19 July 2016 
Initial Creation 
Version 2.0, 15 June 2017 
Section 3.1 Inclusion criteria: Numbering was corrected only for Japanese version. 
Section 3.6 Discontinuation of investigational product 8 D): This section was updated to 
clarify the discontinuation criteria only for Japanese version. 
Section 4 Study plan and timing of procedures, Table 1 Study Plan: Table 1 was corrected to 
indicate that HbA1c is collected as Visit 3, which aligns with Table 4. 
Section 4.2 Treatment Period:  This section was updated to clarify that if a subject selects 
Option 1, 2 or 3 at the IPD visit, no follow up visits are required.  Additionally, text describing 
final follow up visit timing moved up in the section to improve flow of information related to 
visit timing. 
Section 7.7.1 Concomitant medications, Maintenance of asthma controller medication: To 
clarify ICS dose, text changed to indicate a dose of ICS is required prior to Visit 1, and this 
dose should be maintained at a stable dose from Visit 2 until the end of the treatment period. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
3 (101) 
 
 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object. 
 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The clinical study protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 

4 (101) 
 
 
 
 
 
PROTOCOL SYNOPSIS 
 
 
 
A 52-Week, Open-Label, Multicentre Study to Evaluate the Safety of 
Tralokinumab in Japanese Adults and Adolescents with Asthma 
Inadequately Controlled on Inhaled Corticosteroid plus Long-Acting β2- 
Agonist 
 
 
National Co-ordinating Investigator 
 
 
 
 
 
 
Study site(s) and number of subjects planned 
 
Approximately 26 subjects will enter treatment at approximately 4 centres in Japan. 
 
Study period 
Phase of development 
Estimated date of first subject enrolled 
Estimated date of last subject completed 
Q4 2016 
Q2 2018 
3 
 
 
Study design 
 
This is an open-label study designed to evaluate the safety of a fixed 300 mg dose every 2 
weeks (Q2W) of tralokinumab administered subcutaneously in subjects with inadequately 
controlled asthma on medium to high-dose of inhaled corticosteroid plus long-acting β2- 
agonist. 
 
Approximately 26 Japanese subjects will be recruited into the study and receive tralokinumab 
in order to reach 22 completed. 
 
All subjects will receive tralokinumab 300 mg every 2 weeks via subcutaneous injection at the 
study site, over a 52-week treatment period. 
 
After the initial enrolment and confirmation of the entry criteria, subjects will proceed to a 
run-in period of maximum 2 weeks to allow adequate time for all of the eligibility criteria to 
be evaluated. Subjects who meet the eligibility criteria will enter the 52-week treatment 
period. Subjects will be maintained on their currently prescribed inhaled corticosteroid plus 
long-acting β2-agonist and any additional asthma controller medication, without change, from 
enrolment throughout the treatment period. 
Redacted
Redacted
Redacted

5 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
Follow-up visits will be conducted at Weeks 56 and 66. The 14-week extended follow-up 
period is to ensure that adequate evaluation of immunogenicity can be determined. 
 
 
 
 
Objectives 
 
Primary Objective: 
Outcome Measure: 
To assess the safety and tolerability of 
tralokinumab. 
x 
Adverse Events (AEs) and Serious Adverse 
Events (SAEs) 
x 
Laboratory variables 
x 
Physical examinations 
x 
Vital signs 
x 
ECG 
 
 
 
Exploratory Objective: 
Outcome Measure: 
To collect data for the assessment of efficacy 
of tralokinumab 
x 
Asthma Control Questionnaire-6 score (ACQ-6) 
x 
Forced expiratory volume in one second (FEV1) 
Key Outcome Variable: Percent change 
from baseline in pre-dose/pre-BD-FEV1 
x 
Asthma exacerbation 
Key Outcome Measure: Annual asthma 
exacerbation rate 
To explore baseline level and change from 
baseline of biomarkers 
x 
Periostin 
x 
Dipeptidyl peptidase-4 (DPP-4) 
x 
Other biomarkers that may be associated with up- 
regulation of interleukin-13 
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab 
x 
Serum tralokinumab concentration 
x 
Incidence of positive assessments for anti-drug 
antibodies (ADA) and characterization of their 
neutralizing potential 
 
 
Target subject population 
 
Male and female adults and adolescents, 12 to 75 years of age inclusive, with asthma 
inadequately controlled by treatment with inhaled corticosteroid plus long-acting β2 agonist 
treatment. 
 
Duration of treatment 
 
Following an initial enrolment at Week -2, subjects will enter a maximum 2-week run-in 
period which will be followed by a 52-week treatment period. The first dose of tralokinumab 

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Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
will be administered at Week 0. Subsequent doses will be administered every 2 weeks up until 
Week 50 (for a total of 26 doses) with an end of treatment visit occurring at Week 52. Post 
treatment safety follow up visits will be performed at Weeks 56 and 66. 
 
Investigational product, dosage and mode of administration 
 
Tralokinumab 300 mg (150 mg/mL), will be administered to subjects at the site via 
subcutaneous injection using 2 pre-filled syringes each containing 1 ml. 
 
Statistical methods 
 
No formal sample size calculation was conducted for this study.  Approximately 22 Japanese 
patients who complete the planned 52-weeks treatment period are considered appropriate for 
collecting additional safety information of tralokinumab (300 mg SC Q2W) among Japanese 
patients.  With an assumed drop-out rate of 15% during the 52-weeks treatment period, 
approximately 26 Japanese patients are needed to be dosed. 
 
The interim and final analyses of the study are primarily descriptive using descriptive 
statistics.  Where appropriate, an exact 95% confidence interval will be calculated.  No 
hypothesis testing will be conducted for this study. 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
 
 
 
TABLE OF CONTENTS 
PAGE 
 
 
 
TITLE PAGE ...........................................................................................................1 
 
VERSION HISTORY ..............................................................................................2 
 
PROTOCOL SYNOPSIS.........................................................................................4 
 
TABLE OF CONTENTS.........................................................................................7 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................13 
 
1. 
INTRODUCTION .................................................................................................16 
 
1.1 
Background and rationale for conducting this study .............................................16 
 
1.2 
Rationale for study design and doses .....................................................................17 
 
1.3 
Benefit/risk and ethical assessment........................................................................18 
 
1.4 
Study Design ..........................................................................................................19 
 
2. 
STUDY OBJECTIVES..........................................................................................21 
 
2.1 
Primary objective ...................................................................................................21 
 
2.2 
Exploratory objectives ...........................................................................................21 
 
3. 
SUBJECT SELECTION, ENROLMENT, TREATMENT, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ......................22 
 
3.1 
Inclusion criteria ....................................................................................................22 
 
3.2 
Exclusion criteria ...................................................................................................25 
 
3.3 
Subject enrolment ..................................................................................................27 
 
3.4 
Procedures for handling incorrectly enrolled subjects ...........................................28 
 
3.5 
Restrictions during and after the study ..................................................................28 
 
3.6 
Discontinuation of investigational product ............................................................28 
3.6.1 
Procedures for discontinuation of a subject from investigational product ............30 
 
3.7 
Criteria for withdrawal...........................................................................................30 
3.7.1 
Screen failures........................................................................................................30 
3.7.2 
Withdrawal of the informed consent or assent.......................................................30 
 
3.8 
Discontinuation of the study ..................................................................................30 
 
4. 
STUDY PLAN AND TIMING OF PROCEDURES.............................................32 
 
4.1 
Enrolment/Screening period ..................................................................................36 
4.1.1 
Enrolment (Visit 1) ................................................................................................36 
4.1.2 
Screening / Run-in (Visit 1-2)................................................................................36 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
4.1.3 
Treatment period (Visit 2)......................................................................................37 
4.1.4 
Re-screening ..........................................................................................................37 
 
4.2 
Treatment period ....................................................................................................37 
 
4.3 
Follow-up period....................................................................................................39 
 
5. 
STUDY ASSESSMENTS .....................................................................................39 
 
5.1 
Assessments ...........................................................................................................39 
5.1.1 
Assessment of asthma exacerbations .....................................................................39 
5.1.2 
Spirometry..............................................................................................................41 
5.1.2.1 
Pre-BD and post-BD FEV1 assessment .................................................................42 
5.1.3 
Periostin/DPP4 .......................................................................................................43 
 
5.2 
Safety assessments .................................................................................................43 
5.2.1 
Laboratory safety assessments ...............................................................................43 
5.2.2 
Pregnancy Test .......................................................................................................49 
5.2.3 
Physical examination .............................................................................................49 
5.2.3.1 
Complete physical examination .............................................................................49 
5.2.3.2 
Brief physical examinations...................................................................................49 
5.2.4 
ECG........................................................................................................................49 
5.2.4.1 
Resting 12-lead ECG .............................................................................................50 
5.2.5 
Vital signs ..............................................................................................................50 
5.2.5.1 
Pulse, blood pressure and respiration rate..............................................................50 
5.2.5.2 
Body temperature ...................................................................................................50 
5.2.6 
Other safety assessments........................................................................................51 
5.2.6.1 
Serology .................................................................................................................51 
5.2.6.2 
Infections................................................................................................................51 
 
5.3 
Other assessments ..................................................................................................51 
5.3.1 
Weight and height ..................................................................................................51 
5.3.2 
Patient reported outcomes ......................................................................................51 
5.3.2.1 
Asthma Control Questionnaire (ACQ-6) ...............................................................51 
 
5.4 
Pharmacokinetics and Immunogenicity .................................................................52 
5.4.1 
Collection of samples.............................................................................................52 
5.4.2 
Determination of drug concentration .....................................................................52 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................52 
5.4.4 
Immunogenicity .....................................................................................................53 
5.4.5 
Total IgE ................................................................................................................54 
5.4.6 
Phadiatop®..............................................................................................................54 
 
5.5 
Biomarkers .............................................................................................................54 
 
5.6 
Biological Samples ................................................................................................54 
5.6.1 
Storage, re-use and destruction of biological samples ...........................................54 
5.6.2 
Labelling and shipment of biological samples.......................................................55 
5.6.3 
Chain of custody of biological samples .................................................................55 
5.6.4 
Withdrawal of Informed Consent or Assent for donated biological samples ........55 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT ..............................56 
 
 
 
6.1 
Definition of adverse events ..................................................................................56 
 
6.2 
Definitions of serious adverse event ......................................................................56 
 
6.3 
Recording of adverse events ..................................................................................57 
6.3.1 
Time period for collection of adverse events .........................................................57 
6.3.2 
Follow-up of unresolved adverse events................................................................57 
6.3.3 
Adverse Event Variables........................................................................................57 
6.3.4 
Assessment of causality .........................................................................................58 
6.3.5 
Adverse events based on signs and symptoms.......................................................59 
6.3.6 
Adverse events based on examinations and tests...................................................59 
6.3.7 
Hy’s Law................................................................................................................59 
6.3.8 
Disease progression ...............................................................................................59 
 
6.4 
Reporting of serious adverse events.......................................................................60 
 
6.5 
Overdose ................................................................................................................61 
 
6.6 
Pregnancy...............................................................................................................61 
6.6.1 
Maternal exposure..................................................................................................61 
6.6.2 
Paternal exposure ...................................................................................................62 
 
6.7 
Management of IP related toxicities ......................................................................62 
 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ....................62 
 
7.1 
Identity of investigational product(s) .....................................................................62 
 
7.2 
Dose and treatment regimens .................................................................................63 
 
7.3 
Labelling ................................................................................................................65 
 
7.4 
Storage ...................................................................................................................65 
 
7.5 
Compliance ............................................................................................................65 
 
7.6 
Accountability ........................................................................................................65 
 
7.7 
Concomitant and other treatments .........................................................................66 
7.7.1 
Concomitant medications.......................................................................................66 
7.7.2 
Restrictions during and after the study ..................................................................67 
7.7.2.1 
Asthma medication restrictions..............................................................................67 
7.7.2.2 
Other medication restrictions .................................................................................69 
7.7.2.3 
Bronchial Thermoplasty.........................................................................................69 
7.7.3 
Other treatments .....................................................................................................69 
 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA ............................................69 
 
8.1 
Statistical considerations........................................................................................69 
 
8.2 
Sample size estimate ..............................................................................................70 
 
8.3 
Definitions of analysis sets ....................................................................................70 
8.3.1 
Efficacy analysis set...............................................................................................70 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
8.3.2 
Safety analysis set ..................................................................................................70 
 
 
8.3.3 
PK analysis set .......................................................................................................70 
8.3.4 
PRO analysis set ....................................................................................................70 
 
8.4 
Outcome measures for analyses .............................................................................70 
8.4.1 
General Definitions ................................................................................................70 
8.4.1.1 
Definition of baseline and subject baseline variables ............................................70 
8.4.1.2 
Visit and period windows ......................................................................................71 
8.4.2 
Calculation or derivation of efficacy variables ......................................................71 
8.4.2.1 
Exacerbation rate....................................................................................................71 
8.4.2.2 
Forced expiratory volume in 1 second ...................................................................72 
8.4.3 
Calculation or derivation of patient reported outcome variables ...........................72 
8.4.3.1 
Asthma Control Questionnaire (ACQ-6) ...............................................................72 
8.4.4 
Calculation or derivation of safety variable(s).......................................................73 
8.4.4.1 
Adverse events .......................................................................................................73 
8.4.4.2 
Other significant adverse events ............................................................................74 
8.4.4.3 
Laboratory variables ..............................................................................................74 
8.4.4.4 
ECG........................................................................................................................75 
8.4.4.5 
Physical examination .............................................................................................75 
8.4.4.6 
Vital signs ..............................................................................................................75 
8.4.5 
Calculations or derivation of Pharmacokinetic and Immunogenicity 
variables .................................................................................................................76 
 
8.5 
Methods for statistical analyses .............................................................................76 
8.5.1 
Safety and tolerability ............................................................................................76 
8.5.1.1 
Adverse events .......................................................................................................76 
8.5.1.2 
Laboratory data ......................................................................................................77 
8.5.1.3 
ECG........................................................................................................................78 
8.5.1.4 
Vital Signs..............................................................................................................78 
8.5.2 
Exploratory analysis...............................................................................................78 
8.5.2.1 
Exacerbation Rate ..................................................................................................78 
8.5.2.2 
Lung Function ........................................................................................................79 
8.5.2.3 
ACQ-6 defined asthma control ..............................................................................79 
8.5.2.4 
Analysis of Immunogenicity variables ..................................................................79 
8.5.3 
Analysis of pharmacokinetics ................................................................................80 
 
8.6 
Interim Analysis .....................................................................................................80 
 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA ..........................80 
 
9.1 
Training of study site personnel.............................................................................80 
 
9.2 
Monitoring of the study .........................................................................................80 
9.2.1 
Source data .............................................................................................................81 
9.2.2 
Study agreements ...................................................................................................81 
 
9.3 
Study timetable and end of study ...........................................................................81 
 
9.4 
Data management by AstraZeneca ........................................................................81 
 
10. 
ETHICAL AND REGULATORY REQUIREMENTS .........................................82 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
10.1 
Ethical conduct of the study...................................................................................82 
 
10.2 
Subject data protection...........................................................................................83 
 
10.3 
Ethics and regulatory review..................................................................................83 
 
10.4 
Informed consent and assent ..................................................................................83 
 
10.5 
Changes to the protocol and informed consent or assent form ..............................84 
 
10.6 
Audits and inspections ...........................................................................................84 
 
11. 
LIST OF REFERENCES .......................................................................................85 
 
 
 
 
LIST OF TABLES 
 
Table 1 
Study Plan.................................................................................................32 
 
Table 2 
Laboratory Safety Values .........................................................................44 
 
Table 3 
Clinical Chemistry (serum) Tests schedule ..............................................45 
 
Table 4 
Haematology/Haemostasis (whole blood) schedule.................................46 
 
Table 5 
Urinalysis schedule...................................................................................47 
 
Table 6 
Volume of blood to be drawn from each subject......................................48 
 
Table 7 
Identity of Investigational Product ...........................................................63 
 
Table 8 
Estimated daily doses for inhaled corticosteroids ....................................94 
 
Table 9 
Asthma medication restrictions ................................................................99 
 
Table 10 
Other medication restrictions .................................................................100 
 
 
 
 
LIST OF FIGURES 
 
Figure 1 
Study Flow Chart......................................................................................20 
 
Figure 2 
Injection sites and rotation scheme...........................................................64 
 
 
 
 
LIST OF APPENDICES 
 
Appendix A 
Additional Safety Information..................................................................87 
 
Appendix B 
International Airline Transportation Association (IATA) 6.2 
Guidance Document .................................................................................89 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law............................................................................90 
 
Appendix D 
Maintenance Therapy Equivalence Table ................................................94 
 
Appendix E 
Anaphylaxis:  definition criteria, signs and symptoms, and 
management..............................................................................................95 
 
Appendix F 
Restricted and Prohibited Medications.....................................................99 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
 
 
Abbreviation or 
special term 
Explanation 
 
ACQ-6 
Asthma Control Questionnaire-6 
 
ADA 
Anti-Drug Antibodies 
 
AE 
Adverse event 
 
AAER 
Annual Asthma Exacerbation Rate 
 
ALP 
Alkaline Phosphate 
 
ALT 
Alanine Aminotransferase 
APFS 
Accessorized Prefilled Syringe 
AST 
Asparate Aminotransferase 
BD 
Bronchodilator 
 
Β-HCG 
Beta-Human Chorionic Gonadotropin 
 
BUN 
Blood Urea Nitrogen 
 
CO2 
Carbon Dioxide 
 
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form (electronic/paper) 
CRP 
C-Reactive Protein 
CSA 
Clinical Study Agreement 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
 
DPP-4 
Dipeptidyl Peptidase-4 
 
EC 
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC) 
 
ECG 
Electrocardiogram 
 
ED 
Emergency Department 
 
ER 
Emergency Room 
 
EOT 
End of Treatment 
 
FEF 25-75% 
Forced Expiratory Flow at 25-75% of the forced vital capacity 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
 
Abbreviation or 
special term 
 
Explanation 
 
FEV1 
Forced Expiratory Volume in 1 second 
 
FSH 
Follicle-Stimulating Hormone 
 
GCP 
Good Clinical Practice 
Unless otherwise noted, ‘GCP’ shall mean ‘the International Conference on 
Harmonisation Tripartite Guideline for Good Clinical Practice’ (ICH GCP) 
and the Japanese ‘Good Clinical Practice for Trials on Drugs (Ministry of 
Health, Labour and Welfare [MHLW] Ordinance No. 28, 27 March 1997, 
partially revised by MHLW Ordinance and their related notifications’ (GCP 
Ordinance). 
 
GGT 
Gamma-Glutamyl Transpeptidase 
 
GINA 
Global Initiative for Asthma 
 
GLI 
The Global Lung Function Initiative 
GMP 
Good Manufacturing Practice 
HbA1c 
Glycosylated haemoglobin 
HIV 
Human Immunodeficiency Virus 
 
IATA 
International Air Transport Association 
 
ICH 
International Conference on Harmonisation 
 
ICS 
Inhaled Corticosteroids 
 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IL-13 
Interleukin-13 
 
IP 
Investigational Product 
 
IPD 
Investigational Product Discontinuation 
 
IRB 
Investigational Review Board 
 
ISF 
Investigator Study File 
 
ITT 
Intent-to-Treat 
 
IUO 
Investigator Use Only 
 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
JRS 
Japanese Respiratory Society 
LABA 
Long-Acting β2-Agonist 
LSLV 
Last Subject Last Visit 
 
LTRA 
Leukotriene Receptor Antagonists 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
 
Abbreviation or 
special term 
 
Explanation 
 
MAb 
Monoclonal Antibody 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
nAb 
Neutralizing Antibodies 
OAE 
Other Significant Adverse Event 
 
OCS 
Oral Corticosteroids 
PD 
Pharmacodynamic(s) 
PEF 
Peak Expiratory Flow 
PEO 
Performance Evaluation Only 
 
PI 
Principal Investigator 
 
PK 
Pharmacokinetic(s) 
 
PMDA 
Pharmaceuticals and Medical Devices Agency 
 
PNV 
Predicted Normal Value 
PRO 
Patient Reported Outcome 
PT 
Preferred Term 
Q2W 
Every 2 Weeks 
 
SABA 
Short-Acting β2-Agonist 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
Th2 
T Helper 2 Cells 
 
TBL 
Total Bilirubin 
 
TLC 
Total Lung Capacity 
ULN 
Upper Limit of Normal 
UNS 
Unscheduled 
WBDC 
Web Based Data Capture 
 
WOCBP 
Women of Childbearing Potential 

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Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
 
1. 
INTRODUCTION 
 
1.1 
Background and rationale for conducting this study 
 
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction 
and airway hyper-responsiveness, with a global prevalence of approximately 300 million 
patients (GINA 2016). 
 
Approximately 5% to 10% of asthma patients have severe asthma, many of whom may be 
inadequately controlled by inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) 
in combination with additional controller therapies (Bateman et al 2010). These patients are at 
risk of asthma exacerbations, have a large medical need, and represent the greatest economic 
burden (Accordini et al 2006). 
 
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Wenzel 2012). There is 
considerable evidence that interleukin 13 (IL-13) is a key mediator in the pathogenesis of 
asthmatic disease. IL-13 is secreted predominantly by CD4+ T-helper 2 (Th2) cells and IL-13 
receptors are expressed on a number of cell types including those involved in the pathogenesis 
of asthma (Hershey 2003). There is evidence to support that IL-13 can increase development 
of airway hyper-responsiveness (Wardlaw et al 1988), potentiate bronchoconstriction 
(Grunstein et al 2002), increase the number of mucus-secreting cells and promote airway 
fibrosis in asthma (Wills-Karp et al 1998). 
 
Tralokinumab is a human recombinant monoclonal antibody (MAb) of the immunoglobulin 
G4 subclass that specifically binds human IL-13, blocking interactions with the IL-13 
receptor. Tralokinumab is in development for the treatment of severe asthma. A phase 2a 
study (MI-CP199) provided evidence of improvement of lung function (forced expiratory 
volume in 1 second (FEV1)), following the addition of subcutaneous (SC) tralokinumab to 
standard asthma controller medications. Doses of 300 and 600 mg every 2 weeks of 
tralokinumab both resulted in comparable effects in FEV1 that were greater than that observed 
with a 150 mg dose (Piper et al 2013). Since low pre-bronchodilator (BD) FEV1 has been 
identified as a strong independent predictor of subsequent asthma exacerbations, it is plausible 
that the addition of tralokinumab will reduce the rate of asthma exacerbations in this 
population (Reddel et al 2009). 
 
In a phase 2b (CD-RI-CAT-354-1049) study with tralokinumab in adults with uncontrolled, 
severe asthma requiring high dose ICS and LABA, the efficacy and safety of the 2 regimens 
(300 mg every 2 weeks (Q2W) or, 300 mg Q2W for 12 weeks, followed by a 300 mg every 4 
weeks (Q4W) maintenance dosing [Q2/4W]) vs. placebo, was evaluated over a treatment 
period of 52 weeks. The primary endpoint for this study was the annualised asthma 
exacerbation rate (AAER) over 52 weeks, with secondary endpoints including pulmonary 
function, patient reported outcomes, including asthma symptoms. In the overall intent-to-treat 
phase 2b population, an increase from baseline in pre BD FEV1 to the end of treatment was 
seen with the Q2W dosing regime, but not with the Q2/4W dosing regime. In this phase 2b 

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Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
study, a subpopulation reversible on entry (FEV1 reversibility ≥ 12% and ≥200ml in FEV1) an 
AAER reduction that was greater for the tralokinumab 300 mg Q2W cohort versus the Q2/4W 
cohort was seen. A further reduction of AAER was observed in a subgroup of reversible 
subjects with high (> median) serum periostin, a biomarker induced by IL-13 (Brightling et al 
2015). This is the population which is studied in the ongoing pivotal studies in severe asthma 
studied in phase 3. The safety profile of all doses studied so far has been acceptable (for 
further details see the investigators brochure (IB)). 
 
The purpose of this long term safety study is to provide additional safety data of tralokinumab 
in the treatment of Japanese subjects with severe uncontrolled asthma despite treatment with 
ICS-LABA and any other additional controller medication. The study will evaluate the safety 
of Tralokinumab with regards to adverse events, physical examination as well as other safety 
parameters. 
 
The main reason for this study is to provide additional safety data in Japanese patients.  This 
need for additional safety is mainly driven by lower than expected recruitment of Japanese 
patients in the Pivotal phase 3 program.  Additional Japanese patients are expected to be 
sufficient. 
 
 
1.2 
Rationale for study design and doses 
 
This is an open-label un-controlled study designed to evaluate the safety and tolerability of a 
fixed dose of tralokinumab (300 mg) administered via SC injection every 2 weeks throughout 
a 52-week treatment period. Exacerbation-prone asthma subjects who remain uncontrolled on 
ICS-LABA, and who demonstrate a pre-bronchodilator (pre-BD) FEV1 of ≥40% predicted at 
either Visit 1 (enrolment/run-in) or Visit 2 (treatment), will be registered into the study. 
 
Previous efficacy studies of tralokinumab, including a phase 2b study with subjects on high 
dose ICS-LABA with or without additional asthma controller medications, have been 
conducted in adult subjects (18-75 years of age), and provide the basis for this long term 
safety study. Pharmacokinetic evaluations in adolescents with asthma confirm that the same 
dose as for adults is applicable and since it is expected that adolescent subjects (12-17 years of 
age) will respond similarly to adults.  Adolescent subjects are therefore to be included as part 
of the study population. 
 
Analysis of data from both phase 2 studies, MI-CP199 and 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 MI- 
CP199) or 300 mg Q2/4W (in study CD-RI-CAT-354-1049). Furthermore, an effect on AAER 
was observed with the 300 mg Q2W dosing regimen, but not with the Q2/4W dosing regimen 
in study CD-RI-CAT-354-1049. Since the safety profile in the CD-RI-CAT-354-1049 study 
was acceptable in both treatment cohorts, and no clear safety related dose-response pattern 
was identified, the dose of 300 mg Q2W has been selected for evaluation in this long term 
safety study. 

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Pharmacokinetic/pharmacodynamic (PK/PD) modelling using all data obtained to date has 
also confirmed that a dose of 300 mg Q2W will result in near maximal increase in pre-BD 
FEV1 in the phase 3 subject population. 
 
Subjects will receive maintenance therapy that includes their usual dose of ICS- LABA and 
additional asthma controllers (see section 7.7.2). 
 
1.3 
Benefit/risk and ethical assessment 
 
There are few treatment options for subjects whose asthma remains uncontrolled on ICS- 
LABA (GINA 2016). The evidence base for oral add-on therapies (i.e. oral corticosteroids 
(OCS), leukotriene inhibitors (LTRAs), and xanthenes) is limited. Anti-immunoglobulin E 
(IgE) therapy (i.e., omalizumab) improves control in a subset of subjects with severe asthma 
associated with IgE-mediated allergy to a perennial allergen. Hence, new therapies are needed 
for asthma management in subjects who remain uncontrolled on standard of care. 
 
IL-13 is targeted as it plays a role in the allergic/Th2 type response which is a signature of 
asthma. An anti-IL-13 treatment may therefore be useful in treatment of asthma. Data from 
phase 2 studies support this notion. Thus, in a 24-week phase 2a study (MI-CP199) 
tralokinumab at a dose of 300 mg SC every 2 weeks (the dose proposed for the phase 3 
program) provided improvement of lung function (FEV1), when added to standard asthma 
controller medications.  In addition, the efficacy of tralokinumab has been studied in a 1 year 
long phase 2b study (CD-RI-CAT-354-1049) targeting adult subjects whose asthma was 
poorly controlled by high dose ICS-LABA. In this study, tralokinumab at a fixed dose of ≥ 
300 mg SC every other week produced improvements in multiple metrics of asthma control, 
including the annualised asthma exacerbation rate (AAER), lung function, ACQ-6 scores, and 
symptoms, in a subpopulation who demonstrated reversibility of FEV1 upon study entry. 
 
At the time of the start of this study approximately 2260 subjects have been exposed to 
tralokinumab at various doses and for different periods of time. The ongoing phase 3 trials 
have contributed more than 1250 of these subjects. 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 defence 
against helminthic parasitic infections, a theoretical risk for such infestations exists. IL-13 
may also play a role in regulating tumours (Hallett et al 2012), and although evidence for this 
is scarce and inconclusive, this theoretical risk needs to be considered. In conjunction with the 
performance of routine pharmacovigilance activities risk minimization measures therefore 
include exclusion of subjects with untreated parasitic infection and active or recent 
malignancy. 
 
As with all biologics therapies, anti-drug antibodies (ADA), including neutralizing antibodies 
(nAb), may develop. Development of ADA to tralokinumab has been rare in the phase 1 and 2 
studies conducted thus far (<1% overall). Theoretical risks due to development of ADA 

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include decreased drug efficacy and hypersensitivity reactions (e.g., anaphylaxis or immune 
complex disease) and observation following administration of tralokinumab is therefore 
mandated. 
 
Pharmacokinetic modelling suggests that exposure to tralokinumab is slightly higher in 
adolescents (12-17 years of age) than that in adults; however, considering the overall 
variability of tralokinumab PK, and the absence of safety findings at doses at or above 300 mg 
every other week in the phase 2 studies, dose adjustment is not considered to be required for 
subjects in this age group. 
 
In summary, the efficacy and safety data obtained to date support the continued clinical 
development of tralokinumab in adult and adolescent subjects with uncontrolled asthma. 
 
A detailed assessment of the risk/benefit of tralokinumab in subjects with asthma is given in 
the IB. 
 
1.4 
Study Design 
 
This is an open-label study designed to evaluate the safety of a fixed 300 mg dose of 
tralokinumab administered SC in subjects with uncontrolled asthma receiving ICS (≥500 μg 
fluticasone propionate dry powder formulation equivalents total daily dose) and a LABA, and 
having a history of asthma exacerbations. 
 
Subjects will receive tralokinumab 300 mg, every 2 weeks via subcutaneous injection at the 
study site, over a 52-week treatment period. 
 
Approximately 26 subjects will enter treatment at approximately 4 sites in Japan. 
 
After initial enrolment and confirmation of entry criteria, subjects will enter a run-in period of 
maximum 2 weeks to allow adequate time for all of the eligibility criteria to be evaluated. 
Subjects who meet eligibility criteria will enter a 52-week treatment period. The first dose of 
tralokinumab will be administered at Week 0. Subsequent doses will be administered every 2 
weeks up until Week 50 (for a total of 26 doses) with an end of treatment (EOT) visit 
occurring at Week 52.  Subjects will be maintained on their currently prescribed ICS-LABA 
and any additional maintenance asthma controller medications, without change, from 
enrolment throughout the run-in and treatment period.  All subjects will have site visits every 
2 weeks. 
 
Follow-up visits will be conducted at Weeks 56 and 66. The extended follow-up period is to 
ensure adequate determination of immunogenicity. 

 
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Study Flow Chart 
 
 
 
 
 
 
 
 
*the run-in period can be maximum 2 weeks in duration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. 
STUDY OBJECTIVES 
 
2.1 
Primary objective 
 
Primary Objective: 
Outcome Measure: 
To assess the safety and tolerability of 
tralokinumab 
x 
Adverse Events (AEs) and Serious Adverse 
Events (SAEs) 
x 
Laboratory variable 
x 
Physical examinations 
x 
Vital signs 
x 
ECG 
 
 
2.2 
Exploratory objectives 
 
Exploratory Objective: 
Outcome Measure: 
To collect data for the assessment of efficacy 
of tralokinumab 
x Asthma Control Questionnaire-6 score 
(ACQ-6) 
x Forced expiratory volume in one second 
(FEV1) 
Key Outcome Variable: Percent change from 
baseline in pre-dose/pre-BD-FEV1 
x Asthma exacerbation 
Key Outcome Measure: Annual asthma 
exacerbation rate 
To explore baseline level and change from 
baseline of biomarkers 
x 
Periostin 
x 
Dipeptidyl peptidase-4 
x 
Other biomarkers that may be associated with up- 
regulation of interleukin-13 
To evaluate the pharmacokinetics and 
immunogenicity of tralokinumab 
x 
Serum tralokinumab concentration 
x 
Incidence of positive assessments for anti-drug 
antibodies (ADA) and characterization of their 
neutralizing potential 
Results from the exploratory analyses, if performed, may be reported separately from the 
Clinical Study Report. 

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3. 
SUBJECT SELECTION, ENROLMENT, TREATMENT, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
 
3.1 
Inclusion criteria 
 
For inclusion in the study, subjects should fulfil the following criteria: 
 
1.   Provision of informed consent prior to any study specific procedures for subjects who are 
at, or over the age of majority. For subjects aged <20 years a written informed consent 
should be obtained from the subject and his or her legally acceptable representative. 
 
2.   Japanese female and male aged from 12 to 75 years, inclusively at time of enrolment 
(Visit 1). 
 
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 vasectomized 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 define above, from enrolment, throughout the study duration and within 16 
weeks after last dose of Investigational Product (IP), and have negative serum pregnancy 
test result at Visit 1. 
* Not approved in Japan 
 
Women not of childbearing potential are define 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 or more prior to the 
planned date of enrolment without an alternative medical cause. The following age- 
specific requirements apply: 
 
x 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. 
 
x 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 ≥40 and <150 kg at enrolment (Visit 1). 

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5.   Documented physician-diagnosed asthma for at least 12 months prior to enrolment with 
the subject having received an asthma controller regimen requiring treatment with 
medium-to-high dose ICS for at least 6 of the 12 months prior to enrolment (Visit 1). 
 
6.   Documented treatment with ICS at a total daily dose corresponding to ≥500 μg fluticasone 
propionate dry powder formulation equivalents (>200 μg for patients with asthma aged 15 
years or younger) and a LABA for at least 3 months prior to Visit 1.  The ICS and LABA 
can be parts of a combination product, or given by separate inhalers. For ICS-LABA 
combination preparation, the highest strength approved maintenance dose will meet this 
ICS criterion. 
 
x In order to aid the assessment, ICS equivalents for high-dose and 
medium-dose fluticasone propionate dry powder, as published by the 
Global Initiative for Asthma (GINA 2016) guidelines, are presented in 
Appendix D. The Investigator will assess the subject’s total daily ICS 
dose and determine that it corresponds to ≥500 μg fluticasone 
propionate dry powder formulation equivalents. If the subject is on two 
or more different types of ICS, these can form parts of an addition, and 
the sum, however approximate, will be assessed. 
 
The below defines the minimally acceptable documentation for subject inclusion: 
 
1.   Signed and dated notes from a referring physician, including name and 
dose of the ICS-LABA inhaler (or names and dosages, if used as separate 
inhalers). 
 
2.   Evidence of prescriptions for ICS-LABA medications that demonstrate 
coverage for the duration specified in Inclusion criteria 6 and 7. 
 
3.   Documented communication (e.g., phone conversation) clarifying that the 
subject received treatment with ICS-LABA for asthma. The name, dosage, 
and duration of use for each medication must be recorded. This option 
should be used only if reasonable attempts to procure subject records have 
been unsuccessful. 
 
7.   Additional maintenance asthma controller medications are allowed according to standard 
practice of care. These medications must be stable for one month prior to enrolment (Visit 
1). Furthermore, after enrolment, the subject’s background maintenance medication for 
asthma shall remain unchanged throughout the study. 
 
8.   At Visit 1 or 2 the subject must have a pre-bronchodilator (pre-BD) FEV1 value of ≥40% 
of predicted normal value (PNV). Prior to the lung function measurement, the subject 
should withhold the BD for the effect duration specific to the BD. 
 
9.   At least 1 documented asthma exacerbation in the 12 months prior to the date of the 
informed consent is obtained that required use of a systemic corticosteroid. In case of 

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subjects who are re-screened within 30 days of their screen failure date; the 12 months can 
be calculated from the date that the first informed consent was obtained. 
 
The below defines what is acceptable to document exacerbations: 
 
x Discharge summaries from hospital, emergency department, or an 
urgent care facility indicating that a subject was hospitalized/treated 
with systemic steroids for an asthma exacerbation. 
 
x Signed and dated notes from referring physician, including information 
regarding diagnosis and treatment of an exacerbation with systemic 
steroids. 
 
x Subjects can provide evidence of prescriptions for system steroids used 
during an exacerbation. 
 
x A documented conversation between the referral physician or nurse 
certifying that a subject was treated for an exacerbation with steroids at 
their clinic or under their supervision. The dates (month/year) of the 
exacerbations and verbal confirmation that appropriate prescriptions 
were provided is necessary. This option should be used only if 
reasonable attempts to procure subject records have been unsuccessful. 
 
A combination of the above is acceptable to document the required exacerbation. However, it 
is necessary for the Investigator to document how they obtained confirmation of the subject’s 
asthma exacerbation(s). It is the Investigator’s responsibility to ensure subject eligibility into 
the clinical study. In cases where the Investigator feels that alternative records to the above 
constitutes acceptable documentation, the Study Physician will be contacted for their 
assessment of eligibility prior to enrolment. Every attempt should be made to obtain 
appropriate source documentation of medical records. 
 
10. ACQ-6 score ≥1.5 at Visit 1 or Visit 2. 
 
Prior to entering treatment at Visit 2, 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 additional asthma controller medication including an increase in ICS 
dose during run-in. 
 
13. A pre-BD FEV1 of ≥40% of the subject’s PNV at Visit 2, if not met at Visit 1. 
 
14. Ability to perform acceptable inhaler and spirometry techniques. 
 
15. ACQ-6 score of ≥1.5 at Visit 2, if not met at Visit 1. 

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3.2 
Exclusion criteria 
 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
 
1.   Clinically important pulmonary disease other than asthma (e.g., active lung infection, 
COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome 
associated with obesity, lung cancer, alpha 1 anti-trypsin deficiency, and primary ciliary 
dyskinesia) or ever been diagnosed with pulmonary or systemic disease, other than 
asthma, that are associated with elevated peripheral eosinophil counts (e.g., allergic 
bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic 
syndrome). 
 
2.   Any disorder, including but not limited to, cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator and could: 
 
x Affect the safety of the subject throughout the study 
 
x Influence the findings of the studies or their interpretations 
 
x Impede the subject’s ability to complete the entire duration of study 
 
3.   Known history of allergy or reaction to any component of the IP formulation. 
 
4.   History of anaphylaxis following any biologic therapy. 
 
5.   A helminth parasitic infection diagnosed within 6 months prior to enrolment (Visit 1). 
 
6.   History of clinically significant infection, including acute upper or lower respiratory 
infections, requiring antibiotics or antiviral medication within 30 days prior enrolment 
(Visit 1) or during the run-in period. 
 
7.   Tuberculosis requiring treatment within 12 months prior to enrolment (Visit 1). 
 
8.   Any clinically significant abnormal findings in physical examination, vital signs, ECG, 
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 prior to enrolment (Visit 1), or 
a condition associated with poor compliance as judged by the Investigator. 

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10. Confirmed positive test for hepatitis B/hepatitis C serology at screening: a) Hepatitis B 
surface antigen positive OR b) Hepatitis B core antibody positive with negative hepatitis B 
surface antibody OR c) Hepatitis C antibody positive.  Subjects with a history of hepatitis 
B vaccination without a history of hepatitis B are allowed to be enrolled. 
 
11. History of any known primary immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at enrolment, or the subject taking antiretroviral 
medications as determined by medical history and/or subject’s verbal report. 
 
12. Current tobacco smoking (smoking must have stopped for ≥3 months prior to enrolment) 
or a history of tobacco smoking for ≥10 pack-years (one pack year = 20 cigarettes smoked 
per day for 1 year). 
 
13. History of cancer: 
 
x Subjects who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible provided 
that the subject is in remission and curative therapy was completed at least 
12 months prior to enrolment (Visit 1). 
 
x Subjects who have had other malignancies are eligible provided that the 
subject is in remission and curative therapy was completed at least 5 years 
prior to enrolment (Visit 1). 
 
14. Use of immunosuppressive medication (including but not limited to: methotrexate, 
troleandomycin, cyclosporine, azathioprine, systemic corticosteroids including regular 
treatment with OCS or intramuscular long-acting depot corticosteroids, or any 
experimental anti-inflammatory therapy) within 3 months prior to enrolment (Visit 1). 
 
15. Clinically significant asthma exacerbation, in the opinion of the Investigator, including 
those requiring use of OCS 30 days prior to enrolment (Visit 1) or during the run-in 
period. 
 
16. Receipt of immunoglobulin or blood products within 30 days prior to enrolment (Visit 1). 
 
17. Receipt of any marketed or investigational biologic agent within 4 months or 5 half-lives 
prior to enrolment (Visit 1), whichever is longer. 
 
18. Receipt of live attenuated vaccines 30 days prior to enrolment (Visit 1) and during the 
study including the follow-up period: 
 
x Receipt of inactive/killed vaccinations (e.g., inactive influenza) are 
allowed provided they are not administered within 5 days before/after 
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19. Receipt of any investigational non-biologic agent within 30 days or 5 half-lives prior to 
enrolment (Visit 1), whichever is longer. 
 
20. Previous receipt of tralokinumab (CAT-354). 
 
21. Initiation of new allergen immunotherapy or change in existing immunotherapy is not 
allowed within 30 days prior to enrolment (Visit 1). However, allergen immunotherapy 
initiated prior to this period may be continued provided there is a span of at least 5 days 
between the immunotherapy and IP administration. 
 
22. Current use of oral or ophthalmic non-selective β-adrenergic antagonist (e.g., propranolol). 
 
23. Current use of five-lipoxygenase inhibitors (e.g., Zileuton) or roflumist. 
 
24. Subjects that have undergone bronchial thermoplasty. 
 
25. Major surgery within 8 weeks prior to the enrolment visit, or planned in-subject surgery or 
hospitalization during the study period. 
 
26. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥2.5 times the 
upper limit of normal (ULN) at enrolment. 
 
27. Pregnant, currently breast-feeding, or lactating women. 
 
28. Previous treatment in the present study. 
 
29. Concurrent enrolment in another clinical study where the subject is receiving an IP. 
 
30. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site). 
 
31. Employees of the clinical study site or any other individuals directly involved with the 
planning or conduct of the study, or immediate family members of such individuals. 
 
32. Individuals who are legally institutionalized. 
 
Procedures for withdrawal of incorrectly enrolled subjects see Section 3.4. 
 
3.3 
Subject enrolment 
 
Investigator(s) should keep a record (i.e., the subject screening log) of subjects who entered 
pre-study screening.  The pre-screening/screening log will be evaluated periodically by 
AstraZeneca and/or its delegates during routine monitoring visits. 
 
The Investigator(s) will: 
 
1. 
Obtain signed informed consent or assent from the potential subject, or their legal 
representative, before any study specific procedures are performed. 

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2. 
Assign potential subject a unique enrolment code, beginning with ‘E#’ via the 
Interactive Web Response System/Interactive Voice Response System 
(IWRS/IVRS) 
 
3. 
Determine subject eligibility. See Section 3. 
 
4. 
Subjects who enter the treatment period will receive tralokinumab. IP will be 
dispensed via the IWRS/IVRS. Enrolled subjects who discontinue will not be 
replaced. If a subject withdraws from participation in the study then his/her 
enrolment code cannot be re-used. 
 
3.4 
Procedures for handling incorrectly enrolled subjects 
 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication.  There can be no exceptions to this rule.  Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be initiated 
on treatment, and must be withdrawn from the study. 
 
Where a subject does not meet all the eligibility criteria but is enrolled in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 
immediately, and a discussion should occur between the AstraZeneca study physician and the 
investigator regarding whether to continue or discontinue the patient from treatment. The 
AstraZeneca study physician must ensure all decisions are appropriately documented. 
 
3.5 
Restrictions during and after the study 
 
x 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. 
 
x Subject must abstain from donating blood, plasma from the time of informed consent or 
assent and for 16 weeks (5 half-lives) after last dose of IP. 
 
3.6 
Discontinuation of investigational product 
 
Subjects will be discontinued from IP in the following situations: 
 
1.   Subject decision.  The subject is at any time free to discontinue treatment, without 
prejudice to further treatment. 
 
2.   The subject experiences an AE that, in the opinion of the Investigator, contraindicates 
further dosing. 
 
3.   The development of any risk to the subject as judged by the Investigator or 
AstraZeneca. 
 
4.   Severe non-compliance with the study protocol. 

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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% 
increase of differential count of leukocytes) 
 
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 encourage 
to continue to undergo all study related visits/procedures for the full 52-week study period in 
order to support the final safety analysis for tralokinumab (see section 8). The reason for 
premature discontinuation of IP will be documented in the source documentation and recorded 
in the electronic case report form (eCRF). 
 
It is essential to collect as much data as possible for all subjects throughout the study and 
especially all potential endpoint events. Complete withdrawal from the study (i.e., withdrawal 
of consent) has a direct negative impact on the potential validity of all study data and should 
be avoided wherever possible. 
 
If the subject permanently discontinues IP prior to their completion of the study and wishes to 
continue with study assessments, they may choose from 3 different follow-up options, as 
described in Section 4.2. 
 
 
 
 
 
 
1A subject is considered lost to follow up when any of the following attempts of contact are failed: 3 attempts of 
either phone calls, faxes or emails; having sent 1 registered letter/certified mail. 

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3.6.1 
Procedures for discontinuation of a subject from investigational product 
 
At any time, subjects are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments (See Section 3.7), without prejudice to 
further treatment.  A subject that decides to discontinue investigational product will always be 
asked about the reason(s) and the presence of any adverse events by an Investigator(s). They 
will be seen and assessed by an Investigator(s). Adverse events will be followed up (See 
Section 6). 
 
If a subject is withdrawn from study, see Section 3.7. 
 
3.7 
Criteria for withdrawal 
 
3.7.1 
Screen failures 
 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not initiate IP.  These patients should have the reason for study withdrawal 
recorded as ‘Incorrect Enrolment’ (i.e., patient does not meet the required inclusion/exclusion 
criteria).  This reason for study withdrawal is only valid for screen failures (not patients 
treated with IP). 
 
3.7.2 
Withdrawal of the informed consent or assent 
 
Subjects are free to withdraw from the study at any time (i.e., from receiving IP and/or 
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 withdraw, and the presence of any adverse events (AE) by an Investigator(s). 
The Investigator will follow up AEs outside of the clinical study. 
 
If a subject withdraws from participation in the study, then his/her enrolment code cannot be 
reused. Withdrawn subjects will not be replaced. 
 
If the subject only withdraws consent for the retention of blood samples for future exploratory 
use (e.g., study of markers of asthma, identifying potential new drug targets for asthma, or for 
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. 
 
3.8 
Discontinuation of the study 
 
The study may be stopped if, in the judgment of AstraZeneca, trial subjects are placed at 
undue risk because of clinically significant findings that: 
 
x 
meet individual stopping criteria or are otherwise considered significant 
 
x 
are assessed as causally related to study drug, 

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x 
are not considered to be consistent with continuation of the study 
 
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented. 
 
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests. 

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Study Code D2210C00029 
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32 (101) 
 
 
 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
 
Table 1 
Study Plan 
 
Assessment/ 
activity 
Enrol 
-ment 
 
Treatment 
EOT 
FU 
FU 
IPD 
UNS3 
V11 
V22 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
V9 
 
V10 
 
V11 
V12 
V13 
 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
V29 
V30 
W-2- 
0 
 
W0 
 
W2 
 
W4 
 
W6 
 
W8 
 
W10 
 
W12 
W14 
 
W16 
 
W18 
W20 
W22 
 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
W56 
W66 
Visit window (days)4 
N/A 
 
0 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+7 
+7 
N/ 
A 
N/ 
A 
Informed 
consent/ 
assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
Criteria 
X 
 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X  
 
 
 
 
 
 
 
 
 
Medical and 
asthma 
history 
X 
 
 
 
 
 
 
 
 
 
 
Complete 
Physical 
examination 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Brief 
Physical 
examination 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
(V9 
only) 
 
X 
X 
(V13 
only) 
 
X 
X 
X 
(V17 
only) 
X 
X 
(V21 
only) 
X 
X 
(V25 
only) 
X 
(V27 
only) 
X 
X 
X 
Height 
X  
 
 
 
 
 
 
 
 
 
X5 
X5 
Weight 
X  
 
 
 
 
 
 
 
 
 
X 
X 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
33 (101) 
 
 
 
Assessment/ 
activity 
Enrol 
-ment 
 
Treatment 
EOT 
FU 
FU 
IPD 
UNS3 
V11 
V22 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
V9 
 
V10 
 
V11 
V12 
V13 
 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
V29 
V30 
W-2- 
0 
 
W0 
 
W2 
 
W4 
 
W6 
 
W8 
 
W10 
 
W12 
W14 
 
W16 
 
W18 
W20 
W22 
 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
W56 
W66 
Visit window (days)4 
N/A 
 
0 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+7 
+7 
N/ 
A 
N/ 
A 
Vital Signs6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X  
 
 
 
 
 
 
 
 
 
X 
X 
Clinical 
Chemistry 
X  
 
 
X  
 
X  
 
 
 
 
X 
X 
X 
X 
X 
Haematology 
X  
 
X 
 
X  
 
X  
X 
(V8 
only) 
 
X 
X 
(V12 
only) 
 
X 
X 
(V16 
only) 
X 
X 
(V20 
only) 
X 
X 
(V24 
only) 
X 
(V26 
only) 
X 
X 
X 
X 
X 
Glycosylated 
haemoglobin 
(HbA1c) 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
Urinalysis 
(dipstick)7 
X  
 
 
X  
 
X  
 
 
 
 
X 
X 
X 
X 
X 
Urine 
pregnancy 
test 
(dipstick)8 
 
 
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  
 
 
 
 
 
 
 
 
Serology 
(Hepatitis 
B, C;HIV- 
1;HIV-2) 
X 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
34 (101) 
 
 
 
Assessment/ 
activity 
Enrol 
-ment 
 
Treatment 
EOT 
FU 
FU 
IPD 
UNS3 
V11 
V22 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
V9 
 
V10 
 
V11 
V12 
V13 
 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
V29 
V30 
W-2- 
0 
 
W0 
 
W2 
 
W4 
 
W6 
 
W8 
 
W10 
 
W12 
W14 
 
W16 
 
W18 
W20 
W22 
 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
W56 
W66 
Visit window (days)4 
N/A 
 
0 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+7 
+7 
N/ 
A 
N/ 
A 
Serum β- 
HCG 
X  
 
 
 
 
 
 
 
 
 
FSH9 
X  
 
 
 
 
 
 
 
 
 
ACQ-6 at 
the site 
X 
 
X  
 
 
 
 
X 
(V8 
only) 
 
 
 
X 
X 
X 
X 
Pre-BD, 
Spirometry 
X 
 
X  
 
X  
 
X  
X 
(V8 
only) 
 
 
 
X 
X 
X 
X 
X 
X 
Post-BD, 
Spirometry 
 
X  
 
 
 
 
 
 
 
 
X 
X 
PK 
 
X 
 
X  
 
 
X  
 
 
 
 
X 
X 
X 
ADA/nAb 
 
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 
Enter 
Treatment 
 
X  
 
 
 
 
 
 
 
 
IP 
Administration 
 
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 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
35 (101) 
 
 
 
Assessment/ 
activity 
Enrol 
-ment 
 
Treatment 
EOT 
FU 
FU 
IPD 
UNS3 
V11 
V22 
 
V3 
 
V4 
 
V5 
 
V6 
 
V7 
 
V8 
V9 
 
V10 
 
V11 
V12 
V13 
 
V14 
V15 
V16 
V17 
V18 
V19 
V20 
V21 
V22 
V23 
V24 
V25 
V26 
V27 
V28 
V29 
V30 
W-2- 
0 
 
W0 
 
W2 
 
W4 
 
W6 
 
W8 
 
W10 
 
W12 
W14 
 
W16 
 
W18 
W20 
W22 
 
W24 
W26 
W28 
W30 
W32 
W34 
W36 
W38 
W40 
W42 
W44 
W46 
W48 
W50 
W52 
W56 
W66 
Visit window (days)4 
N/A 
 
0 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+3 
+7 
+7 
N/ 
A 
N/ 
A 
Concomitant 
medications 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood sample 
for Periostin 
 
X  
 
 
 
 
X 
(V8 
only) 
 
 
 
X 
X 
X 
Blood sample 
DPP4 and 
other 
biomarkers 
 
 
X 
 
 
 
 
 
 
X 
(V8 
only) 
 
 
 
X 
X 
X 
1 
Visit 1 can be performed over a period of 3-working days, with the exception of documentation of informed consent and assent (if applicable) which can 
be completed up to 30 days prior to Visit 1. Visit 1 can occur within 2 weeks before Visit 2. 
2 
The run-in period can be maximum 2 weeks in duration. Visit 2 is considered day 0. 
3 
UNS (Unscheduled Visit): At unscheduled visits for assessing asthma exacerbation, assessments indicated in Table 1 must be performed. For other 
unscheduled visits assessments may be performed per investigators judgement. 
4 
All visits are to be scheduled based on the date of entering treatment period and not from the date of the previous visit. 
5 
Height assessed for adolescent subjects only (from 12 to 17 years, inclusively at time of Visit1). 
6 
Vital signs will be taken pre-dose prior to administration of IP. Subjects will be observed 2 hours post treatment for visits 2, 3, 4, 5 and 6 with vital signs 
taken every 30 minutes. For all other visits where IP is administered, subjects will be observed for a minimum of 1 hour, with vital signs taken every 30 
minutes. 
7 
Urine sample will only be sent to central lab for urinalysis if any dipstick parameters are assessed as abnormal. 
8 
For WOCBP, urine pregnancy test (dipstick) to be done at centre at each treatment visit prior to IP administration. 
9 
FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 months. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
36 (101) 
 
 
4.1 
Enrolment/Screening period 
 
4.1.1 
Enrolment (Visit 1) 
 
Each potential subject who is at, or over the age of majority 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, 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 when they have had their BD medications withheld in accordance with the 
spirometry instructions (see section 5.1.2). The registration of the subject’s enrolment via 
IWRS/IVRS should occur on the day when the Visit 1 procedures are performed. 
 
Visit 1 assessments are primarily concerned with assessing the subject’s eligibility 
(inclusion/exclusion) criteria, including their asthma disease state, the requisite level of 
severity based on maintenance medications, exacerbation history, and the current level of 
control based on an initial ACQ-6 score. 
 
Spirometry will also be performed at Visit 1. Subjects must have a pre-BD FEV1 value of 
≥40% of their PNV in order to proceed in the study (as per section 3.1, criterion 8) at Visit 1 
or Visit 2. If not, the subject will be screen failed. 
 
Other study assessments and procedures to be performed at this visit include the recording of 
the subject’s demographics, a complete physical examination (including height and weight), 
vital signs, an ECG, recording the subject’s medical/surgical history and concomitant 
medications, collection of blood samples for haematology/clinical chemistry, serology, 
collection of a urine sample for urinalysis, and a pregnancy test for WOCBP. 
 
A record of physician-diagnosed asthma, ICS-LABA use, use of other asthma controllers (see 
section 3.1, criteria 5, 6 and 7) and asthmas exacerbations over the prior year (section 3.1, 
criterion 9) is required for source documentation. A subject’s verbal history suggestive of 
asthma symptoms and/or prior asthma exacerbations, but without supporting documentation, 
is not sufficient to satisfy these inclusion criteria. 
 
4.1.2 
Screening / Run-in (Visit 1-2) 
 
The run-in period (i.e., from Visit 1 - 2) is maximum 2 weeks in duration. The subject should 
remain on their current asthma treatment with no changes throughout the entire run-in period. 
Assessments applicable for the run-in period are listed in Table 1. 
 
The subject’s eligibility should be evaluated at each visit during the screening/run-in period 
with the relevant documentation entered in the source and eCRF. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
37 (101) 
 
 
4.1.3 
Treatment period (Visit 2) 
 
Lung function with measurement of pre-BD and post-BD FEV1 will be performed at Visit 2. 
Subjects should have a pre-BD FEV1 of ≥40% of the subject’s PNV, if not met at Visit 1. 
 
The subject will complete the ACQ-6 at Visit 2. 
 
4.1.4 
Re-screening 
 
Subjects who experience an asthma exacerbation within 30 days prior to ICF date or during 
the screening/run-in phase should be screen failed. The subject 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 of informed consent is obtained or during the screening/run-in period 
may also be re-screened. 
 
Re-screening for the above mentioned reasons is allowed only once for the subject.  Subjects 
should be re-screened no later than 3 months failing initial enrolment. 
 
If the reason for screen failure was transient (including but not limited to equipment failure 
and unforeseen personal events that mandate missing screening visits), subject may potentially 
be re-screened.  These cases should be discussed with the AstraZeneca Study Physician and 
documented approval for re-screening should be filed in the Investigator Study File (ISF). 
 
Re-screening for subjects who have screen-failed due to an ACQ-6 score of <1.5 is not 
allowed. 
 
Any re-screened subject will be enrolled and reassigned their originally assigned enrolment 
number after signing a new Informed Consent Form (ICF), or assent form, and after all run-in 
assessments have been performed as listed in Table 1 (with the exception of testing for HIV1, 
HIV2, hepatitis B and C, and FSH). Re-enrolment is only allowed once for any subject 
regardless of whether this is due to an exacerbation or infection. The subject may not be re- 
screened if any other eligibility criteria are failed. 
 
4.2 
Treatment period 
 
Inclusion criteria at time for entering treatment period will be confirmed at Visit 2. Before 
entering treatment period the subject’s compliance with their usual asthma controller ICS- 
LABA and other asthma controller medication must be confirmed (see section 3.1, inclusion 
criteria 6 and 7). 
 
Subjects confirmed as eligible will enter treatment at Visit 2. Subjects will be administered 
tralokinumab 300 mg via subcutaneous injection at the study site Q2W for a total of 26 doses. 
 
The first dose of IP will be administered following enrolment through IWRS/IVRS at Visit 2. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
38 (101) 
 
 
The subject will receive 52 weeks of treatment, with the last dose of tralokinumab 
administered at Visit 27 (Week 50). 
 
Subject will have scheduled visits at 2-week intervals to complete protocol-specific 
assessments and IP administration, as listed in Table 1. Restrictions as set out in section 7.7.2 
will continue to apply throughout the treatment period. In case of an asthma 
worsening/exacerbation (see section 5.1.1), subjects should be evaluated at the study site, 
when feasible, at an unscheduled visit, or ordinary visit if the worsening happens to fall within 
a scheduled visit window. 
 
Subjects will have brief physical exams performed at time listed in Table 1.  A complete 
physical exam will be performed at Visit 28 (EOT). 
 
At Week 52 subjects will come to the site for Visit 28 (EOT).  The final follow up visits (i.e., 
29, and 30) are to occur 4 weeks (+7 days) and 14 weeks (+7 days) from the date of the EOT 
visit, respectively. 
 
Subjects who prematurely discontinue IP (see section 3.6) should return to the study site and 
complete procedures described for the IP Discontinuation Visit (IPD visit), see Table 1. 
 
At the IPD visit, the subject will be given three options as to how they will be followed up: 
 
1.   Ideally, the subject should return for all regular clinic visits and perform all scheduled 
assessments until he/she completes a total of 52 weeks in the study, or 
 
2.   The subject will be followed up on a monthly basis via telephone calls until the subject 
completes 52 weeks in the study.  No other procedures will be performed. Or, 
 
3.   The subject will be contacted at 52 weeks post entering the treatment period.  No other 
study assessments will be performed prior to this contact. 
 
For Option 1, all procedures will be done at each visit as indicated in Table 1.  For Options 2 
and 3, AEs/SAEs, changes in concomitant medications and asthma exacerbation information 
are the minimum elements that must be collected at each contact. 
 
The subject’s and legally acceptable representative’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. 
 
If the subject chooses Option 1, they will complete the IP Discontinuation visit immediately 
and then the EOT visit at week 52. Should the subject choose Option 2 or 3 above, they will 
complete the IP Discontinuation visit immediately and then only a follow up telephone call at 
week 52. For all Options, no follow up visits are required. 
 
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 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
39 (101) 
 
 
(i.e., subject initially choosing Option 1, can continue with options 2 or 3, subjects initially 
choosing Option 2 can continue with Option 3). 
 
Subjects who do not wish to have any follow up contact at all, will be withdrawn from the 
study. 
 
Completion, or early termination of IP treatment, will be registered via the IWRS/IVRS for 
each subject. 
 
4.3 
Follow-up period 
 
Subjects will have follow-up visits (29 and 30) at Weeks 56 and 66, respectively. 
 
 
5. 
STUDY ASSESSMENTS 
 
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the electronic Case 
Report Forms (eCRF) as specified in the study protocol and in accordance with the 
instructions provided. 
 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be archived 
at the study site. 
 
5.1 
Assessments 
 
5.1.1 
Assessment of asthma exacerbations 
 
For the purpose of the protocol, an asthma exacerbation will be defined as a worsening of 
asthma that leads to any of the following: 
 
x 
Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids 
 
x 
An ER or urgent care visit (defined as evaluation and treatment for <24 hours in 
an ED or urgent care center) due to asthma that required systemic corticosteroids 
(as per above) 
 
x 
An inpatient hospitalization (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma 
 
For the purpose of the protocol, worsening of asthma is defined as new or increased symptoms 
and/or signs (i.e., physical examination or lung function) that can be concerning to the subject 
(subject-driven). 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
40 (101) 
 
 
If an exacerbation event is not associated with deterioration in at least one of the pre-specified 
subject-drive objective measurements, the Investigator will have to justify the decision for 
defining the event as an exacerbation.  Events that are not supported by any objective 
assessment will be deemed not to be a protocol-defined exacerbation. 
 
In order to calculate the number of exacerbations experienced by a subject during the 52-week 
treatment period, the following rule will be applied: 
 
x 
The start of an exacerbation is defined as the start date of systemic corticosteroids, 
ER or urgent care visit requiring systemic corticosteroids, or hospital admission 
due to asthma, whichever occurs earlier, and the end date is defined as the last day 
of systemic corticosteroids or ER or urgent care visit or hospital discharge, 
whichever occurs later. 
 
Additional systemic corticosteroid treatments, ER or urgent care visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation.  In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled. 
 
The subject may remain in the study after an exacerbation and continue to receive IP if the 
Investigator judges that it is medically appropriate for the subject to do so. 
 
Reasonable attempts should be made by the Investigator to bring the subject into the study site 
for evaluation of a subject initiated asthma worsening, particularly when it results in 
additional treatment being prescribed.  Study site evaluations for asthma worsening may occur 
as an unscheduled visit or as part of an ordinary site visit if the worsening happens to be 
coincident with a scheduled visit window. 
 
A copy of the medical record should be obtained for exacerbations evaluated and treated at 
non-study sites (e.g., by the primary care HCP or at an ED/hospital) and details entered into 
the exacerbation eCRF module in a timely fashion.  Changes in concomitant medication due 
to exacerbation must be recorded in the appropriate module of the eCRF. 
 
Maximum follow-up time for a subject is approximately 52 weeks; defined as the time from 
entering treatment (Visit 2) to the date of Visit 28. For a subject lost to follow-up, this will be 
defined as the time from entering treatment period to the time point after which an 
exacerbation could not be assessed (i.e., the last contact date). 
 
Exacerbations that occur after a subject has discontinued IP should still be accounted for when 
deriving the total number of exacerbations; and likewise, the follow-up time will reflect the 
follow-up time regardless of whether or not the subjects is still on IP. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
41 (101) 
 
 
5.1.2 
Spirometry 
 
General requirements 
 
Pulmonary function will be measured by spirometry at the study site using the site’s own 
equipment. Spirometry will be performed by the Investigator or authorized delegate according 
to the Japanese Respiratory Society (JRS) guidelines (The Japanese Respiratory Society 
2004). 
 
Time of day for schedule site visit spirometry 
 
Spirometry testing can be initiated anytime throughout the day according to the schedule 
provided in Table 1.  All post-enrolment spirometry assessments should be performed within 
±1.5 hours of the time that the enrolment spirometry was performed. 
 
Subjects should be instructed not to use their maintenance twice daily LABA (or ICS- 
LABA) within 12 hours before the scheduled site visit spirometry as this will affect the 
pre-BD FEV1 value, they may be taken subsequently at the site. For theophylline and once 
daily BDs a 48 hour washout period is required. For the same reason, subjects should not 
use their SABA within 6 hours before scheduled spirometry/ECG assessments. 
 
Options for handling subjects who have inadvertently taken their asthma medication within 
the restricted window are described in section 7.7.2. 
 
Subjects that have a spirometry assessment at an unscheduled visit due to a worsening of 
asthma do not need to follow the washout instructions. 
 
Spirometry technique 
 
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements. Subjects should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the site. All spirometry manoeuvres (irrespective of whether to 
obtain values for FEV1, FVC, FEF 25-75%) should be performed with the subject seated in an 
upright position. If this is not comfortable for the subject, standing is permitted. The same 
position should be used by the subject for each forced expiratory manoeuvre from enrolment 
throughout the study.  The head must not be tilted during manoeuvres and the thorax should 
be able to move freely; hence tight clothing should be loosened. A nose-clip should be used 
for the manoeuvre. Mouthpieces of the same dimension and shape should be used by the 
subject form enrolment throughout the study. 
 
The spirometry manoeuvre consists of three phases, the first is the maximal inspiration, the 
second is a “blast” of exhalation (to obtain the FEV1 value) and the last is a continuation to 
complete exhalation. The subject should inhale rapidly and completely from functional 
residual capacity. It is important that the preceding inspiration is fast and that any pause at full 
inspiration be minimal (i.e. only for 1-2 seconds). The subject should be prompted to “blast”, 
not just “blow”, and they should be encouraged to fully exhale until the end of test criteria are 
met. If the patient feels dizzy, the manoeuvre should be stopped, since syncope could follow 
due to prolonged interruption of venous return to the thorax. Manoeuvres that do not meet the 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
42 (101) 
 
 
end of test criteria should not be used to satisfy the requirement of three acceptable 
manoeuvres. However early termination, by itself, is not a reason to eliminate all the results 
from such a manoeuvre from further consideration. 
 
To allow recording of the FVC value, it is important that the whole manoeuvre lasts for at 
least 6 seconds. Ensure that none of the following has occurred:  coughing during 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 JRS acceptability criteria with 
the highest value and second highest value for FEV1 and FVC meeting the 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 criteria is not fulfilled after 
the maximum number of manoeuvres has been performed, the highest of the FEV1 and FVC 
value that is deemed acceptable should be selected. 
 
The mean forced expiratory flow between 25% and 75% of the FVC (FEF 25-75%) is taken 
from the blow with the largest sum of FEV1 and FVC.  The FEF 25-75% must be measured 
with an accuracy of at least +5% of reading or +0.2 L whichever is greater. It is highly 
dependent on the validity of the FVC measurement and the level of expiratory effort. 
 
Order of administration of usual asthma controller medication and IP relative to 
scheduled pre- and post- BD spirograms. 
 
When spirometry is performed the subject’s usual asthma controller medication, BD and IP 
dose, should be withheld until after the final post-BD spirogram are complete. 
 
Record keeping 
 
A signed and dated copy of the pre- and post- BD printout must be kept at the study site for 
source data verification. The printout must be marked with the study code, subject enrolment 
code, date and time of measurement, and visit number (i.e., if the printout is not on archive- 
quality paper). 
 
Spirometry references 
 
FEV1, expressed as percent of the PNV, will be calculated as follows: 
FEV1% of PNV = (FEV1 measured / FEV1 PNV) x 100 
5.1.2.1 
Pre-BD and post-BD FEV1 assessment 
 
The initial (pre-BD) FEV1 measurement (Sections 5.1.2) must be completed before 
commencing the post-BD assessment. 
 
As before, ensure that the subject has withheld each of their theophylline and BD medications 
for the minimum period of time specified in Section 7.7.2 and Appendix F. If the subject did 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
43 (101) 
 
 
not withhold their medications as specified, the post-BD assessment should be rescheduled 
within the next 7 days; other visit assessments may be completed as planned. 
 
Albuterol 90 μg metered dose or Salbutamol 100 μg metered dose will be used in the post-BD 
assessment. Up to 4 doses may be administered at Visit 2. The dose should be adjusted if there 
is any concern about the effect on the subject’s heart rate, tremor or any other safety parameter 
during the assessment; the reason should be noted in the subject’s medical records. 
 
A spacer device should be used for administration of the SABA; nebulizers should not be 
used. 
 
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 (4 inhalations) of the SABA to TLC and hold their breath for 5-10 
seconds before subject exhales. 
 
After resting for 15-20 minutes, proceed to measure FEV1 following the technique described 
in Section 5.1.2. 
 
5.1.3 
Periostin/DPP4 
 
An investigational use only (IUO)/performance evaluation only (PEO) assay is being 
specifically developed and validated as a companion diagnostic for tralokinumab to address 
the potential identification of a target population with an enhanced response rate based on the 
presence of high serum periostin and/or DPP4 as an indicator of IL-13 driven asthma.  The 
performance characteristics of the assay have not been established. No clinical decision or 
patient notification should be made based on the results obtained with this product. 
 
A baseline periostin and DPP4 concentration level using the investigational assay may be 
determined for each subject enrolled in the trial. Analysis will be performed by the central 
laboratory. Blood sample will be obtained at Visit 2, 8, 15, 28 and IPD visit. These samples 
may be used in existing and/or future clinical studies in vitro diagnostic assays. 
 
Instructions for sample collection, processing, storage, and shipment will be included in a 
separate laboratory manual provided to the sites. 
 
5.2 
Safety assessments 
 
5.2.1 
Laboratory safety assessments 
 
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at visits in accordance with the schedule outlined in Table 1.  Haematology, 
Clinical chemistry, and Urinalysis samples should be collected at unscheduled visits for 
assessing asthma exacerbation, at a minimum.  Other unscheduled visits may be initiated as 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
44 (101) 
 
 
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 chemistry, haematology, and urinalysis tests are presented in Table 2, 
Table 3, Table 4, and Table 5, respectively. 
 
The following laboratory variables will be measured: 
 
Table 2 
Laboratory Safety Values 
 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum) 
B-Haemoglobin (Hb) 
S-Alkaline phosphatise (ALP) 
B-Leukocyte count 
S-Alanine transaminase (ALT) 
B-Leukocyte differential count (absolute count) 
S-Aspartate transaminase (AST) 
 
B-Platelet count 
S-Bilirubin, total 
 
B-Hematocrit 
S-Blood urea nitrogen (BUN) 
B-Mean corpuscular volume (MCV) 
S- Calcium, total 
B-Red blood Cell (RBC) count 
S-Carbon dioxide, (CO2) 
B-HbA1c 
S-Chloride 
S-Creatinine 
 
S-Creatinine kinase 
 
Urinalysis 
S-C-Reactive Protein (CRP) 
 
U-Nitrite (dipstick) 
S-Gamma-glutamyl transpeptidase (GGT) 
U-Bilirubin (dipstick) 
S-Glucose 
U-Glucose (dipstick) 
S-Phosphorus 
U-Blood (dipstick) 
S-Potassium 
U-Protein (dipstick) 
S-Sodium 
U-Ketones (dipstick) 
S-Total cholesterol 
 
Urine microscopy and urine casts (as required*) 
S-Uric acid 
Urine culture (as required*) 
 
NB. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥ 2xULN please refer 
to Appendix C for further instructions. 
 
*Urine samples will be analysed locally and sent for analysis at the central lab only when a 
positive dipstick result for any parameter is observed. 

Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
45 (101) 
 
 
Table 3 
Clinical Chemistry (serum) Tests schedule 
 
Visit 
V1 
V4 
V6 
V15 
V22 
 V28/ 
EOT 
 
 
 
IPD 
Visit 
 
 
 
UNS 
Visit 
 
Week 
-2-0 
4 
 8 
26 
40 
52 
N/A 
N/A 
ALP 
 X 
X 
X 
 X 
 X 
 X 
  X 
 X 
ALT 
 X 
X 
X 
 X 
 X 
 X 
  X 
 X 
AST 
 X 
X 
X 
 X 
 X 
 X 
  X 
 X 
BUN 
 X 
X 
X 
 X 
 X 
 X 
  X 
 X 
Calcium, total 
 X 
 
 
 
  
 X 
  X 
 X 
Chloride 
 X 
 
 
 
  
 X 
  X 
 X 
CO2 
 X 
 
 
 
  
 X 
  X 
 X 
Creatinine 
 X 
X 
X 
 X 
 X 
 X 
  X 
 X 
Creatinine kinase 
 X 
CRP 
X 
 
GGT                                  X              X              X              X              X              X              X              X 
Glucose                             X                                                                                     X              X              X 
Phosphorus                        X                                                                                     X              X              X 
Potassium                          X                                                                                     X              X              X 
Sodium                              X                                                                                     X              X              X 
Total bilirubin                   X              X              X              X              X              X              X              X 
Total cholesterol               X                                                                                     X              X              X 
Uric acid                           X                                                                                     X              X              X 

 
Clinical Study Protocol 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
Table 4 
Haematology/Haemostasis (whole blood) schedule 
 
VISIT 
V1 V3 V4 V6 V8 V10 V12 V14 V16 V18 V20 V22 V24 V26 V28 
(EOT) 
V29 
(FU) 
V30 
(FU) 
IPD 
Visit 
UNS 
Visit 
Week 
-2- 
2 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
56 
66 
N/A 
N/A 
0  
 
 
 
 
 
 
 
B- 
Haemoglobin 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-Leukocyte 
count 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-Leukocyte 
differential 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
count 
 
 
 
 
 
 
 
 
 
(absolute 
 
 
 
 
 
 
 
 
 
count) 
 
 
 
 
 
 
 
 
 
B-Platelet 
count 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-Hematocrit 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-Mean 
corpuscular 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
volume 
 
 
 
 
 
 
 
 
 
B-Red blood 
cell count 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HbA1c 
 
 
X  
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
46 (101) 

Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
47 (101) 
 
 
Table 5 
Urinalysis schedule 
 
VISIT 
V1 
V4 
V6 
V15 
V22 
V28 
(EOT) 
IPD 
Visit 
UNS 
Visit 
Week 
-2-0 
4 
8 
26 
40 
52 
N/A 
N/A 
U-Nitrite (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
U-Bilirubin (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
U-Glucose (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
U-Blood (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
U-Protein (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
U-Ketones (dipstick) 
X 
X 
X 
X 
X 
X 
X 
X 
Urine microscopy and urine 
casts (as required)* 
 
Urine culture (as required)* 
* Urine samples will be analysed locally and sent for analysis at the central lab only when a positive dipstick 
result for any parameter is observed. 

Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
48 (101) 
 
 
The total volume of blood that will be collected from each subject during the study is 
presented in Table 6. 
 
 
 
Table 6 
Volume of blood to be drawn from each subject 
 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 2 
(mL) 
 
Safety 
Clinical chemistry 
2.5 
6 
15 
 
Haematology 
(including HbA1c) 
 
2 
17 
34 
 
FSH, β-HCG1 
1 
1 
1 
 
Serology 
7.5 
1 
7.5 
 
IgE 
2.5 
2 
5 
Phadiatop® 
2.5 
1 
2.5 
 
Periostin 
6 
4 
24 
 
DPP4 and other biomarkers 
10 
4 
40 
 
ADA/nAb 
3.5 
5 
17.5 
 
PK 
3.5 
6 
21 
 
 
 
Total 
167.5 
1 Female subjects only 
2 The number of samples may be changed due to additional sampling at unscheduled visits, and the blood volume 
required may be altered to fit the assay requirements. 
 
 
 
Urine will be tested locally and sent for analysis at the central lab only when a positive 
dipstick result for any parameter is observed. Blood samples for determination of 
haematology/haemostasis and clinical chemistry will be performed at a central laboratory. For 
information on methods of collection, assessment, labelling, storage and shipment of samples, 
please refer to the separate Laboratory Manual. 
 
A copy of the laboratory result report should be signed and dated by the Investigator and 
retained at the study site. 
 
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results report should be signed and dated, and retained 
at site as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3. 

Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
49 (101) 
 
 
5.2.2 
Pregnancy Test 
 
The following tests are applicable to female subjects only, and will be conducted in 
accordance with the schedule provided in Table 1. 
 
x 
Serum β-human chorionic gonadotropin (β-HCG) – the test done at enrolment 
(Visit 1) only, for WOCBP and adolescent females (analyzed at central laboratory) 
 
x 
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. 
 
x 
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 results must be confirmed with serum β-HCG. 
 
5.2.3 
Physical examination 
 
Physical examinations (complete and brief) will be performed in accordance with schedule 
provided in Table 1. 
 
Baseline data will be collected at Visit 1. Any new finding(s) or aggravated existing 
finding(s), judged as clinically significant by the Investigator, will be reported as an AE as 
described in section 6.1. 
 
5.2.3.1 
Complete physical examination 
 
The complete physical examination will be performed and include an assessment of the 
following: general appearance, skin, head and neck (including eyes, ears, nose, mouth and 
throat), lymph nodes, abdomen, musculoskeletal (including spine and extremities), 
cardiovascular, respiratory, and neurological systems. 
 
5.2.3.2 
Brief physical examinations 
 
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system. 
 
5.2.4 
ECG 
 
All ECG assessments must be performed using an electrocardiogram (ECG) device.  ECGs 
will be performed in accordance with schedule provided in Table 1.  ECG assessments will be 
performed prior to blood drawing, spirometry, IP administration and BD administration. 
 
For all subjects, the printouts of the ECG will be collected and signed, dated and stored at the 
study site along with a signed and dated photocopy of each printout (i.e., if the printout is not 
on archive-quality paper). 

50 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
5.2.4.1 
Resting 12-lead ECG 
 
A 12-lead ECG will be taken in supine position, after the subject has been resting for at least 5 
minutes. The assessment should be performed before interventions with the subject (e.g., 
spirometry and administration of asthma-related medications and IP). 
 
A standard ECG with Data will be frozen and then locked to prevent further data entry/editing 
a recommended paper speed of 25 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 ECG findings. In case of 
discrepancy between the Investigator’s interpretation and that provided by the ECG machine 
(if applicable), the Investigator’s interpretation takes precedence and should be noted on the 
printout and recorded in the eCRF. Two identical copies of the ECG will be produced and 
quality checked and kept in case of further need for re-evaluation. 
 
It is highly recommended that the same machine be used for all ECG assessments throughout 
the subject’s participation in the study. 
 
ECG data and evaluation will be performed by the site Investigator and recorded in the eCRF. 
 
5.2.5 
Vital signs 
 
Pre-dose vital signs (i.e., pulse, blood pressure, respiration rate and body temperature) will be 
obtained in accordance with schedule provided in Table 1. 
 
Vital signs will be taken prior to blood drawing, IP administration, and, if possible, usual 
asthma controller medication. At Visits 2 through 6, subjects should be observed for a 
minimum of 2 hours after IP administration for the appearance of any acute drug reactions. 
For the remaining visits involving IP administration, subjects will be observed for a minimum 
of 1 hour after IP administration for any such reaction. 
 
Vital signs should also be taken prior to BD administration, if applicable for that visit. 
 
5.2.5.1 
Pulse, blood pressure and respiration rate 
 
Pulse rate and blood pressure should be measured after the subject has been resting for at least 
5 minutes.  The measurement will be taken in 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 (i.e., how many times the chest rises) for one minute. 
 
5.2.5.2 
Body temperature 
 
Body temperature will be measure in degrees Celsius prior to IP administration, in accordance 
with local standards. 

51 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
5.2.6 
Other safety assessments 
 
5.2.6.1 
Serology 
 
Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, hepatitis C 
antibody, HIV-1 and HIV-2 antibodies will be assessed at enrolment (Visit 1) only.  All 
testing for these will be performed at a central laboratory. 
 
Instructions for sample collection, processing, storage and shipment will be provided in a 
separate laboratory manual provided to the sites. 
 
5.2.6.2 
Infections 
 
The severe infections, defined as/resulting in: 
 
x life-threatening 
 
x requiring hospitalization 
 
x requiring treatment with antiviral medications, intravenous antibiotics 
or medications for helminth parasitic infections or, 
 
x a permanent discontinuation of study drug 
must be entered in the infection module in the eCRF. 
5.3 
Other assessments 
 
5.3.1 
Weight and height 
 
Weight and height will be measured in accordance with the schedule provided in Table 1. 
 
The subject’s weight will be recorded in kilograms, and height will be recorded in 
centimetres. Weight and height measurements will be performed in light clothing and with 
shoes off. 
 
5.3.2 
Patient reported outcomes 
 
Patient reported outcomes data will be captured on paper.  Additional details concerning the 
assessment can be found in the subsequent sections 5.3.2.1. 
 
5.3.2.1 
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. 

52 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤0.75 
indicate well-controlled asthma, scores between 0.75 and <1.5 indicate partly controlled 
asthma, and a score ≥ 1.5 indicates uncontrolled asthma (Juniper et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful. 
 
The questionnaire will be completed on paper. 
 
ACQ-6 score of ≥1.5 is required either at Visit 1 or 2 to determine eligibility to enter the 
treatment period (see section 3.1, inclusion criteria 10).  Once enrolled, subjects will be asked 
to complete the ACQ-6 once approximately every 14 weeks throughout the treatment period 
(see Table 1, Study Plan). 
 
The Investigator/authorized delegate will provide the ACQ-6 questionnaire to the subject at 
each visit shown in Table 1 and review for completeness. 
 
5.4 
Pharmacokinetics and Immunogenicity 
 
5.4.1 
Collection of samples 
 
Blood samples for determination of tralokinumab in serum will be collected pre-dose at the 
times presented in Table 1.  It is important that date and time of each SC injection and sample 
collection be recorded for each subject. 
 
Instructions for sample collection, labelling, processing, storage, and shipment will be 
provided in a separate Laboratory Manual provided to the sites. 
 
The volume of blood that will be collected from each subject for these assessments is 
presented in Table 6. 
 
5.4.2 
Determination of drug concentration 
 
Samples for determination of tralokinumab concentration in serum will be analysed 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. 
 
5.4.3 
Storage and destruction of pharmacokinetic samples 
 
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses. 

53 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, 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 
; see details in the 
Laboratory Manual). 
 
5.4.4 
Immunogenicity 
 
Instructions for immunogenicity (ADA/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-drug antibodies 
 
The pre-dose serum samples to measure presence of ADA will be collected according to the 
schedule of study procedures (see Table 1). 
 
The presence or absence of ADA will be determined in the serum samples using a validated 
bioanalytical method.  A tiered testing scheme will be employed, with the first step being 
screening.  Samples found positive in the screening step will be tested in the confirmatory 
step. 
 
Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titer 
determination and will be analysed for the presence of nAb. 
 
Neutralizing antibodies (nAb) 
 
Neutralizing antibodies will be assessed at Visits 2, 15, 28 (EOT), 29 and 30 (Weeks 0, 26, 52, 
56, and 66, respectively) according to the tiered testing scheme outlined above. 
 
The presence of 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. 
Redacted

54 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
5.4.5 
Total IgE 
 
Testing for IgE will be performed at Visits 2, 28 (EOT) (Weeks 0 and 52, respectively) and 
IPD according to the schedule of study procedures (see Table 1). 
 
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate Laboratory Manual provided to the sites. 
 
5.4.6 
Phadiatop® 
Testing for phadiatop® will be performed at Visit 2 (Week 0). 
 
The analysis for these will be performed by central laboratory. Instructions for sample 
collection, processing, storage, and shipment will be provided in a separate Laboratory 
Manual provided to the sites. 
 
5.5 
Biomarkers 
 
Blood (serum) samples will be collected pre-dose according to the schedule in Table 1, to 
evaluate the pharmacology of tralokinumab, including but not limited to, periostin and DPP4. 
 
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. 
 
5.6 
Biological Samples 
 
The subject’s consent or assent to the use of donated biological samples is mandatory. 
 
Biological samples (i.e., blood, plasma, serum) will be collected and may be analysed 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. 

55 (101) 
Clinical Study Protocol Synopsis 
Drug Substance Tralokinumab (CAT-354) 
Study Code D2210C00029 
Version 2.0 
Date 15 June 2017 
 
 
5.6.2 
Labelling and shipment of biological samples 
 
The Principal Investigator ensures 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 B ‘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 is maintained for all samples throughout their lifecycle. 
 
The Principal Investigator, or delegate, at each site will keep 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 keeps full traceability of the samples while in storage and during use until 
used, or disposed of, or until further shipment and keeps documentation of receipt of arrival. 
 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites, and auditing of external laboratory providers. 
 
Samples retained for further use are registered in the Fisher Bioservices, or designate, during 
the 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 donated biological samples, the samples 
will be disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. As collection of the 
biological samples 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: 
 
x 
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca 
 
x 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented 

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x 
Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site 
x 
Ensures that the subject and AstraZeneca are informed about the sample disposal. 
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
 
 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
 
6.1 
Definition of adverse events 
 
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
 
The term AE is used to include both serious and non-serious AEs. 
 
For cases where it could be suspected that a tissue-derived medicine has been contaminated by 
a pathogen, information about any of the above conditions (including infection) should be 
collected. 
 
6.2 
Definitions of serious adverse event 
 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 
x 
Results in death 
 
x 
Is immediately life-threatening 
 
x 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
 
x 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
 
x 
Is a congenital abnormality or birth defect 

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x 
Is an important medical event that may jeopardise the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
 
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study 
Protocol. 
 
6.3 
Recording of adverse events 
 
6.3.1 
Time period for collection of adverse events 
 
Adverse Events including Serious Adverse Events will be collected from the time the subject 
signs the informed consent or assent form, throughout the treatment period and the follow-up 
periods i.e., Visit 29 (week 56) and Visit 30 (week 66). 
 
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; 
 
x 
AE (verbatim) 
 
x 
The date when the AE started and stopped 
 
x 
Maximum intensity* of the AE 
 
x 
Whether the AE is serious or not 
 
x 
Investigator causality rating against the Investigational Product (yes or no) 
 
x 
Action taken with regard to investigational product 
 
x 
AE caused subject’s withdrawal from study (yes or no) 
 
x 
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) 

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

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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 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
 
6.3.6 
Adverse events based on examinations and tests 
 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, and vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the 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 
uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non- 
mandated parameters should be reported as AE(s). 
 
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 C 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: 
 
x 
the sign or symptom is serious according to definitions, see Section 6.2, 
 
x 
the subject discontinues the study due to the sign or symptom, and/or 

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x 
the sign or symptom is new to the subject or not consistent with the subject’s pre- 
existing asthma history (defined as within 1 year of Visit 1, as judged by the 
Investigator) 
 
Asthma exacerbations should not be recorded as AEs after enrolment/treatment, unless it 
fulfils any of the above criteria. All asthma exacerbations should be recorded in the 
exacerbation eCRF as per section 5.1.1. 
 
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 the study on the AE form. 
 
6.4 
Reporting of serious adverse events 
 
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF. 
 
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours  of when he or she becomes aware of it. 
 
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it. 
 
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative(s). 
 
If the WBDC system is not available, then the Investigator or other study site personnel 
reports a SAE to the appropriate AstraZeneca representative by telephone. 
 
The AstraZeneca representative(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. 

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6.5 
Overdose 
 
Overdose for this trial is defined as any dose of Tralokinumab over 600 mg SC given in a 
period of 14 days. An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the Overdose CRF 
module. 
An over dose without associated symptoms is only reported on the Overdose CRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative(s) works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
 
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. 
For other overdoses, reporting must occur within 30 days. 
 
6.6 
Pregnancy 
 
All pregnancies (including outcome of the pregnancy) in subjects 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 
informs the appropriate AstraZeneca representatives within 1 day (i.e., immediately) but no 
later than 24 hours of when he or she becomes aware of it. 
 
The designated AstraZeneca representative works 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. 

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The pregnancy module in the eCRF is used to report the pregnancy and the pregnancy 
outcome module will be used to report the outcome of the pregnancy. 
 
6.6.2 
Paternal exposure 
 
There is no restriction on fathering children or donating sperm during the study. 
 
6.7 
Management of IP related toxicities 
 
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions must be immediately available 
when IP is being administered.  Study site personnel must be trained to recognize and treat 
anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are provided in 
Appendix E. 
 
Anaphylaxis will be defined as serious reaction that is rapid onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifest as one of 3 clinical scenarios: 
 
1.   The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue or both, and at least one of the following:  a) respiratory 
compromise, or b) reduced blood pressure or symptoms of end-organ 
dysfunction 
 
2.   Two or more of the following that occur rapidly after exposure: involvement of 
the skin/mucosal tissue; respiratory compromise, reduced blood pressure or 
associated symptoms and/or, persistent gastrointestinal symptoms 
 
3.   Reduced blood pressure after exposure 
 
Subjects will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration. At Visits 2 through 6, subjects should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, subjects will be observed for a minimum of 1 hour after IP 
administration for any such reaction. 
 
If any anaphylactic reaction occurs, in order to help understand the potential drug-relatedness 
of any acute reaction, a blood sample should be drawn during the event for additional ADA 
testing (if not already scheduled as per Table 1 for this visit).  A blood sample will be drawn 
from the subject as soon as possible after the event, at 60 minutes ± 30 minutes after the event, 
and at discharge for analysis of serum tryptase. The serum tryptase will be tested at the local 
lab or central lab where applicable. 
 
 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
 
7.1 
Identity of investigational product(s) 
 
All investigational product will be manufactured in accordance with GMP. 

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Tralokinumab administered in the study will be a clear to opalescent, colourless to yellow 
solution free from, or practically free, from visible particles. 
 
Subjects will enter treatment at Visit 2 (Week 0), and will receive tralokinumab 300 mg, Q2W 
(26 doses). 
 
Each subject will receive two injections of 150 mg tralokinumab at each dosing interval to 
receive a total dose of 300 mg.  The identity details for the IP are found in Table 7. 
 
Table 7 
Identity of Investigational Product 
 
Investigational 
product 
Concentration and 
Formulation 
Dosage form and 
strength 
Manufacturer 
 
Tralokinumab 
Formulated at a 
nominal concentration 
of 150 mg/mL in 
50mM sodium 
acetate/acetic acid 
buffer, 85mM sodium 
chloride, 0.01% (w/v) 
PS-80 pH 5.5 solution. 
 
150 mg/mL solution 
for injection in an 
accessorized pre-filled 
syringe, 1.0 mL fill 
volume. 
 
MedImmune 
 
 
 
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 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 long pre-filled 
syringe barrel with a ½ inch 27 gauge (approximately 13 mm) thin wall staked in needle, rigid 
needle shield, plunger stopper) and a safety device. The PFS-SA is an unapproved device in 
Japan. 
 
7.2 
Dose and treatment regimens 
 
The IP will be administered at the study site on treatment visits and within visit windows as 
specified in Table 1. A minimum interval of 7 days is required between 2 dosing visits. 
 
IP administration 
 
IP will be administered by a qualified, 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. 

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The person administering the dose will wipe the skin surface of the upper arm, anterior thigh 
or abdomen with alcohol, and allow to air dry.  The skin will be pinched to isolate the SC 
tissue from the muscle.  The needle will be inserted at a 90-degree angle approximately 
halfway into the SC tissue. The IP will be slowly injected (at least 5-second duration is 
recommended) into the SC tissue using gentle pressure. The area should not be massaged after 
injection. 
 
It is advised that the site of injection of IP be rotated such that the subject receives IP at a 
different anatomical site at each treatment visit. The suggested injection site rotation sequence 
is presented below in Figure 2. 
 
Figure 2 
Injection sites and rotation scheme 
 
 
 
In cases when rotation of the injection site is not favourable for the subject and/or 
Investigator, the injection site, along with the reason why the site was changed, should be 
recorded in the source documents and eCRF for each such occurrence. 
 
Further details on IP administration are provided in the IP Handling Instructions.  IP 
administration must be carried out according to these instructions. 
 
Post IP Administration (Visits 2-6) 
 
At each visit, the subject will be observed for the appearance of any acute drug reactions, for a 
minimum of 2 hours with vital signs taken every 30 minutes, until stable. 
 
Post IP Administration (Visits 7-27) 
 
At each visit, the subject will be observed for the appearance of any acute drug reactions, for a 
minimum of 1 hour with vital signs taken every 30 minutes, until stable. 
 
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: 

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x 
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) 
 
x 
The subject, in the opinion of the Investigator, is experiencing an acute or 
emerging asthma exacerbation 
 
x 
The subject is febrile (defined as ≥38°C; ≥100.4°F) within 72 hours prior to IP 
administration 
 
7.3 
Labelling 
 
Labelling of the IP will be carried out by AstraZeneca or designees in accordance with current 
GMP. Labels will be prepared in accordance with GCP Ordinance. Details are specified in the 
document explaining the reconstitution procedures and other handling procedures for the 
investigational products. 
 
7.4 
Storage 
 
Tralokinumab is to be stored at the study site in a secured facility with limited access and 
controlled temperature.  The temperature should be monitored on a daily basis and 
documented in the temperature monitoring log. 
 
A description of the appropriate storage conditions is specified in the document explaining the 
reconstitution procedures and other handling procedures for the investigational products. 
The IP must be kept in the original outer container and under conditions specified on the label. 
Site staff should not use the affected IP, and should immediately contact their AstraZeneca 
representative for further guidance in the following cases: 
 
x Temperature excursion upon receipt, or during storage at the study site 
 
x Damaged kit upon receipt, or 
 
x Damaged syringe/cartridge, 
 
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 
 
Study drug will not be distributed to the study site until the contract is concluded between the 
study site and AstraZeneca. The Investigational Product Storage Manager is responsible for 

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managing the study drug from receipt by the study site until the return of all unused study 
drug to AstraZeneca.  AstraZeneca will provide the study documents ‘Procedures for drug 
accountability’ and ‘Procedures for drug storage’ which describes the specific requirements. 
The Investigator(s) is responsible for ensuring that the subject has returned all unused study 
drug. 
 
A qualified healthcare professional at the site, or the AstraZeneca monitor will account for 
they study drug received at the site, unused study drug and for appropriate destruction. 
Certificates delivery and return should be signed. 
 
In case of malfunctioning APFS, the centre should contact the AstraZeneca monitor to initiate 
a product complaint process according to applicable guidelines. 
 
7.7 
Concomitant and other treatments 
 
7.7.1 
Concomitant medications 
 
Information about any treatment in the 3 months prior to the date of the subject’s informed 
consent or assent, and all the concomitant treatments given during the study, with reason for 
the treatment, will be collected by the Investigator/authorized delegate at each visit (as shown 
in Table 1), and recorded in the eCRF. 
 
Note: to satisfy inclusion criterion 6, the history of continuous treatment with ICS 
corresponding to ≥500 μg fluticasone propionate dry powder formulation equivalents plus a 
LABA for at least 3 month prior to Visit 1 should be documented in source and recorded in 
the eCRF (see section 3.1 and 4.1.1). 
 
Maintenance of asthma controller medication 
 
All subjects are required to be treated with a dose of ICS corresponding to ≥500 μg fluticasone 
propionate dry powder formulation equivalents (as outline in Appendix D) 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 evaluate the safety of tralokinumab as an add-on treatment and 
therefore the maintenance asthma controller therapy should be maintained at a stable dose 
from Visit 2 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 
the source along with rational for change and recorded in the eCRF. 
 
Maintenance medication is not regarded as an IP, but will be provided/reimbursed by 
AstraZeneca according to local regulations, in order to maintain appropriate oversight and 
access to this concomitant therapy. 

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Subjects on maintenance treatment with theophylline should have a documented blood 
concentration levels with 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-agonsists (SABA) 
 
Regularly scheduled SABA use in the absence of any asthma symptoms is discouraged from 
enrolment 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. 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). Any such use should be documented in medical notes and recorded in the eCRF. 
 
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. Any such use should be documented in medical notes and recorded in 
the eCRF. 
 
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 
enrolment and throughout the study duration. 
 
Use of theophylline and once daily bronchodilators 
 
Use of theophylline and once daily BDs is allowed at the discretion of the Investigator. 
However, use of these drugs should be stabilized as least 1 month prior to the subject entering 
the study. Also, a 48 hour minimum wash-out period is required before spirometry if a subject 
is using theophylline or a once-daily BD. Should the subject be taking theophylline or the 
once daily BD in the evening, it is advised that the Investigator ask the subject to reschedule 
their theophylline or BD regimen to morning use, if there are no medical reasons to prevent 
this change. 

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Asthma medication restrictions on the days of scheduled site visit spirometry 
 
Pre- and/or post-dose spirometry assessments will be performed at the study site at scheduled 
visits (see Table 1).  Restriction to a subject’s maintenance medication is required prior to the 
spirometry as described below (also see section 5.1.2): 
 
Visit 1 
 
Subjects will be asked to withhold their twice daily BD therapy (including ICS-LABA) for 
12-24 hours prior to the assessment of FEV1 for eligibility (see Section 3.1, Inclusion criteria 
8). For once daily BDs the required washout is ≥48 hours. 
 
Treatment period (Visit 2 – 27) 
 
Subjects will be asked to withhold their usual BD and SABA as outlined in the section above 
for Visit 1. 
 
The subject’s usual asthma controller medications may be administered, following completion 
of the pre-BD spirometry. The suggested order of administration of the subject’s usual asthma 
controller, per protocol SABA (on visits where post-BD spirometry is assessed), and IP 
administration relative to scheduled pre and post-BD spirometry is given in section 5.1.2. 
 
If the subject has taken their usual ICS-LABA and/or any other BD without appropriate 
washout period (see Visit 1 above) before the site visit, the Investigator/authorized delegate 
should remind the subject of the importance of withholding their BD for an appropriate time 
and reschedule the visit for another day, within the allowed window. 
 
If the subject has taken rescue SABA within 6 hours of the planned site visit spirometry they 
should ideally 1) remain at the site until such time that the 6 hour window has been reached 
or, 2) return on another day, within the visit window. If neither of these options is feasible for 
the subject, spirometry may be performed with a notation indicating that the pre-BD 
spirometry was conducted within 6 hours of SABA use. 
 
Asthma medication restrictions on unscheduled visits 
 
Asthma medication restrictions on unscheduled visit 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 ECG assessment 
 
Subjects should be instructed not to take their usual asthma controller medication prior to 
scheduled ECG assessment. Use of SABA should be avoided within 6 hours prior the ECG 
assessment. 
 
The medication restriction is waived for the enrolment ECG at Visit 1. 

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7.7.2.2 
Other medication restrictions 
 
x 
Use of oral or systemic immunosuppressive medication is not allowed. Topical 
administration of immunosuppressive medication may be allowed at the discretion 
of the Investigator. Systemic corticosteroids are allowed in case of an asthma 
exacerbation. Please see section 3.2, Exclusion criteria 14 and 17, for examples 
and further details. 
 
x 
Receipt of live attenuated vaccines within 30 days prior to entering study 
treatment and during the study, including the follow up period, is not allowed. 
Inactive/killed vaccines (e.g., inactive influenza vaccine) are allowed provided 
they are not administered within 5 days before/after any dosing visit. 
 
x 
Subject should not receive allergen immunotherapy injection within 5 days 
before/after any dosing visit. 
 
x 
Subjects should not take any other excluded medications: 
 
x Oral or ophthalmic non-selective β-adrenergic antagonist (e.g., 
propranolol) 
 
x Five-lipoxygenase inhibitors (e.g., Zileuton), or roflumilast 
 
A table with medication-related restrictions is present in Appendix F. 
 
7.7.2.3 
Bronchial Thermoplasty 
 
Subjects should not undergo bronchial thermoplasty during the entire study (Visit 1 to Visit 
30). 
 
7.7.3 
Other treatments 
 
Other treatments which are considered necessary for the subject’s safety and well-being, may 
be given at the discretion of the Investigator. Any such treatments are to be recorded in the 
appropriate section of the eCRF. 
 
 
8. 
STATISTICAL ANALYSES BY ASTRAZENECA 
 
8.1 
Statistical considerations 
 
The main objectives of this study are to show safety and tolerability of tralokinumab with 
regards to AEs, SAEs, laboratory variables, physical examination, vital signs and ECG. 
 
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to first subject treated 
and any subsequent amendments will be documented, with final amendments completed prior 
to database lock. Analyses will be performed by AstraZeneca or its representatives. 

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8.2 
Sample size estimate 
 
No formal sample size calculation was conducted for this study.  Approximately 22 Japanese 
patients who complete the planned 52-weeks treatment period are considered appropriate for 
collecting additional safety information of tralokinumab (300 mg SC Q2W) among Japanese 
patients.  With an assumed drop-out rate of 15% during the 52-weeks treatment period, 
approximately 26 Japanese patients are needed to be dosed. 
 
The interim and final analyses of the study are primarily described using descriptive statistics. 
Where appropriate, an exact 95% confidence interval (CI) may be calculated.  No hypothesis 
testing will be conducted for this study. 
 
8.3 
Definitions of analysis sets 
 
Safety objectives will be analyzed based on the Safety population. Exploratory 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. 
 
8.3.1 
Efficacy analysis set 
 
Full analysis set: All subjects receiving any IP will be included in the full analysis set, 
irrespective of their protocol adherence and continued participation in the study. 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 at least one dose of investigational 
product will be included in the safety analysis set. All safety summaries and ADA analyses 
and summaries will be based on this analysis set. 
 
8.3.3 
PK analysis set 
 
PK analysis set (PK): All subjects in the full analysis set who received Tralokinumab; 
including PK blood samples that are assumed not to be affected by factors such as protocol 
deviations (e.g., disallowed medication, or incorrect study medication received). All PK 
summaries will be based on this analysis set. 
 
8.3.4 
PRO analysis set 
 
PRO exploratory variables will be evaluated based on the full analysis set. 
 
8.4 
Outcome measures for analyses 
 
8.4.1 
General Definitions 
 
8.4.1.1 
Definition of baseline and subject baseline variables 
 
For laboratory data, baseline will be defined as the latest non-missing assessment prior to start 
of treatment. 

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For spirometry variables, the measurement recorded at the baseline visit (Visit 2) will be used 
as baseline. If the Visit 2 measurement is missing, the last non-missing value before Visit 2 
will be used as baseline instead. For post-BD FEV1, the measurement after the first BD 
administration is the baseline. 
 
The baseline for the PRO variable, ACQ-6 will be collected at Visit 2. 
Absolute change from baseline is computed as (post-treatment value – baseline value). 
Percent change from baseline is computed as ((post-treatment value – baseline value) / 
baseline value) × 100%. If either the post-treatment 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 summaries no windows will be applied. 
 
For patient reported questionnaire ACQ-6, the window is the same as the protocol-defined 
visit windows. For local laboratory data, and all vital signs, the visit recorded in the WBDC 
system will be used. 
 
For the central laboratory results and other endpoints that present visit-based data, the 
variables will be summarized based on the scheduled days with adjusted analysis-defined visit 
windows. 
 
A more detailed definition of visit and period windows will be provided in the statistical 
analysis plan. 
 
8.4.2 
Calculation or derivation of efficacy variables 
 
8.4.2.1 
Exacerbation rate 
 
Asthma exacerbation is defined in Section 5.1.1. In order to calculate the number of 
exacerbations experienced by a subject during the 52-week treatment period the following rule 
will be applied: 
 
• 
The start of an exacerbation is defined as the start date of systemic corticosteroids, ER 
or urgent care visits requiring systemic corticosteroids, or hospital admissions due to asthma, 
whichever occurs earlier, and the end date is defined as the last day of systemic corticosteroids 
or ER or urgent care visit or hospital discharge, whichever occurs later. 
 
Additional systemic corticosteroid treatments, ER or urgent care visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to asthma occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled. 
 
Maximum follow-up time for a subject is approximately 52 weeks; defined as the time from 
start of study treatment to the date of Visit 28. For a subject lost to follow-up, this will be 

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defined as the time from start of study treatment 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 2 date + 
1). 
 
8.4.2.2 
Forced expiratory volume in 1 second 
 
The percent change from baseline in pre-dose/pre BD FEV1 to each of the post-treatment 
visits (post Visit 2), up to and including the end of 52-week treatment visit (Visit 28), will be 
used as an exploratory efficacy variable. 
 
The absolute change from baseline to each of the post-treatment visits (post Visit 2) up to and 
including the end of 52-week study treatment visit (Visit 28) will also be used as an 
exploratory efficacy variable. 
 
The same exploratory efficacy variables will be derived for pre-dose/post- BD FEV1. 
 
8.4.3 
Calculation or derivation of patient reported outcome variables 
 
Patient-reported outcomes data will be captured on paper and entered into the WBDC system. 
 
8.4.3.1 
Asthma Control Questionnaire (ACQ-6) 
 
In the ACQ-6 questionnaire the subjects are asked to recall the status of their asthma during 
the previous week with regards to symptom, use of short acting β-agonists and BD. The 
questionnaire includes questions on 
 
1. 
Awoken at night by symptoms 
 
2. 
Limitation of normal daily activities 
 
3. 
Waking in the morning with symptoms 
 
4. 
Dyspnoea 
 
5. 
Wheeze 
 
6. 
Daily rescue medication 
 
The questions of the ACQ-6 are measured on a 7-point scale scored from 0 (totally controlled) 
to 6 (severely uncontrolled). The ACQ-6 score is computed as the un-weighted mean of the 
responses. 
 
Other variables based on ACQ-6 to report include: 

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x 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 
 
x 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 
 
x Subjects asthma control as measured by ACQ-6 score: 
 
o Well controlled : ACQ-6 score ≤ 0.75 
 
o Partly controlled : 0.75 < ACQ-6 score  <  1.5 
 
o Not well controlled : ACQ-6 score ≥ 1.5 
 
8.4.4        Calculation or derivation of safety variable(s) 
 
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
haematology, clinical chemistry, urinalysis, and reported AEs. 
 
Change from baseline (Visit 2) to each post-baseline time point where scheduled assessments 
were made will be calculated for relevant measurements. 
 
8.4.4.1     Adverse events 
 
Adverse events experienced by the subjects will be collected throughout the entire study and 
will be coded by the AstraZeneca designee using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA). 
 
AE data will be categorized according to their onset date into the following study periods: 
 
x AEs occurring during run-in (onset date ≥ Visit 1 and before the first dose of study 
treatment) 
 
x AEs occurring during study (onset date ≥ the first day of study treatment) 
 
x AEs occurring during treatment (onset date ≥ the first day of study treatment and ≤ the 
last day of study treatment + 2 weeks) 
 
x AEs occurring post-treatment (onset date > the last day of study treatment + 2 weeks) 

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The timing of AEs will be assigned to the period in which they first occurred. If an AE has a 
missing onset date, then unless the stop date of the AE indicates otherwise, this will be 
considered an on treatment event. Similarly, if an AE has a partial onset date, then unless the 
partial onset date or the stop date indicates otherwise, this will be considered an on treatment 
AE. 
 
8.4.4.2 
Other significant adverse events 
 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations due to AEs. 
 
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR. 
 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment. 
 
8.4.4.3 
Laboratory variables 
 
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
parameters will be taken at the times detailed in the CSP, and will be assessed in a central 
laboratory. The parameters outlined in Table 2, Table 3, Table 4 and Table 5 in Section 5.2.1, 
will be collected. Laboratory data will be reported in SI units. 
 
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent scheduled assessment will be calculated. Baseline is defined as the last available 
value measured prior to the first dose of study treatment. The change from baseline is defined 
as the treatment period value minus the baseline period value. There will be no imputation for 
missing values. 
 
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The AstraZeneca extended 
reference ranges will be used for laboratory variables (where they exist). All values (absolute 
and change) falling outside the reference ranges will be flagged. 
Urinalysis data will be categorised as negative (0), trace or positive (+) at each time-point. 
For the purposes of haematology, clinical chemistry and urinalysis shift tables, baseline will 
be defined as the latest non-missing assessment prior to start of treatment, and on-treatment 
will be defined as the latest non-missing assessment whilst the subject is ongoing on 
treatment. 
 
For the liver function tests: AST, ALT, ALP, GGT and total bilirubin, the multiple of the 
AstraZeneca ULN (not extended) range will be calculated for each data point. 

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Multiple = Value / ULN 
 
i.e., if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2. 
 
Subjects who meet any of the following criteria at any point during the study will be flagged: 
 
x AST ≥ 3x ULN 
 
x ALT ≥ 3x ULN 
 
x TBL ≥ 2xULN 
 
8.4.4.4 
ECG 
 
Twelve-lead ECG measurements will be recorded in accordance with the protocol, with the 
baseline visit being defined as Visit 1. 
 
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant. 
 
8.4.4.5 
Physical examination 
 
Complete and brief physical examinations will be performed at time points specified in Table 
1. Only information on whether the assessment was performed or not will be recorded. 
 
Any new finding(s), or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE. 
 
8.4.4.6 
Vital signs 
 
Pre-dose vital signs (pulse, systolic blood pressure, diastolic blood pressure, respiration rate 
and body temperature) will be obtained in accordance with the schedule provided in Table 1. 
 
Changes in vital signs variables between baseline and each subsequent scheduled assessment 
will be calculated. Baseline will be defined as the last value prior to the first dose of study 
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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8.4.5 
Calculations or derivation of Pharmacokinetic and Immunogenicity variables 
 
Blood samples (processed to serum) for pharmacokinetic and immunogenicity assessments 
will be collected from all subjects at baseline prior to first IP administration at Visit 2, at 
multiple time points before IP administrations during the treatment period, and at selected 
time points in the follow-up phase of the study. Anti-drug antibodies assessments will be 
conducted utilizing a tiered approach (screen, confirm, titer). These validated methods are 
conducted using a bridging assay format and statistically determined floating screening assay 
cut point factor and confirmatory assay cut point. The minimal sample dilution is 1:13. Titer 
values are reported as the reciprocal of the highest dilution that yields a value above the cut 
point. Samples from pre-defined study time points that confirm positive for ADA will also be 
tested for neutralizing ADA/nAb activity. Both ADA and nAb will be summarized using 
descriptive statistics as described in Section 8.5.2.4. 
 
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 analysis of the study endpoints will include all data captured during the entire study 
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. 
 
Summary data will be presented in tabular format. Categorical data will be summarized by the 
number and percentage of subjects in each category. Continuous variables for parametric data 
will be summarized by descriptive statistics including N, mean, SD, median, and range. All 
data will be listed. Data listings will be sorted by subject number. 
 
8.5.1 
Safety and tolerability 
 
All safety variables will be summarized using the safety analysis set. 
 
8.5.1.1 
Adverse events 
 
AEs will be summarized separately for the treatment and study periods, as defined in Section 
6.3. AEs occurring during the run-in period, or occurring post-treatment (as per the definition 
above) will be listed, but not summarized. 
 
An overall summary table will be produced showing the number and percentage of subjects 
with at least 1 AE in any of the following categories; AEs, SAEs, deaths due to AE, DAEs, 

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and other significant adverse events (OAEs). The total number of AEs in the different AE 
categories in terms of AE counts will also be presented (i.e., accounting for multiple 
occurrences of the same event in a subject). 
 
AEs will be summarized by SOC and PT assigned to the event using MedDRA. For each PT, 
the number and percentage of subjects reporting at least one occurrence will be presented i.e., 
for a subject multiple occurrences of an AE will only be counted once. 
 
AEs (by PT) will be summarized by causality and maximum intensity. If a subject reports 
multiple occurrences of the same AE, the maximum intensity will be taken as the highest 
recorded maximum intensity (the order being mild, moderate, and severe). SAEs, OAEs, 
DAEs, and deaths will also be summarized in separate tables. 
 
The rate of AEs per person-years at risk, calculated as (number of subjects reporting 
AE)/(total time at risk of AE), will also be reported. Rates will typically be expressed in terms 
of events per 100 subject-years. 
 
Separate listings of subjects with AEs, SAEs, death due to AE, or discontinuations due to AEs 
will be presented. 
 
8.5.1.2 
Laboratory data 
 
All continuous laboratory parameters will be summarized by absolute value at each visit, 
together with the corresponding changes from baseline. The summary statistics presented will 
be the minimum, 1st quartile, median, 3rd quartile, maximum, mean and SD. 
 
AstraZeneca defined 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. 

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In order to identify potential Hy’s Law cases, maximum post baseline total bilirubin will be 
plotted against maximum post baseline ALT, expressed as multiples of ULN. This plot will be 
repeated to show maximum post baseline total bilirubin against maximum post baseline AST, 
expressed as multiples of ULN. These plots will be produced on a log scale and reference 
lines will be included at 2xULN for total bilirubin and at 3xULN for ALT/AST. 
 
For all subjects who meet the biochemical criteria for Hy’s law (potential Hy’s Law), a 
Subject Safety Narrative will be produced, and the relevant laboratory parameters will be 
tabulated showing all visits for these subjects. Subjects with elevated ALT or AST, and 
elevated total bilirubin, at any time may be explored further graphically using individual 
subject profile plots. 
 
For urinalysis data, a shift table will be generated to present changes from baseline to EOT. 
The number of subjects with treatment-emergent changes will also be summarized. Here, 
treatment-emergent changes are defined as None/Trace at baseline to Positive, at any visit 
after baseline. 
 
Any data outside the AstraZeneca normal and extended reference ranges will be explicitly 
noted on the listings that are produced. 
 
8.5.1.3 
ECG 
 
The Investigator’s assessment of the 12-lead ECG (normal or abnormal) will be listed for all 
subjects, along with detailing whether any abnormalities were clinically significant or not. 
 
The number and percentage of subjects with clinically significant abnormal ECGs will be 
summarized by visit. 
 
8.5.1.4 
Vital Signs 
 
Vital signs data will be presented in the same way as described in Section 8.5.1.2 for the 
clinical laboratory data, and will be presented using AstraZeneca defined reference ranges, 
and clinically important change criteria. 
 
All recorded vital signs data will be listed. 
 
8.5.2 
Exploratory analysis 
 
Exploratory analyses will be based on the following analysis sets: all analyses of efficacy 
variables will be based on the full analysis set, all analyses of pharmacokinetic variables will 
be based on the PK analysis set, and all analyses of Immunogenicity variables will be based 
on the safety analysis set. 
 
8.5.2.1 
Exacerbation Rate 
 
The annual exacerbation rate, as described in section 8.4.2.1, will be summarized descriptively 
at week 52. The individual exacerbation criteria (ER or UC visits due to asthma that required 

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systemic corticosteroids, hospitalization due to asthma, or use of systemic corticosteroids) will 
be summarized descriptively. 
 
8.5.2.2 
Lung Function 
 
The percent change from baseline in pre-dose/pre-BD FEV1 will be summarized descriptively 
by visit. Summary statistics for pre-dose/pre-BD FEV1, including the change from baseline 
will be summarized descriptively by visit. 
 
Pre-dose/post-BD FEV1 will be summarized as described above for pre-dose/pre-BD FEV1. 
 
8.5.2.3 
ACQ-6 defined asthma control 
 
Change in mean score from baseline for ACQ-6 will be summarized descriptively by visit. 
The mean ACQ-6 score will also be summarized descriptively by visit. 
 
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. Additionally, the number and 
percentage of subjects achieving an improvement, no change, or deterioration as per Section 
8.4.3.1, ACQ-6 will also be summarized. 
 
8.5.2.4 
Analysis of Immunogenicity variables 
 
ADA status (positive vs negative) at each visit will be summarized descriptively including 
number of subjects, mean, standard deviation, median, and range of the actual ADA titers by 
visit, where possible, will be provided. The ADA status across the study for each subject 
(positive vs negative) will also be classified and summarized. 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. The ADA-positive 
subjects across the study may also be divided into persistent positive versus transient positive. 
A subject will be considered as persistent positive if he/she has positive ADAs for at least two 
consecutive visits. Otherwise, the subject will be considered as transient ADA positive. The 
associations between ADA and AE/SAEs may be summarized for both persistent positive 
subjects versus transient positives subjects. 
 
Neutralizing antibody evaluations will be conducted on 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. 

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8.5.3 
Analysis of pharmacokinetics 
 
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 may be conducted, where 
appropriate. 
 
8.6 
Interim Analysis 
 
An interim analysis may be conducted for this study.  Interim results of the study may be 
included for communication with regulatory authorities, where required/requested. 
 
 
9. 
STUDY AND DATA MANAGEMENT BY ASTRAZENECA 
 
9.1 
Training of study site personnel 
 
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them on any study specific procedures, the WBDC system 
RAVE and IVRS/IWRS, PRO. 
 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
 
9.2 
Monitoring of the study 
 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
 
x 
Provide information and support to the Investigator(s) 
 
x 
Confirm that facilities remain acceptable 
 
x 
Confirm that the investigational team is adhering to the protocol, that data are 
being accurately and timely recorded in the CRFs, that biological samples are 
handled in accordance with the Laboratory Manual and that study drug 
accountability checks are being performed 
 
x 
Perform source data verification (a comparison of the data in the CRFs with the 
subject’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating subjects. 
This will require direct access to all original records for each subject (e.g., clinic 
charts) 

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x 
Ensure withdrawal of informed consent to the use of the subject’s biological 
samples is reported and biological samples are identified and disposed 
of/destroyed accordingly, and the action is documented, and reported to the 
subject. 
 
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct. 
 
9.2.1 
Source data 
 
Source data are any data are any data generated as a result of the subject’s inclusion in the 
study (including run-in and/or follow up related to the study) and includes all related medical 
examinations and other records. 
 
9.2.2 
Study agreements 
 
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this CSP and the Study Agreement, the terms of CSP shall prevail with 
respect to the conduct of the study and the treatment of subjects and in all other respects, not 
relating to study conduct or treatment of subjects, the terms of the Study Agreement 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. 
 
9.3 
Study timetable and end of study 
 
The end of the study is defined as ‘the last visit of the last subject undergoing the study’. The 
study is expected to start in 4Q 2016 and to end by 2Q 2018. The study may be terminated at 
individual centres if the study procedures are not being performed according to GCP, or if 
recruitment is slow.  AstraZeneca may also terminate the entire study prematurely if concerns 
for safety arise within this study or in any other study with 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 
Data Management Plan 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 RAVE at the study site. 
 
Site personnel will be trained on use of the WBDC system and will be responsible for entering 
data on the observations, tests and assessments specified in the protocol into the WBDC 
system.  eCRF Instructions will be provided to the personnel at the study site as guidance for 
performing data entry.  Data entered in the WBDC system will be immediately saved to a 
central database and all changes will be tracked in the system’s audit trail.  All data will be 

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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.  All entries to the study database will be available in an audit trail. When 
all data have been coded, validated, signed and locked, clean file will be declared.  Data will 
be frozen and then locked to prevent further data entry/editing. A copy of the eCRFs will be 
provided to an archived at the study site when the study has been locked. 
 
The 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 the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  All coding will be 
performed by the Medical Coding Team at the AstraZeneca Data Management Centre. 
 
Serious Adverse Event (SAE) Reconciliation 
 
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site. 
 
Data associated with human biological samples 
 
Data associated with biological samples will be transferred from laboratory(ies) internal or 
external to AstraZeneca. 
 
Management of external data 
 
Data Management with determine the format of the data to be received from external vendors 
and coordinates the flow of data to an external environment or clinical database (as 
applicable). 
 
Data management will ensure that the data collection tool (e.g., paper PRO, 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 ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 

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10.2 
Subject data protection 
 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant protection and privacy 
legislation. 
 
10.3 
Ethics and regulatory review 
 
An IRB should approve the final study protocol, including the final version of the Informed 
Consent Form and any other written information and/or materials to be provided to the 
subjects. The head of the study site will ensure the distribution of these documents to the 
applicable IRB, and the Principal Investigator to the Investigator and study site staff. 
 
The opinion of the IRB should be given in writing. The head of the study site should submit a 
notification of direction/determination as well as the IRB written approval to AstraZeneca and 
the Principal Investigator before enrolment of any subject should into the study. 
 
The IRB should approve all advertising used to recruit subjects for the study. 
 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
 
The head of the study site should seek the opinion of the IRB with respect to the 
appropriateness of continuing the study at the study site at least once a year when the duration 
of the study exceeds one year. The Principal Investigator should submit progress reports to the 
IRB via the head of the study site at the time of the protocol re-approval. 
 
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the ICF, should be approved by the national regulatory authority with notification 
provided, according to local regulations.  AstraZeneca will handle the distribution of any of 
these documents to the national regulatory authorities. 
 
AstraZeneca will provide Regulatory Authorities, IRB, the head of the study site and the 
Principal Investigator with safety updates/reports according to local requirements. 
 
The head of the study site should submit a written report to the IRB providing the details of all 
safety relative information reported by AstraZeneca. 
 
10.4 
Informed consent and assent 
 
The Principal Investigator(s) at each centre will: 
 
x 
Ensure each subject is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study 
 
x 
Ensure each subject is notified that they are free to discontinue from the study at 
any time 

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x 
Ensure that each subject is given the opportunity to ask questions and allowed time 
to consider the information provided 
 
x 
Ensure each subject provides signed and dated informed consent before conducting 
any procedure specifically for the study 
 
x 
Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File 
 
x 
Ensure a copy of the signed Informed Consent Form is given to the subject 
 
x 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are 
described in the informed consent form that is approved by an IRB. 
 
10.5 
Changes to the protocol and informed consent or assent form 
 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.  If it is necessary for the Clinical Study Protocol to be amended, 
the amended Clinical Study Protocol should be submitted to the Head of the Study Site.  If the 
changes are of an administrative nature, it is submitted to the IRB.  If the changes have a 
significant impact on the safety of the subjects, the scientific value of the study, the conduct 
and management of the study, and the quality of any investigational product used in the study, 
it should be approved by the IRB.  If applicable, AstraZeneca should submit a notification to 
the regulatory authority before it is implemented.  If the amended Clinical Study Protocol 
requires a change to a particular centre's Informed Consent Form, then AstraZeneca and the 
centre's IRB should be notified by the Principal Investigator.  Approval of the revised 
Informed Consent Form by AstraZeneca and by the IRB is required before the revised form is 
used. 
 
10.6 
Audits and inspections 
 
Authorised representatives of AstraZeneca, a regulatory authority, or an IRB may perform 
audits or inspections at the centre, including source data verification.  The purpose of an audit 
or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements.  The Investigator will contact AstraZeneca immediately if contacted 
by a regulatory agency about an inspection at the 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, Ostlund O, Sears MR, et al. Overall asthma 
control: the relationship between current control and future risk. J Allergy Clin Immunol. 
2010 Mar;125(3):600-8, 608.e1-608.e6. doi: 10.1016/j.jaci.2009.11.033. Epub 2010 Feb 11. 
 
Brightling et al 2015 
Brightling CE, Chanez P, Leigh R, O'Byrne PM, Korn S, She D, et al. Efficacy and safety of 
tralokinumab in patients with severe uncontrolled asthma: a randomized, double-blind, 
placebo-controlled, phase 2b trial. Lancet Respir Med. 2015 Sep;3(9):692-701. doi: 
10.1016/S2213-2600(15)00197-6. Epub 2015 Jul 28. 
 
GINA 2016 
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma 
(GINA). Available from: URL: http://ginasthma.org/ 
 
Grunstein et al 2002 
Grunstein MM1, Hakonarson H, Leiter J, Chen M, Whelan R, Grunstein JS, et al. IL-13- 
dependent autocrine signaling mediates altered responsiveness of IgE-sensitized airway 
smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2002 Mar;282(3):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. 
doi: 10.1158/0008-5472.CAN-12-3544. Epub 2012 Dec 7. 
 
Hershey 2003 
Hershey GK1. IL-13 receptors and signaling pathways: an evolving web. J Allergy Clin 
Immunol. 2003 Apr;111(4):677-90; quiz 691. 
 
Juniper et al 2006 
Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well- 
controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir 
Med. 2006 Apr;100(4):616-21. Epub 2005 Oct 13. 
 
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. doi: 10.1016/j.jaci.2010.06.022. Epub 2010 Aug 7. 

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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 
Feb;41(2):330-8. doi: 10.1183/09031936.00223411. Epub 2012 Jun 27. 
 
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 Jul 1;180(1):59-99. doi: 
10.1164/rccm.200801-060ST. 
 
Sampson et al 2006 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson NF Jr, Bock SA, Branum A, 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. 2006 Feb;117(2):391-7. 
 
The Japanese Respiratory Society 2004 
The Japanese Respiratory Society, Pulmonary Physiology Committee. Respiratory function 
examinations: Spirometry, flow volume curves, and lung diffusing capacity, Medical Review, 
2004 
 
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 Jan;137(1):62-9. 
 
Wenzel 2012 
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat 
Med. 2012 May 4;18(5):716-25. doi: 10.1038/nm.2678. 
 
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 Dec 18;282(5397):2258-61. 

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Appendix A 
Additional Safety Information 
 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life threatening 
‘Life-threatening’ means that the 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. 
 
x 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine 
 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
 
x 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
 
x 
Development of drug dependency or drug abuse 
 
 
 
 
A Guide to Interpreting the Causality Question 
 
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug. 

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

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

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Appendix C 
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law 
 
Introduction 
 
This Appendix describes the process to be followed in order to identify and appropriately 
report cases of Hy’s Law.  It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries.  Specific guidance on the managing liver abnormalities can 
be found in Section 6.3.7 of the protocol. 
 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The investigator is responsible for determining whether a patient meets 
potential Hy’s Law (PHL) criteria at any point during the study. 
 
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether 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. 
 
Definitions 
 
Potential Hy’s Law (PHL) 
 
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication  irrespective of an increase in Alkaline Phosphatase 
(ALP). 
 
Hy’s Law (HL) 
 
AST or ALT ≥ 3x ULN  together with TBL ≥ 2xULN, where no other reason, other than the 
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. 
 
Identification of Potential Hy’s Law Cases 
 
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any patient who meets any of the following identification criteria in 
isolation or in combination: 
 
x 
ALT ≥ 3xULN 

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x 
AST ≥ 3xULN 
 
x 
TBL ≥ 2xULN 
 
 
 
 
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: 
 
x 
Request a repeat of the test (new blood draw) by the central laboratory 
 
x 
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: 
 
x 
Determine whether the patient meets PHL criteria (see Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results) 
 
 
 
 
Follow-up 
 
Potential Hy’s Law Criteria not met 
 
If the patient does not meet PHL criteria the Investigator will: 
 
x 
Inform the AstraZeneca representative that the patient has not met PHL criteria. 
 
x 
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol. 
 
Potential Hy’s Law Criteria met 
 
If the patient does meet PHL criteria the Investigator will: 
 
x 
Notify the AstraZeneca representative who will then inform the central Study Team 
 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data.  Subsequent to 
this contact the Investigator will: 

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x 
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated 
 
x 
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. This includes deciding which the tests available in the Hy’s 
law lab kit should be used. 
 
x 
Complete the three Liver CRF Modules as information becomes available 
 
x 
If at any time (in consultation with the Study Physician) the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures 
 
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: 
 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
 
x 
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: 
 
x
Report an SAE (report term ‘Hy’s Law’) according to AstraZeneca standard processes. 
 

 
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply 
 

 
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned. 

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If, there is an unavoidable delay, of over 3 weeks, in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made: 
 
x 
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above 
 
x 
Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are met.  Update the SAE report according to the outcome of the 
review 
 
 
 
 
References 
 
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf 

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Appendix D 
Maintenance Therapy Equivalence Table 
 
Estimated Daily Doses for Inhaled Corticosteroids 
 
Table 8 
Estimated daily doses for inhaled corticosteroids 
 
Asthma Therapy 
Inhaled Corticosteroid 
Total Daily Dose (μg/day) 
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 
>400 to 800 
>800 - 1600 
 
Budesonide, if as delivered dose (eg 
Symbicort®) 
>320 to 640 
>640 - 1280 
 
Mometasone furoate 
≥400 
≥800 
1 
The acceptable medium ICS dose for this study is bolded. 

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Appendix E 
Anaphylaxis:  definition criteria, signs and symptoms, and 
management 
 
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, corticosteroid, etc, and medical 
equipment to treat anaphylactic reactions must be immediately available at the 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-bronchospasma, stridor, 
reduced PEF, hypoxemia). 

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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 

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 Change in voice 
 
 Metallic taste 
 
 Nausea, vomiting, diarrhea, abdominal cramps and bloating 
 
 Lightheadedness 
 
 Headache 
 
 Uterine cramps 
 
 Generalized warmth 
 
4. Management of Acute Anaphylaxis 
 
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. 
 
Possibly appropriate, subsequent measures depending on response to epinephrine 
 
a)  Please 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 
 
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. 

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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. 
 
References 
 
Johansson et al 2004 
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised nomenclature for 
allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, 
October 2003. J Allergy Clin Immunol. 2004May;113(5):832-6 

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Appendix F 
Restricted and Prohibited Medications 
 
Asthma medication restrictions 
 
Table 9 
Asthma medication restrictions 
 
Medication 
Prohibited/Restricted 
Details 
Maintenance treatment with 
long-acting bronchodilators 
(including ICS-LABA) 
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, and ECG (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 
discourage, except as urgent 
treatment during an asthma 
exacerbation. 
SABA should not be used 
within 6 hours prior to 
scheduled site visit spirometry 
and ECG with the exception of 
any unscheduled visits due to 
asthma worsening. 

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Medication 
Prohibited/Restricted 
Details 
Additional Maintenance 
Controllers 
Allowed with restriction 
Stable dose for 1 month prior to 
Visit 1; stable dose during the 
treatment period. 
Subjects on theophylline should 
have blood concentration levels 
within therapeutic range 
documented before/at Visit 1. 
Subject should be instructed not 
to use additional once daily 
bronchodilators within 48 hours 
of the scheduled site visit 
spirometry with the exception of 
any unscheduled visits due to 
asthma worsening. 
Short acting anticholinergics 
(i.e., ipratropium) 
Restricted 
Not allowed from enrolment 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. 
Zileuton 
Prohibited 
Not allowed 30 days prior to 
Visit 1; during treatment period 
 
 
Other medication restrictions 
 
Table 10 
Other medication restrictions 
 
Medication 
Prohibited/Restricted 
Details 
Live Attenuated Vaccines 
Prohibited 
Not allowed 30 days prior to 
entering treatment, during 
treatment and follow up periods. 
Inactive/killed vaccinations 
(e.g., inactive influenza) 
Restricted 
Allowed provided they are not 
administered within 5 day 
before or after any dosing visit 
Any immunomodulators or 
immunosuppressives 
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 

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Medication 
Prohibited/Restricted 
Details 
Blood products or 
immunoglobulin therapy 
Prohibited 
Not allowed 30 days prior to the 
date of ICF; during treatment 
period 
Any marketed (e.g., 
omalizumab) or investigational 
biologic treatment 
Prohibited 
Not allowed 4 months or 5 half- 
lives (whichever is longer) prior 
to Visit 1; during treatment 
period; 4 months or 5 half-lives 
(whichever is longer) after the 
last dose of the investigational 
product 
Other Investigational Products 
(including investigational use of 
an approved drug) 
Prohibited 
Not allowed 30 days or 5 half- 
lives (whichever is longer) prior 
to Visit 1; during treatment 
period 
Allergy Immunotherapy 
Restricted 
Allowed if on stable therapy for 
at least 30 days prior to date of 
ICF; no anticipated changes 
during treatment period; subject 
should not receive allergen 
immunotherapy injection within 
5 days before/after any dosing 
visit 
Herbal remedies for the 
treatment of allergic, 
inflammatory, or respiratory 
diseases 
Prohibited 
Not allowed 30 days prior to 
Visit 1; during treatment period 
Roflumilast 
Prohibited 
Not allowed 30 days prior to 
Visit 1; during treatment period 
Oral or ophthalmic non- 
selective β-adrenergic 
antagonist (e.g., propranolol) 
Prohibited 
Patients currently using any oral 
or ophthalmic non-selective β- 
adrenergic antagonist at the time 
of enrolment are not eligible for 
the study. 
Not allowed during treatment 
period. 
Medications not currently 
licensed for use in the treatment 
of asthma 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 

 
 
Document Name: 
d2210c00029-csp-v1 
Document Title: 
D2210C00029 Clinical Study Protocol version 1 
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Notes :  (1) Document details as s tored in ANGEL, an As traZeneca document management s ystem. 
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