Clinical trial NCT04570657
Conditions: Asthma
Keywords: MEDI3506 lung function IL-33 inflammation
Sponsor: AstraZeneca
Start date: 2020-09-17; Completion date: 2023-02-06
Enrollment: 250 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study D9181C00001 is a Phase II, randomised, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy, safety, pharmacokinetics (PK) and immunogenicity of MEDI3506 in adult participants with uncontrolled moderate to severe asthma on standard of care (SOC). Up to approximately 80 sites globally will participate in this study.

Approximately 228 participants will be randomized to 3 treatment groups in a 1:1:1 ratio to receive MEDI3506 dose 1, MEDI3506 dose 2, or placebo.

Detailed description:

Arms: arm 1: Approximately 76 participants will be randomized to this arm to receive the higher dose of MEDI3506 arm 2: Approximately 76 participants will be randomized to this arm to receive the lower dose of MEDI3506 arm 3: Approximately 76 participants will be randomized to this arm. Participants in this group will receive the placebo.
Interventions: intervention 1: MEDI3506 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive multiple doses of MEDI3506 at dose level 1 or dose level 2 intervention 2: Participants will receive multiple doses of placebo

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
MEDI3506
Study Code
D9181C00001
Amendment
4.0
Date
08 March 2022
A Phase II, Randomised, Double-blind, Placebo-controlled Study 
to Assess the Efficacy and Safety of MEDI3506 in Adult 
Participants with Uncontrolled Moderate-to-severe Asthma
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers:
IND number 140910
EudraCT number 2020-000789-40
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. 
Redacted for Public Disclosure 


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Protocol Number: D9181C00001
Amendment Number: 4.0
Study Intervention: MEDI3506 and placebo
Study Phase: II
Short Title: Study to Assess the Efficacy and Safety of Subcutaneously Injected MEDI3506 
in Adults with Uncontrolled Moderate-to-severe Asthma
Acronym: FRONTIER-3
Medical Monitor Name and Contact Information will be provided separately
International co-ordinating investigator
PPD


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 4.0
08 March 2022
Amendment 3.0
25 May 2021
Amendment 2.0
23 February 2021
Amendment 1.0
19 October 2020
Original Protocol
21 May 2020
Amendment 4.0 (08 March 2022)
Overall Rationale for the Amendment:
Changes from Global Protocol Amendment 3.0
The principal reason for this amendment is to remove Part B, the airway hyperresponsiveness 
and remodelling study.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Throughout
Removal of references to and text 
regarding Part B, including SV3 
which only applied to Part B
Given the challenges of 
conducting this study 
the sponsor has, prior to
any participant 
participating in Part B, 
decided to defer 
assessment of the 
effects of MEDI3506 
on airway 
hyperresponsiveness 
and remodelling until 
later in development of 
MEDI3506
Substantial
Throughout
Removal of occurrences of 
‘Part A’
As Part B has been 
removed, Part A is the 
entirety of the study
Substantial
Section 1.3 Schedule of 
Activities
 
 
 
 
 
 
Substantial
Section 2.3.1 Risk 
Assessment
Updated rationale for risk of 
progression of heart failure
To provide information 
based on current data
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.1 Overall 
Design; Section 9.2 
Sample Size 
Determination
Change to permit not capping 
randomisation of participants not 
included in exploratory cough 
sub-study solely to achieve target 
sample size of the sub-study
To avoid completion of 
exploratory sub-study 
delaying completion of 
study overall
Non-substantial
Section 5.1 Inclusion 
Criteria
Criterion 11: Increased the 
maximum permitted BMI to 
40 kg/m2
To maintain 
consistency with other 
MEDI3506 studies in 
context of other 
exclusion criteria
Substantial
Section 5.1 Inclusion 
Criteria 
Criterion 19: Changed historic 
exacerbation requirement from 
one in 12 months to one in 
24 months
To adapt to sustained 
fall in real world 
exacerbation rates 
secondary to the 
ongoing COVID-19 
pandemic
Substantial
Section 5.2 Exclusion 
Criteria
Criterion 1: Removed the 
exclusion of all participants who 
test positive for SARS-CoV-2 at 
SV1. All participants who test 
positive at SV2 continue to be 
excluded.
To permit participants 
who test positive for 
SARS-CoV-2 at SV1, 
but negative at SV2 and 
who do not have 
symptoms meeting any 
other exclusion 
criterion to be 
randomised.
Substantial
Section 5.2 Exclusion 
Criteria
Criterion 3: Rewritten
Revised text to be 
clearer and consistent 
with other AstraZeneca 
studies
Substantial
Section 5.2 Exclusion 
Criteria; Section 1.3 
Schedule of Activities, 
Table 1 Footnote i
Criterion 5: Removal of entire 
criterion which excluded 
participants with an NT-proBNP 
above the upper limit of normal.
Not considered to 
provide additional 
benefit to participant 
safety given other 
mitigations, including 
screening 
echocardiograms
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 5.2 Exclusion 
Criteria
Criterion 13: Removed the 
reference to HbA1c
To permit investigator 
judgement as to 
whether Type 2 
diabetes is well 
controlled (and hence 
not exclusionary) and to 
maintain consistency 
with other MEDI3506 
studies
Substantial
Section 6.5.5 COVID-19 
Vaccination
Removed dose from list of 
information to be recorded
Information is generally 
not available
Non-substantial
Section 8.1.5 Asthma 
Exacerbations
Adjustment of requirements of 
acceptable documentation of 
historical exacerbations. 
Response to changes in 
practical management 
of real world asthma 
exacerbations in context 
of COVID-19 pandemic
Non-substantial
Section 8.5.1 Human 
Biological Samples, 
Appendix D 1 
Use/Analysis of DNA, 
Appendix D 2 Genetic 
Research Plan and 
Procedures
Specified samples will be retained 
for 15 years after the end of the 
study
To align with EU 
guidelines for data 
storage
Non-substantial
Section 8.5.2 
Pharmacokinetics
Removed text specifying how 
many PK samples would be 
collected
Information is available 
in the Schedule of 
Assessments
Non-substantial
Section 8.5.5 Collection 
of Mandatory Samples for 
Biomarker Analysis
Changed IL-33 isoform sample 
from nasal epithelium to nasal 
lining fluid and mRNA 
transcriptome sample from nasal 
to nasal mucosal sample.
Clarification
Non-substantial
Appendix A 6 Data 
Quality Assurance
Changed the length of time 
records and documents are stored 
from 15 to 25 years after study 
completion
To align with EU 
guidelines for data 
storage
Non-substantial
BMI = body mass index; COVID-19 = coronavirus disease 2019; EU = European Union; 
HbA1c = haemoglobin A1c; IL-33 = interleukin-33; NT-proBNP = N terminal prohormone of B type natriuretic 
peptide; PK = pharmacokinetics; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SV = study 
visit.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 13
1.3
Schedule of Activities....................................................................................... 15
2
INTRODUCTION............................................................................................ 23
2.1
Study Rationale ................................................................................................ 23
2.2
Background ...................................................................................................... 23
2.3
Benefit/Risk Assessment................................................................................... 24
2.3.1
Risk Assessment............................................................................................... 24
2.3.1.1
Study Conduct During COVID-19 Pandemic.................................................... 28
2.3.1.2
COVID-19 Mitigations ..................................................................................... 28
2.3.1.3
Vaccination Against COVID-19 ....................................................................... 30
2.3.2
Benefit Assessment........................................................................................... 31
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 31
3
OBJECTIVES AND ENDPOINTS................................................................... 32
4
STUDY DESIGN ............................................................................................. 35
4.1
Overall Design.................................................................................................. 35
4.2
Scientific Rationale for Study Design ............................................................... 37
4.2.1
Rationale for Endpoints .................................................................................... 38
4.2.1.1
Primary Endpoints ............................................................................................ 38
4.2.1.2
Secondary and Safety Endpoints....................................................................... 38
4.2.1.3
Exploratory Endpoints ...................................................................................... 38
4.2.2
Rationale for Study Population ......................................................................... 38
4.2.3
Participant Input into Design............................................................................. 39
4.3
Justification for Dose........................................................................................ 39
4.4
End of Study Definition.................................................................................... 40
4.4.1
Study Stopping Criteria..................................................................................... 40
5
STUDY POPULATION ................................................................................... 41
5.1
Inclusion Criteria .............................................................................................. 41
5.2
Exclusion Criteria ............................................................................................. 44
5.3
Lifestyle Considerations ................................................................................... 48
5.3.1
Meals, Dietary Restrictions, and Caffeine ......................................................... 48
5.3.2
Activity............................................................................................................. 49
5.4
Screen Failures ................................................................................................. 49
6
STUDY INTERVENTION............................................................................... 49


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6.1
Study Interventions Administered..................................................................... 50
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 50
6.2.1
Study Intervention Inspection ........................................................................... 51
6.2.2
Dose Preparation Steps ..................................................................................... 51
6.2.2.1
Treatment Administration................................................................................. 52
6.2.2.2
Monitoring Dose Administration....................................................................... 53
6.2.3
Accountability .................................................................................................. 53
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 53
6.3.1
Methods for Assigning Treatment Groups......................................................... 53
6.3.2
Methods to Ensure Blinding.............................................................................. 54
6.3.3
Methods for Unblinding.................................................................................... 54
6.4
Study Intervention Compliance......................................................................... 55
6.5
Concomitant Therapy........................................................................................ 55
6.5.1
Rescue Medicine............................................................................................... 56
6.5.2
Required Medications ....................................................................................... 56
6.5.3
Medication Withhold Periods............................................................................ 56
6.5.4
Prohibited Medications ..................................................................................... 57
6.5.5
COVID-19 Vaccination .................................................................................... 58
6.6
Dose Modification ............................................................................................ 58
6.7
Intervention after the End of the Study.............................................................. 58
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 58
7.1
Discontinuation of Study Intervention............................................................... 58
7.1.1
Missed doses..................................................................................................... 59
7.2
Participant Withdrawal from the Study ............................................................. 59
7.3
Lost to Follow-up ............................................................................................. 60
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 60
8.1
Efficacy Assessments........................................................................................ 61
8.1.1
In-clinic Spirometry.......................................................................................... 61
8.1.1.1
General requirements........................................................................................ 61
8.1.2
At-home Spirometry ......................................................................................... 63
8.1.3
Airwave Oscillometry....................................................................................... 63
8.1.4
Fractional Exhaled Nitric Oxide........................................................................ 64
8.1.5
Asthma Exacerbations ...................................................................................... 64
8.1.6
CompEx ........................................................................................................... 66
8.1.7
VitaloJAK Cough Monitor (Exploratory Cough Sub-study Only) ..................... 67
8.1.8
Participant Reported Outcome Questionnaires .................................................. 67
8.1.8.1
Daily eDiary ..................................................................................................... 68
8.1.8.2
Cough Visual Analogue Scale (Exploratory Cough Sub-study Only) ................ 68
8.1.8.3
Asthma Control Questionnaire-6....................................................................... 68
8.1.8.4
St George’s Respiratory Questionnaire ............................................................. 69
8.1.8.5
Sino-nasal Outcome Test-22............................................................................. 69
8.1.8.6
Patient Global Impression of Benefit/Risk ........................................................ 70


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8.1.8.7
Study Participant Feedback Questionnaire ........................................................ 70
8.2
Safety Assessments........................................................................................... 70
8.2.1
Medical, Surgical, and Asthma History............................................................. 70
8.2.2
Physical Examinations, Weight, and Height...................................................... 70
8.2.3
Vital Signs........................................................................................................ 71
8.2.4
Electrocardiograms........................................................................................... 71
8.2.5
Echocardiograms .............................................................................................. 72
8.2.6
SARS-CoV-2 Serology Testing ........................................................................ 72
8.2.7
Clinical Safety Laboratory Assessments............................................................ 72
8.3
Adverse Events and Serious Adverse Events..................................................... 74
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 74
8.3.2
Follow-up of AEs and SAEs ............................................................................. 74
8.3.3
Causality Collection.......................................................................................... 75
8.3.4
Disease Under study ......................................................................................... 75
8.3.5
Adverse Events Based on Signs and Symptoms ................................................ 75
8.3.6
Adverse Events Based on Examinations and Tests............................................ 76
8.3.7
Adverse Events of Special Interest.................................................................... 76
8.3.8
Hy’s Law.......................................................................................................... 77
8.3.9
Reporting of Serious Adverse Events................................................................ 77
8.3.10
Pregnancy......................................................................................................... 77
8.3.10.1
Maternal Exposure............................................................................................ 78
8.3.10.2
Paternal Exposure............................................................................................. 78
8.3.11
Medication Error............................................................................................... 78
8.4
Overdose .......................................................................................................... 79
8.5
Human Biological Sample Biomarkers ............................................................. 79
8.5.1
Human Biological Samples............................................................................... 79
8.5.2
Pharmacokinetics.............................................................................................. 80
8.5.2.1
Determination of Drug Concentration ............................................................... 80
8.5.3
Immunogenicity Assessments ........................................................................... 80
8.5.4
Pharmacodynamics........................................................................................... 81
8.5.5
Collection of Mandatory Samples for Biomarker Analysis................................ 81
8.5.6
Other study related biomarker research ............................................................. 82
8.6
Optional Genomics Initiative Sample................................................................ 82
8.7
Health Economics............................................................................................. 83
8.8
Impact of COVID-19 Pandemic........................................................................ 83
9
STATISTICAL CONSIDERATIONS............................................................... 83
9.1
Statistical Hypotheses....................................................................................... 83
9.2
Sample Size Determination............................................................................... 83
9.3
Populations for Analyses .................................................................................. 84
9.4
Statistical Analyses........................................................................................... 84
9.4.1
General Considerations..................................................................................... 85
9.4.2
Efficacy ............................................................................................................ 85
9.4.2.1
Primary Endpoint.............................................................................................. 85
9.4.2.2
Secondary and Exploratory Endpoints............................................................... 85


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9.4.3
Subgroup Analyses ........................................................................................... 86
9.4.4
Safety ............................................................................................................... 86
9.4.5
Other Analyses ................................................................................................. 86
9.4.5.1
Immunogenicity and PK ................................................................................... 86
9.4.5.2
Exploratory Biomarker Outcomes..................................................................... 87
9.4.5.3
Exploratory Analyses........................................................................................ 87
9.5
Interim Analyses............................................................................................... 87
9.6
Data Monitoring Committee ............................................................................. 87
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 88
11
REFERENCES............................................................................................... 131
LIST OF FIGURES
Figure 1
Study Flow Diagram................................................................................ 14
Figure 2
Reversibility algorithm ............................................................................ 62
LIST OF TABLES
Table 1
Schedule of Activities: Screening Period ................................................. 15
Table 2
Schedule of Activities: Study Intervention and Follow-up Periods ........... 18
Table 3
Risk Assessment...................................................................................... 25
Table 4
Objectives and Endpoints......................................................................... 32
Table 5
Study Interventions.................................................................................. 50
Table 6
Study Intervention Dose Preparation........................................................ 52
Table 7
Laboratory Safety Variables..................................................................... 73
Table 8
Populations for Analysis .......................................................................... 84
Table I9
Highly Effective Methods of Contraception........................................... 113
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 89
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 93
Appendix C
Handling of Human Biological Samples .................................................. 98
Appendix D
Optional Genomics Initiative Sample..................................................... 100


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 103
Appendix F
Maintenance Therapy Equivalence Table............................................... 108
Appendix G
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis............ 109
Appendix H
Signs, Symptoms, and Management of Acute Anaphylaxis.................... 110
Appendix I
Contraception Guide.............................................................................. 113
Appendix J
Abbreviations ........................................................................................ 114
Appendix K
Protocol Amendment History................................................................. 118


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase II, Randomised, Double-blind, Placebo-controlled Study to Assess 
the Efficacy and Safety of MEDI3506 in Adult Participants with Uncontrolled 
Moderate-to-severe Asthma
Short Title: Study to Assess the Efficacy and Safety of Subcutaneously Injected MEDI3506 
in Adults with Uncontrolled Moderate-to-severe Asthma
Rationale:
The MEDI3506 pre-clinical profile suggests that MEDI3506 can reduce asthmatic airway 
inflammation, improve epithelial integrity, reduce mucus production, and improve 
muco-ciliary transport. As such, MEDI3506 is hypothesised to impact asthma disease status 
by increasing forced expiratory volume in the first second (FEV1, and other physiological 
measures of lung function) and reducing frequency and severity of asthma exacerbations, 
thereby improving quality of life. This Phase II study aims to assess the efficacy and safety of 
MEDI3506 in adult participants with uncontrolled moderate-to-severe asthma.
Objectives and Endpoints
Objective
Endpoint
Primary
To assess the effect of MEDI3506 compared with 
placebo on lung function, in adult participants with 
uncontrolled moderate-to-severe asthma.
As measured in clinic, change from baseline to 
Week 16 in pre-BD FEV1 (L).
Secondary
To further assess the effect of MEDI3506 compared 
with placebo on lung function, in adult participants 
with uncontrolled moderate-to-severe asthma.
As measured in clinic, change from baseline to 
Weeks 8 and 16 in post-BD FEV1 (L).
To assess the PK of MEDI3506 in adult participants 
with uncontrolled moderate-to-severe asthma.
Serum MEDI3506 concentration-time profiles during 
the intervention and follow-up periods.
To assess the immunogenicity of MEDI3506 in adult
participants with uncontrolled moderate-to-severe 
asthma.
ADA during the intervention and follow-up periods.
To assess the effect of MEDI3506 compared with 
placebo on asthma control in adult participants with 
uncontrolled moderate-to-severe asthma.
Change from baseline to Week 16 in ACQ-6 score.
Proportion of participants with a decrease in ACQ-6 
score of ≥0.5 from baseline to Week 16.
Proportion of participants achieving ACQ-6 well 
controlled status (defined as ACQ-6 score ≤0.75 at 
Week 16).


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Objective
Endpoint
To assess the effect of MEDI3506 compared with 
placebo on health status in adult participants with 
uncontrolled moderate-to-severe asthma.
Change from baseline to Week 16 in SGRQ score.
Proportion of participants with a decrease in SGRQ 
total score of ≥4 points from baseline to Week 16.
To assess the effect of MEDI3506 compared with 
placebo on CompEx in adult participants with 
uncontrolled moderate-to-severe asthma. 
Time to first CompEx event based on the period from 
baseline to Week 16.
CompEx annualised event rate.
To assess the effect of MEDI3506 compared with 
placebo on concentration of FeNO in adult 
participants with uncontrolled moderate-to-severe 
asthma.
Percent change from baseline to Week 16 in 
concentration of FeNO in exhaled breath.
ACQ-6 = asthma control questionnaire-6; ADA = anti-drug antibody(ies); BD = bronchodilator; 
CompEx = composite endpoint for severe exacerbations of asthma; FeNO = fractional exhaled nitric oxide; 
FEV1 = forced expiratory volume in the first second; L = litre(s); PK = pharmacokinetics; SGRQ = St George’s 
respiratory questionnaire.
For safety and exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
Study D9181C00001 is a Phase II, randomised, double-blind, placebo-controlled, 
parallel-group, proof-of-concept study to evaluate the efficacy, safety, pharmacokinetics (PK) 
and immunogenicity of MEDI3506 in adult participants with uncontrolled moderate-to-severe 
asthma on standard of care (SOC). The study has 3 treatment-arms. Participants who fail 
screening can be re-screened.
Disclosure Statement: This is a parallel group treatment study that is participant-, 
investigator-, and sponsor-blinded.
Number of Participants:
Approximately 228 participants will be randomised to achieve 216 evaluable participants.
Intervention Groups and Duration:
Participants will be randomised in a 1:1:1 ratio to receive 
mg MEDI3506, 
mg 
MEDI3506, or placebo every 
 by subcutaneous (SC) injection for a total of 
doses.
Participants will be enrolled in this study for up to 29 weeks. The study comprises of 3 periods 
including the screening period of up to 5 weeks, an intervention period of 16 weeks, and a 
follow-up period of 8 weeks. 
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Data Monitoring Committee:
A Data Safety Monitoring Board (DSMB) has been established to oversee the MEDI3506 
clinical development programme. In addition to a full DSMB 6-month periodic review of 
safety data, the DSMB chair will review unblinded safety data summaries every 3 months; the 
DSMB can meet on an ad hoc basis.
Statistical Methods
A sample size of 216 participants (72 participants per treatment group), randomised 1:1:1 to 
MEDI3506 
mg: MEDI3506 
 mg: placebo, will provide at least 80% power to detect a 
statistically significant difference in change from baseline to Week 16 in pre-bronchodilator 
(BD) FEV1, assuming a difference of 150 mL between placebo and MEDI3506, a 
between-participant standard deviation (SD) of 420 mL and a one-sided-10% alpha level. To 
allow for 5% participants being ineligible for the primary analysis, a total of approximately 
228 participants will be randomised (approximately 76/arm).
Efficacy analyses will be performed using the ITT population. The primary estimand is a 
‘Treatment Policy’ estimand, as follows: the difference in mean change from baseline in FEV1
at Week 16 (MEDI3506 – placebo) will be estimated using a repeated measures mixed effects 
analysis of covariance model, for the ITT population. This will include all available data from 
all visits up to and including Week 16, irrespective of whether the participant discontinued 
study intervention or received rescue therapy.
A similar approach will be taken for the analysis of asthma control questionnaire-6 (ACQ-6), 
St George’s respiratory questionnaire (SGRQ), and fractional exhaled nitric oxide (FeNO). 
The difference in mean change from baseline in post-BD FEV1 at Weeks 8 and 16 will be 
estimated using a repeated measures mixed effects analysis of covariance model, similar to 
that described for the primary efficacy analysis. Data may be log-transformed prior to analysis 
where appropriate. Time to first composite endpoint for severe exacerbations of asthma 
(CompEx) event will be analysed using a Cox proportional hazard model, with treatment 
fitted as a covariate.
MEDI3506 serum concentrations will be tabulated along with descriptive statistics. Mean and 
individual serum MEDI3506 concentration-time profiles will be plotted. Population PK 
modelling may be performed if data allow. Positive antibodies to MEDI3506 will be reported 
by treatment group. If there is a high incidence of anti-drug antibody (ADA), the association 
of ADA with MEDI3506 concentration will be assessed.
1.2
Schema
The general study design is summarised in Figure 1.
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1.3
Schedule of Activities
Once informed consent has been obtained, eDiary provision and training for site and home 
visits should occur first during SV1, followed by patient reported outcome (PRO) 
assessments. PRO assessments should be conducted first at all other visits. For all participants, 
in-clinic spirometry testing must be initiated between 6:00 AM and 11:00 AM during the 
screening or re-screening period, and randomisation visit (SV4). Whenever 
electrocardiograms (ECGs), vital signs, and blood draws are scheduled for the same nominal 
time, the order should be as follows: ECG, vital signs (vital signs can occur immediately after 
ECG using the same rest period), then blood draws. The timing of the first 2 assessments 
should be such that it allows the blood draw (eg, PK blood sample) to occur at the assigned 
nominal time. Whenever FeNO, airwave oscillometry (AO), and spirometry are scheduled for 
the same nominal time, the order should be as follows: FeNO, AO, then spirometry. Nasal 
sampling should be performed last, with nasal lining fluid collection performed before nasal 
epithelium collection (when both are scheduled). Urine samples may be collected at any time 
during the study visit (when scheduled). On days when investigational product is 
administered, all assessments should be performed pre-dose unless otherwise specified in the 
Schedule of Activities. Refer to Section 8 for additional information on assessment ordering 
(eg, pre-, post-dose or multiple timepoints within a visit). In the event that a clinical laboratory 
test result is not available from central laboratories during the screening period, see 
Section 8.2.7.
Table 1
Schedule of Activities: Screening Period
Visit Number
SV1
SV2
SV3
Procedure/Study Day
-35 to -28
-14 to -6
Visit no 
longer 
needed
Study Week
-4
-1
Written ICF 
/assignment 
of SID number
X a
Written informed consent for future use and/or DNA analysis 
(optional)
X
Verify eligibility criteria
X
X
Demographics
X
Baseline asthma assessments
Provision of, and training on use of, home spirometry 
device and eDiary
X
ACQ-6
X
X
SGRQ
X
SNOT-22 (comorbid CRS participants only)
X
At-home eDiary completion and spirometry use
Twice daily throughout 
screening period
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Table 1
Schedule of Activities: Screening Period
Visit Number
SV1
SV2
SV3
Procedure/Study Day
-35 to -28
-14 to -6
Visit no 
longer 
needed
Study Week
-4
-1
Assess adherence to at-home eDiary completion, 
spirometry, and SOC medication use
X
Assessment of asthma exacerbations
X
FeNO
X
X
Airwave oscillometry
X
In-clinic spirometry (pre-BD)
X
X
In-clinic spirometry (post-BD)
X b
X c
Safety assessments
Concomitant medications
X
X
Medical, surgical, and asthma history
X
Physical examination (complete)
X
Weight and height
X
Vital signs
X
ECG
X
Echocardiogram
X d
SARS-CoV-2 PCR test
X e
X f
Assessment of AEs/SAEs
X
X
Collect blood for:
Haematology
X
Coagulation parameters
X
Serum chemistry
X
Serum pregnancy test g
X
FSH (if needed to confirm post-menopausal status in female 
participants aged < 50 years and not on HRT)
X
HbA1c
X
Hepatitis B (HBsAg, anti-HBs, anti-HBc), and C; HIV-1 
and HIV-2
X
IGRA (TB test) h
X
NT-proBNP
X
Exploratory biomarkers (serum)
X
Total IgE (serum)
X
EDN (plasma)
X


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Table 1
Schedule of Activities: Screening Period
Visit Number
SV1
SV2
SV3
Procedure/Study Day
-35 to -28
-14 to -6
Visit no 
longer 
needed
Study Week
-4
-1
Collect urine for:
Urinalysis
X
Urine pregnancy test g
X
Pandemic impact assessment
X
Exploratory cough sub-study only
At-home cough monitoring (for the 24 hours post-clinic 
visit)
X
Cough VAS
X
a
ICF may be signed prior to SV1, providing all screening visits are scheduled to take place within a 28 to 
35 day timeframe.
b
Post-BD spirometry should be performed at SV1 if documented evidence of asthma (see Section 5.1) is 
not already available.
c
Post-BD spirometry should be performed at SV2 if documented evidence of asthma (see Section 5.1) is 
not already available.
d
May be performed any time after signing of informed consent, so that results are available prior to SV4 
(randomisation).
e
Participants are permitted to continue screening if the result from the SARS-CoV-2 PCR test performed 
at SV1 has not been returned by SV2.
f
Test may be performed at either visit or anytime on or after Day -7 such that the results are available 
prior to SV4 (see Exclusion Criterion 1).
g
Female participants of childbearing potential only.
h
See Exclusion Criterion 4.
ACQ-6 = asthma control questionnaire-6; AE = adverse event; anti-HBc = hepatitis B core antibody; 
anti-HBs = hepatitis B surface antibody; BD = bronchodilator; CRS = chronic rhinosinusitis;
ECG = electrocardiogram; EDN = eosinophil derived neurotoxin; FeNO = fractional exhaled nitric oxide; 
FSH = follicle-stimulating hormone; HbA1c = haemoglobin A1c; HBsAg = hepatitis B surface antigen; 
HIV = human immunodeficiency virus; HRT = hormone replacement therapy; ICF = informed consent form; 
IgE = immunoglobulin E; IGRA = interferon gamma release assay; NT-proBNP = N-terminal prohormone of 
B-type natriuretic peptide; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome 
coronavirus 2; SGRQ = St George’s respiratory questionnaire; SID = subject identification; 
SNOT-22 = sino-nasal outcome test-22; 
 SOC = standard of care; 
SV = study visit; TB = tuberculosis; VAS = visual analogue scale.
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Table 2
Schedule of Activities: Study Intervention and Follow-up Periods
Period
Study Intervention
Follow-up
Visit Number
SV4 
(Random-
isation)
SV5 
(TC)
SV6
SV7
SV8
SV9
SV10
SV11
SV12
E/D
Study Day 
1
2
8 (± 3)
29 (± 3)
57 (± 3)
85 (± 3)
113 (± 3)
141 (± 3)
169 (± 3)
Study Week
0
0
1
4
8
12
16
20
24
Efficacy assessments
ACQ-6
X
X
X
X
X
X
X
X
SGRQ
X
X
X
X
X
X
SNOT-22 (comorbid CRS 
participants only)
X
X
X
X
X
X
At-home eDiary completion and 
spirometry use
Twice daily throughout the intervention period.
Assess adherence to at-home eDiary 
completion, spirometry, and SOC 
medication use
X
X
X
X
X
X
X
X
X
Assessment of asthma exacerbations
X
X
X
X
X
X
X
X
X
X
PGI-BR
X
Study participant feedback 
questionnaire (optional)
X
X
X
X
FeNO
X
X
X
X
X
X
X
X
X
Airwave oscillometry 
(pre-administration of study 
intervention)
X
X
X
X
X
X
Airwave oscillometry (4 hours 
post-administration of study 
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Table 2
Schedule of Activities: Study Intervention and Follow-up Periods
Period
Study Intervention
Follow-up
Visit Number
SV4 
(Random-
isation)
SV5 
(TC)
SV6
SV7
SV8
SV9
SV10
SV11
SV12
E/D
Study Day 
1
2
8 (± 3)
29 (± 3)
57 (± 3)
85 (± 3)
113 (± 3)
141 (± 3)
169 (± 3)
Study Week
0
0
1
4
8
12
16
20
24
In-clinic spirometry (pre-BD) (pre-
administration of study intervention)
X
X
X
X
X
X
X
X
X
In-clinic spirometry (4 hours post-
administration of study intervention)
X a
In-clinic spirometry (post-BD)
X
X
X
Safety assessments
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Physical examination
X b
X b 
X b 
X b 
X b 
X b 
X b 
X c 
X c 
Weight
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
ECG
X d
X
X
X
Echocardiogram e
X f
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
Injection site reactions
X
X
X
X
X
X
X
SARS-CoV-2 PCR test g
X
X
X
X
X
X
X
X
X
Collect blood h for:
Haematology
X
X
X
X
X
X
X
X
Coagulation parameters
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
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Table 2
Schedule of Activities: Study Intervention and Follow-up Periods
Period
Study Intervention
Follow-up
Visit Number
SV4 
(Random-
isation)
SV5 
(TC)
SV6
SV7
SV8
SV9
SV10
SV11
SV12
E/D
Study Day 
1
2
8 (± 3)
29 (± 3)
57 (± 3)
85 (± 3)
113 (± 3)
141 (± 3)
169 (± 3)
Study Week
0
0
1
4
8
12
16
20
24
Collect nasal sample for:
Nasal mucosal sampling (lining 
fluid)
X
X
X
X
X
X
X
Nasal mucosal sampling (mRNA) k
X
X
Verify eligibility criteria
X
Randomisation
X
Study intervention administration l
Pandemic impact assessment m
X
X
X
X
X
X
X
X
X
X
Exploratory cough sub-study only
At-home cough monitoring (for the 24 
hours post-clinic visit)
X
Cough VAS
X
a
Airway oscillometry and spirometry performed 4 hours (± 15 minutes) post administration of study intervention will require 4 hours withhold of 
bronchodilator (see Section 6.5.3).
b
Brief physical examination.
c
Complete physical examination.
d
Triplicate ECG. The mean value of each parameter from the triplicate will be used as the baseline value.
e
Echocardiogram and NT-proBNP assessments also to be performed as required, for participants who might be experiencing heart failure, or as soon as 
possible after heart failure might have occurred.
f
May be performed at any time at or between SV9 (Week 12) and SV10 (Week 16) inclusive.
g
Testing may be performed at any point for a participant suspected of having COVID-19. 
h
Prior to administration of study intervention on days when study intervention is administered.
C
C
C
C
C
C
C
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Table 2
Schedule of Activities: Study Intervention and Follow-up Periods
Period
Study Intervention
Follow-up
Visit Number
SV4 
(Random-
isation)
SV5 
(TC)
SV6
SV7
SV8
SV9
SV10
SV11
SV12
E/D
Study Day 
1
2
8 (± 3)
29 (± 3)
57 (± 3)
85 (± 3)
113 (± 3)
141 (± 3)
169 (± 3)
Study Week
0
0
1
4
8
12
16
20
24
i
If not performed at SV4, can be performed at any subsequent visit. As a last resort if the participant has completed the study (and not withdrawn consent) 
but the sample has not been received by the analysing laboratory, the site should ask the participant if he/she would be willing to attend an additional 
optional visit to provide this sample.
j
Female participants of childbearing potential only.
k
If deemed by investigator to be intolerable for individual participant at SV4 (eg, due to nasal polyps), subsequent assessments may be omitted. If this 
assessment is not performed at SV4 for any reason, it should not be repeated at SV10.
l
Participants should be monitored for a minimum of one to 2 hours after administration of study intervention (see Section 8.2.3). If a suspected 
anaphylactic reaction occurs during or within a 24-hour period after administration of study intervention, blood samples for serum tryptase will be 
collected as soon as possible after the event, at 60 ± 30 minutes after the event, at discharge, and between 2 and 4 weeks post-discharge. Immediate care 
of the participant and treatment of the reaction must take priority over collecting blood samples. Additional details on anaphylactic reactions are provided 
in Appendix G and Appendix H.
m
For COVID-19 mitigation, please see Section 2.3.1.2.
ACQ-6 = asthma control questionnaire-6; AE = adverse event; BD = bronchodilator; COVID-19 = coronavirus disease 2019; CRS = chronic rhinosinusitis; 
E/D = early study intervention discontinuation; ECG = electrocardiogram; EDN = eosinophil derived neurotoxin; FeNO = fractional exhaled nitric oxide; 
IgE = immunoglobulin E; IL = interleukin; mRNA = messenger RNA; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; PGI-BR = patient 
global impression of benefit/risk; PK = pharmacokinetic(s); SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
SGRQ = St George’s respiratory questionnaire; SNOT-22 = sino-nasal outcome test-22; 
  SOC = standard of care; 
sST2 = soluble ST2; SV = study visit; TC = telephone contact; VAS = visual analogue scale.
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2
INTRODUCTION
MEDI3506 is a human IgG1 mAb that binds to human IL-33. MEDI3506 binds full length 
and mature forms of human IL-33 with exceptionally high affinity and prevents IL-33 binding 
to soluble (sST2) and membrane-bound forms of ST2 (also known as IL-1RL1) receptor. 
Several clinical and non-clinical studies point to the IL-33/ST2 signalling axis playing a key 
role in the pathogenesis of asthma. Thus, blocking this signalling pathway could be of 
therapeutic benefit in asthma. MEDI3506 is currently in development for the treatment of 
asthma, AD, COPD, and DKD.
2.1
Study Rationale
The MEDI3506 pre-clinical profile suggests that MEDI3506 can reduce asthmatic airway 
inflammation, improve epithelial integrity, reduce mucus production, and improve 
muco-ciliary transport. As such, MEDI3506 is hypothesised to impact on asthma disease 
status by increasing FEV1 (and other physiological measures of lung function) and reducing 
frequency and severity of asthma exacerbations, thereby improving quality of life.
One Phase I clinical study of MEDI3506 (Study D9180C00001) was completed in 
December 2019. Study D9180C00001 was a first in human, randomized, placebo controlled, 
blinded (investigator and participant blinded; sponsor unblinded) clinical study in 
88 participants to evaluate the safety, tolerability, PK, and immunogenicity of single and 
repeated doses of MEDI3506. MEDI3506 was generally found to be safe and well tolerated. 
For further details, refer to the IB.
This Phase II study aims to assess the efficacy and safety of MEDI3506 in adult participants 
with uncontrolled moderate-to-severe asthma.
2.2
Background
Asthma is a chronic inflammatory disease of the airways characterised by bronchial 
hyperreactivity and reversible airflow limitation. International treatment guidelines for asthma 
recommend ICS as first line therapy (GINA 2020). For individuals who are symptomatic on 
medium dose ICS monotherapy, step-up therapy with LABA is the recommended next 
treatment option followed by other controller therapies including leukotriene receptor 
antagonists, theophylline, and oral corticosteroids. ‘Biologic agents’ (eg, omalizumab and 
benralizumab) that inhibit specific molecular targets such as IgE or Th2 cytokines and their 
respective receptors are reserved for those with severe uncontrolled asthma. Furthermore, all 
currently approved asthma controller therapies have little or no impact on the natural history 
of the disease (ie, most people with moderate-severe asthma need life-long therapy). There is 
a clear unmet need for asthma therapies that not only better control symptoms, but lead to 
disease modification.


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Numerous studies have shown a key role for IL-33 in asthma. The genes encoding IL-33 and 
ST2/IL1RL1 have been identified as major susceptibility loci for human asthma in several 
genome wide association studies  (Bonnelykke et al 2014; Gudbjartsson et al 2009; 
Hirota et al 2011; Moffat et al 2010; Shrine et al 2019; Torgerson et al 2011; Wan et al 2012) 
and were among the few genes reproducibly found to be associated with asthma across diverse 
ethnic groups. In addition, a rare IL-33 loss-of-function mutation has been recently described 
that reduces blood eosinophil counts and protects from asthma (Smith et al 2017). The 
protective effect remained, although weaker, after correcting for eosinophil counts, suggesting 
that IL-33 may influence asthma risk in part by controlling blood eosinophil count, and also 
through additional biological pathways (Mousas et al 2017).
Two Phase II studies support a role for anti-IL-33 therapy in asthma treatment. In a 
proof-of-concept study involving adult patients with moderate-to-severe asthma, 
REGN3500 monotherapy (ICS and LABA maintenance therapy were withdrawn during the 
trial) met the primary endpoint of improvement in loss of asthma control and significantly 
improved lung function compared to placebo, meeting a key secondary endpoint 
(NCT03387852). In a separate Phase II clinical study, a single IV dose of etokimab was 
administered to patients with uncontrolled moderate-to-severe asthma despite being on 
treatment with high dose combination ICS plus LABA therapy. Compared with a placebo 
group, asthmatics treated with etokimab had a significant improvement in lung function 
(FEV1) and a reduction in blood eosinophils (NCT03469934).
A detailed description of the chemistry, pharmacology, mechanism of action, and safety of 
MEDI3506 is provided in the IB.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefit, potential risks, and 
mitigation strategies of MEDI3506 may be found in the IB.
2.3.1
Risk Assessment
Potential risks for this study population, study procedures, and MEDI3506 administration and 
mitigation strategies are listed in Table 3. A blinded review of the safety data for AEs will be 
performed regularly and any potential emerging risks highlighted to the DSMB for further 
consideration.


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Table 3
Risk Assessment
Potential Risk of Clinical 
Significance
Rationale for Risk
Mitigation Strategy
Study Population Related
Worsening of asthma control
Efficacy of MEDI3506 on asthma not yet determined.
•
Participants will continue on their current asthma 
controller and reliever treatments as required.
•
Participants will be treated for exacerbations of asthma 
if they occur.
•
eDiary will trigger ‘worsening of asthma alerts’ for 
participants and research sites.
Study Procedure Related
Nasal mucosal sampling (mRNA)
Temporary, minor discomfort (similar to drawing blood).
•
To be performed by appropriately trained staff using 
appropriate personal protective equipment.
•
If deemed by investigator to be intolerable for 
individual participant at SV4 (eg, due to nasal polyps), 
subsequent assessments may be omitted (see Table 2).
MEDI3506/Study Intervention Related
Gastrointestinal adverse reactions.
Observation of what was considered an incidental 
finding of ulcerative colitis in a 26-week toxicity study 
in cynomolgus monkeys (see IB Section◦4.3.1.2). The 
gastrointestinal effects of IL-33 blockade in humans are 
currently unclear. IL-33 is expressed in the 
gastrointestinal tract, where it has multiple downstream 
effects (Hodzic et al 2017). Expression of IL-33 is 
elevated in patients with active ulcerative colitis (see IB 
Section 5.5.1.1).
Exclusion of individuals with history of ulcerative colitis, 
Crohn’s disease, or microscopic colitis diagnosed by either 
gastroenterologist or by histopathology (see Section 5.2).
Serious infections (including 
opportunistic infections and viral 
reactivations).
Mechanism of action of MEDI3506, in particular, the 
role of IL-33 as an “epithelial alarmin” 
(Martin and Martin 2016; see IB Section 5.5.2.1).
Exclusion of individuals with active infection and/or latent 
infections or individuals who are 
immunosuppressed/compromised (see Section 5.2).


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Table 3
Risk Assessment
Potential Risk of Clinical 
Significance
Rationale for Risk
Mitigation Strategy
Progression of heart failure.
 
 
 
•
Exclusion of individuals at risk of developing of heart 
failure (see Section 5.2).
•
Exclusion of individuals with LVEF < 45% (see 
Section 5.2).
•
Monitoring of study participants with echocardiograms 
and NT-proBNP (see Table 2).
Injection site reactions.
This is based on the SC route of administration and the 
nature of MEDI3506 as an exogenous protein substance
(see IB Section 5.5.3.1).
•
Instructions on injection technique including rotation of 
injection sites (see Section 6.2.2.1).
•
Routine monitoring for injection site reactions will be 
undertaken at each SV (see Table 2).
Serious hypersensitivity 
(including Type I to IV 
hypersensitivity reactions) and 
immune complex disease.
As mAb are foreign proteins, they have the potential to 
provoke hypersensitivity reactions. Based on a potential 
risk known to be associated with foreign proteins, 
occurrence of ADA could result in immune complex 
disease (see IB Section 5.5.4.1).
•
Exclude individuals with a known history of allergy or 
severe reaction to:

Any component of the study intervention.

Biologic agents.

Human gamma globulin therapy formulations (see 
Section 5.2).
•
Exclude individuals with hereditary fructose intolerance 
(see Section 5.2).
•
Required monitoring of participants for a minimum of 
one to 2 hours after administration of study intervention 
(see Table 2).
•
Sites must be equipped to diagnose and manage 
anaphylaxis and serious allergic reactions until the 
participant can be transferred to a suitable facility 
(see Table 2 and Appendix H).
•
Serum tryptase will be determined in the event of 
suspected anaphylactic symptoms (see Table 2 and 
Appendix H).
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Table 3
Risk Assessment
Potential Risk of Clinical 
Significance
Rationale for Risk
Mitigation Strategy
Reproductive toxicity.
Consistent with ICH guidance on the timing of 
nonclinical studies, MEDI3506 has not been evaluated in 
embryo-foetal development toxicity studies (see IB 
Section 5.5.5.1).
•
Stipulation of highly effective contraceptive 
requirements for participants (see Appendix I).
•
Female participants may only be included if they have a 
negative pregnancy test during screening and prior to 
administration of study intervention, and agree to use a 
highly effective method of contraception from 
screening until the end of the study (see Section 5.1).
•
Male participants may only be included if they agree to 
use a male condom with (if available) spermicide and 
another highly effective method of contraception during 
the intervention and follow-up periods (see Section 5.1).
ADA = anti-drug antibody(ies); IB = Investigator’s Brochure; ICH = International Council for Harmonisation; IL = interleukin; LVEF = left ventricular ejection 
fraction; mAb= monoclonal antibody(ies); mRNA = messenger RNA; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; SC = subcutaneous; 
sST2 = soluble ST2; SV = study visit.


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Serious infections (including those with SARS-CoV-2) are also a potential risk of MEDI3506. 
AstraZeneca is not aware of any current evidence of a direct link between IL-33, or IL-33 
suppression, and contracting SARS-CoV-2 and early stages of coronavirus disease 2019 
(COVID-19) illness post infection.  Moreover, it is hypothesised that IL-33 suppression might 
be beneficial in the later, hyperinflammatory phase of severe COVID-19 illness; MEDI3506 
will be tested in patients with severe COVID-19 infections as part of the ACcelerating 
COVID-19 Research and Development (ACCORD) study 2 (ACCORD-2; EudraCT number 
2020-001736-95).
2.3.1.1
Study Conduct During COVID-19 Pandemic
Coronavirus disease 2019 (COVID-19) has emerged as a worldwide pandemic disease with 
significant implications for public health. AstraZeneca accepts that a careful risk-benefit 
analysis should be performed in each region before initiating clinical research that impacts the 
clinical resources needed for the COVID-19 pandemic. Specifically, this study would not be 
initiated in regions where local and/or national authorities have issued stay-in-place or 
lock-down orders. Hence, AstraZeneca will commence this study when local and national 
governments indicate that it is acceptable to perform clinical studies. Furthermore, each study 
site must have appropriate measures to ensure safety of site staff and participants, and this 
study would be paused if local or national governments or sites determine that they can no 
longer support safe conduct of clinical research. AstraZeneca will monitor countries and sites, 
and the study will not begin until local and national governments and clinical sites have 
indicated that it is acceptable to conduct clinical studies and the safety of site staff and 
participants can be ensured. 
If during study conduct, local or national governments or sites determine that the current 
environment can no longer support safe conduct of clinical research, this study would be 
paused.
2.3.1.2
COVID-19 Mitigations
In order to exclude higher risk participants, the age range is set at 18 to < 65 years inclusive at 
time of enrolment.
Severe asthma is a risk-factor for severe COVID-19 illness, and the following participants will 
not be included in the study (see Exclusion Criteria 1 and 2, Section 5.2). 
1
Participants with active COVID-19 infection at screening.  
2
Participants with a history of significant COVID-19 illness within 6 months of enrolment.
(a) Participants with history of COVID-19 pneumonia diagnosed based on 
radiological assessment.
(b) Participants with history of COVID-19 and significant findings from pulmonary 
imaging tests.


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(c) Participants with history of COVID-19 requiring hospitalisation and/or oxygen 
supplementation therapy.
Because the run-in period ranges from 28-35 days, participants will be tested for active 
SARS-CoV-2 infection using a PCR test targeting SARS-CoV-2 at 2 screening visits (see 
SOA; see Table 1, Section 1.3), and those with a positive result prior to randomisation will 
become screen failures. 
Participants suspected of having contracted COVID-19 should be managed according to local 
and national guidelines to prevent spread of COVID-19 infection to staff and patients. These 
participants, as well as any who test positive for SARS-CoV-2, should not be automatically 
discontinued from investigational product or be withdrawn from the study. Investigators 
should refer to Section 7 when considering participant discontinuation or withdrawal 
decisions. Sites will be required to provide documentation of a COVID-19 screening and 
mitigation plan that describes how and where participants would be tested if they are 
suspected to have SARS-CoV-2 infection. The plans should also describe mitigation activities 
designed to protect site staff and others at the site, including other participants and patients.
Investigators should ensure that potential participants with significant risk factors for 
COVID-19 related complications are not enrolled as per Exclusion Criterion 13 (Section 5.2).
It is recognised that depending on the location and facilities of a clinical site, study visit 
attendance may place participants at risk of exposure to SARS-CoV-2. Furthermore, it is 
recognised that more general population-level measures to reduce infection rates (eg, travel 
restrictions) may inhibit the ability of participants to attend study visits. Necessary healthcare 
responses at sites to the pandemic (eg, additional infection control measures) may also inhibit 
the ability of a clinical site to effectively and properly conduct the study. Study visit 
attendance for dosing and for clinical assessments of treatment response are critical for the 
scientific value of the study.
Therefore, investigators should not enrol participants unless they have reasonable confidence 
that throughout the duration of the study:

Participants will be able to attend study visits, whilst avoiding contact with concentrations 
of COVID-19 patients (eg, hospital entrances used by such patients); and

The site will be able to conduct the study effectively and safely, considering relevant 
national and local factors.
The primary endpoint will be analysed using a repeated measures mixed effect model which, 
in the event of missing data, uses all data that are available. The sponsor will monitor the 
number of discontinuations, withdrawals, missed visits and other missing data.


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AstraZeneca will routinely conduct risk-based enrolment assessments on a country and site 
level during the pandemic phase of COVID-19, and study monitoring will focus, in part, on 
AEs associated with new onset SARS-CoV-2 infection and participants withdrawn due to 
COVID-19 illness. 
All site staff should wear personal protective equipment in accordance with local or national 
guidelines.  
If, for reasons related to the COVID-19 pandemic, a participant is not able to attend their 
scheduled visit with in the ± 3 day visit window, they can have their visit rescheduled within 
14 days of the original scheduled visit; however, visits that cannot be rescheduled within a 
14 day window must be skipped and participants should continue at the next scheduled visit.
During the COVID-19 pandemic, on-site visits may be replaced by a telemedicine visit if 
allowed by local/regional guidelines. Having a telemedicine contact with the participants will 
allow collection of data for AEs, concomitant medications, adherence to the eDiary and PRO 
measures to be reported and documented. The term telemedicine visit refers to remote contact 
with the participants using telecommunications technology including phone calls, virtual or 
video visits, and mobile health devices.
2.3.1.3
Vaccination Against COVID-19
There are no clinical data available to assess the interaction (if any) of MEDI3506 with any 
COVID-19 vaccine.
The sponsor accepts that vaccination against COVID-19, when and where it is available and 
participants are eligible according to applicable guidelines, is in the participant’s best interest. 
Consequently, vaccination during the study is, in general, permitted and any delays in 
vaccination due to study participation should be minimised.
To help ensure the interpretability of safety data, receipt of COVID-19 vaccine (either first or 
subsequent dose) is prohibited within 30 days before randomisation or within 7 days before or 
after any dose of study intervention (Section 6.5.4). Receipt of, at least, the first dose of 
COVID-19 vaccine more than 30 days before randomisation, without significantly delaying 
enrolment, should be preferred but may not be possible, eg, not locally available at the time, 
participant not eligible at the time, express participant decision not to be vaccinated. 
Otherwise, vaccination may be performed at any time outside the prohibited 7-day window 
before or after any dose of study intervention. If the (approximate) date of a subsequent dose 
of COVID-19 vaccination is known, then enrolment of the participant should be timed so that 
the dose is not within 30 days prior to scheduled randomisation. If this date is not known then 
enrolment into the study should not be delayed. If an enrolled participant does (unexpectedly) 
receive COVID-19 vaccine within 30 days prior to scheduled randomisation, the site should 
contact the AstraZeneca Study Physician for advice on how the situation should be managed.


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2.3.2 Benefit Assessment
The purpose of this Phase II, proof-of-concept clinical study is to evaluate the efficacy and 
safety of MEDI3506 in adult participants with uncontrolled moderate-to-severe asthma. For 
participants randomised to MEDI3506, there is a potential benefit in terms of improvement of 
their asthma status. However, the efficacy of MEDI3506 in participants with asthma is yet to 
be determined. Participants may derive benefit from health assessments (eg, ECG, 
echocardiogram, clinical laboratory safety measurements, and SOC adherence monitoring) 
performed as part of the study.
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the measures to minimise risk to participants in this study, the potential 
risks in association with MEDI3506 are justified by the potential benefit in terms of 
improvement of their asthma status.


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3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objective
Endpoint
Primary 
To assess the effect of MEDI3506 compared 
with placebo on lung function, in adult 
participants with uncontrolled 
moderate-to-severe asthma.
As measured in clinic, change from baseline to Week 16 
in pre-BD FEV1 (L).
Secondary 
To further assess the effect of MEDI3506 
compared with placebo on lung function, in adult 
participants with uncontrolled 
moderate-to-severe asthma.
As measured in clinic, change from baseline to Weeks 8 
and 16 in post-BD FEV1 (L).
To assess the PK of MEDI3506 in adult 
participants with uncontrolled 
moderate-to-severe asthma.
Serum MEDI3506 concentration-time profiles during the 
intervention and follow-up periods.
To assess the immunogenicity of MEDI3506 in 
adult participants with uncontrolled 
moderate-to-severe asthma.
ADA during the intervention and follow-up periods.
To assess the effect of MEDI3506 compared 
with placebo on asthma control in adult 
participants with uncontrolled 
moderate-to-severe asthma.
Change from baseline to Week 16 in ACQ-6 score.
Proportion of participants with a decrease in ACQ-6 score 
of ≥0.5 from baseline to Week 16.
Proportion of participants achieving ACQ-6 well 
controlled status (defined as ACQ-6 score ≤0.75 at 
Week 16).
To assess the effect of MEDI3506 compared 
with placebo on health status in adult 
participants with uncontrolled 
moderate-to-severe asthma.
Change from baseline to Week 16 in SGRQ score.
Proportion of participants with a decrease in SGRQ total 
score of ≥4 points from baseline to Week 16.
To assess the effect of MEDI3506 compared 
with placebo on CompEx in adult participants 
with uncontrolled moderate-to-severe asthma. 
Time to first CompEx event based on the period from 
baseline to Week 16. 
CompEx annualised event rate.
To assess the effect of MEDI3506 compared 
with placebo on concentration of FeNO in adult 
participants with uncontrolled 
moderate-to-severe asthma.
Percent change from baseline to Week 16 in concentration 
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Table 4
Objectives and Endpoints
Objective
Endpoint
Safety
To assess the safety and tolerability of 
MEDI3506 compared with placebo, in adult 
participants with uncontrolled 
moderate-to-severe asthma.
During the intervention and follow-up periods:
•
AEs, SAEs, AESIs
•
Vital signs
•
Clinical chemistry, haematology, and urinalysis
•
ECGs
•
LVEF as measured by echocardiogram
•
NT-proBNP
•
Number of participants seropositive for 
SARS-CoV-2 at end of study who were seronegative 
at randomisation visit
•
For participants testing positive for SARS-CoV-2 (by 
PCR or serology test), during the intervention and 
follow-up periods, the number and proportion of 
patients with COVID-19 AEs/SAEs and the 
proportion asymptomatic.
Exploratory
To further assess the longitudinal effect of 
MEDI3506 compared with placebo on lung 
function in adult participants with uncontrolled 
moderate-to-severe asthma.
As measured at home, change from baseline up to 
Week 24 in 2-weekly mean PEF and FEV1
To assess the effect of MEDI3506 compared 
with placebo on airway hyperresponsiveness in 
adult participants with uncontrolled 
moderate-to-severe asthma.
Change from baseline to Weeks 8 and 16 in FEV1% 
reversibility.
To assess the effect of MEDI3506 compared 
with placebo on asthma related inflammatory 
blood biomarkers in adult participants with 
uncontrolled moderate-to-severe asthma.
Change from baseline to Weeks 1, 4, 8, 12, 16, 20 and 24 
in inflammatory blood biomarker levels, including but not 
limited to:
•
•
Serum IL-5.
•
Serum IL-13.
•
Serum TSLP.
Change from baseline to Weeks 4, 16, and 24 in plasma 
EDN.
Change from baseline to Weeks 16 and 24 in total IgE.
Change from baseline to Week 16 in:
•
sST2.
•
Proinflammatory gene signatures in whole blood.
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Table 4
Objectives and Endpoints
Objective
Endpoint
To assess the longitudinal effect of MEDI3506 
compared with placebo on small airway function 
in adult participants with uncontrolled 
moderate-to-severe asthma.
Change from baseline to Weeks 1, 4, 8, 12, and 16 in 
airway reactance and resistance as assessed by AO 
parameters, including but not limited to:
•
R5
•
R20
•
R5-R20
•
AX
To assess the longitudinal effect of MEDI3506 
compared with placebo on lung function in adult 
participants with uncontrolled 
moderate-to-severe asthma.
As measured in clinic, change from baseline in pre-BD 
FEV1 to Weeks 1, 4, 8, 12, 20, and 24.
To assess the acute effect of MEDI3506 
compared with placebo on pre-BD FEV1 in 
adult participants with uncontrolled 
moderate-to-severe asthma.
As measured in clinic, change in pre-BD FEV1 (L) from 
pre-administration of study intervention to 4 hours 
post-administration of MEDI3506 or placebo at Day 1.
To assess the effect of MEDI3506 compared 
with placebo on asthma control in adult 
participants with uncontrolled 
moderate-to-severe asthma.
During the intervention period (baseline to Week 16):
•
Annualised rate of asthma exacerbations.
•
Annualised rate of hospitalised asthma 
exacerbations.
To assess the longitudinal effect of MEDI3506 
compared with placebo on asthma control and 
health status in adult participants with 
uncontrolled moderate-to-severe asthma.
Change from baseline to Weeks 1, 4, 8, 12, and 24 in 
ACQ-6 score.
Change from baseline to Weeks 4, 12, and 24 in SGRQ 
score.
Change from baseline up to Week 24 in 2-weekly mean 
daily rescue medication usage (puffs/day).
Change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in:
•
Asthma symptom score.
•
Mean number of night-time awakenings.
To assess the benefit-risk profile of MEDI3506 
as perceived by adult participants with 
uncontrolled moderate-to-severe asthma.
PGI-BR at Week 16.
To evaluate 
and inflammatory blood 
biomarkers that may predict an efficacy response 
to MEDI3506 in adult participants with 
uncontrolled moderate-to-severe asthma.
 
 
Association of allergen-specific IgE status with primary 
and secondary efficacy endpoints at Week 16.
To assess the effect of MEDI3506 compared 
with placebo on asthma related inflammatory 
airway biomarkers in adult participants with 
uncontrolled moderate-to-severe asthma.
Percent change from baseline to Weeks 1, 4, 8, 12, 16, 20, 
and 24 in concentration of FeNO.
Change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in 
exploratory biomarkers measured in nasal lining fluid.
Change from baseline to Week 16 in mRNA nasal 
transcriptome.
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Table 4
Objectives and Endpoints
Objective
Endpoint
To assess the effect of MEDI3506 compared 
with placebo on nasal symptom control in a 
subset of adult participants with uncontrolled 
moderate-to-severe asthma who have comorbid 
CRS.
Change from baseline to Weeks 1, 4, 8, 12, and 16 in 
SNOT-22 score.
Exploratory cough sub-study
To evaluate the effect of MEDI3506 compared 
with placebo on objective cough measures in 
adult participants with uncontrolled 
moderate-to-severe asthma
Change from baseline to Week 16 in:
•
Daily (ie, 24 hour) cough frequency.
•
Awake time cough frequency.
•
Night-time cough frequency.
•
Cough VAS.
ACQ-6 = asthma control questionnaire-6; ADA = anti-drug antibody(ies); AE = adverse event; AESI = adverse 
event of special interest; AO = airwave oscillometry; BD = bronchodilator; COVID-19 = coronavirus 
disease 2019; CompEx = composite endpoint for severe exacerbations of asthma; CRS = chronic rhinosinusitis; 
ECG = electrocardiogram; EDN = eosinophil derived neurotoxin; FeNO = fractional exhaled nitric oxide; 
FEV1 = forced expiratory volume in the first second; IgE = immunoglobulin E; IL = interleukin; L = litre(s);
LVEF = left ventricular ejection fraction; mRNA = messenger RNA; NT-proBNP = N-terminal prohormone of 
B-type natriuretic hormone; PCR = polymerase chain reaction; PEF = peak expiratory flow; PGI-BR = patient 
global impression of benefit/risk; PK = pharmacokinetic(s); SAE = serious adverse event; SARS-CoV-2 = severe 
acute respiratory syndrome coronavirus 2; SGRQ = St George’s respiratory questionnaire; SNOT-22 = sino-nasal 
outcome test-22; 
 sST2 = soluble ST2; TSLP = thymic stromal 
lymphopoietin; VAS = visual analogue scale.
4
STUDY DESIGN
4.1
Overall Design
Study D9181C00001 is a Phase II, randomised, double-blind, placebo-controlled, 
parallel-group, proof-of-concept study to evaluate the efficacy, safety, PK and 
immunogenicity of MEDI3506 in adult participants with uncontrolled moderate-to-severe 
asthma on SOC.
Approximately 228 participants will be randomised in a 1:1:1 ratio to achieve 216 evaluable 
participants. Participants will receive 
mg MEDI3506, 
mg MEDI3506, or placebo 
 by SC injection for a total of  doses. The randomisation will be stratified according to 
cough sub-study participation. Note that the exploratory cough sub-study may not be activated 
in all countries.
Participants who fail screening can be re-screened. 
Participants will be enrolled in this study for up to 29 weeks. The study comprises of 3 periods 
including the screening period of up to 5 weeks, an intervention period of 16 weeks, and a 
follow-up period of 8 weeks. 
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4.2
Scientific Rationale for Study Design
Interleukin-33, an ‘alarmin’ cytokine, is expressed by epithelial and endothelial cells. Its 
cognate receptor, ST2, is expressed by several cell types including ILC2s, Th2 cells, Th1 
cells, regulatory T cells, and mast cells. IL-33 release in airways is triggered by airway 
epithelial cell injury resulting from environmental factors such as airborne allergens 
(Cayrol and Girard 2018; Scott et al 2018), cigarette smoke (Weng et al 2018) and respiratory 
tract viruses (Kearley et al 2015). 
Interleukin-33 stimulates ILC2s, mast cells and other airway cells to generate a variety of 
soluble pro-inflammatory mediators such as IL-4, IL-5, and IL-13. In turn, these mediators 
amplify the pro-inflammatory effects of IL-33 by recruiting immune cells, including 
eosinophils, into airways. In asthma, airway inflammation is causative in manifestation of 
symptoms and damage to structural cells. This inflammation indirectly also causes 
mal-adaptive epithelial repair and airway wall re-modelling / thickening of the airway wall; 
characteristic features of severe asthma. The functional consequences of airway wall 
inflammation and thickening in asthma are reduced lung function (FEV1) and increased 
sensitivity to bronchoconstrictor agents such as methacholine ie, bronchial hyperreactivity. 
Thus, evidence suggests that IL-33 initiates and drives the cardinal features linked to the 
development and persistence of asthma. Consequently, neutralising IL-33 activity in asthmatic 
airways, would be expected to improve lung function, reduce airwall thickening and reduce 
bronchial hyperreactivity.
Data from large-scale genome-wide association studies strongly associate the IL-33 gene 
locus and the ST2 gene locus with increased risk of asthma (Bonnelykke et al 2014; 
Gudbjartsson et al 2009; Hirota et al 2011; Moffat et al 2010; Torgerson et al 2011; 
Wan et al 2012). Furthermore, one SNP in the IL-33 gene has been shown to generate a 
truncated, non-functional IL-33 protein. The pleiotropic pro-inflammatory effects of IL-33 in 
airways in conjunction with the genetic linkage to asthma risk provide strong evidence that 
neutralisation of IL-33 signalling may have significant therapeutic benefit in asthma. 
However, since asthma is a heterogeneous disease, it is not clear whether all asthmatics will 
benefit equally from anti-IL-33 therapy. In particular, individuals whose asthma develops 
early in life (< 25 years of age) are more likely to have family members with asthma ie, have a 
‘heritable’ form of asthma, and so more likely to have IL-33 mediated disease.
This Phase II proof-of-concept study will evaluate the efficacy and safety of MEDI3506 in 
patients with persistent moderate-to-severe asthma inadequately controlled on ICS plus 
LABAs. To explore whether IL-33 variants predict response to MEDI3506, this study will test 
the effects of anti-IL-33 therapy in adults whose asthma developed before the age of 25 years.


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4.2.1
Rationale for Endpoints
4.2.1.1
Primary Endpoints 
The primary endpoint is absolute change in pre-BD FEV1. Pre-BD FEV1 is a valid and reliable 
quantitative tool to assess changes in airway obstruction in asthma over time.
4.2.1.2
Secondary and Safety Endpoints 
Safety, PK, and immunogenicity endpoints will be evaluated to inform risk-benefit analyses 
and determine optimal dosing regimen for MEDI3506 in asthma. PROs (ACQ-6 and SGRQ) 
reliably identify participants with uncontrolled asthma. CompEx is a composite score of 
asthma control composed of data gathered using an eDiary and asthma exacerbation reporting 
that has predictive value in assessing whether an intervention reduces asthma exacerbations of 
asthma (Fuhlbrigge et al 2017). FeNO is a reliable quantitative tool to assess changes in 
asthma inflammation over time.
4.2.1.3
Exploratory Endpoints
Airwave oscillometry (AO) is a sensitive, non-invasive measure of airway function that 
concomitantly assesses peripheral (small) and central (large) airways function. FEV1% 
reversibility allows for assessment of changes in irreversible airway obstruction. Although not 
statistically powered, asthma exacerbation rates will be captured. Blood samples will be 
collected from participants for the assessment of biomarkers that are relevant to asthma 
disease pathology and/or the mechanism of action of MEDI3506. Collection of epithelial nasal 
fluid and cells will be performed on participants to assess biomarkers and the mRNA nasal 
transcriptome, as sampling in the upper airway may provide biomarker data that are more 
reflective of lung pathology compared with systemic biomarkers. 
 
 
Many patients with asthma have comorbid CRS. The SNOT-22, a validated questionnaire 
measuring nasal symptoms in participants with CRS, will be performed and evaluated in 
participants with comorbid CRS. Changes in SNOT-22 will be used to assess the impact of 
MEDI3506 on CRS.
In the exploratory cough sub-study, objective cough monitoring will assess the impact of 
MEDI3506 on this important symptom of asthma, related to inflammation and airway 
hyperresponsiveness.
4.2.2
Rationale for Study Population
Clinical efficacy of MEDI3506 has yet to be established in asthma. This study aims to 
determine the effects of MEDI3506 on airway function in asthmatics with uncontrolled 
moderate-to-severe disease receiving standard of care (see Section 5.1 for inclusion criteria). 
Asthmatics with early onset disease will be eligible but not those with late onset disease (onset 
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after age of 25 years). The early onset population of asthmatics is more likely to have IL-33 
driven disease based on genome wide association study data (Gorbacheva et al 2018).
4.2.3 Participant Input into Design
The AstraZeneca Patient Partnership Program is an internal working group that enables study 
participant feedback on clinical trial study designs. During study development, the Patient 
Partnership Program influenced the following aspects of the study design:

Provision written into protocol to rotate injection sites (Section 6.2.2.1).

Participant training for the eDiary and spirometry devices used at-home will be supported 
by trouble shooting and technical guidance (does not directly affect protocol).

Participants may be provided with a single source study guide providing study rationale 
and guidance in seeking additional support from sites (does not directly affect protocol).

There may be ongoing communications with participants such as newsletters and regular 
site contact (does not directly affect protocol).

Site facilities were explored to support participant focused visits such as out of office or 
telephone contact visits (does not directly affect protocol).

Reimbursement and travel assistance (including alternatives to the use of public 
transportation systems) may be considered based on site feedback (does not directly affect 
protocol).
In addition, a study coordinator review of the SOA took place in order to ensure the SOA 
were feasible and realistic, particularly in terms of visit duration. This consultation led to:

Text describing the order that assessments should be performed on SV days added to the 
schedule of activities introductory text (Section 1.3).

Footnote ‘a’ added to the schedule of activities: screening period (Table 1) to allow 
flexibility for ICF to be signed at a separate, stand-alone visit in order for the participant 
to have sufficient time to read and absorb the study information.
4.3
Justification for Dose
The highest dose of MEDI3506 administered to participants in this study will be 
mg by 
SC injection
. This dose is predicted to have a lower exposure, in terms of maximum 
concentration at steady-state (Cmax,ss ; approximately 2.4-fold) and AUC (approximately 
1.1-fold), compared with the highest dose administered (ie, single dose of 300 mg IV 
MEDI3506) in the Phase I clinical study (Study D9180C00001; refer to IB for further details).
Exposures (ie, mean Cmax,ss of 1,276 μg/mL, and AUC0-4 weeks at steady-state of 
28,012 μg•day/mL) achieved at the 26-week NOAEL of 150 mg/kg in cynomolgus monkeys 
(refer to the IB for further detail) are approximately 38- and 47-fold higher than predicted at 
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the proposed highest dose of 
mg SC 
 in this Phase II clinical study (refer to the IB 
for additional details).
The optimal serum concentration for MEDI3506 efficacy in asthma is not known. A mouse 
challenge model suggests a target concentration of 20 μg/mL (refer to the IB for additional 
details). Analysis of the PK data from the Phase I clinical study of MEDI3506 predicts that 
mg SC 
 will achieve an average steady-state concentration of 21 μg/mL, similar to 
the target concentration established in the mouse model. In addition, this dose is predicted to 
achieve > 90% suppression of IL-33 in the sputum based on the theoretical PK/PD model. If 
replicated in humans with asthma, 
mg SC 
 is anticipated to achieve near-maximum 
efficacy based on the mouse and PK/PD models, and will be used in this study. The lower 
dose of 
mg 
 SC will be used in this Phase II clinical study to define the efficacy of 
MEDI3506 at lower dose.
4.4
End of Study Definition
An individual participant will be considered to have completed the study if the participant was 
followed through their last protocol-specified visit/assessment (including telephone contact) 
regardless of the number of doses of study intervention that was received.
Participants will not be considered to have completed the study if consent was withdrawn or 
the participant was lost to follow-up (see Sections 7.2 and 7.3). The end of study is defined as 
the last expected visit/contact of the last participant undergoing the study.
4.4.1
Study Stopping Criteria
Discontinuation of specific sites or of the study as a whole are handled in accordance with 
Appendix A 8.
The study may be put on hold pending a full safety data review, if any of the following criteria 
are met:

Two or more (in different participants) reports of new onset symptomatic heart failure 
confirmed by echocardiography.

Two or more (in different participants) reports of new onset non-infective colitis 
confirmed histopathologically.

Five or more (in different participants) reports of ≥Grade 4 severity infection (excluding 
COVID-19 infection), not associated with an asthma exacerbation.

Two or more (in different participants) other clinically significant (≥Grade 4 severity) 
AEs (excluding those described in any of the preceding criteria) in the same system organ 
class (excluding COVID-19 infection and asthma exacerbations) that preclude continuing 
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dosing of the participant, unless obviously not related to the study drug (eg, motor vehicle 
accident).

Participant enrolment is unsatisfactory.

Non-compliance that might significantly jeopardise the validity or integrity of the trial, or 
safety of the participant(s).

Sponsor decision to terminate development.
If the sponsor determines that temporary suspension or termination of the study is required, 
the sponsor will discuss the reasons for taking such action with all participating investigators 
(or head of the medical institution, where applicable). When feasible, the sponsor will provide 
advance notice to all participating investigators (or head of the medical institution, where 
applicable) of the impending action.
If the study is suspended or terminated for safety reasons, the sponsor will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. The sponsor will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination. If the 
study is suspended for safety reasons and it is deemed appropriate by the sponsor to resume 
the study, approval from the relevant regulatory authorities (and IRBs/IECs when applicable) 
will be obtained prior to resuming the study. The investigator shall also promptly inform the 
participant of the study suspension/termination and should assure appropriate participant 
therapy and/or follow-up.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. During the screening period, for any 
clinical laboratory test where the result is not available from central laboratories prior to 
randomisation, a result from a local laboratory may be an acceptable alternative but the 
medical monitor must be consulted first.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply: 
If any criterion cannot be fully assessed at a particular visit (eg, due to awaiting information 
from the participant’s usual physician at SV1 or laboratory results not yet available at SV2), 
the criterion must be fully assessed prior to randomisation:


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Age
1
Participant must be 18 to < 65 years of age inclusive, at the time of signing the ICF.
Type of Participant and Disease Characteristics
2
Documented physician-diagnosed asthma of early onset, defined as development of 
asthma before the age of 25 years. Asthma should be diagnosed > 12 months prior to 
SV1. Acceptable documentation includes any of the following:
(a) Contemporaneous clinical notes, dated > 12 months prior to SV1 and when 
participants were aged < 25 years, showing a diagnosis of asthma.
(b) Contemporaneous clinical notes or pharmacy records, dated > 12 months prior to 
SV1 and when participants were aged < 25 years, showing on-going treatment 
for asthma (note: the indication of asthma must be documented).
(c) Investigator documentation based on communication with the physician who 
treats the participant’s asthma.
3
Treated with medium-to-high dose ICS defined as total daily dose of > 250 g fluticasone 
dry powder or equivalent (see Appendix F for equivalent ICS doses), for at least 
12 months prior to SV1 and on a stable dose for ≥3 months prior to SV1.
4
Stable LABA therapy for ≥3 months prior to SV1 (this may be as a fixed-dose 
combination product, or a separate inhaler).

Treatment with additional asthma controller therapies eg, LAMA, LTRA, 
theophylline (≥1 month at a stable dose) prior to SV1 is allowed. Individuals on 
theophylline must have normal blood levels documented in the 3 months prior to 
SV1. Treatment with oral corticosteroids is allowed if dose has been stable for 
≥3 months.
5
An ACQ-6 score ≥1.5 at SV1, SV2, and SV4 (randomisation).
6
Morning pre-BD FEV1 < 85% predicted normal at SV1.
7
≥70% adherence (days) to eDiary completion both between SV1 and SV2 and in the 
14 days preceding SV4.

An adherent day requires completion of evening and subsequent morning diary 
between SV1 (evening assessment) and SV2 (morning assessment).
8
≥70% adherence to background medication as assessed by eDiary entries both between 
SV1 and SV2 and in the 14 days preceding SV4.
9
Participants must demonstrate ability to perform acceptable inhaler and spirometry 
techniques.
10 Able and willing to comply with the requirements of the protocol including ability to 
read, write, be fluent in the translated language of all participants facing questionnaires 
used at site, and use electronic devices eg, eDiary and spirometry.


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Weight
11 Bodyweight ≥40 kg and BMI < 40 kg/m2.
Reproduction
12 For female participants of childbearing potential (see Appendix I for definition of 
childbearing potential):

A negative serum pregnancy test at SV1.

A negative urine pregnancy test at SV2 and prior to administration of study 
intervention at SV4 (randomisation).
13 Female participants of childbearing potential who are sexually active with a male partner 
must agree to use a highly effective method of contraception from screening until the end 
of the follow-up period at SV12 (Week 24) of the study. See Appendix I for definitions of 
childbearing potential and highly effective methods of contraception.

In countries where spermicide is available, it is strongly recommended for the male 
partner of a female participant of childbearing potential to also use male condom plus 
spermicide throughout this period.

In countries where spermicide is not available, it is strongly recommended for the 
male partner of a female participant of childbearing potential to also use male 
condom throughout this period.
14 There are no contraception requirements for female participants who are not of 
childbearing potential. However, all female participants should refrain from egg cell 
donation and breastfeeding throughout the study.
15 In countries where spermicide is available, male participants who are sexually active with 
a female partner of childbearing potential must agree to use a male condom with 
spermicide and another highly effective method of contraception during the intervention 
and follow-up periods from SV4 (Day 1) through to SV12 (Week 24) of the study. In 
countries where spermicide is not available, male participants who are sexually active 
with a female partner of childbearing potential must agree to use a male condom and 
another highly effective method of contraception during the intervention and follow-up 
periods from SV4 (Day 1) through to SV12 (Week 24) of the study. See Appendix I for 
definitions of childbearing potential and highly effective methods of contraception. Male 
participants should also refrain from biologically fathering a child or donating sperm 
during the same period.
Informed Consent
16 Provision of signed and dated, written informed consent (and any locally required 
authorisation eg, data privacy) for study participation which includes mandatory 


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genotyping (study objective). Note: If a participant declines to participate in the 
mandatory genotyping component of the study, the participant will not be included in the 
study.
17 Optional: provision of signed and dated written Optional Genetic Research Information 
informed consent prior to collection of samples for optional genetic research that supports 
Genomic Initiative.
Type of Participant and Disease Characteristics
18 Participants with documented evidence of asthma as demonstrated by either:

Post-BD reversibility of FEV1 ≥12% and ≥200 mL (15 to 60 min after 
administration of 4 puffs of albuterol/salbutamol), within 12 months prior to SV1, or 
at SV1 or SV2. Note: if the participant cannot perform post-BD spirometry at SV1 or 
needs to perform a repeat assessment of post-BD spirometry, it is also acceptable to 
assess this criterion at SV2, or

Positive methacholine challenge test within the 12 months prior to SV1. A positive 
result is defined as a PC20 ≤8 mg/mL.
19 Documented history of ≥1 asthma exacerbation in 24 months prior to SV1 (see 
Section 8.1.5 for definitions of acceptable documentation and asthma exacerbation). 
20 Morning pre-BD FEV1 ≥40% predicted normal and > 1 L at SV1.
Criteria to be Assessed for Exploratory Cough Sub-study
Informed Consent
21 Provision of written dated separate ICF for the exploratory cough sub-study.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Criteria to be Assessed at SV1 and SV2
If any criterion cannot be fully assessed at SV1 and SV2 (eg, laboratory results not yet 
available), the criterion must be fully assessed prior to randomisation.
Medical Conditions and Diagnostic Assessments
1
Participants with a positive diagnostic PCR test for SARS-CoV-2, the virus responsible 
for COVID-19, at SV2, or anytime on or after Day -7 and prior to SV4. 
2
Participants with a significant COVID-19 illness within 6 months of enrolment:
(a) Participants with a diagnosis of COVID-19 pneumonia based on radiological 
assessment. 


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(b) Participants with diagnosis of COVID-19 with significant findings from 
pulmonary imaging tests.
(c) Participants with a diagnosis of COVID-19 requiring hospitalisation and/or 
oxygen supplementation therapy.
3
Positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core 
antibody, at screening; or known to have tested positive for human immunodeficiency 
virus. 
4
Evidence of active or untreated latent TB infection (LTBI):
(a) Positive interferon gamma release assay (IGRA) test and evidence of symptoms 
suggestive of active TB.
(b) Positive IGRA, or repeated indeterminate IGRAs, no evidence of active TB and 
untreated for LTBI, unable to be treated for, or declines treatment of LTBI.
(c) Participants newly diagnosed with LTBI on initial screening could be considered 
for rescreening if they complete a full course of treatment for LTBI in accordance 
with recommended treatment guidelines prior to rescreening. In this situation, 
repeat IGRA test is not required after completion of treatment for LTBI.
(d) Participants with an indeterminate IGRA should undergo a repeat test and if still 
indeterminate may be enrolled only after being treated for LTBI.
5
This criterion has been removed.
6
An LVEF < 45% measured by echocardiogram during screening.
7
A family history of heart failure defined as either of the following:
(a) ≥2 first degree relatives with clinically significant heart failure, or
(b) ≥1 first degree relative with heart failure known to be heritable (eg, hypertrophic 
cardiomyopathy), unless inheritance is excluded by genetic testing.
8
Major surgery within 8 weeks prior to screening at SV1, or planned inpatient surgery or 
hospitalisation during the screening, intervention or follow-up periods.
9
Donation of blood or blood products in excess of 500 mL within 3 months prior to SV1.
Prior/Concurrent Clinical Study Experience
10 Participation in a clinical study for a medical device within 3 months prior to screening at 
SV1.
Other Exclusions
11 Current smokers or recent ex-smokers ie, have quit e-cigarettes or other inhaled tobacco 
products ≤6 months prior to SV1.
12 Ex-smokers with a total smoking history of > 10 pack years (not applicable for 
e-cigarettes). Note: pack-years are calculated as average number of cigarettes per 


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day × number of years/20. For example, 1 pack year = 20 cigarettes smoked per day for 
1 year or 10 cigarettes per day for 2 years.
Criteria to be Assessed at SV1, SV2, and SV4 (Randomisation)
Medical Conditions and Diagnostic Assessments
13 As judged by the investigator, any evidence of any active medical or psychiatric condition 
or other reason (prior to randomisation) that in the investigator’s opinion makes it 
undesirable for the participant to participate in the study. This includes but is not limited 
to:
(a) Diabetes mellitus, except for participants with type 2 diabetes mellitus that are 
well controlled.
(b) History of heart failure.
(c) Clinically significant or unstable ischemic heart disease, arrhythmia, or 
cardiomyopathy, including acute coronary syndrome within the last 6 months; or 
any history of myocardial infarction.
(d) Clinically significant aortic stenosis.
(e) Systemic hypertension except if well controlled using two or fewer medications 
and stable for at least 6 months.
(f) Known history of primary pulmonary arterial hypertension.
(g) History of an underlying condition that predisposes the participant to infections 
(eg, history of splenectomy, known primary or secondary immune deficiency 
syndromes).
(h) History of ulcerative colitis, Crohn’s disease, or microscopic colitis diagnosed by 
either gastroenterologist or by histopathology.
(i)
Obstructive sleep apnoea.
(j)
History of treatment with cardiotoxic medications (eg, as part of cancer therapy) 
including thiazolidinediones.
14 Any clinically important pulmonary disease other than asthma eg, active lung infection, 
COPD, bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation syndrome 
associated with obesity, lung cancer, history or planned lung lobectomy, alpha-1 
anti-trypsin deficiency, primary ciliary dyskinesia, Churg-Strauss syndrome, allergic 
bronchopulmonary aspergillosis and hyper-eosinophilic syndrome.
15 Any other clinically relevant abnormal findings on physical examination or laboratory 
testing including haematology, coagulation, serum chemistry, or urinalysis between SV1 
and SV4 (randomisation), that in the opinion of the investigator or medical monitor might 
compromise the safety of the participant in the study or interfere with evaluation of the 
study intervention. Abnormal findings include, but are not limited to: 


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(a) ALT or AST > 2 × ULN.
(b) TBL > 1.5 × ULN (unless due to Gilbert’s disease). 
(c) Evidence of chronic liver disease.
(d) Abnormal vital signs, after 10 minutes of supine rest (confirmed by one 
controlled measurement), defined as any of the following:
(i)
SBP < 80 mmHg or ≥150 mmHg.
(ii) DBP < 50 mmHg or ≥95 mmHg.
(iii) Pulse < 45 or > 100 beats per minute.
(e) Signs of pulmonary oedema or volume overload.
(f) Any clinically significant rhythm, conduction, or morphology abnormalities in 
the ECG including but not limited to QTcF (Vandenberk et al 2016) > 450 ms.
16 A known history of severe reaction to any medication including biologic agents or human 
gamma globulin therapy.
17 History of, or a reason to believe, a participant has a history of, drug or alcohol abuse 
within the past 2 years prior to screening.
18 Current diagnosis of cancer.
19 History of cancer, except if treated with apparent success with curative therapy (response 
duration of > 5 years).
20 History of allogeneic bone marrow transplant.
21 A helminth parasitic infection diagnosed within 6 months prior to SV4 (randomisation) 
that has not been treated, or has not responded to SOC therapy.
22 An asthma exacerbation within 8 weeks of SV4 (randomisation; see Section 8.1.5 for 
definitions of acceptable documentation and exacerbation).
Prior/Concomitant Therapy
23 Receiving any prohibited concomitant medications or therapies as specified in the 
protocol, as follows:
(a) Identified any time from SV1 through to SV4 (randomisation):
(i)
Systemic (oral or injectable) corticosteroids within 4 weeks of SV1 (except as 
stable maintenance therapy for asthma [see Inclusion Criterion 4]).
(ii) Live or attenuated vaccines within 4 weeks of SV1. (Note: Vaccines with 
adenoviral vectors that are unable to replicate, eg, ChAdOx1, are not considered 
live attenuated).
(iii) Ig or blood products within 4 weeks of SV1.
(b) Identified at SV4 (randomisation):


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(i)
Any immunotherapy within 3 months of SV4 (randomisation), except for stable 
maintenance dose allergen-specific immunotherapy started at least 4 weeks prior 
to SV1 and expected to continue through to the end of the follow-up period.
(ii) Interferon gamma within 3 months of SV4 (randomisation).
(iii) Investigational products within 4 months or 5 half-lives of SV4 (randomisation).
(iv) Marketed biologics including dupilumab, benralizumab, and mepolizumab 
within 4 months or 5 half-lives of SV4 (randomisation), whichever is longer.
(v) Vaccination against COVID-19 (either first or subsequent dose) within 30 days 
prior to randomisation.
Prior/Concurrent Clinical Study Experience
24 Concurrent enrolment in another clinical study involving a study intervention.
25 Known history of allergy or reaction to any component of the study intervention 
formulation, including hereditary fructose intolerance.
Other Exclusions
26 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
27 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
28 Participant has been committed to an institution by virtue of an order issued either by the 
courts or by a public authority.
5.3
Lifestyle Considerations
Participants must abstain from donating blood and plasma from the time of informed consent, 
and for 16 weeks (5 half-lives) after final administration of study intervention.
5.3.1
Meals, Dietary Restrictions, and Caffeine
1
Participants should avoid eating a large meal for at least 2 hours prior to all spirometry, 
AO and FeNO assessments at the site.
2
Participants should not eat or drink one hour prior to having FeNO assessment.
3
During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (eg, coffee, tea, cola drinks, and chocolate) for 4 hours prior 
to in-clinic spirometry.


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5.3.2
Activity
1
Participants should avoid engaging in strenuous exercise for 2 hours prior to all 
spirometry, AO and FeNO assessments, both in clinic and at home. 
2
Participants should avoid showers/bathing and any activity that will cause heavy 
perspiration whilst wearing the cough monitor, as the cough monitor must not come into 
contact with water.
5.4
Screen Failures
Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, if there is reason to believe the reason for screen failure was temporary. Only one 
rescreening per participant is allowed in the study. The timing of the rescreening should be 
determined by the PI, taking into account the initial reason for screen failure. Prior to 
rescreening, participants must be reconsented and will retain their original SID number.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.




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4
MEDI3506 does not contain preservatives and therefore, any unused portion must be 
discarded.
The unblinded study intervention manager will select the appropriate kits allocated by the 
RTSM to prepare the participant’s dose. The unblinded study intervention manager must 
ensure that only the unblinded team members have access to the areas of the pharmacy where 
the study intervention is being stored and prepared.
6.2.1
Study Intervention Inspection
Each vial allocated for dose preparation should be inspected. MEDI3506 and placebo are 
supplied as a clear to opalescent sterile liquids.
If there are any defects noted with the study intervention, the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section in the IMP manual for 
further instructions.
6.2.2
Dose Preparation Steps
No incompatibilities between MEDI3506 and plastics passing compatibility tests (ie, 
polypropylene and polycarbonate syringes) have been observed.
MEDI3506 and placebo do not contain preservatives and any unused portion must be 
discarded. Preparation of study intervention is to be performed aseptically. Total in use 
storage time from needle puncture of the study intervention vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F). If 
storage time exceeds these limits, a new dose must be prepared from new vials assigned by the 
RTSM.
A vial should be used only one time to prepare a single dose.
To prepare the participant’s dose, the unblinded study intervention manager will select study 
intervention for administration according to the kit identification numbers assigned. A 
summary of the study intervention volumes required and syringes to prepare for SC dose 
administration in each treatment group is provided (Table 6).


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Table 6
Study Intervention Dose Preparation
Contents of 
Vial(s)
Number of Kits
Volume 
Required
Syringes to 
Prepare
Size of 
Syringe
Total Volume of 
Study 
Intervention
mg MEDI3506 Treatment Group 
MEDI3506
mg MEDI3506 Treatment Group a
MEDI3506
Placebo
Placebo Treatment Group
Placebo
a
Do not mix MEDI3506 and placebo in the same syringe.
The dose preparation steps are, as follows:
1
Prepare the assigned MEDI3506 and/or placebo vials for the particular treatment group as 
per Table 6.
2
Withdraw the required volume of MEDI3506 or placebo from each vial using a separate, 
appropriately sized syringe and a separate 18 to 20-gauge 1 to 1.5 inch needle, 
respectively.
3
Remove the 18-20-gauge needle. Replace with a capped 27-gauge 0.5 inch needle until 
administration.
6.2.2.1
Treatment Administration
The first day of dosing is considered Day 1 (SV4).
Female participants of childbearing potential, must have a negative urine pregnancy test prior 
to receiving each dose of study intervention.
MEDI3506 and placebo are not identical in appearance or viscosity. The syringes should be 
kept out of sight of all blinded persons, including the participant, to maintain the blind. Study 
intervention will be administered SC by unblinded site personnel via a 27 gauge 0.5 inch 
needle to the abdomen, back of the arms, or thigh. The 2 injections should be approximately 
1 inch (2.5 cm) apart in the same anatomical region. The unblinded site personnel 
administering the dose will wipe the skin surface of the administration sites with alcohol and 
allow the skin surface to air dry. The skin will be pinched to isolate the SC tissue from the 
muscle. The needle will be fully inserted at a 45 degree angle into the SC tissue. The study 
intervention will be slowly injected (at least 5 seconds’ duration is recommended). The area 
should not be massaged after injection.
CC
I
C
C
CCI
CCI
CCI
CCI
CCI
C
C
CCI
CCI
CCI
C
C
CCI
CCI
CCI
CCI
C
C
CCI
CCI
CCI
CCI


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It is advised that the site of injection be rotated so that the participant receives injections of 
study intervention in different anatomical regions from one visit to the next. In cases when 
rotation of the injection site is not feasible and/or the participant prefers not to rotate injection 
sites, the reason for not rotating the injection site should be documented in the source 
documents.
At each administration the time of the first injection and anatomical region used for both 
injections must be documented in the source documents.
6.2.2.2
Monitoring Dose Administration
After the administration of study intervention, vital signs will be assessed according to the 
SOA, and SC injection sites will be assessed for injection site reactions (Section 8.2.2) by the 
blinded study team. Participants should be monitored for a minimum of one to 2 hours after 
administration of study intervention (see Section 8.2.3).
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognise and treat anaphylaxis 
(Appendix H).
6.2.3
Accountability 
The site’s designated unblinded study intervention manager is required to maintain accurate 
study intervention accountability records. Upon completion of the study, copies of study 
intervention accountability records will be returned to AstraZeneca. All unused study 
intervention will be disposed of following site procedures and upon authorization by 
AstraZeneca, or will be returned to an AstraZeneca-authorised depot if a site is unable to 
dispose of unused study intervention.
6.3
Measures to Minimise Bias: Randomisation and Blinding
6.3.1
Methods for Assigning Treatment Groups
All participants will be centrally assigned to randomised study intervention using an RTSM. 
The randomisation will be stratified according to sub-study participation. Before each site is 
initiated, the log in information and directions for the RTSM will be provided. The RTSM will 
provide to the investigator(s) or pharmacists the kit identification numbers to be allocated to 
the participant at the dispensing visit. Routines for this will be described in the RTSM user 
manual that will be provided to each centre.
Study intervention will be dispensed at the study visits summarised in SOA or per SOC after 
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6.3.2
Methods to Ensure Blinding
This is a double-blinded study in which MEDI3506 and placebo are not identical in 
appearance or viscosity. Neither the participant nor any of the investigator or sponsor staff 
who are involved in the treatment or clinical evaluation of the participants will be aware of the 
treatment received (ICH E9). Since MEDI3506 and placebo are not identical, study 
intervention will be handled by an unblinded study intervention manager at the site and will be 
administered by an unblinded study team member who will not be involved in the 
management of study participants. An independent study intervention monitor will also be 
unblinded to perform study intervention accountability. In the event that the treatment 
allocation for a participant becomes known to the investigator or other study staff involved in 
the management of study participants, AstraZeneca must be notified immediately. If the 
treatment allocation for a participant needs to be known to treat an individual participant for 
an AE (Section 6.3.3), the investigator must notify AstraZeneca immediately. The site will 
maintain a written plan detailing which staff members are blinded/unblinded and the process 
of study intervention preparation and administration used to maintain the blind.
MEDI3506 could reduce eosinophil counts in blood over time. As a precaution, eosinophil, 
basophil, and monocyte data from the haematology laboratory tests (Table 7) will not be 
communicated to blinded sponsor or site personnel during the treatment and follow-up 
periods.
To facilitate the in-stream analysis of PK and ADA samples, the randomisation schedule may 
be provided to limited personnel who have responsibility for analysing the samples. These 
unblinded sample analysts will not have any other involvement with the conduct of the study.
6.3.3
Methods for Unblinding
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study intervention and that potentially require expedited 
reporting to regulatory authorities. Randomisation codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented.
The RTSM will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment is 


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warranted. Participant safety must always be the first consideration in making such a 
determination. If a participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The investigator documents and reports the 
action to AstraZeneca, without revealing the treatment given to participant to the AstraZeneca 
staff.
If unblinding is required by the DSMB (Appendix A 4), details of the methods for unblinding 
(sponsor will remain blinded) will be provided in a separate DSMB charter.
The primary analysis (Section 9.1) will be performed after all participants have completed the 
SV10 (Week 16) assessments or have withdrawn from the study. The sponsor staff will be 
fully unblinded following the Primary Analysis Clinical Data Lock. 
Investigators, participants and site staff will not be made aware of unblinded treatment 
assignments for individual participants who are in the follow-up period until these participants 
have completed the study.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the unblinded study site staff. 
Participants will receive study intervention from unblinded study site personnel, under 
medical supervision. The date, and time if applicable, of each dose administered (first 
injection) in the clinic will be recorded in the source documents and recorded in the eCRF.
6.5
Concomitant Therapy
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF, along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
The medical monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Participants are prohibited from receiving certain concomitant medications (described in 
Section 6.5.4) unless clinically indicated as determined by a physician.
Other than the permitted medications described in the current section, use of concomitant 
medications or therapies from screening through to the early discontinuation visit/end of study 


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is discouraged (except where medically necessary). Medications or therapies that are not 
prohibited and neither compromise participant safety nor affect study data, as judged by the 
investigator, will be permitted and recorded in the appropriate sections of the eCRF.
6.5.1 Rescue Medicine
Systemic corticosteroid therapy may be used in the case of asthma exacerbation during the 
study. Although the use of rescue medications is allowable at any time during the study, the 
use of rescue medications should be delayed, if possible, for at least 2 hours following the 
administration of study intervention. The date and time of rescue medication administration as 
well as the name and dosage regimen of the rescue medication must be recorded.
6.5.2 Required Medications
Participants should continue to use the following medications at stable dose and regimen 
throughout the study, with the exception of medication withhold periods described in 
Section 6.5.3:

Medium-to-high dose ICS.

LABA.

Any additional asthma controller therapies in use at time of screening eg, LAMA, LTRA, 
theophylline.
6.5.3 Medication Withhold Periods
Prior to Scheduled Spirometry, AO, and FeNO Measurement
Participants should withhold the following medications for the specified times prior to 
scheduled spirometry, AO, and FeNO measurement at site:

SABAs and short-acting muscarinic antagonists for at least 6 hours. In the case of 
spirometry and AO post administration of study intervention, SABA should be withheld 
following post-BD spirometry.

Twice daily LABA and/or LAMA-containing therapies for at least 12 hours.

Once daily LABA and/or LAMA-containing therapies for at least 24 hours.

LTRA for at least 24 hours.

Twice daily theophylline for at least 12 hours.

Once daily theophylline for at least 24 hours.
Note: for visits where in-clinic spirometry is performed post-administration of study 
intervention, the medications should be withheld until all spirometry assessments are 
complete.


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Additionally, participants should withhold all BD medications for 4 hours prior to at-home 
spirometry assessments, where possible.
6.5.4 Prohibited Medications
The inclusion and exclusion criteria sections of the protocol define concomitant medications 
that, if taken in the period prior to randomisation, would lead to participant screen failure.
In addition, unless clinically indicated as determined by a physician, participants are not 
permitted to receive any of the following (for the time periods stated):

Any immunosuppressive or immunomodulator therapies (other than corticosteroids): not 
allowed 12 weeks prior to randomisation, during screening and until at least Week 16,
unless there is a medical need as judged by the investigator.

Any immunotherapy including allergen immunotherapy: not allowed 12 weeks prior to 
randomisation, during screening and until at least Week 16, unless there is a medical need 
as judged by the investigator.

Immunoglobulin therapy including (IFN-γ) or blood products: not allowed 30 days prior 
to SV1, during screening and until at least Week 16, unless there is a medical need as 
judged by the investigator.

Live or attenuated vaccines: not allowed 30 days prior to the date of randomisation, and 
during the study including the follow-up period. (Note: Vaccines with adenoviral vectors 
that are unable to replicate, eg, ChAdOx1, are not considered live attenuated).

Vaccination against COVID-19 (either first or subsequent dose) within 30 days before 
randomisation or within 7 days before or after any dose of study intervention.

Study interventions other than MEDI3506 or placebo are not allowed in the screening 
period to follow-up period inclusive.

Marketed biologics are not allowed in the screening period to follow-up period inclusive.

Long-acting beta-agonists as a reliever (eg, Symbicort Maintenance and Reliever 
Treatment): not allowed 15 days prior to SV1, during screening and until at least 
Week 16, unless there is a medical need as judged by the investigator.

Suplatast tosilate (T2 cytokine inhibitor): not allowed within 15 days prior to SV1, during 
screening and until at least Week 16, unless there is a medical need as judged by the 
investigator.
The activity of cytochrome P450 (CYP450) enzymes can be altered by increased levels of 
certain cytokines (eg, IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation 
(Huang et al 2010). Thus, MEDI3506, through its downstream mechanism of action, has the 
potential to normalise the formation of CYP450 enzymes indirectly, through the alteration of 
local and systemic cytokine levels. However, a role for IL-33 in the regulation of CYP450 
enzymes has not been reported. As a precaution, upon initiation or discontinuation of 
MEDI3506, in patients who are receiving concomitant drugs that have a narrow therapeutic 


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index and are CYP450 substrates (eg, warfarin), the investigator should consider whether 
(increased) monitoring is indicated.
6.5.5
COVID-19 Vaccination
If and when a participant receives a COVID-19 vaccination, the following information (if 
available) should be recorded in the patient’s notes:

Brand name (or alternatively name of manufacturer)

Date of administration

Whether dose was first or second dose

Anatomical site/region of administration (eg, left deltoid)

Lot number
Details of how this information should be entered into the eCRF will be provided in separate 
guidelines.
Any AEs suspected to be due to the vaccination should be captured in the AE form including 
the causality assessment related to COVID-19 vaccine.
6.6
Dose Modification
Not applicable.
6.7
Intervention after the End of the Study
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. Note that discontinuation from study intervention is NOT the same thing 
as a withdrawal from the study.
An individual participant will not receive any further study intervention if any of the 
following occur in the participant in question:
1
Withdrawal of consent to further treatment with study intervention.
2
Lost to follow-up.
3
Any anaphylactic reaction to study intervention requiring epinephrine administration.
4
Any SAE of ≥ Grade 4 severity (see Appendix B 2).


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5
Any SAE that is in the Cardiac Disorders system organ class.
6
Confirmed diagnosis of new onset of heart failure and/or progression of heart failure 
during the study, regardless of severity. For a participant with a suspected new onset of 
heart failure and/or progression of heart failure, the participant will discontinue and 
should not be administered study intervention unless and until agreed by the investigator 
and medical monitor that study intervention may continue to be administered until the 
diagnosis is confirmed or refuted.
7
Any other AE that, in the opinion of the investigator or the sponsor, warrants 
discontinuation of further dosing of study intervention.
8
Pregnancy.
9
Following randomisation, the participant meets ≥1 of the exclusion criteria (Section 5.2) 
or fails to meet all of the inclusion criteria (Section 5.1) for study participation, unless the 
PI and medical monitor agree the participant may continue receiving study intervention.
10 The participant misses consecutive doses.
11 Following randomisation, receipt of prohibited medication (Section 6.5.4).
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for assessments at end of treatment and during follow-up, including follow-up of 
any AEs unless consent is withdrawn from further study participation, the participant is lost to 
follow-up, or the participant is enrolled in another clinical study.
See the SOA (Table 2) for data to be collected at the time of E/D and follow-up, and for any 
further evaluations that need to be completed.
7.1.1
Missed doses
A participant not attending for a scheduled dose can continue study intervention at the next 
scheduled visit.  Refer to Section 2.3.1.2 for information on dealing with missed doses as a 
result of the COVID-19 pandemic.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, an E/D visit should be conducted, as 
shown in the SOA (Table 2). See SOA for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed.
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
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the ICF and local regulation. The investigator must 
document the decision on use of existing samples in the site study records and inform the 
Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SOA (Table 1 and Table 2). 
Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SOA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
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
Procedures conducted as part of the participant’s routine clinical management (eg, 
methacholine challenge results) and obtained before signing of the ICF may be utilised 
for screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SOA. This excludes all 
central laboratory assessments, eosinophil counts and NT-proBNP, which need to be 
performed centrally.
8.1
Efficacy Assessments
8.1.1
In-clinic Spirometry
8.1.1.1
General requirements
Lung function parameters including, but not limited to, FEV1 and FVC, will be measured by 
spirometry using equipment provided by a central vendor. Spirometry will be performed by 
the Investigator or authorised delegate according to ATS/ERS guidelines (Miller et al 2005).
The vendor providing central spirometry is responsible for assuring that the spirometer meets 
ATS/ERS recommendations and that the study site personnel who will be performing the 
testing are properly certified. Spirometry calibration will be detailed in a separate vendor 
manual.
Participants should follow the relevant medication and other restrictions beforehand 
(Sections 6.5.3 and 5.3). If any of the specified restrictions are not met, and the assessment 
cannot be sufficiently delayed on the day, the assessment should be rescheduled within the 
allowed visit window.
Time of day for scheduled in-clinic spirometry
Spirometry will be performed at specified visits as detailed in the SOA (Table 1 and Table 2). 
For all participants, spirometry testing must be initiated between 6:00 AM and 11:00 AM 
during the screening or re-screening period, and randomisation visit (SV4).
If possible, all post-randomisation spirometry assessments should be performed within 
± 1.5 hours of the time that the randomisation spirometry was performed. For example, if the 
randomisation spirometry was started at 8:00 AM, then all subsequent spirometry testing 
needs to be initiated between 6:30AM and 9:30 AM.
Spirometry technique
Detailed procedure for performing spirometry will be described in a separate spirometry 
procedures manual. Details regarding assessment of the quality of spirometry and the BTR 
process will also be detailed in the manual.




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The highest technically acceptable pre- and post-BD FEV1 will be used to determine 
reversibility.
Reversibility is calculated as follows:
FEV1% Reversibility = (post-BD FEV1 - pre-BD FEV1)/pre-BD FEV1 × 100
Full details will be included in the vendor manual.
Record keeping
A signed and dated copy of the pre- and post-BD printout must be kept at study sites for 
source data verification. The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number. If a printout cannot be printed, the mean value of 
the measurements will be recorded in the participant’s charts. 
8.1.2
At-home Spirometry
During the study period, participants will be required to monitor lung function at home twice 
daily using an at-home spirometry device. Participants should follow the relevant medication 
and other restrictions beforehand (Section 5.3.2 and Section 6.5.3). Further details will be 
provided in a separate instruction manual.
8.1.3
Airwave Oscillometry
Airwave oscillometry will be performed at specified visits as detailed in the SOA (Table 1 and 
Table 2). Airwave oscillometry is a non-invasive lung function test included in this study to 
evaluate treatment effect on small airway physiology. By measuring participant’s airflow and 
response to sound waves, frequency-dependent resistance and reactance will be calculated by 
the AO system software.
A calibrated system will be used for AO measurements (equipment to be provided by vendor). 
Detailed procedures for performing, recording and analysing AO data will be described in a 
separate manual. Details regarding assessment of the quality of AO and the BTR process will 
also be detailed in the manual and in the Monitoring plan. Prior to scheduling and performing 
AO assessments, the following should be observed:

Participants should perform AO prior to pre-BD spirometry assessments if both tests are 
to be performed on the same visit.

Participants should observe the relevant lifestyle restrictions (see Section 5.3) prior to AO 
assessments.

Participants should observe the medication withhold periods (see Section 6.5.3) prior to 
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If any of the above restrictions are not met, and the assessment cannot be sufficiently delayed 
on the day, the assessment should be rescheduled within the allowed visit window (Table 2).
A signed and dated copy of the results printout from the equipment must be kept at the study 
site for source data verification. The printout must be marked with the study code, SID, date 
and time of measurement, and visit number. A number of parameters including (but not 
limited to) R5, R20 and AX for each assessment will be recorded and analysed. The AO 
assessment at SV6, SV7, SV8, SV9, and SV10 will be performed only if the baseline visit AO 
is performed successfully, as judged by the investigator.
8.1.4
Fractional Exhaled Nitric Oxide
Airway inflammation will be evaluated using a standardised single-breath FeNO test in 
accordance with the SOA (Table 1 and Table 2). A single exhalation technique recommended 
by the manufacturer will be followed (Allakhverdi et al 2007; Alving et al 2017).
The FeNO test will be performed prior to AO and spirometry. Participants should follow the 
relevant medication and other restrictions beforehand (Sections 6.5.3 and 5.3). If any of the 
above restrictions are not met, and the assessment cannot be sufficiently delayed on the day 
the assessment should be rescheduled within the allowed visit window.
The NIOX VERO® Airway Inflammation Monitor will be used to measure FeNO. 
Instructions for use of this monitor will be provided in a separate user’s manual.
NIOX VERO® sensors will be replaced as recommended by the manufacturer. The vendor 
supplying the equipment will be responsible for ensuring that the equipment and procedures 
for the measurement of FeNO are validated prior to the start of the study. 
If possible, all post-randomisation FeNO assessments should be performed within ± 1.5 hours 
of the time that the randomisation FeNO was performed.
8.1.5
Asthma Exacerbations
Definition of Asthma Exacerbation
During the study, an asthma exacerbation will be defined as a change in the participant’s usual 
asthma symptoms that leads to any of the following:
a.
A temporary bolus/burst of systemic corticosteroids (or a temporary increase in stable 
OCS background dose) for at least 3 consecutive days to treat symptoms of asthma 
worsening; a single depo-injectable dose of corticosteroids will be considered equivalent 
to a 3-day bolus/burst of systemic corticosteroids.
b.
An emergency room or urgent care visit (defined as evaluation and treatment for 
< 24 hours in an emergency department or urgent care centre) due to asthma that required 
systemic corticosteroids (as per the above).


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c.
An in-patient hospitalisation (defined as admission to an inpatient facility and/or
evaluation and treatment in a healthcare facility for ≥24 hours).
A hospitalised asthma exacerbation is defined as any worsening of asthma that leads to (c.) 
above.
Note: for each exacerbation, the criterion/criteria met to confirm exacerbation status should be 
documented.
Assessment and Documentation of an Asthma Exacerbation
The list below defines what is acceptable documentation for historical exacerbations.

Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a participant was hospitalised/treated with systemic corticosteroids for an 
asthma exacerbation.

Signed and dated notes from a referring physician, including information regarding 
diagnosis and treatment of an exacerbation with systemic corticosteroids.

Evidence of prescriptions for systemic corticosteroids used during an exacerbation.

A documented conversation between the Investigator (or delegate) and a participant who 
is already on an OCS action plan, including the information necessary to assess Inclusion 
Criterion 19. 

A documented conversation between the treating/referral physician or nurse/nurse 
practitioner certifying that a participant was treated for an exacerbation with 
corticosteroids 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 participant 
records have been unsuccessful.
The guidance below defines assessment of asthma exacerbations.

The start of an exacerbation is defined as the earliest of the following:

Start date of systemic corticosteroids or temporary increase in a stable OCS 
background dose.

Date of emergency room or urgent care visits requiring systemic corticosteroids.

Date of hospital admission due to asthma.

The end date of an exacerbation is defined as the latest of the following:

Last date of systemic corticosteroids or temporary increase in a stable OCS 
background dose.

Date of discharge from emergency room or urgent care visit.

Date of hospital discharge.


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
If less than 7 days have elapsed since the end date of an asthma exacerbation and the start 
date of a new asthma exacerbation, the second event will be considered a relapse of the 
prior asthma exacerbation in the statistical analysis.

All asthma exacerbations that occur during the treatment period and follow-up, must be 
recorded in the exacerbation eCRF. See Section 8.3.6 for additional information on 
recording asthma exacerbations as an AE/SAE during the study.
eDiary data and Exacerbations
Any sustained increase in asthma symptoms as reported via the eDiary (that do not meet the 
definition of criteria of an asthma exacerbation) will be graded as a worsening of asthma. 
Specifically: 

An increase in rescue medication use of 4 or more puffs on at least 2 consecutive days 
compared with the average use during baseline or use of 12 puffs/day on any one day, 
and/or

An additional nebulised β2 agonist use on at least 2 consecutive days compared with the 
average use during baseline, and/or 

An increase of 2 or more nights with awakenings due to asthma requiring rescue 
medication over a 7-day period compared with the average during baseline, and/or

≥6 out of previous 7 nights with awakenings due to asthma requiring rescue medication
Alerts to study site will be triggered for participants who experience a drop in PEF ≥30% on 
2 consecutive days.
If an asthma exacerbation event is not associated with at least one of the above eDiary data 
deterioration criteria, the investigator will have to justify the decision for defining the event as 
an exacerbation and record it in the eCRF. Events that are not supported by any objective 
assessment will be deemed not to be a protocol-defined exacerbation.
Participants will be required to keep a record of their asthma symptoms in the eDiary as per 
the SOA (Table 1 and Table 2). The data captured in the eDiary will also be used to determine 
individuals CompEx events.
8.1.6
CompEx
CompEx is a combination of exacerbations of asthma and diary events (ie, combination of 
eDiary variables). CompEx is a composite surrogate endpoint for exacerbations of asthma, 
recently developed by AstraZeneca (it is not yet a regulatory-approved clinical endpoint). 
Diary events are defined by the threshold and slope criteria using the following 
morning/evening (AM/PM) diary variables:

PEF

Symptom score (0 – 3)


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
Use of rescue medication
CompEx can predict treatment efficacy on exacerbations in early development before running 
traditional long-term exacerbation trials. CompEx can be used broadly in the assessment of 
new therapeutic interventions for asthma (Fuhlbrigge et al 2017; note: the referenced 
publication used the term ‘severe exacerbation’ but used the same definition as used for 
‘exacerbation’ in this protocol; therefore, the term ‘exacerbation’ has been used in this section 
for internal consistency of the protocol.)
8.1.7
VitaloJAK Cough Monitor (Exploratory Cough Sub-study Only)
Objective cough frequency over 24 hours will be measured using an ACM (VitaloJAK™; 
Vitalograph, Buckinghamshire, UK) which will be fitted and worn by the participants for 
approximately 24 hours after the visits detailed in the SOA.
The sites will receive training to ensure the ACM is correctly fitted and activated by site staff, 
and the site staff will be given instructions to provide to the participants on how the ACM 
should be worn during the 24 hour period to ensure data is recorded correctly.
The digitally recorded data recorded on the ACM will be sent to Vitalograph who will 
undertake cough counting for all participants using a standardised process. Details on the 
process to follow will be provided to the sites as part of the ACM training.
Participants will be monitored for 24 hours following SV2 and SV10, and set up of the cough 
monitors should be performed as the final assessment at each of these visits.
Detailed procedures for set up of device, recording and analysing objective cough data will be 
described in a separate manual provided to each site. Details regarding assessment of the 
quality of objective cough monitoring undertaken by the vendor will also be detailed in the
manual.
8.1.8
Participant Reported Outcome Questionnaires
Participants will complete the PRO questionnaires on an electronic device (Section 8.1.8.1) 
supplied to the site according to the SOA (Table 1 and Table 2). PRO questionnaires to be 
completed at the site visits must be completed prior to treatment administration and ideally 
before any discussions of health status or other study procedures, such as collection of 
laboratory samples to avoid biasing the participant’ s responses to the questions. All 
within-window PRO assessments for the morning and evening assessments at home should be 
completed within this set time window programmed into the device and will notify the 
participant when it is time to respond to the questions.


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8.1.8.1
Daily eDiary
During the study period, participants will be required to take their asthma controller therapy 
regularly and complete an eDiary twice daily. 
At SV1, participants will receive a handheld eDiary device to complete twice-daily, daily and 
non-daily PRO assessments during the study. Participants will be provided training on the use 
of the handheld device. Daily assessments will include night-time and daytime asthma 
symptoms (morning and evening diary, respectively), use of inhaled rescue medication in 
response to worsening symptoms, nights with awakenings due to asthma symptoms (morning 
diary only) and background medication use. The PEF data (obtained from the home peak flow 
meter) will be captured at the conclusion of the morning and evening eDiary entry.
Daytime is defined as the time period between the morning lung function assessment (upon 
rising in the morning) and the evening lung function assessment. Night-time is defined as the 
time period between the evening lung function assessment (at bedtime) and the morning lung 
function assessment.
The number of doses of rescue medication (1 dose unit = 1 puff on inhaler) taken will be 
recorded by the participant in the eDiary twice daily. The number of inhalations taken 
between the morning and evening lung function assessments will be recorded in the evening. 
The number of inhalations taken between the evening and morning lung function assessments 
will be recorded in the morning.
Nocturnal awakenings due to asthma symptoms will be recorded by the participant in the daily 
eDiary each morning by answering the question whether he/she woke up during the night due 
to asthma symptoms by a “yes” or “no” response.
Background (inhaled ICS/LABA) medication administration use will be recorded once daily 
in the daily eDiary as “yes” or “no” response. 
The eDiary questions support the analysis of a novel endpoint called CompEx (Section 8.1.6).
8.1.8.2
Cough Visual Analogue Scale (Exploratory Cough Sub-study Only)
Participants will be asked to complete a cough severity visual analogue scale (VAS; 100 mm 
linear scale marked with a horizontal line by the participant, with 0 mm representing ‘‘no 
cough’’ and 100 mm representing “worst cough”) measuring subjective assessment by the 
participant of the prior 24 hours for severity of cough symptoms (Smith et al 2006).
8.1.8.3
Asthma Control Questionnaire-6
The ACQ (Juniper et al 1999) was developed to measure asthma control and has been fully 
validated for use in adults and children 6 to 17 years of age. International guidelines for the 
treatment of asthma have identified that the primary clinical goal of asthma management is to 


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optimise asthma control (minimisation of symptoms, activity limitation, bronchoconstriction, 
and rescue BD use) and thus reduce the risk of life-threatening exacerbations and long-term 
morbidity. The ACQ was developed to meet these criteria by measuring both the adequacy of
asthma control and change in asthma control, which occur either spontaneously or as a result 
of treatment.
In the ACQ-6, participants are asked to recall how their asthma has been during the previous 
week by responding to one BD use question and 5 symptom questions. 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 
scores > 1.5 indicate not well-controlled asthma (Juniper et al 2006). Individual changes of at 
least 0.5 are considered clinically meaningful.
The questionnaire will be completed using the eDiary in accordance with the SOA (Table 1
and Table 2).
8.1.8.4
St George’s Respiratory Questionnaire
The SGRQ is a 50-item PRO instrument developed to measure the health status of patients 
with airway obstruction diseases (Jones et al 1991). The questionnaire is divided into two 
parts: part one consists of 8 items pertaining to the severity of respiratory symptoms in the 
preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial 
impacts of the individual’s respiratory condition. The SGRQ yields a total score and three 
domain scores (symptoms, activity, and impacts). The total score indicates the impact of 
disease on overall health status. This total score is expressed as a percentage of overall 
impairment, in which 100 represents the worst possible health status and 0 indicates the best 
possible health status. Likewise, the domain scores range from 0 to 100, with higher scores 
indicative of greater impairment.
Specific details on the scoring algorithms are provided by the developer in a user manual 
(Jones and Forde 2009). The SGRQ will be completed using the eDiary in accordance with 
the SOA, and a 4-week recall version will be used.
8.1.8.5
Sino-nasal Outcome Test-22
The SNOT-22 is a condition-specific health-related quality of life assessment, which captures 
participant-reported physical problems, functional limitations, and emotional consequences of 
sinonasal conditions (Hopkins et al 2009; Piccirillo et al 2002). The SNOT-22 contains a list 
of 22 symptoms and social/emotional consequences of a participant’s nasal disorder, and 
measures how severe each symptom is and the social/emotional consequences of symptoms 
over a 2-week period on a scale from 0 (no problem) to 5 (problem as bad as it can be). The 
total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate 
poorer outcomes).


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The SNOT-22 will be administered to participants who have comorbid chronic inflammatory 
conditions of the nasal mucosa and/or paranasal sinuses (CRS) on the eDiary according to the 
SOA (Table 1 and Table 2).
8.1.8.6
Patient Global Impression of Benefit/Risk 
The patient global impression of benefit/risk is a 5-item questionnaire assessing the 
participant’s perception of the overall benefits and risks of treatment. The 5 items assess: 
overall trial experience, efficacy, side effects, convenience and overall assessment of the 
benefits and harms of treatment. Items are rated on 5- or 6-point verbal rating scales.
8.1.8.7
Study Participant Feedback Questionnaire
This study will include an option for participants to complete an anonymised questionnaire, 
‘Study Participant Feedback Questionnaire’ for participants to provide feedback on their 
clinical trial experience. Individual participant level responses will not be reviewed by 
investigators. Responses will be used by the sponsor to understand where improvements can 
be made in the clinical trial process. This questionnaire does not collect data about the 
participant’s disease, symptoms, treatment effect or adverse events and therefore would not be 
study data.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SOA (Table 1 and Table 2).
8.2.1
Medical, Surgical, and Asthma History
Complete medical and surgical history will include history of COVID-19, prior and current 
medical conditions, past or current cardiovascular disorders, respiratory, gastrointestinal, 
renal, hepatic, neurological, endocrine, lymphatic, haematologic, immunologic, psychiatric, 
genitourinary, drug and surgical history (including COVID-19 vaccination), or any other 
diseases, disorders, or surgical procedures.
The participant’s asthma history will also be collected and will include questions related to the 
participant’s asthma history, duration of asthma, and asthma medications (both past and 
current).
8.2.2
Physical Examinations, Weight, and Height

Complete and brief physical examinations will be performed by a licensed healthcare 
provider (eg, physician, physician’s assistant, or licensed nurse practitioner).

A complete physical examination will include, but will not be limited to, assessment of 
general appearance, head, ears, eyes, nose, throat, neck, skin, as well as cardiovascular, 
respiratory, abdominal, and nervous systems.

A brief physical examination will include, at a minimum, assessments of cardiovascular, 
respiratory, and nervous systems. Each clinically significant abnormal finding will be 


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recorded in the medical history, and each treatment emergent abnormality, including 
injection site reactions identified by assessing SC injection sites, will be recorded as an 
AE.

Physical examinations, weight and height will be recorded at timepoints specified in the 
SOA (Table 1 and Table 2).
8.2.3
Vital Signs
The nominal timing of vital signs, ECGs, and blood draws is described in the SOA (Table 1
and Table 2). The participant should be in a resting supine position for at least 10 minutes 
prior to the collection of vital signs, as follows:

Oral or tympanic temperature.

DBP.

SBP.

Heart (pulse) rate.

Respiratory rate.
For the first  doses of study intervention, participants are to remain at the site for ≥2 hours or 
until stable, whichever is later. In addition, vital signs will be taken before and immediately 
after administration of study intervention, and at 30, 60, and 120 minutes (± 5 minutes) 
thereafter or until stable, whichever is later. For the final doses of study intervention, 
participants are to remain at the site for ≥ 1 hour or until stable, whichever is later. In addition, 
vital signs will be taken before and immediately after administration of study intervention, and 
at 30 and 60 minutes (± 5 minutes) thereafter. Following the observation period, participant 
discharge will be at the discretion of the investigator.
8.2.4
Electrocardiograms
The nominal timing of vital signs, ECGs, and blood draws is described in the SOA (Table 1
and Table 2). The participant should be in a resting supine position for at least 10 minutes 
prior to the collection of ECGs. At baseline, pre-dose of study intervention at SV4 
(randomisation), triplicate ECGs will be performed (all 3 ECGs within a 5-minute time period, 
at least 1 minute apart). The mean value of each parameter from the triplicate will be used as 
the baseline value. ECGs taken at all other times will be single assessments.
Electrocardiograms will be recorded with 12-lead digital ECG devices at a speed of 
25 mm/second with amplitude recording of 10 mm/mV. Where possible the same make and 
model ECG device should be used for recording all ECGs for a particular participant. At least 
3 full complexes must be recorded. Date and time settings should be checked regularly and 
following time changes for daylight savings time. Skin preparation should be thorough and 
electrode positions should be according to standard 12-lead ECG placements.
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Electrocardiogram device software will be used to assess ECG parameters. All ECGs must be 
reviewed by the PI or a qualified designee before the participant is permitted to leave the 
clinic. Abnormalities and obvious changes in ECG parameters from baseline will be assessed 
by the PI for clinical significance.
Electrocardiogram variables will be collected as follows:

Heart (pulse) rate.

RR interval.

QRS interval.

PR interval.

QT interval.
8.2.5
Echocardiograms
A transthoracic echocardiogram to assess left ventricular ejection fraction will be performed 
and read locally according to the SOA (Table 1 and Table 2).
8.2.6
SARS-CoV-2 Serology Testing
Participants’ serum will be tested for the presence of antibodies to the SARS-CoV-2 virus 
from blood drawn at the visits indicated in the SOA (Section 1.3).
8.2.7
Clinical Safety Laboratory Assessments
The nominal timing of vital signs, ECGs, and blood draws is described in the SOA (Table 1
and Table 2). A laboratory manual will be provided to the sites that specifies the procedures 
for collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. Clinical laboratory safety tests will be 
performed in a central clinical laboratory (note: during the screening period, for any clinical 
laboratory test where the result is not available from central laboratories prior to 
randomisation, a result from a local laboratory may be an acceptable alternative but the 
medical monitor must be consulted first). 
Urine pregnancy tests may be performed at the site using a licensed test (dipstick). Clinically 
significant abnormal laboratory results should be repeated as soon as possible (preferably 
within 24 to 48 hours). 
All local laboratory results will be recorded/filed in the source notes.
The laboratory variables listed in Table 7 will be measured in this study.


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Table 7
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
WBC count with differential
Potassium
RBC count
Sodium
Haematocrit
AST
Platelet count
ALT
Haemoglobin
ALP
Coagulation parameters (PT, INR, and aPTT)
TBL (if result is > 1.5 ULN, indirect and direct 
bilirubin will be measured)
GGT
Urinalysis (dipstick)
Creatinine
Colour and appearance 
Blood urea nitrogen
Specific gravity
Albumin
pH
Total protein
Protein
Uric acid
Microscopy including WBCs, RBCs, and casts.
Glucose
Ketones
Blood
Bilirubin
Leukocytes
Note for haematology: blinding procedures for eosinophil, basophil, and monocyte data are described in 
Section 6.3.2.
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently.
ALP = alkaline phosphatase; ALT = alanine transaminase; aPTT = activated partial thromboplastin time; 
AST = aspartate transaminase; GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international 
normalised ratio; PT = prothrombin time; RBC = red blood cell; TBL = total bilirubin; ULN = upper limit of 
normal; WBC = white blood cell.
Note: In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN 
please refer to Appendix E: ‘Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law’, for further instructions.
Pregnancy Test

Serum beta-human chorionic gonadotropin.

Urine human chorionic gonadotropin.
Other Safety Tests

FSH (if needed to confirm post-menopausal status in female participants aged < 50 years 
and not on HRT).

HbA1c.

Hepatitis B (HbsAg, anti-HBs, and anti-HBc) and C antibodies.

HIV-1 and HIV-2 antibodies.

IGRA (TB test). See Exclusion Criterion 4.


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
Serum tryptase will only be taken in the event of suspected anaphylaxis (Appendix G and 
Appendix H).

NT-proBNP.

SARS-CoV-2 PCR test.
8.3
Adverse Events and Serious Adverse Events
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from signing of ICF throughout the treatment period and 
including the follow-up period. SAEs will be recorded from the time of signing of ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall report the SAE to the sponsor within 24 hours.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at SV12 in the study are followed up by the investigator for as 
long as medically indicated, but without further recording in the eCRF. AstraZeneca retains 
the right to request additional information for any participant with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim).

The date and time when the AE started and stopped.

Severity grade.

Whether the AE is serious or not.

Investigator causality rating against the study intervention (yes or no).

Action taken with regard to study intervention.


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
AE caused participant’s withdrawal from study (yes or no).

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE.

Date investigator became aware of serious AE.

AE is serious due to.

Date of hospitalisation.

Date of discharge.

Probable cause of death.

Date of death.

Autopsy performed.

Causality assessment in relation to study procedure(s).

Causality assessment to other medication.
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility 
that the event may have been caused by the study intervention?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.4 Disease Under study
The investigator should report clinically significant worsening of asthma symptoms, including 
exacerbations, as an AE. Signs and symptoms consistent with a participant’s baseline asthma 
status will not be reported as an AE.
8.3.5 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since you were last asked?’ or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.


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8.3.6 Adverse Events Based on Examinations and Tests
The results from the protocol-mandated laboratory tests and vital signs will be summarised in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values, 
spirometry 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 study intervention, or

Are considered to be clinically relevant as judged by the investigator (which may include 
but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study treatment, eg, dose adjustment or drug 
interruption).
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 (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
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 unless unequivocally 
related to the disease under study.
8.3.7
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to 
understanding of MEDI3506 and may require close monitoring and rapid communication by 
the investigator to AstraZeneca. An AESI may be serious or non-serious. The rapid reporting 
of AESIs allows ongoing surveillance of these events in order to characterise and understand 
them in association with the use of MEDI3506.
The following AESIs will be particularly monitored in this study:

Hepatic function abnormality meeting the definition of Hy’s Law as described in 
Section 8.3.8.

Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis and severe allergic reactions, and immune complex disease.

Injection site reactions.

Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia).


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
Serious infections (including opportunistic infections and viral reactivations), for example 
herpes simplex virus/varicella zoster virus, Epstein Barr virus/cytomegalovirus, TB, 
SARS-CoV-2 and all other opportunistic infections listed in the Guidelines for the 
Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with 
HIV (NIH 2019).

Gastrointestinal adverse events.

Malignancy.
8.3.8 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin 
≥2 × ULN may need to be reported as SAEs. Please refer to Appendix E for further 
instruction on cases of increases in liver biochemistry and evaluation of HL.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, 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 AEs 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 ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness for MEDI3506 is the IB. 
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study participant has received any study intervention.


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8.3.10.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
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 anomaly) should be followed up and documented even if the participant 
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 one day ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy.
8.3.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 12 weeks following the last dose of study intervention.
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until the end of the
follow-up period (SV11 [Week 16]) or date of last contact should, if possible, be followed up 
and documented in the Pregnancy Report Form. Consent from the partner must be obtained 
before the Pregnancy Report Form is completed.
8.3.11
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within one day ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (Initial Fatal/Life-Threatening or follow-up 


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Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B. 
8.4
Overdose
An overdose is defined as a participant receiving a dose of study intervention in excess of that 
specified in the IB, unless otherwise specified in this protocol.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, the investigator 
or other site personnel will inform appropriate AstraZeneca representatives immediately, but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 30 days 
for all other overdoses.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor's Patient Safety data entry site.
8.5
Human Biological Sample Biomarkers
8.5.1
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on handling of human biological 
samples see Appendix C.

Samples will be stored for a maximum of 15 years after the end of the study in line with 
consent and local requirements, after which they will be destroyed/repatriated.


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
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 consented 
for future analyses. 

PK samples may be disposed of or anonymised by pooling. Additional analyses may 
be conducted on the anonymised, pooled PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately
from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years after the end of the study. Additional use includes but is not limited 
to further characterisation of any ADAs, confirmation and/or requalification of the assay 
as well as additional assay development work. The results from future analysis will not be 
reported in the CSR.
8.5.2
Pharmacokinetics

Serum samples will be collected for measurement of serum concentrations of MEDI3506 
as specified in the SOA (Table 1 and Table 2).

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Samples will be collected, labelled, stored, and shipped as detailed in the laboratory 
manual.

Samples from participants who receive placebo may be analysed at minimum selected 
time points to confirm no dosing with MEDI3506 took place.
8.5.2.1
Determination of Drug Concentration
The nominal timing of vital signs, ECGs, and blood draws is described in the SOA (Table 1
and Table 2). The time of the first SC injection will be recorded for each participant as the 
timings will be required for analysing the PK data.
Serum will be collected to evaluate the PK of MEDI3506 according to the SOA. MEDI3506 
concentration in serum will be measured utilizing a validated assay method.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to sites.
8.5.3
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 


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method. Tiered analyses will be performed to include screening, confirmatory, and titre assay 
components. Full details of the methods used will be described in a separate report.
ADA samples may also be further tested for characterisation of the ADA response, including 
possible assessment of neutralising antibody.
Samples will be collected, labelled, stored, and shipped as detailed in the laboratory manual.
8.5.4
Pharmacodynamics
There are no established PD measures for MEDI3506. For exploratory biomarkers that may 
indicate a PD effect, see Section 8.5.5.
8.5.5
Collection of Mandatory Samples for Biomarker Analysis

Samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SOA (Table 1 and Table 2).

Samples include the following:

Nasal mucosal sampling. Nasal mucosa (for mRNA) is collected using a sterile, 
disposable nasal mucosal collection device to curette a sample of nasal mucosa for 
analysis.

Nasal mucosal lining fluid. Nasal mucosal lining fluid is collected using the 
Nasosorption™ FX·i device, which is gently applied to the nasal mucosa to absorb 
mucosal lining fluid from mucosal surfaces.

Whole blood for RNA PAXgene. RNA PAXgene will be used for the collection, 
transport, and storage of whole blood, and the stabilization of intracellular RNA. 
RNA transcript profiling analyses will be performed on RNA PAXgene samples.
Note: If nasal mucosal sampling for mRNA at SV4 (randomisation) is deemed by the 
investigator to have been challenging for individual participant tolerability (eg, due to nasal 
polyps), subsequent nasal sampling may be omitted at the investigator’s discretion.
Biological samples will be collected at specified visits as detailed in the SOA (Table 1 and 
Table 2):

Total IgE (serum).

Allergen-specific IgE (serum).

EDN (plasma).

sST2 (serum).




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drawn at SV4, it may be taken at any visit until the last study visit. Only one sample should be 
collected per participant for genetics during the study.
For storage and destruction of genetic samples, see Appendix D.
8.7
Health Economics
Not applicable.
8.8
Impact of COVID-19 Pandemic
To assess the impact of the COVID-19 pandemic on the study, sites will be asked to complete 
the pandemic impact form at each study visit, according to the SOA (Table 1 and Table 2).
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary efficacy endpoint is the change from baseline in pre-BD FEV1 at Week 16. A 
treatment policy estimand will be applied whereby all available data are included in the 
analysis, irrespective of whether a participant discontinued study intervention or received 
rescue therapy.
The null hypothesis is that the change from baseline in FEV1 at Week 16 for participants 
dosed with MEDI3506 is equal to the change from baseline in FEV1 at Week 16 for 
participants dosed with placebo. The alternative hypothesis is that the change from baseline in 
FEV1 at Week 16 for participants dosed with MEDI3506 is greater than the change from 
baseline in FEV1 at Week 16 for participants dosed with placebo, ie:

H0: Change from Baseline in FEV1 at Week 16 (MEDI3506-placebo) = 0.

H1: Change from Baseline in FEV1 at Week 16 (MEDI3506-placebo) > 0. 
Hypothesis testing will be performed at the one-sided 10% level. If the p-value is < 0.1, reject 
H0 and accept H1. A hierarchical testing strategy will be used to preserve the type I error for 
the comparisons of each of the 2 dose levels of MEDI3506 versus placebo, as follows:

Step 1: Test MEDI3506 600 mg versus placebo in regard to H0

Step 2: If previous step rejects: test MEDI3506 300 mg versus placebo in regard to H0
9.2
Sample Size Determination
A sample size of 216 participants (72 participants per treatment group), randomised 1:1:1 to 
MEDI3506 
mg: MEDI3506 
 mg: placebo, will provide at least 80% power to detect a 
statistically significant difference in change from baseline to Week 16 in pre-BD FEV1, 
CCI
CCI


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assuming a difference of 150 mL between placebo and MEDI3506, a between-participant SD 
of 420 mL and a one-sided- 10% alpha level. To allow for 5% participants being ineligible for 
the primary analysis, a total of approximately 228 participants will be randomised 
(approximately 76/arm).
Up to 60 participants are intended to be included in the cough sub-study (ie, approximately 
20 participants per treatment group). However, given the exploratory nature of the sub-study 
and that it may not be activated in all countries, randomisation of participants not included in 
the sub-study will not be restricted, therefore, sub-study recruitment may not be achieved. 
Since limited data are available on cough monitoring in this population, the sub-study is 
considered exploratory and no formal power calculations have been performed.
9.3
Populations for Analyses
The following populations are defined:
Table 8
Populations for Analysis
Population/Analysis set
Description
ITT population
Participants who are randomised and receive any study intervention. 
Participants will be analysed according to their randomised treatment group.
As-treated Population
Participants who are randomised and receive any study intervention. 
Participants will be analysed according to the treatment they actually 
receive.
PK population
Participants who received at least one dose of MEDI3506 and had at least 
one detectable serum concentration measurement post first dose of study 
intervention. Participants will be analysed according to the treatment they 
actually receive.
ITT = Intent-to-treat; PK = pharmacokinetic(s).
The ITT population will be used to summarise all demographic and baseline characteristics, 
concomitant medications, and efficacy measures. The As-treated population will be used to 
summarise all safety measures (AEs, laboratory tests, ECG, and vital signs). The PK 
population will be used to summarise PK measures.
9.4
Statistical Analyses
All personnel involved with the analysis of the study will remain blinded until Primary 
clinical data lock and until Clinical Study Protocol deviations are identified.
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be developed and finalised before Primary clinical data lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. 


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This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. Any deviations from this plan will be reported in the CSR.
9.4.1
General Considerations
Efficacy analyses will be performed using the ITT population. 
The primary estimand is a ‘Treatment Policy’ estimand, as follows: The difference in mean 
change from baseline in FEV1 at Week 16 (MEDI3506 – placebo) will be estimated using a 
repeated measures mixed effects analysis of covariance model, for the ITT population. This 
will include all available data from all visits up to and including Week 16, irrespective of 
whether the participant discontinued study intervention or received rescue therapy.
Demography and baseline characteristics will be summarised by treatment group for the ITT 
population.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
The difference in mean change from baseline in FEV1 at Week 16 (MEDI3506 – placebo) will 
be estimated using a repeated measures mixed effects analysis of covariance model, for the 
ITT population. The model will include all available data from all visits up to and including 
Week 16, irrespective of whether the participant discontinued study intervention or received 
rescue therapy. No imputation will be made for missing data, as a repeated measures model is 
being applied. The model will include fixed effects for baseline, visit, treatment and the 
baseline by visit and treatment by visit interactions. 
The significance of the treatment effect will be tested at a 10% one-sided level of significance 
as described in Section 9.1.
9.4.2.2
Secondary and Exploratory Endpoints
Change from baseline in ACQ-6, SGRQ and AO parameters will be analysed using a repeated 
measures analysis of covariance model, similar to that described for the primary efficacy 
analysis (Section 9.4.2.1). PRO responder endpoints at Week 16 will be analysed using a 
chi-squared test. 
Objective cough measurements will be analysed using analysis of covariance, and may be 
log-transformed prior to analysis. Estimates of the least square mean change from baseline for 
each treatment, and the difference between them, together with 80% confidence interval and 
one-sided p-values, will be obtained from the model for each visit.
Time to first CompEx event and time to first asthma exacerbation will be analysed using a 
Cox proportional hazard model, with treatment fitted as a covariate. The data will also be 
displayed in a Kaplan-Meier plot. The CompEx event rate will be analysed using negative 


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binomial regression, with the log(follow-up time) included as an offset term. The dependent 
variable will be the number of CompEx events through Week 16, and the model will include 
treatment group as a fixed effect. All available data from participants through to Week 16 will 
be included, irrespective of whether they discontinued study intervention.
Change from baseline to Week 16 in concentration of FeNO will be analysed using a repeated 
measures analysis of covariance model, similar to that described for the primary efficacy 
analysis (Section 9.4.2.1). Where appropriate, endpoints may be log-transformed prior to 
analysis. Estimates of the least square mean change from baseline for each treatment, and the 
difference between them, together with 80% confidence interval and one-sided p-values, will 
be obtained from the model for each visit.
The difference in mean change from baseline in post-BD FEV1, and the change in FEV1 % 
reversibility at Weeks 8 and 16 will be estimated using a repeated measures mixed effects 
analysis of covariance model, similar to that described for the primary efficacy analysis 
(Section 9.4.2.1).
The composite estimand will be the difference between MEDI3506 and placebo response rate 
at Week 16 in the ITT population. Participants with missing data at Week 16 will be 
considered non-responders. For each MEDI3506 group compared with placebo, the odds ratio 
and 80%, and one-sided p-values will be reported.
9.4.3
Subgroup Analyses
Subgroup analyses may be performed and will be described in the SAP. 
9.4.4
Safety
The occurrence of AEs and SAE will be described by System Organ Class, Preferred Term, 
severity, and relationship to the study intervention. Participants will be counted only once for 
each preferred term, once for each system organ class, and by the highest severity of an event. 
Number of participants with elevated liver function tests that meet the HL definition will be 
evaluated. Laboratory evaluations will be summarised with descriptive statistics at each visit 
and change from baseline summarised for each post-baseline visit. Laboratory measurements 
will also be summarised based on the number and percentage of participants above or below a 
pre-specified threshold for each test. The number of participants with clinically significant 
abnormal ECG results based on investigators’ judgments will be summarised at each visit. 
Change from baseline in vital signs will be summarised by visit.
9.4.5
Other Analyses
9.4.5.1
Immunogenicity and PK
Positive antibodies to MEDI3506 will be reported by treatment group. If there is a high 
incidence of ADA, the association of ADA with MEDI3506 concentration will be assessed. In 


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addition, the relationship between ADA and biomarkers, efficacy, and safety may be 
evaluated. MEDI3506 serum concentrations will be tabulated along with descriptive statistics. 
Mean and individual serum MEDI3506 concentration-time profiles will be plotted. Population 
PK modelling may be performed if data allow, but will not be reported in the CSR. The 
potential correlation between PK exposure and biomarkers, and efficacy/safety response may 
be evaluated.
9.4.5.2
Exploratory Biomarker Outcomes
Change from baseline in blood eosinophils, EDN, total IgE and blood neutrophils will be 
analysed using a repeated measures analysis of covariance model, similar to that described for
the primary efficacy analysis, in Section 9.4.2.1. Where appropriate, endpoints may be 
log-transformed prior to analysis. Estimates of the least square mean change from baseline for 
each treatment, and the difference between them, together with 80% confidence interval and 
one-sided p-values, will be obtained from the model for each visit.
Full details of all other exploratory biomarker outcomes will be provided in the SAP.
9.4.5.3
Exploratory Analyses
Full details of all other exploratory analyses will be provided in the SAP.
9.5
Interim Analyses 
No formal interim analyses are planned for this study. 
The primary analysis will occur once all participants have either completed the SV10 
(Week 16) assessments or have withdrawn from the study. The sponsor staff will be fully 
unblinded following the Primary Analysis Clinical Data Lock. Investigators, participants and 
site staff will not be made aware of unblinded treatment assignments for individual 
participants who are in the follow-up period until these participants have completed the study. 
The final analysis will occur when all participants have completed the follow-up period at 
SV12 (Week 24) or have withdrawn from the study.
9.6
Data Monitoring Committee
An independent unblinded DSMB will perform evaluations of safety data, from this study and 
Studies D9180C00002 (in participants with COPD), D9182C00001 (in participants with AD) 
and D9183C00001 (in participants with DKD). Details of the composition of the DSMB, the 
data to be reviewed, and the frequency of the meetings can be found in the DSMB Charter. 
The DSMB will make any necessary recommendations to the sponsor regarding further 
conduct of the studies based on their evaluations of emerging data.
For details on the DSMB, refer to Appendix A 4.


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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol, and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council of International Organisations of Medical 
Sciences International Ethical Guidelines.

Applicable ICH GCP Guidelines.

Applicable laws and regulations.

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies (except those using medical devices), investigator safety reports must be 
prepared for Suspected Unexpected Serious Adverse Reactions according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
A 2
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.


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
Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 3
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 4
Committee’s Structure
An independent DSMB will be formed to evaluate safety data from concurrently conducted 
MEDI3506 Phase II clinical studies in other indications. 
Unblinded review of safety data will be required for indications where the potential risks of 
MEDI3506 are high due to the disease under study and the common comorbidities of 
particular participant populations. Safety data from this study will be provided to the DSMB 


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for oversight of all safety data. Details of the composition of the DSMB, the data to be 
reviewed, and the frequency of the meetings can be found in the DSMB Charter.
A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov, as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 6
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 7
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.


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
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the source data verification 
plan.
A 8
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumours reported during a study should generally be assessed as serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgement on an individual event basis should be 
applied to clarify that the malignant tumour event should be assessed and reported as a 
non-serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.


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Life threatening
‘Life-threatening’ means that the participant 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 
participant’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 participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important medical event or medical treatment
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 jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment.

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm.

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation.

Development of drug dependency or drug abuse.
Severity rating scale
The determination of severity should be made by the investigator based upon medical 
judgment and the severity categories of Grade 1 to 5 (based on the CTCAE criteria, 
NCI 2017) as defined below.
Grade 1
An event of mild intensity that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.


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Grade 2
An event of moderate intensity that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of
daily living, causing discomfort but poses no significant or permanent risk of 
harm to the subject.
Grade 3
A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical 
status of the subject.
Grade 4
An event, and/or its immediate sequelae, that is associated with an imminent 
risk of death.
Grade 5
Death as a result of an event.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 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 Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.


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In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, 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.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:

Occurred.

Was identified and intercepted before the participant received the drug.

Did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant.

Drug not administered as indicated, for example, wrong route or wrong site of 
administration.

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 


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
Wrong participant received the medication (excluding RTSM errors)

Wrong drug administered to participant (excluding RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from RTSM - including those which lead to one of the above 
listed events that would otherwise have been a medication error.

Participant accidentally missed drug dose(s) eg, forgot to take medication.

Accidental overdose (will be captured as an overdose).

Participant failed to return unused medication or empty packaging.

Errors related to background and rescue medication, or SOC medication in open label 
studies, even if an AstraZeneca product.
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
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 record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.


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AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900:
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, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations.

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content.


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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant’s DNA, ie, the entire genome.

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on MEDI3506 continues but no longer than 
15 years after the end of the study or other period as per local requirements.
D 2
Genetic Research Plan and Procedures
Selection of genetic research population
All participants will be asked to participate in this genetic research. Participation in the 
genomics initiative is voluntary and if a participant declines to participate there will be no 
penalty or loss of benefit. The participant will not be excluded from any aspect of the main 
study.
Inclusion criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant.

Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.

Healthy volunteers and paediatric patient samples will not be collected for the Genomics 
Initiative.


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Withdrawal of consent
Participants may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2.
Collection of samples for genetic research
The blood sample for this genetic research will be obtained from the participants at SV4 
(randomisation). Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an AE. If for any 
reason the sample is not drawn at SV4, it may be taken at any visit until the last study visit. 
Only one sample should be collected per participant for genetics during the study.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years after the end of the study, after which they will be destroyed. DNA is a finite 
resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed consent
The genetic component of this study is optional and the participant may participate in other 
components of the main study without participating in this genetic component. To participate 
in the genetic component of the study the participant must sign and date both the consent form 
for the main study and the addendum for the Genomics Initiative component of the study. 
Copies of both signed and dated consent forms must be given to the participant and the 


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original filed at the study centre. The PI is responsible for ensuring that consent is given freely 
and that the participant understands that they may freely withdrawal from the genetic aspect of 
the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, and/or general physician unless required 
to do so by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. However, in exceptional circumstances, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL and HL cases. It is not intended to be a comprehensive guide to the management 
of elevated liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the IMP.
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.
Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, 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. 


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN.

AST ≥3 × ULN.

TBL ≥2 × ULN.
When a participant meets any of the PHL 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 PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative.

Request a repeat of the test (new blood draw) by the central laboratory without delay.

Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result.
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:

Determine whether the participant meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and local 
laboratory results).
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.


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E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central study team.

Within one day of PHL criteria being met, the investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change # in the participant’s 
condition.

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the Hy’s law lab kit should be used.

Complete the three Liver eCRF Modules as information becomes available.
# A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator. 
This may be in consultation with the Study Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible 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, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate. 


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According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca 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:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 15 calendar days 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:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

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 still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.


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E 6
Laboratory tests
Hy’s Law lab kit for central laboratories 
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-transferrin) b
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive.
CMV = cytomegalovirus; EBV = Epstein-Barr virus GGT = gamma glutamyl transferase; HAV = hepatitis A 
virus; HBV = hepatitis B virus; HCV  hepatitis C virus; HEV = hepatitis E virus; Ig = immunoglobulin; 
INR = international normalised ratio; LDH = lactate dehydrogenase.
E 7
References
1
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
2
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix F
Maintenance Therapy Equivalence Table
Estimated daily doses for ICS.
Asthma Therapy
Total Daily Dose (μg/day)
Medium
High
ICS a
Beclomethasone dipropionate (CFC)
> 500 to 1000
> 1000
Beclomethasone dipropionate (HFA)
> 200 to 400
> 400
Budesonide
> 400 to 800
> 800
Ciclesonide
> 160 to 320
> 320
Fluticasone furoate (eg, Arnuity® Ellipta® Breo®)
N/A
200
Fluticasone propionate
> 250 to 500
> 500
Fluticasone propionate (HFA)
> 250 to 500
> 500
Mometasone furoate
> 220 to 440
> 440
Triamcinolone acetonide
> 1000 to 2000
> 2000
ICS in ICS/LABA combination a
Beclomethasone dipropionate (eg, Fostair®)
> 200 to 400
> 400
Fluticasone propionate (HFA; eg, Seretide®, Advair®)
> 250 to 500
> 500
Fluticasone furoate (eg, Relvar® Ellipta®, Breo® Ellipta®)
N/A
184 to 200
Budesonide, if as delivered dose (eg, Symbicort®)
> 400 to 640
> 640
Mometasone Furoate (eg, Dulera®)
> 220 to 400
> 400
a
The ICS doses were derived from GINA 2018 and the ICS/LABA combinations were derived from GINA 
2017 and 2018 and using prescribing information.
CFC = chlorofluorocarbon propellant; GINA = Global Initiative for Asthma; HFA = hydrofluoroalkane 
propellant; ICS = inhaled corticosteroid; LABA = long-acting beta-agonist; N/A = not applicable.


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Appendix G
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death (Sampson et al 2006). They recognise 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalised hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING:
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia).
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours):
(a) Adults: SBP of less than 90 mmHg or greater than 30% decrease from that 
participant’s baseline.
For the purpose of AE reporting, the above criteria should be used to guide retrospective 
judgment as to whether an event was true anaphylaxis. Guidance on the recognition of 
possible anaphylaxis at the time of the event is provided (Appendix H).


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Appendix H
Signs, Symptoms, and Management of Acute Anaphylaxis
Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical 
equipment to treat anaphylactic reactions must be immediately available at study sites, and 
study personnel should be trained to recognise and treat anaphylaxis. Local or national 
guidelines for the recognition and management of acute anaphylaxis should be followed 
where available. Where not available, guidance is provided below.
H 1
Signs and Symptoms 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 oedema.

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.

Rhinorrhoea.

Change in voice.

Metallic taste.

Nausea, vomiting, diarrhoea, abdominal cramps, and bloating.

Lightheadedness.

Headache.

Uterine cramps.

Generalised warmth.


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H 2
Management of Acute Anaphylaxis
H 2.1
Immediate Intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine intramuscularly every 5 to 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.
H 2.2
Possibly Appropriate, Subsequent Measures Depending on Response to 
Epinephrine
1
Place participant in recumbent position and elevate lower extremities.
2
Establish and maintain airway.
3
Administer oxygen.
4
Establish venous access.
5
Normal saline IV for fluid replacement.
H 2.3
Specific Measures to Consider after Epinephrine Injections, Where 
Appropriate
1
Consider epinephrine infusion.
2
Consider H1 and H2 antihistamines.
3
Consider nebulised beta-2 agonist [eg, albuterol (salbutamol)] for bronchospasm resistant 
to epinephrine.
4
Consider systemic corticosteroids.
5
Consider vasopressor (eg, dopamine).
6
Consider glucagon for participant taking b-blocker.
7
Consider atropine for symptomatic bradycardia.
8
Consider transportation to an emergency department or an intensive care facility.
9
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
If a suspected anaphylactic reaction occurs during or within a 24-hour period after 
administration of study intervention, blood samples for serum tryptase should be collected as 
soon as possible after the event, at 60 ± 30 minutes after the event, at discharge, and between 
2 and 4 weeks post discharge. Immediate care of the participant and treatment of the reaction 
must take priority over collecting blood samples.


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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.


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Appendix I
Contraception Guide
Females are considered to be of childbearing potential unless they meet either of the criteria, 
as follows:

Surgically sterilised (including bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy), or

Post-menopausal.
For females aged < 50 years, post-menopausal is defined as having both:

A history of ≥12 months amenorrhea, without an alternative cause, following cessation of 
exogenous sex-hormonal treatment and,

A follicle-stimulating hormone level in the post-menopausal range.
For females aged ≥50 years, post-menopausal is defined as having a history of ≥12 months 
amenorrhea, without an alternative cause, following cessation of exogenous sex-hormonal 
treatment.
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table I9.
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable methods of 
contraception.
Table I9
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (IUS) a
•
Bilateral tubal occlusion
•
Vasectomised partner b
•
Sexual abstinence c
Combined (estrogen and progestogen containing 
hormonal contraception)

Oral (combined pill)

Injectable

Transdermal (patch)
Progestogen-only hormonal contraception

Desogestrel
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy medical testing of surgical success (ie, absence of sperm in ejaculate).
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the 
participant.


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Appendix J
Abbreviations
Abbreviation or special 
term
Explanation
ACM
Ambulatory cough monitoring
ACQ
Asthma control questionnaire
AD
Atopic dermatitis
ADA
Anti-drug antibody(ies)
AE
Adverse Event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine transaminase
anti-HBc
Antibody to hepatitis B core antigen 
anti-HBs
Antibody to hepatitis B surface antigen
AO
Airwave oscillometry
AST
Aspartate transaminase
ATS
American thoracic society
AUC
Area under the concentration-time curve
BD
Bronchodilator
BP
Blood pressure
BTR
Best test report
BMI
Body mass index
CAP
College of American Pathologists
CLIA
Clinical Laboratory Improvement Amendments
Cmax 
Observed maximum concentration
CompEx
Composite endpoint for severe exacerbations of asthma
COPD
Chronic obstructive pulmonary disease
COVID-19
Coronavirus disease 2019
CRO
Contract Research Organisation
CRS
Chronic rhinosinusitis
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP450
Cytochrome P450
DBP
Diastolic blood pressure
DKD
Diabetic kidney disease


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Abbreviation or special 
term
Explanation
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
E/D
Early study intervention discontinuation
EDN
Eosinophil derived neurotoxin
ERS
European Respiratory Society
FDA
Food and Drug Administration
FeNO
Fractional exhaled nitric oxide
FEV1
Forced expiratory volume in the first second
FVC
Forced vital capacity
GCP
Good clinical practice
GINA
Global Initiative for Asthma
GGT
Gamma-glutamyl transferase
GMP
Good manufacturing practice
HbA1c
Haemoglobin A1c
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
HL
Hy’s law
HRT
Hormone replacement therapy
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
ICS
Inhaled corticosteroids
IEC/IRB
Institutional Ethics Committee/Institutional Review Board
IFN
Interferon
Ig
Immunoglobulin
IGRA
Interferon gamma release assay
IL
Interleukin
ILC2s
Type 2 innate lymphoid cells
IMP
Investigation medicinal product
ITT
Intent-to-treat
LABA
Long-acting beta agonist(s)
LAMA
Long-acting muscarinic antagonist(s)
LTBI
Latent tuberculosis infection


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Abbreviation or special 
term
Explanation
LTRA
Leukotriene receptor antagonist(s)
LVEF
Left ventricular ejection fraction
mAb
Monoclonal antibody(ies)
mRNA
Messenger RNA
NCI
National Cancer Institute
NIMP
Non-investigation medicinal product
NOAEL
No observed adverse events level
NT-proBNP
N-terminal prohormone of B-type natriuretic peptide
OCS
Oral corticosteroid(s)
PC20
Provocative concentration causing a 20% decline in FEV
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PEF
Peak expiratory flow
PHL
Potential Hy’s law
PI
Principal Investigator 
PNV
Predicted normal value(s)
PK
Pharmacokinetic(s)
PRO
Patient reported outcome
RTSM
Randomisation and trial supply management
SABA
Short-acting bronchodilator
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic blood pressure
SC
Subcutaneous
SD
Standard deviation
SGRQ
St George’s respiratory questionnaire 
SID
Subject identification
SNOT-22
Sino-nasal outcome test
SNP
Single nucleotide polymorphism
SOA
Schedule of activities
SOC
Standard of care
sST2
Soluble ST2
SV
Study visit
CCI


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Abbreviation or special 
term
Explanation
TB
Tuberculosis
TBL
Total bilirubin
Th
T-helper
TNFα
Tumor necrosis factor alpha
TSLP
Thymic stromal lymphopoietin
ULN
Upper limit of normal
VAS
Visual analogue scale


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Appendix K
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 3.0 (25 May 2021)
Overall Rationale for the Amendment:
Changes from Global Protocol Amendment 2.0
The principal reason for this amendment is to amend the study design to separate the main 
study (Part A) from the airway hyperresponsiveness and remodelling study, Part B, which was 
previously a sub-study.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints
Table of objectives and endpoints 
divided into 3 separate tables to 
present those objectives specific 
to Part A, Part B, and both Part A 
and Part B, respectively.
To add clarity to the 
presentation of study 
objectives and 
endpoints in the 
protocol.
Non-substantial
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints
For Part B endpoints: added new 
timepoint (Week 12 compared 
with baseline) for FEV1% 
reversibility and post BD FEV1
(L); specified timepoints of 
Week 16 compared with baseline 
for proportion of participants who 
achieve at least one doubling 
concentration improvement in 
methacholine PC20 and Week 12 
compared with baseline for 50% 
reduction in post BD FEV1
reversibility.
To amend study 
endpoints as 
appropriate for the 
change to a 2-part study 
design.
Non-substantial
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design
Added details of the design of 
Part B: approximately 
44 evaluable participants to be 
randomised in a 1:1 ratio to 
receive 
 mg MEDI3506 or 
placebo 
 by SC injection for 
a total of doses. 
To amend the study 
design to divide it into 
2 parts: Part A (main 
study) and Part B 
(airway 
hyperresponsiveness 
and remodelling study).
Substantial
Section 1.1 Synopsis,
Section 9.1 Statistical 
Hypotheses, Section 9.2 
Sample Size 
Determination, 
Added details for Part B of 
sample size calculation and 
analysis of primary and secondary 
endpoints.
To specify the 
statistical methods for 
Part B.
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.4 Statistical 
Analyses
Section 1.3 Schedule of 
Activities, Section 4.1 
Overall Design, 
Section 8.1.7 VitaloJAK 
Cough Monitor, 
Section 8.1.8.2 Cough 
Visual Analogue Scale, 
Section 8.1.9 
Methacholine Challenge 
Testing, Section 8.1.10 
Inspiratory/Expiratory 
Computed Tomography
Clarification added that the 
exploratory cough sub-study 
applies to Part A only, that Part B 
comprises the exploratory airway 
hyperresponsiveness and 
remodelling study, and that SV3 
only applies to Part B.
To take into account the 
change to a 2-part study 
design.
Non-substantial
Section 1.3 Schedule of 
Activities, Section 4.1 
Overall Design
Specified that for Part A and 
Part B at SV1, post-BD 
spirometry is to be performed if 
documented evidence of asthma 
is not already available. In Part A 
at SV2 it should be performed if 
documented evidence of asthma 
is not already available and in 
Part B at SV2 it is to be 
performed regardless of 
availability of documented 
evidence.
To take into account the 
change to a 2-part study 
design.
Non-substantial
Section 1.3 Schedule of 
Activities
Clarified that on days when 
investigational product is 
administered, all assessments 
should be performed pre-dose 
unless otherwise specified.
For clarity.
Non-substantial
Section 1.3 Schedule of 
Activities
For Part B, specified that 
echocardiogram may be 
performed any time after signing 
informed consent.
To ensure that results 
are available prior to 
methacholine challenge 
testing and CT scan.
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.3 Schedule of 
Activities, Section 5.1 
Inclusion Criteria, 
Section 6.2.2.1 Treatment 
Administration
Updated wording regarding 
pregnancy testing in female 
participants.
To ensure clarity on 
pregnancy testing.
Non-substantial
Section 1.3 Schedule of 
Activities
Clarified provision for airwave 
oscillometry and in-clinic 
spirometry to be performed 
4 hours post-administration of 
study intervention at SV4 
(Randomisation).
To add clarity for 
timing of pre- and post-
dose airwave 
oscillometry and 
in-clinic spirometry 
assessments.
Non-substantial
Section 1.3 Schedule of 
Activities
In Part B, methacholine challenge 
testing and inspiratory/expiratory 
CT moved from SV9 to SV10. 
Added provision that in-clinic 
spirometry post-BD for Part B is 
at SV9, and for Part A is at SV10.
The creation of a 
separate study Part B 
(rather than a 
sub-study) removed 
logistical constraints, 
meaning that 
methacholine challenge 
testing and 
inspiratory/expiratory 
CT can now occur at 
SV10.
Non-substantial
Section 1.3 Schedule of 
Activities
Specified that the mean value of 
each parameter from the triplicate 
ECG will be used as the baseline 
value.
For clarity.
Non-substantial
Section 1.3 Schedule of 
Activities, Section 2.3.1 
Risk Assessment
Clarified that methacholine 
challenge testing and CT scans 
will only be performed in Part B. 
To specify potential 
risks of clinical 
significance that are 
applicable to Part B 
only.
Non-substantial
Section 2.3.1.1 Study 
Conduct During 
COVID-19 Pandemic
Specified that respiratory testing 
at locations other than the primary 
study site may be required in 
Part B of the study; consequently, 
participants in Part B could be at 
increased risk for exposure to 
individuals with COVID-19.
To specify the impact 
of the COVID-19 
pandemic on Part B. 
AstraZeneca recognises 
that conduct of Part B is 
very challenging during 
the acute pandemic 
phase; therefore, it will 
be activated only when 
safe and feasible.
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.2.1 Rationale 
for Endpoints
Added rationale for the Part B 
primary endpoint (change in 
methacholine PC20). Clarified that 
objective cough monitoring will 
only be performed in the Part A 
exploratory cough sub-study.
To add rationale for the 
Part B primary endpoint 
and clarify those 
exploratory endpoints 
that apply only to 
Part A. 
Non-substantial
Section 4.3 Justification 
for Dose
Clarified that the MEDI3506 dose 
of 
mg SC 
 will be used 
in Part A and Part B but the lower 
dose of
mg 
 SC will 
only be used in Part A.
To specify which part 
of the study each dose 
of MEDI3506 will be 
used.
Non-substantial
Section 5 Study 
Population
Section restructured to present 
inclusion and exclusion criteria in 
the following order: those 
applicable to both Part A and 
Part B, those applicable to Part A 
only, and those applicable to 
Part B only. As a consequence, 
some renumbering of inclusion 
criteria has occurred.
To provide clarification 
and aid sites to apply 
study inclusion and 
exclusion criteria 
appropriately for Part A 
and Part B.
Non-substantial
Section 5.2 Exclusion 
Criteria
Clarification of a positive IGRA 
test in the context of treated latent 
TB infection
To avoid exclusion of 
participants who have 
been treated for latent 
TB infection but still 
have a positive IGRA 
test
Non-substantial
Section 5.1.1, Criteria to 
be Assessed at SV1, 
Section 5.1.2, Criteria to 
be Assessed at SV2 and 
SV4 (Randomisation), 
Section 5.1.3 Criteria to 
be Assessed for 
Exploratory Airway 
Hyperresponsiveness and 
Remodelling Sub study, 
Section 5.2.1 Criteria to 
be Assessed at SV1 and 
SV2, Section 5.2.2 
Criteria to be Assessed at 
SV1, SV2 and SV4 
(Randomisation)
Section headings revised to 
reflect change in structure from 
specifying criteria at specific SVs 
to specifying criteria applicable to 
both Part A and Part B, Part A 
only, and Part B only.
As a consequence of 
restructuring the study 
population section.
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 5.1.4 Criteria to 
be Assessed for 
Exploratory Cough 
Sub-study, Section 5.2.3 
Criteria to be Assessed 
for Exploratory Airway 
Hyperresponsiveness and 
Remodelling Sub study at 
SV2 and SV3
Sections removed and criteria 
moved to relevant restructured 
sections.
As a consequence of 
restructuring the study 
population section.
Non-substantial
Section 5.1 Inclusion 
Criteria
Inclusion criterion regarding 
documented history of ≥1asthma 
exacerbation in 12 months prior 
to SV1 to be applicable to Part A 
only.
To avoid negatively 
affecting recruitment, 
as asthma in 
participants who meet 
this criterion may be 
too severe for 
methacholine challenge 
testing in Part B.
Non-substantial
Section 5.1 Inclusion 
Criteria
For Part B: clarified that inclusion 
criterion regarding morning 
pre-BD FEV1 is ≥ 60% predicted 
normal and > 1.5 L at SV1 and 
SV2. Clarified that methacholine 
PC20 ≤ 8 mg/mL at SV2 serves as 
documented evidence of asthma.
As a consequence of the 
change to a 2-part study 
design and restructuring 
of the study population 
section.
Non-substantial
Section 5.2 Exclusion 
Criteria
Exclusion Criterion 23(i) updated 
to specify that systemic 
corticosteroids within 4 weeks of 
SV1 is allowed if use is as stable 
maintenance therapy for asthma.
To correct an error in 
protocol whereby stable 
maintenance therapy 
was permitted by 
Inclusion Criterion 5 
(now Inclusion 
Criterion 4) but 
prohibited by the 
original wording of 
Exclusion Criterion 23
Non-substantial
Section 6.2.2.2 
Monitoring Dose 
Administration
Stated that assessment of 
injection site reactions after 
administration of study 
intervention will be carried out by 
the blinded study team.
To clarify that the 
personnel who perform 
the assessment will be 
blinded to study 
treatment.
Non-substantial
Section 6.3.1 Methods for 
Assigning Treatment 
Groups
Added details of stratification 
according to study part and 
sub-study participation.
To take into account the 
change to a 2-part study 
design.
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 6.3.3 Methods for 
Unblinding, Section 9.4 
Statistical Analyses, 
Section 9.5 Interim 
Analyses
Specified, separately for Part A 
and Part B, timing of the primary 
analysis, sponsor staff unblinding, 
and unblinding of all personnel 
involved with the study analysis.
To take into account the 
change to a 2-part study 
design.
Non-substantial
Section 6.5.3 Medication 
Withhold Periods
Updated list of medication 
withhold periods to be applied 
prior to scheduled spirometry, 
AO, and FeNO measurement and 
added list of medication withhold 
periods to be applied prior to 
methacholine challenge testing.
For clarity and to align 
medication withhold 
periods prior to 
methacholine challenge 
testing with ERS 2017 
MCT guidelines.
Non-substantial
Section 6.5.5 COVID-19 
Vaccination
Updated the list of information to 
be recorded (if available) if and 
when a participant receives a 
COVID-19 vaccination.
To ensure collection of 
all data that may be 
needed to assess 
potential interaction 
between COVID-19 
vaccine and 
MEDI3506.
Non-substantial
Section 8.3.10.1 Maternal 
Exposure, 
Section 8.3.10.2 Paternal 
Exposure, Appendix B 2 
Definition of Serious 
Adverse Events
Changed “congenital 
abnormality” to “congenital 
anomaly”.
To align with the latest 
AstraZeneca Clinical 
Study Protocol 
template, in which this 
change was made to 
align with regulatory 
requirements.
Non-substantial
Section 8.5.2 
Pharmacokinetics
Specified that samples from 
participants who receive placebo 
may be analysed to confirm no 
dosing with MEDI3506.
For clarification.
Non-substantial
Section 8.5.3 
Immunogenicity
Assessments
Specified that ADA samples may 
be tested for neutralising 
antibody.
For clarification.
Non-substantial
Section 9.4.5.2 
Exploratory Biomarker 
Outcomes
Specified that change from 
baseline in EDN and total IgE 
will be analysed for Part A only.
Measurement in Part A 
only is considered 
sufficient.
Non-substantial
Section 9.6 Data 
Monitoring Committee
Reference to 
Study D9180C00001 changed to 
Study D9180C00002.
To correct an error
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Throughout
Minor editorial and document 
formatting revisions.
Minor, therefore have 
not been summarised.
Non-substantial
ADA = anti-drug antibody(ies); AO = airwave oscillometry; BD = bronchodilator; COVID-19 = coronavirus 
disease 2019; CT = computed tomography; ECG = electrocardiogram; EDN = eosinophil derived neurotoxin; 
ERS = European Respiratory Society; FeNO = fractional exhaled nitric oxide; FEV1 = forced expiratory volume 
in the first second; Ig = immunoglobulin; IGRA = interferon gamma release assay; L = litre(s); 
MCT = methacholine challenge testing; PC20 = provocative concentration causing a 20% decline in FEV; 
 SC = subcutaneous; SV = study visit; TB = tuberculosis.
Amendment 2.0 (23 February 2021)
Overall Rationale for the Amendment:
Changes from Global Protocol Amendment 1.0
The principal reason for this amendment is to respond to the recent regulatory 
authorisations/approvals of vaccines against COVID-19 and ensure the protocol is clear with 
respect to them.
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
Section 1.3 Schedule 
of Activities, 
Section 8.1.1 In-clinic 
Spirometry
Added that the timing of 
in-clinic spirometry at 
randomisation visit (SV4) 
should be initiated between 
6:00 AM and 11:00 AM.
To correct a text 
omission in previous 
version of protocol; 
no change to actual 
conduct of the 
spirometry assessment
Non-substantial
Section 1.3 Schedule 
of Activities, Section 
5 Study Population, 
Section 8.2.7 Clinical 
Safety Laboratory 
Assessments
Added provision that 
during the screening 
period, in the event that 
clinical laboratory test 
results are not available 
from central laboratories, 
local laboratories can be 
used following 
consultation with medical 
monitor.
To increase flexibility 
for clinical laboratory 
testing due to 
practical limitations in 
receiving test results.
Non-substantial
Section 1.3 Schedule 
of Activities, 
Section 2.3.1.2 
COVID-19 
Mitigations, 
Section 5.2.1 Criteria 
to be Assessed at SV1 
and SV2
Added provision that 
participants are permitted 
to continue screening if the 
result from the 
SARS-CoV-2 PCR test 
performed at SV1 has not 
been returned by SV2 or 
SV3, and that the test may 
be performed at either SV2 
or SV3 or anytime on or 
To increase flexibility 
for COVID-19 PCR 
testing due to 
practical limitations in 
receiving test results.
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
after Day -7 such that the 
results are available prior 
to SV4.
Section 1.3 Schedule 
of Activities, 
Section 5.1.1 Criteria 
to be Assessed at SV1, 
Section 5.1.2 Criteria 
to be Assessed at SV2 
and SV4 
(Randomisation)
Clarification that all 
female participants should 
have a pregnancy test. 
To ensure clarity on 
testing all females for 
pregnancy.
Non-substantial
Section 1.3 Schedule 
of Activities, 
Section 5.2.1 Criteria 
to be Assessed at SV1 
and SV2, 
Section 8.2.7 Clinical 
Safety Laboratory 
Assessments
Added provision for 
retesting of IGRA.
To permit retesting of 
participants with a 
positive IGRA test 
result, following 
investigator feedback. 
A negative IGRA test 
result is still required 
for eligibility.
Non-substantial
Section 2.3.1.3 
Vaccination Against 
COVID-19
New section added to 
inform investigators of the 
sponsor’s approach to 
COVID-19 vaccination in 
Study D9181C00001.
Provide clarification 
to investigators and to 
help ensure 
interpretability of 
safety data.
Non-substantial
Section 5.2.1 Criteria 
to be Assessed at SV1 
and SV2
Added provision for 
retesting of NT-proBNP.
To permit retesting of 
participants with a 
NT-proBNP result 
greater than the upper 
limit of the laboratory 
reference range if this 
is clinically 
unexpected. An 
acceptable NT-
proBNP result is still 
required.
Non-substantial
Section 5.1.2 Criteria 
to be Assessed at SV2 
and SV4 
(Randomisation)
Adjustment to the periods 
to which the adherence 
criteria apply.
To remove a 
discrepancy between 
the criteria and the 
periods used to 
calculate certain 
relevant baseline 
values.
Non-substantial
Section 6.3.2 Methods 
to Ensure Blinding
Added allowance that 
limited personnel that have 
responsibility for analysing 
To facilitate in-stream 
analysis of PK and 
ADA samples. 
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
PK and ADA samples can 
have access to the 
randomisation schedule. 
Section 5.2.2 Criteria 
to be Assessed at SV1, 
SV2 and SV4 
(Randomisation), 
Section 6.5.4 
Prohibited 
Medications
Clarification that 
adenoviral vector vaccines 
are not considered live 
attenuated.
Addition of certain 
restrictions on when 
vaccines against 
COVID-19 may be 
administered.
Provide clarification 
to investigators and to 
help ensure 
interpretability of 
safety data.
Non-substantial
Section 6.5.5 
COVID-19 
Vaccination, 
Section 8.2.1 Medical, 
Surgical, and Asthma 
History
New text added on 
recording COVID-19 
vaccination
To clarify the need for 
recording of receipt of 
COVID-19 
vaccination.
Non-substantial
COVID-19 = coronavirus disease 2019; IGRA = interferon gamma release assay; NT-proBNP = N terminal 
prohormone of B type natriuretic peptide; PCR = polymerase chain reaction; SV = study visit.
Amendment 1.0 (19 October 2020)
Overall Rationale for the Amendment:
Changes from Original Global Protocol
The principal reasons for this amendment are to provide a harmonised global protocol by 
incorporating the changes from local amendments USA-1.0 and GER-1.0, to remove the 
interim analysis based on FeNO data, and clarify and correct some wording issues. 
The FDA requested changes to the protocol to reflect that all AEs that occur during the study 
should, in relation to study stopping criteria, be treated as related to study drug, unless clearly 
unrelated. The FDA requested additional information on study stopping criteria and a 
standardised toxicity grading scale to be incorporated in the individual and study stopping 
criteria.
The Paul-Ehrlich-Institut requested a change to the protocol to clearly state that the use of 
prohibited medications will lead to discontinuation and to add this point to the list of the 
discontinuation criteria.
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
Section 1.1 Synopsis, 
Section 6.3.3.1 
Unblinding for interim 
Removal of references to 
the interim analysis for 
the study.
Changes in pipeline 
and clinical 
development timing 
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
analysis, Section 9.4 
Statistical Analyses, 
Section 9.5 Interim 
Analyses
made interim 
analysis 
unnecessary.
Section 3 Objectives and 
Endpoints
Removal of airway
volume and airway 
resistance CT scan 
measures from airway 
remodelling endpoint.
Airway volume and 
airway resistance 
are not provided by 
the vendor 
providing the CT 
scan data.
Non-substantial
Section 4.4.1 Study 
Stopping Criteria
New section added.
The FDA requested 
the addition of 
study stopping 
criteria.
Non-substantial
Section 6.2 
Preparation/Handling/
Storage/Accountability of 
Interventions
Addition of list item #1 to 
the section.
To confirm that 
dispensation and 
dosing should 
happen on the same 
day of study 
intervention 
allocation in the 
RTSM system.
Non-substantial
Section 6.2.2 Dose 
Preparation Steps
Addition of ‘respectively’ 
to step 2 of the dose 
preparation steps.
Clarification to 
instructions as use 
of word ‘separate’ 
in the instructions is 
to prevent 
MEDI3506 and 
placebo being 
mixed in one 
syringe, not to 
prevent 2 vials of 
MEDI3506 being 
mixed in one 
syringe.
Non-substantial
Section 7.1 
Discontinuation of Study 
Intervention
Reference to relatedness 
of SAEs as a reason to 
discontinue participants 
from the study removed 
and ‘any SAE of 
≥Grade 4 severity’ 
added.
To address the 
comment from the 
FDA regarding 
concerns on the 
attribution of 
causality of AEs to 
a study drug.
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
Section 7.1 
Discontinuation of Study 
Intervention
New discontinuation 
criterion added.
The PEI required 
the addition of this 
discontinuation 
criterion.
Non-substantial
Appendix B 2 Definition 
of Serious Adverse 
Events
Severity rating scale 
updated from 
‘mild/moderate/severe’ to 
a Grade 1 to 5 scale based 
on CTCAE criteria.
In order to align 
with the 
standardised 
toxicity grading 
used to assess 
individual study 
intervention 
discontinuation 
criteria.
Non-substantial
Throughout
Minor editorial and 
document formatting 
revisions
Minor, therefore 
have not been 
summarised
Non-substantial
AE = adverse event; CT = computerised tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; FDA = Food and Drug Administration; PEI = Paul-Ehrlich-Institut; RTSM = randomisation and trial 
supply management; SAE = serious adverse event.
Changes from local protocol amendment USA-1.0 (04 August 2020)
Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-substantial
Section 1.1 Synopsis, 
Section 6.3.3.1 Unblinding 
for interim analysis, Section 
9.4 Statistical Analyses, 
Section 9.5 Interim 
Analyses
Removal of 
references to the 
interim analysis for 
the study.
Changes in pipeline and 
clinical development 
timing made interim 
analysis unnecessary.
Non-substantial
Section 3 Objectives and 
Endpoints
Removal of airway 
volume and airway 
resistance CT scan 
measures from 
airway remodelling 
endpoint.
Airway volume and 
airway resistance are 
not provided by the 
vendor providing the 
CT scan data.
Non-substantial
Section 6.2 
Preparation/Handling/
Storage/Accountability of 
Interventions
Addition of list 
item #1 to the 
section.
To confirm that 
dispensation and dosing 
should happen on the 
same day of study 
intervention allocation 
in the RTSM system.
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Section # and Name
Description of 
Change
Brief Rationale
Substantial/Non-substantial
Section 6.2.2 Dose 
Preparation Steps
Addition of 
‘respectively’ to 
step 2 of the dose 
preparation steps.
Clarification to 
instructions as use of 
word ‘separate’ in the 
instructions is to prevent 
MEDI3506 and placebo 
being mixed in one 
syringe, not to prevent 2 
vials of MEDI3506 
being mixed in one 
syringe.
Non-substantial
Section 7.1 Discontinuation 
of Study Intervention
New 
discontinuation 
criterion added.
The PEI required the 
addition of this 
discontinuation 
criterion.
Non-substantial
Throughout
Minor editorial and 
document 
formatting 
revisions
Minor, therefore have 
not been summarised
Non-substantial
AE = adverse event; CT = computerised tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; FDA = Food and Drug Administration; PEI = Paul-Ehrlich-Institut; RTSM = randomisation and trial 
supply management.
Changes from local protocol amendment GER-1.0 (01 October 2020)
Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
Section 1.1 Synopsis, 
Section 6.3.3.1 
Unblinding for interim 
analysis, Section 9.4 
Statistical Analyses, 
Section 9.5 Interim 
Analyses
Removal of references to 
the interim analysis for 
the study.
Changes in pipeline 
and clinical 
development timing 
made interim 
analysis 
unnecessary.
Non-substantial
Section 3 Objectives and 
Endpoints
Removal of airway 
volume and airway 
resistance CT scan 
measures from airway 
remodelling endpoint.
Airway volume and 
airway resistance 
are not provided by 
the vendor 
providing the CT 
scan data.
Non-substantial
Section 4.4.1 Study 
Stopping Criteria
New section added.
The FDA requested 
the addition of 
study stopping 
criteria.
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-substantial
Section 6.2 
Preparation/Handling/
Storage/Accountability of 
Interventions
Addition of list item #1 to 
the section.
To confirm that 
dispensation and 
dosing should
happen on the same 
day of study 
intervention 
allocation in the 
RTSM system.
Non-substantial
Section 6.2.2 Dose 
Preparation Steps
Addition of ‘respectively’ 
to step 2 of the dose 
preparation steps.
Clarification to 
instructions as use 
of word ‘separate’ 
in the instructions is 
to prevent 
MEDI3506 and 
placebo being 
mixed in one 
syringe, not to 
prevent 2 vials of 
MEDI3506 being 
mixed in one 
syringe.
Non-substantial
Section 7.1 
Discontinuation of Study 
Intervention
Reference to relatedness 
of SAEs as a reason to 
discontinue participants 
from the study removed 
and ‘any SAE of 
≥Grade 4 severity’ 
added.
To address the 
comment from the 
FDA regarding 
concerns on the 
attribution of 
causality of AEs to 
a study drug.
Non-substantial
Appendix B 2 Definition 
of Serious Adverse 
Events
Severity rating scale 
updated from 
‘mild/moderate/severe’ to 
a Grade 1 to 5 scale based 
on CTCAE criteria.
In order to align 
with the 
standardised 
toxicity grading 
used to assess 
individual study 
intervention 
discontinuation 
criteria.
Non-substantial
Throughout
Minor editorial and 
document formatting 
revisions
Minor, therefore 
have not been 
summarised
Non-substantial
AE = adverse event; CT = computerised tomography; CTCAE = Common Terminology Criteria for Adverse 
Events; FDA = Food and Drug Administration; RTSM = randomisation and trial supply management; 
SAE = serious adverse event.


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Alving et al 2017
Alving K AR, Crater G, LaForce C F, Rickard K. Validation of a new portable exhaled nitric 
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Bonnelykke et al 2014
Bonnelykke K, Sleiman P, Nielsen K, Kreiner-Moller E, Mercader JM, Belgrave D et al. A 
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Hirota et al 2011
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study identifies three new susceptibility loci for adult asthma in the Japanese population. Nat 
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Hodzic et al 2017
Hodzic Z, Schill EM, Bolock AM, Good M. IL-33 and the intestine: The good, the bad, and 
the inflammatory. Cytokine. 2017;1001-10.
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severe allergic asthma. Allergy. 2018;73(11):2192-204.


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Document Name: d9181c00001-csp-amendment-4
Document Title:
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SAP_001.pdf: 
Statistical Analysis Plan  
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10 Jan 2023 
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Statistical Analysis Plan 
Study Code 
D9181C00001 
Edition Number 
Final 3.0 
Date 
10 Jan 2023 
A Phase II, Randomised, Double-blind, Placebo-controlled Study 
to Assess the Efficacy and Safety of MEDI3506 in Adult 
Participants with Uncontrolled Moderate-to-severe Asthma 
(FRONTIER3) 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
TABLE OF CONTENTS .......................................................................................................... 2 
LIST OF TABLES .................................................................................................................... 5 
LIST OF FIGURES ................................................................................................................... 6 
LIST OF ABBREVIATIONS ................................................................................................... 7 
AMENDMENT HISTORY ..................................................................................................... 10 
1 
STUDY DETAILS ............................................................................................... 12 
1.1 
Study objectives .................................................................................................... 12 
1.2 
Study design ......................................................................................................... 15 
1.3 
Number of participants ......................................................................................... 16 
2 
ANALYSIS SETS ................................................................................................ 16 
2.1 
Definition of analysis sets ..................................................................................... 16 
2.2 
Violations and deviations ..................................................................................... 17 
3 
PRIMARY AND SECONDARY VARIABLES ................................................. 17 
3.1 
General principles ................................................................................................. 17 
3.1.1 
Baseline definitions .............................................................................................. 17 
3.1.2 
Study day .............................................................................................................. 18 
3.1.3 
Absolute, relative and percent change from baseline ........................................... 18 
3.1.4 
Analysis visit and study phase windows .............................................................. 19 
3.1.5 
Handling of missing data ...................................................................................... 24 
3.1.5.1 
Imputation of partially missing AE dates ............................................................. 25 
3.1.5.2 
Imputation of partially missing medication dates ................................................. 26 
3.1.6 
Derivation of durations ......................................................................................... 26 
3.1.6.1 
Time since Asthma diagnosis (years) ................................................................... 26 
3.1.6.2 
Age at onset of asthma (years).............................................................................. 27 
3.1.6.3 
Time since Asthma symptoms started (years) ...................................................... 27 
3.1.6.4 
Time since last exacerbation (months) ................................................................. 27 
3.1.6.5 
Duration of exposure (days) ................................................................................. 27 
3.1.6.6 
Time from first IP administration to AE onset (days) .......................................... 27 
3.1.6.7 
Time from last IP administration to AE onset (days) ........................................... 27 
3.1.6.8 
Time from first IP administration to death (days) ................................................ 27 
3.1.6.9 
Time from last IP administration to death (days) ................................................. 27 
3.1.7 
Derivation of subgroups ....................................................................................... 27 
3.2 
Baseline assessments and other subject-specific characteristics .......................... 30 
3.2.1.1 
Demographics and subject-specific characteristics .............................................. 30 
3.2.1.2 
Medical history ..................................................................................................... 30 
3.2.1.3 
Prior and concomitant medication ........................................................................ 30 
3.2.1.4 
Asthma history ...................................................................................................... 31 
3.2.1.5 
Substance usage .................................................................................................... 31 
3.3 
Derivation of primary variable ............................................................................. 31 
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3.4 
Derivation of secondary variables ........................................................................ 31 
3.4.1 
Pharmacokinetics (PK) ......................................................................................... 31 
3.4.2 
Immunogenicity (serum) ...................................................................................... 31 
3.4.2.1 
ADA definitions.................................................................................................... 32 
3.4.2.2 
Categories of ADA responses ............................................................................... 32 
3.4.3 
Asthma control questionnaire-6 (ACQ-6) ............................................................ 33 
3.4.4 
St George’s respiratory questionnaire (SGRQ) .................................................... 34 
3.4.5 
Post-BD FEV1 ....................................................................................................... 34 
3.4.6 
Asthma CompEx ................................................................................................... 34 
3.4.7 
Fractional Exhaled Nitric Oxide (FeNO) ............................................................. 39 
3.5 
Derivation of safety variables ............................................................................... 40 
3.5.1 
Adverse events (AEs) ........................................................................................... 40 
3.5.1.1 
Adverse events of special interest......................................................................... 40 
3.5.2 
Vital signs variables .............................................................................................. 40 
3.5.3 
Laboratory variables ............................................................................................. 41 
3.5.3.1 
Other safety tests................................................................................................... 42 
3.5.3.2 
SARS-CoV-2 serology testing .............................................................................. 42 
3.5.4 
Electrocardiogram (ECG) ..................................................................................... 42 
3.5.5 
Echocardiogram .................................................................................................... 43 
3.6 
Derivation of exploratory variables ...................................................................... 43 
3.6.1 
Airwave oscillometry (AO) variables ................................................................... 43 
3.6.2 
Patient reported outcome (PRO) variables ........................................................... 44 
3.6.2.1 
Asthma symptom score......................................................................................... 44 
3.6.2.2 
Rescue medication usage ...................................................................................... 45 
3.6.2.3 
Nights with awakening due to asthma .................................................................. 45 
3.6.2.4 
Home FEV1 ........................................................................................................... 45 
3.6.2.5 
Home peak expiratory flow (morning and evening) ............................................. 45 
3.6.3 
FEV1% reversibility and FEF25-75% .................................................................. 45 
3.6.4 
Asthma exacerbation ............................................................................................ 45 
3.6.5 
Patient Global Impression of Benefit/Risk (PGI-BR) .......................................... 46 
3.6.6 
Asthma related inflammatory blood biomarkers .................................................. 46 
3.6.7 
Sino-nasal Outcome Test-22 (SNOT-22) ............................................................. 47 
3.7 
Derivation of exploratory cough sub-study variables ........................................... 47 
4 
ANALYSIS METHODS ...................................................................................... 48 
4.1 
General principles ................................................................................................. 48 
4.1.1 
Statistical Hypotheses ........................................................................................... 49 
4.1.2 
Repeated measures mixed effects analysis of covariance model (MMRM) ........ 50 
4.1.3 
Analysis of covariance (ANCOVA) ..................................................................... 51 
4.1.4 
Chi-squared test .................................................................................................... 53 
4.1.5 
Negative binomial regression ............................................................................... 53 
4.1.6 
Cox proportional hazards ...................................................................................... 53 
4.2 
Analysis of variables............................................................................................. 53 
4.2.1 
Disposition of subjects .......................................................................................... 53 
4.2.2 
Important protocol deviations ............................................................................... 54 
4.2.3 
Baseline assessments and other subject-specific characteristics .......................... 55 
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4.2.3.1 
Demographics and subject-specific characteristics .............................................. 55 
4.2.3.2 
Medical history ..................................................................................................... 55 
4.2.3.3 
Prior and concomitant medication ........................................................................ 55 
4.2.3.4 
Asthma history ...................................................................................................... 55 
4.2.3.5 
Substance usage .................................................................................................... 56 
4.2.3.6 
Other assessments at Screening ............................................................................ 56 
4.2.4 
Analysis of primary efficacy endpoint ................................................................. 56 
4.2.4.1 
Primary analysis of the primary endpoint ............................................................. 56 
4.2.4.2 
Supportive analysis of the primary endpoint ........................................................ 56 
4.2.4.3 
Subgroup analysis for the primary endpoint ......................................................... 56 
4.2.4.4 
Exploratory analysis of the primary endpoint ...................................................... 57 
4.2.5 
Analysis of secondary endpoints .......................................................................... 57 
4.2.5.1 
Analysis of lung function parameters measured in clinic ..................................... 57 
4.2.5.2 
Analysis of ACQ-6 ............................................................................................... 58 
4.2.5.3 
Analysis of SGRQ ................................................................................................ 58 
4.2.5.4 
Analysis of Asthma CompEx ............................................................................... 58 
4.2.5.5 
Analysis of FeNO ................................................................................................. 59 
4.2.6 
Analysis of exploratory endpoints ........................................................................ 59 
4.2.6.1 
Analysis of AO ..................................................................................................... 59 
4.2.6.2 
Analysis of FEV1% reversibility and FEF25-75% .............................................. 60 
4.2.6.3 
Analysis of asthma exacerbation .......................................................................... 60 
4.2.6.4 
Analysis of PGI-BR .............................................................................................. 60 
4.2.6.5 
Analysis of SNOT-22 ........................................................................................... 60 
4.2.6.6 
Analysis of diary data and home spirometry ........................................................ 60 
4.2.7 
Analysis of safety endpoints ................................................................................. 61 
4.2.7.1 
Analysis of AEs .................................................................................................... 61 
4.2.7.2 
Analysis of vital signs ........................................................................................... 64 
4.2.7.3 
Analysis of laboratory measurements ................................................................... 64 
4.2.7.4 
Analysis of ECG ................................................................................................... 65 
4.2.7.5 
Analysis of echocardiogram ................................................................................. 65 
4.2.7.6 
Other safety tests................................................................................................... 65 
4.2.8 
Other analysis ....................................................................................................... 66 
4.2.8.1 
Immunogenicity and PK ....................................................................................... 66 
4.2.8.2 
Analysis of blood biomarkers ............................................................................... 66 
4.2.8.3 
Exploratory analyses ............................................................................................. 67 
5 
INTERIM ANALYSIS ......................................................................................... 68 
6 
CHANGES OF ANALYSIS FROM PROTOCOL .............................................. 68 
7 
REFERENCES ..................................................................................................... 69 
8 
APPENDIX .......................................................................................................... 70 
Redacted for Public Disclosure 


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LIST OF TABLES 
Table 1 
Objectives and Endpoints ............................................................................ 12 
Table 2 
Populations for Analysis ............................................................................. 16 
Table 3 
Analysis visit windows for in-clinic spirometry, FeNO, vital signs, 
SARS-Cov-2 PCR test, exploratory biomarkers (serum) ........................... 19 
Table 4 
Analysis visit windows for ACQ-6, haematology, coagulation 
parameters, serum chemistry and immunogenicity ..................................... 20 
Table 5 
Analysis visit windows for SNOT-22, Airwave Oscillometry and 
urinalysis ..................................................................................................... 20 
Table 6 
Analysis visit windows for SGRQ .............................................................. 21 
Table 7 
Analysis visit windows for NT-proBNP assessment .................................. 21 
Table 8 
Analysis visit windows for ECGs and total IgE (serum) ............................ 21 
Table 9 
Analysis visit windows for PGI-BR, SARS-Cov-2 serology testing, sST2 
(serum), nasal mucosal sampling (mRNA), at-home cough monitoring 
and cough VAS ........................................................................................... 22 
Table 10 
Analysis visit windows for echocardiogram ............................................... 22 
Table 11 
Analysis visit windows for EDN (plasma) .................................................. 22 
Table 12 
Analysis visit windows for nasal mucosal sampling (lining fluid) ............. 22 
Table 1 
Labelling of 2-weekly periods .................................................................... 23 
Table 2 
Study phase windows .................................................................................. 24 
Table 3 
Timing for assessment of CompEx slope criterion ..................................... 36 
Table 46 
Rolling windows of time ............................................................................. 39 
Table 17 
Vital sign reference ranges .......................................................................... 41 
Table 18 
Laboratory safety variables ......................................................................... 41 
Table 19 
ECG reference ranges ................................................................................. 43 
Redacted for Public Disclosure 


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LIST OF FIGURES 
No table of figures entries found. 
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LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation 
ACM 
Ambulatory cough monitoring 
ACQ 
Asthma control questionnaire 
ADA 
Anti-drug antibody(ies) 
AE 
Adverse Event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AO 
Airwave oscillometry 
AST 
Aspartate transaminase 
BD 
Bronchodilator 
BMI 
Body mass index 
BP 
Blood pressure 
CompEx 
Composite endpoint for severe exacerbations of asthma 
COVID-19 
Coronavirus disease 2019 
CRS 
Chronic rhinosinusitis 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DBP 
Diastolic blood pressure 
E/D 
Early study intervention discontinuation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDN 
Eosinophil derived neurotoxin 
FeNO 
Fractional exhaled nitric oxide 
FEF25-75% 
Forced expiratory flow at 25-75% 
FEV1
Forced expiratory volume in the first second 
FVC 
Forced vital capacity 
GGT 
Gamma-glutamyl transferase 
GINA 
Global Initiative for Asthma 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICS 
Inhaled corticosteroids 
Ig 
Immunoglobulin 
IL 
Interleukin 
Redacted for Public Disclosure 


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Abbreviation or special term 
Explanation 
ILC2s 
Type 2 innate lymphoid cells 
IP 
Investigational product 
ITT 
Intent-to-treat 
L 
Liter 
LABA 
Long-acting beta agonist(s) 
LAMA 
Long-acting muscarinic antagonist(s) 
LTRA 
Leukotriene receptor antagonist(s) 
LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody(ies) 
MRD 
minimum required dilution 
mRNA 
Messenger RNA 
NC 
Not calculable 
NQ 
Not quantifiable 
NR 
Not reportable 
NS 
No sample 
NT-proBNP 
N-terminal prohormone of B-type natriuretic peptide
OCS 
Oral corticosteroid(s) 
PA 
Primary analysis 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PHL 
Potential Hy’s law 
PK 
Pharmacokinetic(s) 
PRO 
Patient reported outcome 
 
SABA 
Short-acting bronchodilator 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SD 
Standard deviation 
SGRQ 
St George’s respiratory questionnaire 
SNOT-22 
Sino-nasal outcome test 
 
SOA 
Schedule of activities 
CCI
CCI
CCI
CCI
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Abbreviation or special term 
Explanation 
SOC 
System Organ Class 
sST2 
Soluble suppression of tumorigenicity 2 
SV 
Study visit 
TBL 
Total bilirubin 
TSLP 
Thymic stromal lymphopoietin 
ULN 
Upper limit of normal 
URC 
Unblinded review committee 
VAS 
Visual analogue scale 
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AMENDMENT HISTORY 
Category*: 
Change refers to 
Date 
Description of change 
In line with 
the CSP? 
Rationale 
Other 
31 Aug 2022 
•
Rearranging of the study endpoints to mimic the CSP
•
Removal of text regarding airway hyperresponsiveness
and remodelling (previously a sub-study);
•
Change to accomodate not capping randomisation of
participants not included in exploratory cough sub-study
solely to achieve target sample size of the sub-study;
•
Introduction of the ‘All randomised subject’ population
•
Additional text added about derivation rules for actual
arm;
•
Additional text added to clarify the meaning of
‘detectable serum concentration measurement post first
dose’ for PK population;
•
Analysis visit windows for parameters previously missed
have been added together with the definition of the
analysis phases;
•
Minor adjustments on imputation rules for missing data
and on PK concentration data presentation;
•
Additional text added to clarify the derivation rules for
analysis subgroups;
•
Adjustments on the definition of the treatment emergent
adverse events (TEAE);
•
Clarification around AE of special interest;
•
Additional text added to clarify the derivation and
presentation of summary statistics;
•
Additional text added to clarify the fixed effects to be
used in the ANCOVA, MMRM and the back-up solutions
in case of non-convergence;
Y 
CSP amendment v1 to 
v4; Improvements 
resulting from study 
team discussions and 
reviews. 
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• 
Additional text added to clarify the reportable results for 
variables log-normally distributed; 
• 
Removal of representation of lab measurements outside 
predefined criteria as no predefined criteria are available; 
• 
Removal of statistical analysis on methacholine challenge 
testing and inspiratory/ixpiratory CT imaging as no more 
required;  
• 
Additional text added to introduce the primary analysis; 
• 
Shift tables for minimum values of haematology and 
chemistry laboratories from baseline have been added; 
• 
The recovery time formula related to asthma CompEx 
events occurred during the intervention and follow-up 
combined period has been corrected due to a previous 
mistake; 
• 
Clarification on rolling windows of time for asthma 
CompEx has been added; 
• 
An additional spirometry parameter (FEF25-75%) will be 
explored. 
Other 
10 jan 2023 
• 
Added 4 PD biomarkers analyses (section 4.2.8.2 
Analysis of blood biomarkers) 
• 
Added that also for the eosinophils the values will be log 
transformed prior to the analysis 
• 
Modified ECG normal ranges table 
Yes 
Missing 4 PD 
biomarkers in previous 
version 
* Pre-specified categories are  
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other 
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1 
STUDY DETAILS 
1.1 
Study objectives 
Table 1 
Objectives and Endpoints 
Objective 
Endpoint 
Primary  
To assess the effect of MEDI3506 compared 
with placebo on lung function, in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
As measured in clinic, change from baseline to Week 16 
in pre-BD FEV1 (L). 
Secondary  
To further assess the effect of MEDI3506 
compared with placebo on lung function, in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
As measured in clinic, change from baseline to Weeks 8 
and 16 in post-BD FEV1 (L). 
To assess the PK of MEDI3506 in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
Serum MEDI3506 concentration-time profiles during the 
intervention and follow-up periods. 
To assess the immunogenicity of MEDI3506 in 
adult participants with uncontrolled 
moderate-to-severe asthma. 
ADA during the intervention and follow-up periods. 
To assess the effect of MEDI3506 compared 
with placebo on asthma control in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
Change from baseline to Week 16 in ACQ-6 score. 
Proportion of participants with a decrease in ACQ-6 score 
of ≥ 0.5 from baseline to Week 16. 
Proportion of participants achieving ACQ-6 well 
controlled status (defined as ACQ-6 score ≤ 0.75 at 
Week 16). 
To assess the effect of MEDI3506 compared 
with placebo on health status in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
Change from baseline to Week 16 in SGRQ score. 
Proportion of participants with a decrease in SGRQ total 
score of ≥ 4 points from baseline to Week 16. 
To assess the effect of MEDI3506 compared 
with placebo on CompEx in adult participants 
with uncontrolled moderate-to-severe asthma.  
Time to first CompEx event based on the period from 
baseline to Week 16.  
CompEx annualised event rate. 
To assess the effect of MEDI3506 compared 
with placebo on concentration of FeNO in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
Percent change from baseline to Week 16 in concentration 
of FeNO in exhaled breath. 
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Table 1 
Objectives and Endpoints 
Objective 
Endpoint 
Safety 
To assess the safety and tolerability of 
MEDI3506 compared with placebo, in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
During the intervention and follow-up periods: 
• 
AEs, SAEs, AESIs 
• 
Vital signs 
• 
Clinical chemistry, haematology, and urinalysis 
• 
ECGs 
• 
LVEF as measured by echocardiogram 
• 
NT-proBNP 
• 
Number of participants seropositive for 
SARS-CoV-2 at end of study who were seronegative 
at randomisation visit 
• 
For participants testing positive for SARS-CoV-2 (by 
PCR or serology test), during the intervention and 
follow-up periods, the number and proportion of 
patients with COVID-19 AEs/SAEs and the 
proportion asymptomatic. 
Exploratory 
To further assess the longitudinal effect of 
MEDI3506 compared with placebo on lung 
function in adult participants with uncontrolled 
moderate-to-severe asthma. 
As measured at home, change from baseline up to 
Week 24 in 2-weekly mean PEF and FEV1  
To assess the effect of MEDI3506 compared 
with placebo on airway hyperresponsiveness in 
adult participants with uncontrolled 
moderate-to-severe asthma. 
Change from baseline to Weeks 8 and 16 in FEV1% 
reversibility. 
To assess the effect of MEDI3506 compared 
with placebo on asthma related inflammatory 
blood biomarkers in adult participants with 
uncontrolled moderate-to-severe asthma. 
Change from baseline to Weeks 1, 4, 8, 12, 16, 20 and 24 
in inflammatory blood biomarker levels, including but not 
limited to: 
• 
 
• 
Serum IL-5.* 
• 
Serum IL-13.* 
• 
Serum TSLP.* 
Change from baseline to Weeks 4, 16, and 24 in plasma 
EDN. 
Change from baseline to Weeks 16 and 24 in total IgE. 
Change from baseline to Week 16 in: 
• 
sST2. 
• 
Proinflammatory gene signatures in whole blood.* 
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Table 1 
Objectives and Endpoints 
Objective 
Endpoint 
To assess the longitudinal effect of MEDI3506 
compared with placebo on small airway function 
in adult participants with uncontrolled 
moderate-to-severe asthma. 
Change from baseline to Weeks 1, 4, 8, 12, and 16 in 
airway reactance and resistance as assessed by AO 
parameters, including but not limited to: 
• 
R5 
• 
R20 
• 
R5-R20 
• 
AX 
To assess the longitudinal effect of MEDI3506 
compared with placebo on lung function in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
As measured in clinic, change from baseline in pre-BD 
FEV1 to Weeks 1, 4, 8, 12, 20, and 24. 
To assess the acute effect of MEDI3506 
compared with placebo on pre-BD FEV1 in 
adult participants with uncontrolled 
moderate-to-severe asthma. 
As measured in clinic, change in pre-BD FEV1 (L) from 
pre-administration of study intervention to 4 hours 
post-administration of MEDI3506 or placebo at Day 1. 
To assess the effect of MEDI3506 compared 
with placebo on asthma control in adult 
participants with uncontrolled 
moderate-to-severe asthma. 
During the intervention period (baseline to Week 16): 
• 
Annualised rate of asthma exacerbations. 
• 
Annualised rate of hospitalised asthma 
exacerbations. 
To assess the longitudinal effect of MEDI3506 
compared with placebo on asthma control and 
health status in adult participants with 
uncontrolled moderate-to-severe asthma. 
Change from baseline to Weeks 1, 4, 8, 12, and 24 in 
ACQ-6 score. 
Change from baseline to Weeks 4, 12, and 24 in SGRQ 
score. 
Change from baseline up to Week 24 in 2-weekly mean 
daily rescue medication usage (puffs/day). 
Change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in: 
• 
Asthma symptom score. 
• 
Mean number of night-time awakenings. 
To assess the benefit-risk profile of MEDI3506 
as perceived by adult participants with 
uncontrolled moderate-to-severe asthma. 
PGI-BR at Week 16. 
 
 
 
 
 
 
 
To assess the effect of MEDI3506 compared 
with placebo on asthma related inflammatory 
airway biomarkers in adult participants with 
uncontrolled moderate-to-severe asthma. 
Percent change from baseline to Weeks 1, 4, 8, 12, 16, 20, 
and 24 in concentration of FeNO. 
Change from baseline to Weeks 4, 8, 12, 16, 20, and 24 in 
exploratory biomarkers measured in nasal lining fluid.* 
Change from baseline to Week 16 in mRNA nasal 
transcriptome.* 
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Table 1 
Objectives and Endpoints 
Objective 
Endpoint 
To assess the effect of MEDI3506 compared 
with placebo on nasal symptom control in a 
subset of adult participants with uncontrolled 
moderate-to-severe asthma who have comorbid 
CRS. 
Change from baseline to Weeks 1, 4, 8, 12, and 16 in 
SNOT-22 score. 
Exploratory cough sub-study 
To evaluate the effect of MEDI3506 compared 
with placebo on objective cough measures in 
adult participants with uncontrolled 
moderate-to-severe asthma 
Change from baseline to Week 16 in: 
• 
Daily (ie, 24 hour) cough frequency. 
• 
Awake time cough frequency. 
• 
Night-time cough frequency. 
• 
Cough VAS. 
ACQ-6 = asthma control questionnaire-6; ADA = anti-drug antibody(ies); AE = adverse event; AESI = adverse 
event of special interest; AO = airwave oscillometry; BD = bronchodilator; COVID-19 = coronavirus 
disease 2019; CompEx = composite endpoint for exacerbations of asthma; CRS = chronic rhinosinusitis; 
ECG = electrocardiogram; EDN = eosinophil derived neurotoxin; FeNO = fractional exhaled nitric oxide; 
FEV1 = forced expiratory volume in the first second; IgE = immunoglobulin E; IL = interleukin; L = litre(s); 
LVEF = left ventricular ejection fraction; mRNA = messenger RNA; NT-proBNP = N-terminal prohormone of 
B-type natriuretic hormone; PCR = polymerase chain reaction; PEF = peak expiratory flow; PGI-BR = patient 
global impression of benefit/risk; PK = pharmacokinetic(s); SAE = serious adverse event; SARS-CoV-2= severe 
acute respiratory syndrome coronavirus 2; SGRQ = St George’s respiratory questionnaire; SNOT-22 = sino-nasal 
outcome test-22;
; sST2 = soluble ST2; TSLP = thymic stromal 
lymphopoietin; VAS = visual analogue scale. * These endpoints will not be included in the CSR. 
 
1.2 
Study design 
Study D9181C00001 is a Phase II, randomised, double-blind, placebo-controlled, parallel 
group, proof of concept study to evaluate the efficacy, safety, PK and immunogenicity of 
MEDI3506 in adult participants with uncontrolled moderate to severe asthma on standard of 
care. 
Approximately 228 participants will be randomised in a 1:1:1 ratio to achieve 216 evaluable 
participants. Participants will receive 
 mg MEDI3506, 
mg MEDI3506, or placebo 
 by SC injection 
. The randomisation will be stratified according to 
sub-study participation (exploratory cough sub-study).  
Participants will be enrolled in this study for up to 29 weeks. The study comprises of 3 periods 
including the screening period of up to 5 weeks, an intervention period of 16 weeks, and a 
follow-up period of 8 weeks. Details of the schedule of assessment (SoA) can be found in the 
clinical study protocol (CSP).  
 
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1.3 
Number of participants 
A sample size of 216 participants (72 participants per treatment group), randomised 1:1:1 to 
MEDI3506 
 mg: MEDI3506 
 mg: placebo, will provide at least 80% power to detect a 
statistically significant difference in change from baseline to Week 16 in pre-BD FEV1, 
assuming a difference of 150 mL between placebo and MEDI3506, a between-participant SD 
of 420 mL and a one-sided- 10% alpha level. To allow for 5% participants being ineligible for 
the primary analysis, a total of approximately 228 participants will be randomised in the study 
(approximately 76/arm). 
Up to 60 participants  are intended to be included in the cough sub-study (approximately 20 
participants per treatment group). However, given the exploratory nature of the sub-study and 
that it may not be activated in all countries, randomisation of participants not included in the 
sub-study will not be restricted, therefore, sub-study recruitment may not be achieved. Since 
limited data are available on cough monitoring in this population, the sub-study is considered 
exploratory and no formal power calculations have been performed. 
2 
ANALYSIS SETS 
2.1 
Definition of analysis sets 
The following populations are defined: 
Table 2 
Populations for Analysis 
Population/Analysis set 
Description 
All Subjects 
Participants who have signed the informed consent form during screening 
period. 
All randomised subjects 
Participants who are randomised. Participants will be analysed according to 
their randomised treatment group. 
ITT population 
Participants who are randomised and receive any study intervention. 
Participants will be analysed according to their randomised treatment group. 
As-treated Population 
Participants who are randomised and receive any study intervention. 
Participants will be analysed according to the treatment they actually 
receive as follows: 
Highest dose actually received at 
any visit 
Actual arm 
0 mg MEDI3506 (Placebo) 
Placebo 
> 0 mg and ≤ 
 mg MEDI3506 
 mg MEDI3506 
> 
mg MEDI3506 
mg MEDI3506 
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Table 2 
Populations for Analysis 
Population/Analysis set 
Description 
PK population 
Participants who received at least one dose of MEDI3506 and had at least 
one detectable serum concentration measurement post first dose of study 
intervention. A participant is considered as having at least one detectable 
serum concentration measurement post first dose if has at least one plasma 
concentration that is not below the LLOQ after the first dose. Participants 
will be analysed according to the treatment they actually receive.  
Exploratory cough sub-study 
Subset of the ITT population including those participants who are 
participating in the exploratory cough sub-study. 
ITT = Intent to treat; PK = pharmacokinetic(s). 
 
The ITT population will be used to summarise all demographic and baseline characteristics, 
concomitant medications, and efficacy measures. The Exploratory cough sub-study population 
will be used to summarise sub-study specific efficacy measures. The As-treated population 
will be used to summarise all safety measures (AEs, ADA, laboratory tests, ECG, and vital 
signs). The PK population will be used to summarise PK measures. 
2.2 
Violations and deviations 
The list of important protocol deviations (IPDs) is provided in the Protocol Deviation Plan 
(PDP).  
In addition, any protocol deviation related to COVID-19 will be captured with the prefix 
“COVID-19” for CSR reporting. 
3 
PRIMARY AND SECONDARY VARIABLES 
3.1 
General principles 
3.1.1 
Baseline definitions 
In general, the last measurement prior to first injection of IP will serve as the baseline 
measurement for efficacy and safety endpoints. If Visit 4 (Day1) measurement is missing, the 
last non-missing value before Visit 4 (Day 1) will be used as baseline instead. If there is no 
result collected prior to Visit 4, then baseline value will be set to missing and will not be 
imputed. In the scenario where there are two assessments on Visit 4 (Day 1) prior to first dose, 
one with time recorded and the other without time recorded, the one with time recorded would 
be selected as baseline. 
An exception from the general rule will be ECGs. The mean value of each parameter from the 
triplicate measurements at Visit 4 (Week 0) pre-dose will be used as the baseline value.  
For bi-weekly summaries, such as 2-weekly mean number of night-time awakenings, 2-
weekly mean daily rescue medication usage, 2-weekly mean FEV1, 2-weekly mean PEF,  
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baseline would be defined as the mean from last 2 weeks (14 days) results before Visit 4 
(Week 0), ie from evening of Study Day -14 to the morning of Study Day 1. If there are fewer 
than 10 completed days in the 14-day baseline period (where a complete day = entry from the 
evening AND the following morning) then baseline will be set to missing.  
For CompEx analysis the mean from last 2 weeks (14 days) results before Visit 4 (Week 0) 
should be derived separately for morning and evening assessments. If there are fewer than 7 
completed days in the 14-day baseline period (where a complete day = entry from the evening 
AND the following morning) then baseline for CompEx event will be set to missing. To note: 
PEF is expected to be collected with 3 measurements for each morning and evening 
assessment. The maximum value provided by the vendor (both morning and evening for the 2-
weekly mean analysis and separately for the CompEx analysis) should be used to derive the 
baseline and any post-baseline assessments. 
3.1.2 
Study day 
Whenever data are summarised over time, study day will be calculated based on the actual 
assessment date in relation to date of first IP administration. 
If actual assessment date is prior to first IP administration, then study day will be: 
Study day = Actual assessment date – first IP administration date. 
If actual assessment date is on or after first IP administration, then study day will be: 
Study day = Actual assessment date – first IP administration date + 1. 
3.1.3 
Absolute, relative and percent change from baseline 
Absolute and percent change from baseline will be derived as follows: 
Absolute change from baseline outcome variables = (post-randomisation value – baseline  
  
value). 
Percent change from baseline = ((post-randomisation value – baseline value) / baseline  
  
value) × 100. 
For variables log normally distributed, the relative change from baseline is calculated as the 
visit log transformed value minus the baseline log transformed value. 
If either the post-randomisation value or the baseline value is missing, then the changes from 
baseline value will also be set to missing. 
Percentage change from baseline will not be calculated for participants where the result at 
baseline is 0. 
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3.1.4 
Analysis visit and study phase windows 
For the exacerbation and CompEx related analyses no analysis visit windows will be applied. 
For PK related analyses no analysis visit windows will be applied and the actual visits and 
timepoints will be used instead. 
Visit windows will be used for all assessments to allow for by-visit analyses, since not all 
assessments might be performed on the scheduled day. Unless specified otherwise, the 
efficacy and safety analyses will be based on the analysis visit windows. The actual 
assessment day will be mapped to the planned study visit following the analysis visit 
windowing rules below:  
• 
If more than one assessment falls within a visit window, the closest non-missing 
assessment to the scheduled day will be used in the analysis. 
• 
If more than one non-missing assessment actual dates are equidistant from the target day, 
the earlier assessment will be used in the analysis.  
• 
If more then one assessment is selected (i.e. due to teste repetitions) the average for 
numerical values  / worst case for categorical values will be used I the analysis 
 
The visit windows for the visits following baseline are constructed in such a way that the 
upper limit of the interval falls half way between the two visits, rounded up to the nearest 
integer. The lower limit of each window will be the mean of the two adjacent planned study 
days +1, rounded up to the nearest integer, except for the first post-treatment visit. 
Table 3 
Analysis visit windows for in-clinic spirometry, FeNO, vital signs, 
SARS-Cov-2 PCR test, exploratory biomarkers (serum) 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV6 
Week 1 
Week 1 
8 
All assessments on or after the first 
administration of investigational product 
to Day 19 
SV7 
Week 4 
Week 4 
29 
20 to 43  
SV8 
Week 8 
Week 8 
57 
44 to 71  
SV9 
Week 12 
Week 12 
85 
72 to 99  
SV10 
Week 16 
Week 16 
113 
100 to 127  
SV11 
Week 20 
Week 20 
141 
128 to 155  
SV12 
Week 24 
Week 24 
169 
≥ 156   
SV = Study Visit. 
 
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For vital signs, if the selected day is a dosing day, timepoints as per SOA within the day need 
to be considered (ie, Baseline, Day1: post-dose, Day1: 30m, Day1: 60m, Day1: 120m, Week1, 
etc...). 
 
For in-clinic spirometry pre-BD at day 1 timepoint at 4 hour post dose need also to be 
considered. 
Table 4 
Analysis visit windows for ACQ-6, haematology, coagulation 
parameters, serum chemistry and immunogenicity  
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV6 
Week 1 
Week 1 
8 
All assessments on or after the first 
administration of investigational product 
to Day 19 
SV7 
Week 4 
Week 4 
29 
20 to 43 
SV8 
Week 8 
Week 8 
57 
44 to 71 
SV9 
Week 12 
Week 12 
85 
72 to 99 
SV10 
Week 16 
Week 16 
113 
100 to 141 
SV12 
Week 24 
Week 24 
169 
≥142 
SV = Study Visit. 
Table 5 
Analysis visit windows for SNOT-22, Airwave Oscillometry and 
urinalysis  
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV6 
Week 1 
Week 1 
8 
All assessments on or after the first 
administration of investigational product 
to Day 19 
SV7 
Week 4 
Week 4 
29 
20 to 43 
SV8 
Week 8 
Week 8 
57 
44 to 71 
SV9 
Week 12 
Week 12 
85 
72 to 99 
SV10 
Week 16 
Week 16 
113 
≥100 
SV = Study Visit. 
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Table 6 
Analysis visit windows for SGRQ  
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV7 
Week 4 
Week 4 
29 
All assessments on or after the first 
administration of investigational product 
to Day 57 
SV9 
Week 12 
Week 12 
85 
58 to 99 
SV10 
Week 16 
Week 16 
113 
100 to 141 
SV12 
Week 24 
Week 24 
169 
≥142 
SV = Study Visit. 
 
Table 7 
Analysis visit windows for NT-proBNP assessment 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
 
All assessments prior to the first 
administration of investigational product 
SV8 
Week 8 
Week 8 
57 
All assessments on or after the first 
administration of investigational product 
to Day 71 
SV9 
Week 12 
Week 12 
85 
72 to 99 
SV10 
Week 16 
Week 16 
113 
100 to 141 
SV12 
Week 24 
Week 24 
169 
≥142 
SV = Study Visit. 
 
Table 8 
Analysis visit windows for ECGs and total IgE (serum) 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV10 
Week 16 
Week 16 
113 
All assessments on or after the first 
administration of investigational product 
to Day 141 
SV12 
Week 24 
Week 24 
169 
≥142 
SV = Study Visit. 
 
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Table 9 
Analysis visit windows for PGI-BR, SARS-Cov-2 serology testing, sST2 
(serum), nasal mucosal sampling (mRNA), at-home cough monitoring 
and cough VAS 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV10 
Week 16 
Week 16 
113 
All assessments on or after the first 
administration of investigational product 
SV = Study Visit. 
 
Table 10 
Analysis visit windows for echocardiogram 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV9 
Week 12 
Week 12 
85 
All assessments on or after the first 
administration of investigational product 
SV = Study Visit. 
 
Table 11 
Analysis visit windows for EDN (plasma)  
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
SV7 
Week 4 
Week 4 
29 
All assessments on or after the first 
administration of investigational product 
to Day 71 
SV10 
Week 16 
Week 16 
113 
72 to 141 
SV12 
Week 24 
Week 24 
169 
≥142 
SV = Study Visit. 
 
Table 12 
Analysis visit windows for nasal mucosal sampling (lining fluid) 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV4 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of investigational product 
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Protocol 
Visit 
Week 
Analysis Visit 
Scheduled 
Study Day 
Visit Window for Analysis (Days) 
SV7 
Week 4 
Week 4 
29 
All assessments on or after the first 
administration of investigational product 
to Day 43  
SV8 
Week 8 
Week 8 
57 
44 to 71  
SV9 
Week 12 
Week 12 
85 
72 to 99  
SV10 
Week 16 
Week 16 
113 
100 to 127  
SV11 
Week 20 
Week 20 
141 
128 to 155  
SV12 
Week 24 
Week 24 
169 
≥ 156   
SV = Study Visit. 
 
Daily at-home eDiary (e.g., PEF, pre-BD FEV1, FEV1, rescue medication usage, asthma 
symptom score, awakenings) will primarily be summarised and analysed as 2-weekly 
averages, separately. The assessment period of visit windows are defined in the below table.  
Table 1 
Labelling of 2-weekly periods 
2-weekly period 
Adjusted defined 
windows visit 
Scheduled day 
Baseline: as defined in Section 3.1.1 
Baseline 
1 
Period 1: Evening of Day 1 – Morning of Day 15 
Week 2 
15 
Period 2: Evening of Day 15 – Morning of Day 29 
Week 4 
29 
Period 3: Evening of Day 29 – Morning of Day 43 
Week 6 
43 
Period 4: Evening of Day 43 – Morning of Day 57 
Week 8 
57 
Period 5: Evening of Day 57 – Morning of Day 71 
Week 10 
71 
Period 6: Evening of Day 71 – Morning of Day 85 
Week 12 
85 
Period 7: Evening of Day 85 – Morning of Day 99 
Week 14 
99 
Period 8: Evening of Day 99 – Morning of Day 113 
Week 16 
113 
Period 9: Evening of Day 113 – Morning of Day127 
Week 18 
127 
Period 10: Evening of Day 127 – Morning of Day 141 
Week 20 
141 
Period 11: Evening of Day 141 – Morning of Day 155 
Week 22 
155 
Period 12: Evening of Day 155 – Morning of Day 169 
Week 24 
169 
 
The Early Discontinuation and unscheduled visits will be included when applying the visit 
windows to ensure that all available data are used in the analysis.  
For bi-weekly summaries, the mean of all non-missing observations within an assigned 
window is calculated. If there are fewer than 10 completed days in the 14 day period (where a 
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complete day = entry from the evening AND the following morning) then the analysis value 
will be set to missing.  
Finally, for the purpose of the statistical analysis, the assessments will be allocated to the study 
phase in which they are collected as reported below.  
Table 2 
Study phase windows 
Study phase 
Phase Window for Analysis (Days) 
Pre-treatment  
Prior to the first administration of investigational product (day <1a) 
On-treatment  
≥ day 1b to last dose date plus 28 days (included) 
Follow-up 
> last dose date plus 28 days 
a Includes all measurements collected before first dose of IP. If the measurement is collected on day 1 it cannot be 
determined if it was done before or after the first dose of IP (due to missing time and/or planned time point), 
then it will be considered as collected after first dose of IP. 
b Includes all measurements collected on the day of first dose of IP, at the time of IP intake and after. 
Unless otherwise specified, the study phase will be mainly used for safety analysis (e.g., 
laboratories, adverse events) and for CompEx analysis.  
3.1.5 
Handling of missing data 
No imputation for missing efficacy endpoints will be done. Repeated measures mixed effect 
model (MMRM) will be used which, in the event of missing data, uses all data that are 
available.  
Laboratory values of the form “<x” (ie below the lower limit of quantification) will be 
imputed as “0.5x LLOQ” in the calculation of summary statistics but displayed as “<x” in the 
listings. No imputation will be done for laboratory values of the form “>x” (ie above the upper 
limit of quantification) and the value “>x” will be displayed in the listings. Note that 0 should 
not be used as an imputed value in case the endpoint requires a log transformation. 
Additionally, adverse events that have missing causality (after data querying) will be assumed 
to be related to study drug. 
For missing ADA data, no imputation is planned.  
PK plasma concentrations below the lower limit of quantification will be reported as NQ (Not 
Quantifiable) in the listings with the LLOQ defined in the footnotes of the relevant TFLs. 
Individual PK plasma concentrations that are Not Reportable will be reported as NR and those 
that are missing will be reported as NS (No Sample) in the listings. PK plasma concentrations 
that are BLQ, NR or NS will be handled as follows for the provision of descriptive statistics: 
• 
Any values reported as NR or NS will be excluded from the summary tables and 
corresponding figures. 
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• 
At a time point where less than or equal to 50% of the concentration values are BLQ, all 
NQ values will be set to the LLOQ, and all descriptive statistics will be calculated 
accordingly. 
• 
At a time point where more than 50% (but not all) of the values are BLQ, the gmean, 
gmean ± gSD and gCV% will be set to NC (Not calculable). The maximum value will be 
reported from the individual data, and the minimum and median will be set to BLQ. 
• 
If all concentrations are BLQ at a time point, no descriptive statistics will be calculated 
for that time point. The gmean, minimum, median and maximum will be reported as BLQ 
and the gCV% and gmean ± gSD as NC.  
• 
The number of values below LLOQ (n < LLOQ) will be reported for each time point 
together with the total number of collected values (n). 
Three observations > LLOQ are required as a minimum for a PK plasma concentration to be 
summarised. Two observations > LLOQ are presented as minimum and maximum with the 
other summary statistics as NC. 
3.1.5.1 
Imputation of partially missing AE dates 
Date and time of AE are mandatory eCRF fields. No imputations are expected. In the rare 
cases of missing date, following rules will be applied. Completely missing AE dates are not 
imputed. 
Partially missing AE end dates are imputed as below:  
• 
If the AE is ongoing, the end date is stated to missing.  
• 
If the AE is not ongoing, and if only the day is missing: Assume the last day of the 
collected month. 
• 
If the AE is not ongoing, and the month is missing: Assume 31-DEC of the collected 
year. 
 
After applying these rules, if the imputed AE end date is after the end of study date, the AE 
end date is set to the end of study date. 
Before proceeding with the AE start date imputation, the AE end date are imputed as 
described above.  
Only partial AE start dates are imputed. Dates which are completely missing are not imputed. 
Partial dates are imputed as described below:  
• 
If the day is missing and:  
− 
If the month and year are different from the month and year of the first dose of IP, 
assume 01-MMM-YYYY.  
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−
If the month and year are the same as the first dose of IP month and year and the end
date is on or after (including ongoing / missing) the first dose of IP, then assume the
date of the first dose of IP.
−
If the month and year are the same as the first dose of IP month and year and the end
date is prior to the first dose of IP, then assume the end date.
•
If the month is missing and:
−
If the year is different from the year of first dose of IP, assume 01-JAN-YYYY of the
collected year.
−
If the year is the same as the first dose of IP year and the end date is on or after
(including ongoing / missing) the first dose of IP, then assume the date of the first
dose of IP.
−
If the year is the same as the first dose of IP and the end date is prior to the first dose
of IP, then assume the end date.
After applying these rules, if the imputed AE start date is after a complete AE end date then 
assume the same date as the complete AE end date; if the end date is missing and the imputed 
AE start date is after the end of study date then assume the end of study date. 
3.1.5.2 
Imputation of partially missing medication dates 
Both, completely missing and partially missing concomitant medication start dates are not 
imputed. 
Completely missing medication end dates are not imputed. Partially missing concomitant 
medication end dates are imputed as below:  
•
If the medication is ongoing, the end date is set to missing.
•
If the medication is not ongoing, and if only the day is missing: Impute with the last day
of the collected month.
•
If the medication is not ongoing, the month is missing: Impute with 31-DEC of the
collected year.
After applying these rules, if the imputed date is after the end of study date, the medication 
end date is set to the end of study date. 
3.1.6 
Derivation of durations 
3.1.6.1 
Time since Asthma diagnosis (years) 
Time from asthma first diagnosis date to screening will be calculated as (date of first diagnosis 
of asthma minus date informed consent signed plus one) divided by 365.25. 
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3.1.6.2 
Age at onset of asthma (years) 
Age at onset of asthma will be calculated as the age (years) at screening minus time since 
asthma diagnosis (Section 3.1.6.1), rounded to the below integer. 
3.1.6.3 
Time since Asthma symptoms started (years) 
Time from asthma first symptoms date to screening will be calculated as (date of first 
symptoms of asthma minus date informed consent signed plus one) divided by 365.25. 
3.1.6.4 
Time since last exacerbation (months) 
Time since last asthma exacerbation date to screening will be calculated as (date of most 
recent exacerbation minus date informed consent signed plus one) divided by 365.25 and 
multiplied by 12. 
3.1.6.5 
Duration of exposure (days) 
Exposure duration is calculated only for participants in the As-treated population as the total 
number of days on study drug. Exposure is calculated as (the study drug last injection date 
plus 28 days) minus study drug first injection date plus one. If any of the first or last dates are 
missing or partially missing, then imputed dates will not be used, and study drug exposure is 
set to missing. 
3.1.6.6 
Time from first IP administration to AE onset (days) 
Time from first IP administration to AE onset will be calculated as date of AE onset minus 
date of first IP administration plus one. 
3.1.6.7 
Time from last IP administration to AE onset (days) 
Time from last IP administration to AE onset will be calculated as date of AE onset minus 
date of last IP administration plus one. 
3.1.6.8 
Time from first IP administration to death (days) 
Time from first IP administration to death will be calculated as date of death minus date of 
first IP administration plus one. 
3.1.6.9 
Time from last IP administration to death (days) 
Time from last IP administration to death will be calculated as date of death minus date of last 
IP administration plus one. 
3.1.7 
Derivation of subgroups 
Following subgroups will be explored. Any participants with a missing value for the defined 
subgroup will be excluded from the analysis of that subgroup. Subgroups will only be 
explored if there is at least 20% of the total participants in that subgroup. 
•
Gender (male vs female);
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In addition to the pre-specified sub-group analysis, further exploratory work may be carried 
out using sub-group identification methodology (e.g. SIDES). This analysis will be post-hoc 
and not included in the delivery of TFLs.  
3.2 
Baseline assessments and other subject-specific characteristics 
Demographic and subject characteristics, medical history and nicotine and alcohol use are 
collected pre-treatment as per study protocol’s SoA. 
3.2.1.1 
Demographics and subject-specific characteristics 
Demographic and subject characteristics include age, age group (≥ 18 – < 50; ≥ 50 – 65), age 
group for EudraCT reporting purpose (≥ 18 – < 65; ≥ 65), sex, race, ethnic group, country, 
height (cm), weight (kg), body mass index (BMI) (kg/m²), previous treatments containing ICS 
and combination of products containing ICS, asthma characteristics at baseline. Age in years 
will be used as provided in the IWRS (Interactive Web Response System). BMI (kg/m²) is 
calculated as described in Section 3.5.2. 
Height, weight and BMI are allocated to the analysis visits as per Section 3.1.4. Evaluations 
with missing or partially missing dates cannot be imputed to any analysis visit. Only baseline 
values are included in the demographic and subject characteristics. 
3.2.1.2 
Medical history 
Medical history includes disease related and relevant medical history as collected in eCRF. 
Disease related and relevant medical history are coded with Medical Dictionary for 
Regulatory Activities (MedDRA) version 25.0 or higher. 
3.2.1.3 
Prior and concomitant medication 
The WHO-DD March 2022 B3 Global or later is used to classify medications by WHO 
Anatomical Therapeutic Chemical (ATC) classification of ingredients.  
The imputation method described in Section 3.1.5.2 is used in case of medication stop date 
partially missing. Completely missing stop date are not to be imputed. Completely missing or 
partially missing concomitant medication start dates are not imputed. 
After the end date imputation, the medications will be classified as either prior or concomitant 
(but not both) according to its stop date. Prior medication is defined as any medication with a 
stop date prior to the first dose of IP (exclusive). Concomitant medication is defined as any 
medication with a stop date on or after the first dose of study drug, or any medication taken 
prior to study drug and that is ongoing. Medications with completely missing stop date are 
classified as concomitant. 
CCI
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Disallowed medications will include medications defined as prohibited according to CSP. 
They will be defined following a physician review (prior to any study delivery) of the unique 
combinations of ATC code classifications and generic terms captured and detailed in the 
Integrated Data Review Plan (IDRP). 
3.2.1.4 
Asthma history 
The participant’s asthma history will also be collected and will include questions related to the 
following: 
• 
Asthma first diagnosed date; 
• 
First appearance of asthma symptoms date; 
• 
Most recent exacerbation date; 
• 
Number of asthma exacerbations within previous 12 months prior to screening (including 
exacerbations resulted in non-emergency room treatment, emergency room treatment, 
hospitalization). 
 
3.2.1.5 
Substance usage 
Alcoholic beverages status and consumption, and past smoking status (cigarettes, cigars, 
pipes, smokeless tobacco and non-tobacco nicotine products) together with the consumption 
of cigarettes in pack-years will be collected. 
3.3 
Derivation of primary variable 
The primary efficacy variable is the pre-bronchodilator (BD) forced expiratory volume in the 
first second (FEV1) (L). Pre-BD FEV1 (L) will be measured by in-clinic spirometry at visits 
SV1, SV2, SV4, SV6, SV7, SV8, SV9, SV10, SV11, SV12 and E/D. The primary efficacy 
endpoint is the change from baseline to Week 16 in pre-BD FEV1 (L). 
3.4 
Derivation of secondary variables 
3.4.1 
Pharmacokinetics (PK) 
Serum samples will be collected for measurement of serum concentrations of MEDI3506 at 
visits SV4, SV6, SV7, SV8, SV9, SV10, SV11, SV12 and E/D. Additional details are 
provided in Section 3.1.5. 
3.4.2 
Immunogenicity (serum) 
Blood samples for determination of anti-drug antibodies (ADA) in serum will be assessed at 
visits SV4, SV6, SV7, SV8, SV9, SV10, SV12 and E/D. 
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3.4.2.1 
ADA definitions 
ADA detection at sample level: 
• 
A sample is considered to be ADA positive if the titre is greater than or equal to the 
minimum required dilution (MRD) of the assay. 
• 
A sample is considered to be ADA negative if the titre is <MRD of the assay. 
 
ADA detection at participant level: 
• 
A participant is considered ADA positive if at least one collected sample is tested positive 
at any time during the study, including baseline and/or post-baseline (see definition for 
ADA prevalence in Section 3.4.2.2).  
• 
A participant is considered ADA negative if collected samples are tested negative at all 
timepoints, including baseline and post-baseline. 
 
Subjects with a missing baseline ADA assessment should be assumed to be ADA negative as 
a conservative approach to ensure that all subjects are included in all analyses. 
Treatment-related ADA development at participant level: 
Treatment-emergent ADA positive (TE-ADA+) is defined as being either of treatment-
induced ADA positive (ADA negative at baseline and at least one post-baseline ADA 
positive) and treatment-boosted ADA positive (ADA positive at baseline and baseline titre is 
boosted by greater than the variability of the assay (ie ≥ 4-fold increase) at ≥ 1 post-baseline 
timepoint). Treatment-emergent ADA negative (TE-ADA-) is defined as ADA positive but 
not fulfilling the definition of TE-ADA positive.  
The median of maximum titres is calculated based on the maximum titre for each ADA 
positive participant within each treatment group (including baseline and post-baseline 
measurements). 
3.4.2.2 
Categories of ADA responses 
Baseline is defined as the last ADA assessment prior to the first dose of investigational 
product (IP). 
Numbers and proportions of: 
• 
Participants who are ADA positive at any time during the study, including baseline and/or 
post-baseline (also generally referred to as ADA positive). The proportion of ADA-
positive participants in a population is known as ADA prevalence.  
• 
Participants who are ADA negative at all assessments, including baseline and post-
baseline (also generally referred to as ADA negative). 
• 
Participants who are ADA positive at baseline only. 
• 
Participants who are ADA positive at baseline and at least one post-baseline assessment. 
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• 
Participants who are treatment-emergent ADA positive (see definition in Section 3.4.2.1), 
reported overall and separately as treatment-induced and treatment-boosted subjects. The 
percentage of TE-ADA+ participants in a population is known as ADA incidence. 
• 
Participants who are treatment-emergent ADA negative (see definition in Section 
3.4.2.1). 
• 
Participants who are persistently ADA positive, which is defined as ADA negative at 
baseline and having at least 2 post-baseline ADA positive measurements with ≥ 16 weeks 
between first and last positive, or an ADA positive result at the last available post 
baseline assessment. 
• 
Participants who are transiently ADA positive, defined as ADA negative at baseline and 
at least one post-baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive. 
• 
Participants who are ADA positive with maximum titre > median of maximum titres. 
 
3.4.3 
Asthma control questionnaire-6 (ACQ-6) 
The questionnaire will be completed using the eDiary in accordance with the SoA of the CSP. 
In the ACQ-6, participants are asked to recall how their asthma has been during the previous 
week by responding to one BD use question and 5 symptom questions. 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. If response to any of the questions is 
missing, the ACQ-6 score will be missing. Mean scores of ≤ 0.75 indicate well-controlled 
asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 
indicate not well-controlled asthma (Juniper et al 2006). Individual changes of at least 0.5 are 
considered clinically meaningful. 
The key outcome variable for the ACQ-6 will be the change in mean score from baseline to 
Week 16. The change in mean score from baseline to each of the post-randomisation 
assessments will also be derived (see Section 3.1.3). 
Other variables based on ACQ-6 to report include: 
• 
Proportion of participants with a decrease in ACQ-6 score of ≥ 0.5 from baseline to 
Week 16 (Yes=1/No=0): 
− 
Yes: change from baseline ACQ-6 score to ACQ-6 score at Week 16: ≤ -0.5. 
− 
No: change from baseline ACQ-6 score to ACQ-6 score at Week 16: > -0.5. 
• 
Proportion of participants achieving ACQ-6 well controlled status (Yes=1/No=0): 
− 
Yes: ACQ-6 score at Week 16 ≤ 0.75. 
− 
No: ACQ-6 score at Week 16 > 0.75. 
 
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Participants with missing or non-evaluable ACQ-6 score will be considered as not achieving 
ACQ-6 response. 
3.4.4 
St George’s respiratory questionnaire (SGRQ) 
The SGRQ is a 50-item PRO instrument developed to measure the health status of subjects 
with airway obstruction diseases (Jones et al 1991). The SGRQ yields a total score and three 
domain scores (symptoms, activity, and impacts). The total score indicates the impact of 
disease on overall health status. This total score is expressed as a percentage of overall 
impairment, in which 100 represents the worst possible health status and 0 indicates the best 
possible health status. Likewise, the domain scores range from 0 to 100, with higher scores 
indicative of greater impairment. Specific details on the scoring algorithms are provided by 
the developer in a user manual (Jones and Forde 2009). The principle of calculation of total 
score and domain scores in accordance with user manual are provided in Appendix A. 
The SGRQ will be completed using the eDiary in accordance with the SoA of the CSP, and a 
4 week recall version will be used. 
The key outcome variable for the SGRQ will be the change in mean total and domain scores 
from baseline to Week 16, but the change in mean total and domain scores from baseline to 
each of the post-randomisation assessments will also be derived (see Section 3.1.3). 
Other variables based on SGRQ to report include: 
• 
Proportion of participants with a decrease in SGRQ score of ≥ 4 points from baseline to 
Week 16 (Yes=1/No=0): 
− 
Yes: change from baseline SGRQ score to SGRQ score at Week 16: ≤ -4. 
− 
No: change from baseline SGRQ score to SGRQ score at Week 16: > -4. 
 
Participants with missing or non-evaluable SGRQ score will be considered as not achieving 
SGRQ response. 
3.4.5 
Post-BD FEV1 
Secondary efficacy variable is the post-BD FEV1 and will be measured by in-clinic spirometry 
at visits SV1, SV2, SV4, SV8 and SV10. The secondary endpoint is the absolute change from 
baseline to Weeks 8 and 16 in post-BD FEV1 (L) (see Section 4.2.5). 
3.4.6 
Asthma CompEx 
Asthma CompEx is a combination of exacerbations of asthma and diary events (ie, 
combination of eDiary variables). Asthma CompEx is a composite surrogate endpoint for 
exacerbations of asthma, recently developed by AstraZeneca (it is not yet a regulatory-
approved clinical endpoint). 
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Diary events are defined by the threshold and slope criteria using the following 
morning/evening (AM/PM) diary variables: 
• 
PEF (variable 1=V1= morning PEF; variable 2=V2= evening PEF). 
• 
Symptom score (0 – 3) (variable 5=V5= morning symptom score; variable 6=V6= 
evening symptom score). 
• 
Use of rescue medication (variable 3=V3= morning rescue medication usage; variable 
4=V4= evening rescue medication usage). 
 
A subject will be considered to have a CompEx event if the subject has one or both of the 
following: 
1 
An asthma exacerbation, 
2 
A diary event, which is defined as either the threshold criterion or the slope criterion (or 
both), as defined below, being met for ≥2 consecutive days. 
 
For this purpose, “2 consecutive days” means strictly the same 2 consecutive days when 
assessing multiple requirements within those days.  For the eDiary data (which is captured 
twice during the day), one day will be defined by the morning/evening pairing for consistency 
with published precedent for the CompEx endpoint. (Note: other eDiary endpoints in this trial 
will use an evening/morning pairing to define one day.)  The morning eDiary recordings 
captured on the first day of treatment will not be included in the calculation of the CompEx 
endpoint. 
Threshold criterion: 
(a) ≥15% decrease from baseline in either morning (V1) or evening home-based PEF 
(V2),  
and at least one of the following: 
(b) ≥1.5 doses increase from baseline in rescue medication in either the morning (for 
preceding night, V3) or evening (for preceding day, V4), 
(c) ≥1 score increase from baseline, or the absolute maximal symptom score, in either 
the morning (V5) or evening (V6). 
 
For (b), the number of doses of rescue medication is defined as the number of puffs of inhaler 
recorded in the morning and evening, respectively. 
For (c), the asthma symptom score (scored 0-3) as described in Section 3.6.2.1 (V1-V6), 
provided those non-missing values meet the criterion. 
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The end date of a CompEx event is defined as the latest of the exacerbation or objective 
deterioration end dates which meets the definition. Diary event end date is defined as the latest 
Day 1 (in notation from Table 3  
Timing for assessment of CompEx slope criterion) from 
any series of rolling 2 consecutive days which last qualifies using either the threshold or slope 
criterion. 
 
The event duration is defined as the end date minus the start date plus 1. 
If the end date of the first CompEx event and the start date of the second CompEx event are 
less than 7 days apart for any subject, then these will be counted as one CompEx event. 
For CompEx analyses, only on-treatment events (based on the period from baseline to last 
dose date +28 days) will be considered. A supplementary analysis including events in the 
period from baseline to end of follow-up (Week 24) will also be conducted. 
Time-to-first event will be defined as: [Start date of first event or censoring – date of 1st dose] 
+ 1. 
Date of first event will be the first start date of a CompEx event as defined above. For 
participants who do not experience an on-treatment CompEx event, date of censoring will be 
the minimum between the date of last dose plus 28 days, and the last day of eDiary recording 
during the on-treatment period. For the analysis of CompEx during combined treatment and 
follow-up period, date of censoring will be the minimum between the date of end of study 
visit, and the last day of eDiary recording during combined treatment and follow-up period . 
For recurrent events, there must be a gap of 7 days between events ie, at least 7 days between 
end date of first CompEx event and start date of second CompEx event. Events that occur 
closer in time will be collapsed into one event.   
The time during the event and the 7 days after each event will not be considered when 
defining time at risk for the CompEx event rate. Time at risk will be defined as [Date of last 
treatment plus 28 days– date of 1st dose] + 1 – recovery time. For the analysis of CompEx 
during combined treatment and follow-up period, the time at risk will be defined as [date of 
end of study visit – date of 1st dose] + 1 – recovery time. 
The annualised rate of asthma CompEx events, during intervention period (Baseline to last 
dose date +28 days) per participant will be calculated as: 
Annualised rate of asthma CompEx events during intervention period = 
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Total number of asthma CompEx events 
(Date of last dose of IP +  28 –  Date of the first dose of IP −recovery time +  1)/365.25 
where the recovery time is defined as: 
෍[𝑚𝑚𝑚𝑚𝑚𝑚(𝑖𝑖𝑡𝑡ℎ 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 7, 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 28) − 𝑖𝑖𝑡𝑡ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 1]
𝑘𝑘
𝑖𝑖=1
 
The annualised rate of asthma CompEx events, during intervention and follow-up periods 
(Baseline to Week 24) per participant will be calculated as: 
Annualised rate of asthma CompEx events during intervention and follow-up periods = 
Total number of asthma CompEx events 
(Date of last follow up –  Date of the first dose of IP −recovery time +  1)/365.25 
Where the recovery time is defined as: 
෍[𝑚𝑚𝑚𝑚𝑚𝑚(𝑖𝑖𝑡𝑡ℎ 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 7, 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑢𝑢𝑢𝑢) − 𝑖𝑖𝑡𝑡ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 1]
𝑘𝑘
𝑖𝑖=1
 
Rolling windows of time:  
The deterioration criteria for the individual diary variables are defined as a combination of 
threshold criteria and regression slope criteria during each rolling window. Each rolling 
window contains 6 consecutive days, including 2 consecutive days for threshold assessment 
(Window Day 0 and 1), and 5 preceding consecutive days for regression slope assessment 
(Window Day -4 to 0). For this purpose, “2 consecutive days” means the same 2 consecutive 
days when assessing multiple threshold requirements. Similarly, ‘5 preceding consecutive 
days’ means the same 5 preceding consecutive days when assessing multiple slope 
requirements. 
Rolling 
Window 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
…… 
n 
n+1 
n+2 
n+3 
n+4 
n+5 
  
1 
Window Day 
-
4 
-
3 
-
2 
-
1 
0 
1 
  
  
  
  
  
  
  
  
  
Threshold 
Assessment 
 
 
 
 
x 
x 
  
  
  
  
  
  
  
  
  
Slope Assessment 
x 
x 
x 
x 
x 
 
  
  
  
  
  
  
  
  
  
  
2 
Window Day 
  
-
4 
-
3 
-
2 
-
1 
0 
1 
  
  
  
  
  
  
  
  
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The deterioration criteria are assessed for a series of rolling windows over the entire study 
duration. For example, Window 1 includes ‘Study Day 1’ through ‘Study Day 6’, Window 2 
rolls one day forward that includes ‘Study Day 2’ through ‘Study Day 7’, Window 3 rolls one 
day forward that includes ‘Study Day 3’ through ‘Study Day 8’, and so on so forth, as 
illustrated in the table below: 
Table 46  
Rolling windows of time 
 
3.4.7 
Fractional Exhaled Nitric Oxide (FeNO) 
Percent change from baseline to Week 16 in concentration of FeNO in exhaled breath is a 
secondary endpoint of this study. Additionally, percent and relative change from baseline to 
Weeks 1, 4, 8, 12, 16, 20, and 24 will be analysed as exploratory endpoints. 
Airway inflammation will be evaluated using a standardised single-breath FeNO test at visits 
SV1, SV2, SV4, SV6, SV7, SV8, SV9, SV10, SV11, SV12 and E/D. Two acceptable FeNO 
measurements will be performed to establish repeatability; up to 8 measurements can be 
performed. The mean value of the measurements, as provided by the vendor, will be used in 
the statistical analysis. Percent and relative change from baseline in FeNO will be derived in 
accordance with Section 3.1.3 of this SAP. 
Rolling 
Window 
Study Day 
1 
2 
3 
4 
5 
6 
7 
8 
…… 
n 
n+1 
n+2 
n+3 
n+4 
n+5 
Threshold 
Assessment 
  
 
 
 
 
x 
x 
  
  
  
  
  
  
  
  
Slope Assessment 
  
x 
x 
x 
x 
x 
 
  
  
  
  
  
  
  
  
  
3 
Window Day 
  
  
-
4 
-
3 
-
2 
-
1 
0 
1 
  
  
  
  
  
  
  
Threshold 
Assessment 
  
  
 
 
 
 
x 
x 
  
  
  
  
  
  
  
Slope Assessment 
  
  
x 
x 
x 
x 
x 
 
  
  
  
  
  
  
  
  
…… 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
n 
Window Day 
  
  
  
  
  
  
  
  
  
-
4 
-3 
-2 
-1 
0 
1 
Threshold 
Assessment 
  
  
  
  
  
  
  
  
  
  
  
  
  
x 
x 
Slope Assessment 
  
  
  
  
  
  
  
  
  
x 
x 
x 
x 
x 
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3.5 
Derivation of safety variables 
3.5.1 
Adverse events (AEs) 
AEs will be collected from signing of ICF throughout the intervention period and including 
the follow-up period. SAEs will be recorded from the time of signing of ICF. AEs will be 
coded with MedDRA version 25.0 or higher.  
AE data will be allocated to the study phase (as defined in section 3.1.4) according to their 
onset date. AEs will be defined as treatment emergent adverse events (TEAEs) if they have an 
onset, during the on-treatment phase. AEs with a missing start date will be considered as on-
treatment. 
 
3.5.1.1 
Adverse events of special interest 
The following AESIs will be particularly monitored in this study: 
• 
Hepatic function abnormality meeting the definition of Hy’s Law as described in Section 
8.3.8 of the protocol. 
• 
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis and severe allergic reactions, and immune complex disease. 
• 
Injection site reactions. 
• 
Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia). 
• 
Serious infections (including opportunistic infections and viral reactivations), for example 
herpes simplex virus/varicella zoster virus, Epstein Barr virus/cytomegalovirus, TB, 
SARS-CoV-2 and all other opportunistic infections listed in the Guidelines for the 
Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with 
HIV. 
• 
Gastrointestinal adverse events. 
• 
Malignancy. 
 
AEs will be assigned to a specific category based on investigator’s judgement, using a 
checkbox on the AE CRF page. In addition, standardized MedDRA queries (SMQs) will be 
utilized when possible, and a selection of HLTs, SOCs and/or PTs will be utilized to represent 
other situations, to perform a cross-check with eCRF categories.  A comprehensive list will be 
provided by the patient safety team prior to any study delivery.  
3.5.2 
Vital signs variables 
Vital signs assessments (body temperature, diastolic blood pressure (DBP), systolic blood 
pressure (SBP), heart (pulse) rate and respiratory rate) will be performed at visits SV1, SV4, 
SV6, SV7, SV8, SV9, SV10, SV11, SV12 and E/D. For SV4 and SV7 vital signs will be taken 
before and immediately after administration of study intervention, and at 30, 60, and 120 
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minutes (± 5 minutes). For SV8 and SV9 vital signs will be taken before and immediately 
after administration of study intervention, and at 30 and 60 minutes (± 5 minutes) thereafter. 
Height will be assessed at SV1 only. Weight will be assessed at SV1, SV4, SV10, SV12 and 
E/D. 
Body mass index will be calculated from the height (in meters) and weight (in kilograms) as 
follows: BMI = weight / (height^2). 
Additionally, vital signs values will be classified as normal (if value is between lower and 
upper limit), low (if value is below the lower limit), and high (if value is above the upper 
limit) according to the normal reference ranges (Table ): 
Table 17 
Vital sign reference ranges 
Parameter 
Standard Unit 
Lower limit 
Upper limit 
Change Criteria 
Body temperature 
°C 
 
>37 
±1 
DBP 
mmHg 
<60 
>100 
±15 
SBP 
mmHg 
<90 
>160 
±30 
Heart (pulse) rate 
beats/min 
<50 
>100 
±20 
Respiratory rate 
breath/min 
<12 
>24 
±3 
BMI 
kg/m² 
<18.5 
≥35 
 
High value (H) is defined as upper reference limit. High change (HC) is defined as increase 
from baseline greater than prespecified criterion. Low value (L) is defined as below lower 
reference limit. Low change (LC) is defined as decrease from baseline greater than 
prespecified criterion. 
3.5.3 
Laboratory variables 
Clinical Safety Laboratory will be performed at visits SV1, SV4, SV6, SV7, SV8, SV9, SV10, 
SV12 and E/D, except for urinalysis that will be performed at visits SV1, SV4, SV6, SV7, 
SV8, SV9, SV10 and E/D. Clinically significant abnormal laboratory results are defined by 
the investigator. 
Following haematology, clinical chemistry and urinalysis parameters will be assessed: 
Table 18 
Laboratory safety variables 
Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) 
WBC count with differential 
Potassium 
RBC count 
Sodium 
Haematocrit 
AST 
Platelet count 
ALT 
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Haemoglobin 
ALP 
Coagulation parameters (PT, INR, and aPTT) 
TBL (if result is > 1.5 ULN, indirect and direct 
bilirubin will be measured) 
GGT 
Urinalysis (dipstick) 
Creatinine 
Colour and appearance  
Blood urea nitrogen 
Specific gravity 
Albumin 
pH 
Total protein 
Protein 
Uric acid 
Microscopy including WBCs, RBCs, and casts. 
 
Glucose 
 
Ketones 
 
Blood 
 
Bilirubin 
 
Leukocytes 
 
Note for haematology: blinding procedures for eosinophil, basophil, and monocyte data are described in 
Section 6.3.2 of the protocol. 
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently. 
ALP = alkaline phosphatase; ALT = alanine transaminase; aPTT = activated partial thromboplastin time; 
AST = aspartate transaminase; GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international 
normalised ratio; PT = prothrombin time; RBC = red blood cell; TBL = total bilirubin; ULN = upper limit of 
normal; WBC = white blood cell. 
 
3.5.3.1 
Other safety tests 
• 
NT-proBNP (only at SV1, SV8, SV9, SV10, SV12 and E/D) 
• 
SARS-CoV-2 PCR test (performed anytime between Day -7 and Day -4 as the results are 
needed prior to randomisation. Testing may then be performed at any point during the 
study intervention and follow-up periods for a participant suspected of having COVID-
19) 
 
3.5.3.2 
SARS-CoV-2 serology testing 
Participants’ serum will be tested for the presence of antibodies to the SARS-CoV-2 virus 
from blood drawn at the visits SV4, SV10 and E/D. 
3.5.4 
Electrocardiogram (ECG) 
ECG variables will be collected at visits SV1, SV4, SV10, SV12, and E/D as follows: 
• 
Heart (pulse) rate 
• 
RR interval 
• 
QRS interval 
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• 
PR interval 
• 
QT interval 
 
Additionally, QT correction using Bazett’s and Fridericia’s formulas will be calculated as 
follows (unless already derived directly from the CRF): 
 
QTcB = QT/(RR^½), 
 
QTcF = QT/(RR^⅓), 
where QT is measured in msec and RR is measured in sec. 
Categorical ECG interpretation (normal, abnormal clinically significant, abnormal not 
clinically significant) will be provided by the investigator. 
Table 19 
ECG reference ranges 
Parameter 
Standard Unit 
Lower limit 
Upper limit 
Change 
criteria 
Heart (pulse) rate 
beats/min 
<50 
>100 
 
RR interval 
ms 
<600 
>1200 
 
QRS interval 
ms 
<80 
>120 
 
PR interval 
ms 
<120 
>200 
 
QT interval 
ms 
N/A 
>450 male >470 female 
+30 
QTcB interval 
ms 
N/A 
>450 male >470 female 
+30 
QTcF interval 
ms 
N/A 
>450 male >470 female 
+30 
 
3.5.5 
Echocardiogram 
A transthoracic echocardiogram to assess left ventricular ejection fraction (LVEF) will be 
assessed any time after signing of informed consent, so that results are available prior to 
randomisation and then at any time at or between SV9 and SV10 inclusive. 
3.6 
Derivation of exploratory variables 
3.6.1 
Airwave oscillometry (AO) variables 
Airwave oscillometry will be performed at SV2, SV4, SV6, SV7, SV8, SV9 and SV10. 
Airwave oscillometry is a non-invasive lung function test included in this study to evaluate 
treatment effect on small airway physiology. 
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The parameters R5, R20, R5-R20 and AX for each assessment will be recorded and analysed. 
The AO assessment at SV6, SV7, SV8, SV9, and SV10 will be performed only if the baseline 
visit AO is performed successfully, as judged by the investigator. 
3.6.2 
Patient reported outcome (PRO) variables 
Patient-reported outcome data will be captured via an ePRO device. For all outcomes based on 
the ePRO devices, analyses will be based on data up to and including Week 24. 
For asthma symptom score, rescue medication use and home peak expiratory flow, 2-weekly 
means will be calculated. A 2-weekly mean is calculated as the sum of all non-missing daily 
measures/scores over 14 sequential days divided by the number of days with non-missing 
measures/scores. For nights with awakenings due to asthma, the 2-weekly mean will be the 
percentage of times the participant answered “yes” to ‘did your asthma cause you to wake up’ 
and “yes” to ‘did you use rescue medication upon awakening’. For derivation of the 2-weekly 
mean scores see Section 3.1.4. Note that the first 2-weekly mean in the treatment period will 
be based on the evening recording on day 1 up to and including the morning recording on day 
15. The daytime score is recorded in the evening and the night-time score is recorded the 
following morning; 2-weekly periods are defined as follows (where Day 1 is the day of 
randomisation) 
Where a total score is calculated within a day (e.g. Asthma symptom score), this calculation 
will span two calendar days –  the daytime value recorded in evening of day X, and the night-
time value recorded on morning of day x+1. E.g. the asthma symptom score on Day 1 will be 
the day time score recorded on the evening of Day 1 + the night-time score recorded on the 
morning of Day 2. 
Where only night-time scores/results are of interest, the morning entries on the second day of 
a period up to and including the morning entry on the last day of the period (or morning of the 
last day of study for the last period/last IP intake) will be considered. Where only daytime 
scores/results are of interest, the evening entries on the first day of the period up to and 
including the evening entry on the second last day of the period (or evening before the last day 
of study/last IP intake) will be considered. 
3.6.2.1 
Asthma symptom score 
Asthma symptoms during night-time and daytime will be recorded by the participant each 
morning and evening in the asthma daily diary. Each symptom item will be recorded using a 
scale 0 – 3, where 0 indicates no asthma symptoms. Asthma symptom daytime score 
(recorded in the evening), night-time score (recorded in the morning), and total score will be 
calculated and presented separately. 
The daily asthma symptom total score will be calculated by taking the sum of the daytime and 
night-time asthma symptom scores recorded each day. If a participant is missing a value for 
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either night-time or daytime asthma symptom score on a given day, then the total score for 
that day will be set to missing. 
The outcome variable is the change from baseline through Week 24 in 2-weekly mean daily 
asthma symptom total score. 2-weekly means and change from baseline for daytime and 
night-time scores will also be calculated for the 2-weekly periods according to Table 1 
(Section 3.1.4). 
3.6.2.2 
Rescue medication usage 
During the study period, participants will be required to document rescue medication usage in 
the eDiary twice daily. Daytime use is recorded in the evening and night-time use is recorded 
in the morning.  
The outcome variable is the 2-weekly mean daily rescue medication usage (puffs/day) and 
will be calculated for the 2-weekly periods according to Table 1  (Section 3.1.4).  
3.6.2.3 
Nights with awakening due to asthma 
Bi-weekly mean change from baseline in the number (percentage) of nights with awakening 
due to asthma that required rescue medication will be calculated as the outcome variable for 
the 2-weekly periods according to Table 1 (Section 3.1.4). 
3.6.2.4 
Home FEV1 
Bi-weekly mean absolute changes from baseline home FEV1 will be calculated for the 2-
weekly periods according to Table 1 (Section 3.1.4). 
3.6.2.5 
Home peak expiratory flow (morning and evening) 
Bi-weekly mean absolute changes from baseline PEF will be calculated for the 2-weekly 
periods according to Table 1 (Section 3.1.4). 
3.6.3 
FEV1% reversibility and FEF25-75% 
Exploratory variable are the FEV1% reversibility and FEF25-75%. They will be measured by 
in-clinic spirometry at visits SV1, SV2, SV4, SV8 and SV10. Reversibility is calculated as 
follows: 
FEV1% reversibility = (post-BD FEV1 - pre-BD FEV1)/pre-BD FEV1 × 100 
The exploratory endpoint is the change from baseline to Weeks 8 and 16 in FEV1% 
reversibility and FEF25-75%. 
3.6.4 
Asthma exacerbation 
Asthma exacerbation will be assessed throughout the duration of the study. 
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Time to first asthma exacerbation will be calculated as start date of asthma exacerbation 
minus date of 1st dose plus 1. 
The annualised rate of asthma exacerbation during intervention period (Baseline to last dose 
date +28 days) per participant will be calculated as: 
Annualised exacerbation rate during intervention period =  
𝑁𝑁𝑁𝑁. 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼 +  28 − 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 1𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑡𝑡𝑖𝑖𝑖𝑖𝑖𝑖+  1) / 365.25 
The annualised rate of hospitalised asthma exacerbation during intervention period per 
participant will be calculated as: 
Annualised hospitalised exacerbation rate during intervention period =  
𝑁𝑁𝑁𝑁. 𝑜𝑜𝑜𝑜 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑤𝑤ℎ𝑖𝑖𝑐𝑐ℎ 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑖𝑖𝑖𝑖 ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜
(𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝐼𝐼𝐼𝐼 + 28 − 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 𝑜𝑜𝑜𝑜 1𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑−𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡+  1) / 365.25 
The recovery time is defined as: 
෍[𝑚𝑚𝑚𝑚𝑚𝑚(𝑖𝑖𝑡𝑡ℎ 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 7, 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑙𝑙𝑙𝑙𝑙𝑙𝑙𝑙 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑜𝑜𝑜𝑜 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖+ 28)
𝑘𝑘
𝑖𝑖=1
− 𝑖𝑖𝑡𝑡ℎ 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑+ 1] 
3.6.5 
Patient Global Impression of Benefit/Risk (PGI-BR) 
The PGI-BR is a 5-item questionnaire assessing the participant’s perception of the overall 
benefits and risks of treatment at SV10. The 5 items assess: overall trial experience, efficacy, 
side effects, convenience and overall assessment of the benefits and harms of treatment. Items 
are rated on 5- or 6-point verbal rating scales. 
3.6.6 
Asthma related inflammatory blood biomarkers 
Asthma related inflammatory blood biomarkers will be assessed at visits SV1, SV4, SV7, 
SV8, SV9, SV10, SV11, SV12 and E/D and will include following parameters: 
• 
plasma EDN 
• 
total IgE 
• 
sST2 
• 
Allergen-specific IgE 
 
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3.6.7 
Sino-nasal Outcome Test-22 (SNOT-22) 
The SNOT-22 is a condition-specific health-related quality of life assessment, which captures 
participant-reported physical problems, functional limitations, and emotional consequences of 
sino-nasal conditions (Hopkins et al 2009; Piccirillo et al 2002). The SNOT-22 contains a list 
of 22 symptoms and social/emotional consequences of a participant’s nasal disorder, and 
measures how severe each symptom is and the social/emotional consequences of symptoms 
over a 2-week period on a scale from 0 (no problem) to 5 (problem as bad as it can be). The 
total score is the sum of item scores and has a range from 0 to 110 (higher scores indicate 
poorer outcomes). 
The SNOT-22 will be administered to participants who have comorbid chronic inflammatory 
conditions of the nasal mucosa and/or paranasal sinuses (CRS) on the eDiary according to the 
SoA of the CSP. The exploratory endpoint will be the change from baseline through Week 16 
in SNOT-22. 
3.7 
Derivation of exploratory cough sub-study variables 
Objective cough measurements 
Objective cough frequency over 24 hours will be measured using an ACM (VitaloJAK™; 
Vitalograph, Buckinghamshire, UK) which will be fitted and worn by the participants for 
approximately 24 hours after the visits SV2 and SV10. The digitally recorded data will be sent 
to Vitalograph who will undertake cough counting for all participants using a standardised 
process. Following parameters will be provided: 
• 
Daily cough frequency. 
• 
Awake time cough frequency. 
• 
Night-time cough frequency. 
 
All frequency data will be recorded to two decimal places. The minimum recording time for 
the measurement to be ‘done’ is 1 hour, however the minimum recording time required for 
analysis is 18 hours within the 24-hour interval, and subjects’ data with recording time 
< 18 hours will be excluded from analysis. 
Cough VAS 
Participants will be asked to complete a cough severity VAS (100 mm linear scale marked 
with a horizontal line by the participant, with 0 mm representing ‘‘no cough’’ and 100 mm 
representing “worst cough”) measuring subjective assessment by the participant of the prior 
24 hours for severity of cough symptoms (Smith et al 2006). Exploratory endpoint will be the 
change from baseline to Week 16 in cough VAS. 
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4 
ANALYSIS METHODS 
The primary analysis will occur once all participants have either completed the SV10 (Week 
16) assessments or have withdrawn from the study. The sponsor staff will be fully unblinded 
following the Primary Analysis Database Lock. Investigators, participants and site staff will 
not be made aware of unblinded treatment assignments for individual participants who are in 
the follow-up period until these participants have completed the study.  
The final analysis will occur when all participants have completed the follow-up period at 
SV12 (Week 24) or have withdrawn from the study. 
4.1 
General principles 
Efficacy analyses will be performed using the ITT population. Demography and baseline 
characteristics will be summarised by treatment group for the ITT population. 
Treatment groups will be displayed as follows: 
• 
MEDI3506 
 mg 
• 
MEDI3506 
mg 
• 
Placebo 
 
The standard descriptive summary statistics for a set of continuous data are n, mean, standard 
deviation, median, minimum value and maximum value. Other summary statistics (e.g., 
standard error (SE) least-squares mean (LSmean), confident interval (CI)) may be suitable in 
addition. For log transformed data geometric mean and coefficient of variation (CV) will be 
presented in addition to the standard descriptive summary statistics. Concentration data will be 
summarised using descriptive statistics, including n, n<lower limit of quantification, 
arithmetic mean, arithmetic standard deviation (SD), geometric mean, coefficient of variation 
(CV%), geometric mean -/+ geometric SD (gSD), minimum, median, and maximum values. 
The geometric mean is calculated as the exponential of the arithmetic mean calculated from 
data on a natural log scale. The geometric CV% is calculated as 100 x sqrt[exp(s2)-1], where s 
is the SD of the data on the natural log scale. The geometric mean -/+ gSD is calculated as 
exp(mean(log(PK Conc)) -/+ std(log(PK Conc))). 
For continuous data the mean, median, geometric mean, first quartile (Q1), third quartile (Q3), 
LSmean, CI, SD and SEwill be rounded to 1 additional decimal place compared to the 
analysed data. Minimum and maximum will be displayed with the same accuracy as the 
analysed data. Coefficient of variation (CV%), where reported, will always be reported to 1 
decimal place. 
For categorical data, percentages will be rounded to 1 decimal place. 
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PK concentration descriptive statistics will all be presented as follows:  
• 
Arithmetic mean, arithmetic SD, geometric mean, geometric CV%, Geometric Mean -/+ 
gSD, median: 4 significant figures 
• 
Minimum, maximum: 3 significant figures 
• 
Data listing: same significant figures as supplied from bioanalysis. 
 
The primary analysis will be performed after all participants have completed SV10 (Week 16) 
or have withdrawn from the study. At the time of the primary analysis all data collected on 
and prior to data cut-off date (i.e., Week 16 visit date for the last subject) will be cleaned. For 
the purpose of the statistical analysis, data cut-off rules might be implemented and described 
in a separate document. 
All data collected until the time of the final DBL will be included in the final analysis. No cut-
off rules will be implemented for the final analysis. 
4.1.1 
Statistical Hypotheses 
The primary efficacy endpoint is the change from baseline in pre-BD FEV1 at Week 16. A 
treatment policy estimand will be applied whereby all available data are included in the 
analysis, irrespective of whether a participant discontinued study intervention or received 
rescue therapy. 
The null hypothesis is that the change from baseline in FEV1 at Week 16 for participants 
dosed with MEDI3506 is equal to the change from baseline in FEV1 at Week 16 for 
participants dosed with placebo. The alternative hypothesis is that the change from baseline in 
FEV1 at Week 16 for participants dosed with MEDI3506 is greater than the change from 
baseline in FEV1 at Week 16 for participants dosed with placebo, ie: 
• 
H0: Change from Baseline in FEV1 at Week 16 (MEDI3506-placebo) = 0. 
• 
H1: Change from Baseline in FEV1 at Week 16 (MEDI3506-placebo) > 0.  
 
Hypothesis testing will be performed at the one-sided 10% level. If the p-value is < 0.1, reject 
H0 and accept H1. A hierarchical testing strategy will be used to preserve the type I error for 
the comparisons of each of the 2 dose levels of MEDI3506 versus placebo, as follows: 
• 
Step 1: Test MEDI3506 
 mg versus placebo in regard to H0 
• 
Step 2: If previous step rejects: test MEDI3506 
 mg versus placebo in regard to H0 
 
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4.1.2 
Repeated measures mixed effects analysis of covariance model 
(MMRM) 
The repeated measures mixed effects analysis of covariance model (MMRM) will be used to 
fit change from baseline for continuous endpoints at each visit, for the ITT population. The 
model will include all available data from all visits up to and including the target visit, 
irrespective of whether the participant discontinued study intervention or received rescue 
therapy. No imputation will be made for missing data, as a repeated measures model is being 
applied. The model will include fixed effects for baseline, background medication use, 
geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and 
treatment by visit interactions. Visits within subject are considered as repeated measurements. 
An unstructured covariance matrix will be used to describe the correlations between 
observations on a participant between visits. The denominator degrees of freedom will be 
calculated using the Kenward-Rogers method. In the event that the model with unstructured 
covariance matrix fails to converge,  an autoregressive (1) covariance matrix will be used 
instead. If also the autoregressive (1) does not converge, a compound symmetry covariance 
matrix will be used. If the model still does not converge, the baseline by visit effect will be 
deleted from the model. Estimates of the least square mean change from baseline in endpoint 
variable for each treatment, and the difference between them, together with two-sided 80% 
confidence interval, will be obtained from the model for each visit. The significance of the 
treatment effect will be tested at a 10% one-sided level of significance as described in Section 
4.1.1. 
The reportable results from the model will be: 
• 
The least-square means (LSMeans) change from baseline at certain visit and their 
standard errors for each group 
• 
The difference in change from baseline at certain visit between active treatments groups 
and placebo (LSMeans difference) together with its two-sided 80% confidence interval 
(CI) 
• 
The one-sided p-value for the difference in change from baseline at certain visit between 
active treatment groups and placebo 
 
If the dependent variable is considered to be normally distributed, the variable fitted in the 
model will be the change from baseline; the MMRM and the reportable results will be those 
described above. 
On the other hand, if the dependent variable is considered to be log-normally distributed, the 
variable fitted in the model will be the change from baseline in logarithmical scale, with the 
logarithm of the baseline value as a covariate. Change from baseline in logarithmic scale is 
defined as the log-transformation of the post-baseline visit value minus the log-transformation 
of the baseline value. 
The MMRM will be as described above but the reportable results from the model will be: 
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• 
For the percent change: 
− 
Back transformed LSmeans for each group, which correspond to the estimated 
percent change from baseline; back transformed LSmeans is derived as 
[EXP(LSMean)-1]*100;  
− 
Two-sided 80% CI of the back transformed LSmeans for each group; 80% CI of the 
back transformed LSmeans is derived as [EXP(Lower limit of the 80% CI of the 
LSmean)-1]*100; [EXP(Upper limit of the 80% CI of the LSmean)-1]*100; 
• 
For the relative change: 
− 
Back transformed LSmeans for each group, which correspond to the estimated 
relative change from baseline; back transformed LSmeans is derived as 
EXP(LSMean);  
− 
Two-sided 80% CI of the back transformed LSmeans for each group; 80% CI of the 
back transformed LSmeans is derived as EXP(Lower limit of the 80% CI of the 
LSmean); EXP(Upper limit of the 80% CI of the LSmean); 
• 
For the comparison: 
− 
The estimated geometric LSMean ratio between active groups and placebo; the ratio 
is calculated as EXP(LSMean difference); 
− 
The Two-sided 80% CI of the ratio; the 80% CI of the ratio is calculated as 
EXP(Lower limit of the 80% CI of the LSmean difference)0; EXP(Upper limit of the 
80% CI of the LSmean difference); 
− 
One-sided p-value. 
 
Note that a ratio lower than 1 means that the active treatment group shows a higher decrease 
(or a lower increase) compared to the placebo group. On the other hand, a ratio greater than 1 
means that the active treatment group shows a lower decrease (or a higher increase) compared 
to the placebo group. 
The MMRM will be applied using PROC MIXED (SAS procedure).  
4.1.3 
Analysis of covariance (ANCOVA)  
An ANCOVA model will be used to analyse change from baseline for continuous endpoints 
collected at only one post-baseline visit. The treatment group will be considered as a fixed 
effect of the model, with the baseline value, background medication use, geographic region 
and baseline ICS total daily dose as covariates. Comparisons of MEDI3506 
 mg versus 
placebo and MEDI3506 
 mg versus placebo will be assessed within the same model. The 
restricted maximum likelihood (REML) approach will be used for the estimation of the 
variance and covariance parameters of the linear model; one-sided difference test, with alpha 
level at 10% will be used for the treatment comparisons. No imputation will be made for 
missing data.  
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The reportable results from the model will be: 
• 
The LSmeans and their standard errors for each treatment group; 
• 
The difference between active treatment groups and placebo (LSmean difference) 
together with its two-sided 80% CI; 
• 
The one-sided p-value for the difference between active treatment groups and placebo. 
 
If the parameter results to be normally distributed, the variable fitted in the model will be the 
change from baseline; the ANCOVA model and the reportable results will be those described 
above.  
On the other hand, if the parameter results to be log-normally distributed, the variable fitted in 
the model will be the change from baseline in logarithmical scale. Change from baseline in 
logarithmical scale is defined as the log-transformation of the post-baseline visit value minus 
the log-transformation of the baseline value. 
The ANCOVA model will be as described above but the reportable results from the model will 
be: 
• 
For the percent change: 
− 
Back transformed LSmeans for each group, which correspond to the estimated 
percent change from baseline; back transformed LSmeans is derived as 
[EXP(LSMean)-1]*100;  
− 
Two-sided 80% CI of the back transformed LSmeans for each group; 80% CI of the 
back transformed LSmeans is derived as [EXP(Lower limit of the 80% CI of the 
LSmean)-1]*100; [EXP(Upper limit of the 80% CI of the LSmean)-1]*100; 
• 
For the relative change: 
− 
Back transformed LSmeans for each group, which correspond to the estimated 
relative change from baseline; back transformed LSmeans is derived as 
EXP(LSMean);  
− 
Two-sided 80% CI of the back transformed LSmeans for each group; 80% CI of the 
back transformed LSmeans is derived as EXP(Lower limit of the 80% CI of the 
LSmean); EXP(Upper limit of the 80% CI of the LSmean); 
• 
For the comparison: 
− 
The estimated geometric LSMean ratio between active groups and placebo; the ratio 
is calculated as EXP(LSMean difference); 
− 
The Two-sided 80% CI of the ratio; the 80% CI of the ratio is calculated as 
EXP(Lower limit of the 80% CI of the LSmean difference)0; EXP(Upper limit of the 
80% CI of the LSmean difference); 
− 
One-sided p-value. 
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4.1.4 
Chi-squared test 
The chi-square test will be used to assess the difference in proportion of responders. The 
difference between active treatment groups versus placebo will be presented with the two-
sided 80% confidence intervals the one-sided p-values. 
4.1.5 
Negative binomial regression 
Negative binomial regression will be used for the analysis of event rates. In this study the 
response variable in the model will be the number of asthma CompEx events, the number of 
asthma exacerbations, or the number of hospitalised asthma exacerbations experienced by a 
participant. The model will include treatment group, background medication, geographic 
region and baseline ICS total daily dose as covariates. The logarithm of the participant’s 
corresponding follow-up time will be used as an offset variable in the model to adjust for 
participants having different exposure times during which the events occur. 
The standard parameterization approach (NB2) of the negative binomial model will be applied 
using PROC GENMOD (SAS procedure).  
The estimated annualised event rate in each group, the estimated treatment effect (ie, the rate 
ratio of each treatment group versus placebo), corresponding two-sided 80% CI, and one-
sided p-value for the rate ratio will be presented. The estimate of the negative binomial 
overdispersion parameter will also be reported.  
4.1.6 
Cox proportional hazards 
Time to first asthma CompEx event/ first asthma exacerbation data will be analysed using Cox 
proportional hazard model including treatment group, background medication, geographic 
region and baseline ICS total daily dose as covariates. Results of the analysis will be 
summarised as hazard ratios, two-sided 80% confidence intervals and one-sided p-values. 
Time to first asthma CompEx event/ asthma exacerbation will be displayed graphically using 
a Kaplan-Meier plot. 
4.2 
Analysis of variables 
4.2.1 
Disposition of subjects 
Subject dispositions (number and percentage of participants enrolled, participants randomised, 
participants not randomised (incl. reasons), participants who received at least one dose of 
study IP, participants who did not receive treatment, participants who completed the 
treatment, participants who did not complete treatment (incl. reasons), participants who 
completed the study and participants withdrawn from study (incl. reasons)) will be presented 
in a summary table for each treatment group and overall. A listing including all standardized 
disposition terms will be also provided for all discontinued subjects. The table will be based 
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on ‘All Subjects’ population and repeated for the ITT population. The listing will be based on 
the ITT population. 
The number of participants belonging to each analysis population will be presented in a 
summary table by treatment group and overall. Listing of all participants excluded from any 
analysis set will be also provided. The listing will include reason for exclusion from 
respective. 
The number and percentage of subject recruitment by region and country will be presented for 
the ITT population. 
The number and percentage of participants with one or more disruption due to COVID-19 
pandemic will be presented by treatment group and overall. A listing of all participants 
affected by the COVID-19 related study disruption , and a description of how the individual’s 
participation was altered, will be produced. COVID-19 related study disruptions can be: 
• 
Visit related (if visit is impacted by global/country situation, then contact mode will be 
specified); 
• 
Study drug related (if study drug administration or location was impacted by 
global/country situation; who performed a study drug administration); 
• 
Concomitant medication related (if when treatment was stopped due to any global/country 
related situations ie: epidemic/pandemic, healthcare crisis etc.); 
• 
Withdrawal from study (if primary reason for ending study is related to global/country 
situation). 
 
Participants with reported issues in the clinical trial management system due to COVID-19 
will be listed. 
Randomisation scheme and codes as well as subjects receiving the various batch of 
investigational product will be listed. 
Number and percent of participants remaining on treatment, discontinued treatment but still in 
study, and participants withdrawn from the study at each scheduled visit will be summarised. 
Participants completing the study will be listed. 
Number and percentage of participants in sub-study will be summarised for the ITT 
population. 
4.2.2 
Important protocol deviations 
The number and percentage of participants with at least one IPD, including COVID-19 related 
IPD, will be summarised based on the categories specified in the Protocol Deviation Plan 
(PDP), for each treatment group and overall.  
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All IPDs will be also listed based on the ITT population. All issues reported due to COVID-19 
pandemic, regardless of whether the type of issue is considered a protocol deviation or not, 
will be listed separately (see Section 4.2.1). 
4.2.3 
Baseline assessments and other subject-specific characteristics 
4.2.3.1 
Demographics and subject-specific characteristics 
All demographic and subject-specific characteristics reported in section 3.2.1.1 will be 
presented in summary tables for each treatment group and overall; age, height, weight and 
BMI will be summarised descriptively; all the other demographic and subject-specific 
characteristics will be summarised as categorical variables with the number and percentages 
of participants by categories. Only the baseline measurement for height, weight and BMI will 
be considered. 
All demographic and subject-specific characteristics will be also provided in listings. The 
tables and the listings will be based on the ITT population. 
4.2.3.2 
Medical history 
Medical history as described in section 3.2.1.2 will be presented in summary tables as number 
and percentages of participants by System Organ Class (SOC) and Preferred Term (PT) for 
each treatment group and overall. Participants with multiple events in the same SOC/PT will 
be counted only once in that SOC/PT. Participants with events in more than one SOC/PT will 
be counted once in each of those SOC/PT. Tables will be sorted alphabetically by SOC and 
PT. The tables will be based on the ITT population. 
4.2.3.3 
Prior and concomitant medication 
The number and percentage of participants receiving prior or concomitant medication, 
excluding ICS and ICS containing medications, (by ATC4 classification system codes and 
generic name) will be presented by treatment in separate tables for the ITT population. 
A separate table will be presented for participants who take disallowed concomitant 
medications, excluding ICS and ICS containing medications. Percentages will be calculated 
relative to the number of participants in the ITT population. 
All medications will also be listed by subject for the ITT population. 
4.2.3.4 
Asthma history 
Asthma characteristics at baseline (age at asthma onset (Section 3.1.6.2), time since asthma 
diagnosis (Section 3.1.6.1), time since asthma symptoms started (Section 3.1.6.3), time since 
last asthma exacerbation (Section 3.1.6.4), total number of asthma exacerbations within 
previous 12 months prior to screening, including exacerbations resulted in non-emergency 
room treatment, emergency room treatment, hospitalization (Section 3.2.1.4)) will be 
summarised by treatment and overall for the ITT population. Descriptive summary statistics 
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will be produced for previous and concomitant treatments containing ICS and combination of 
products containing ICS. Asthma characteristics at baseline and previous and concomitant 
treatments containing ICS and combination of products containing ICS will also be listed for 
the ITT population. 
4.2.3.5 
Substance usage 
Summary statistics will be produced by substance usage category (never, former, current), by 
treatment group and overall, for alcohol and tobacco use (as specified in Section 3.2.1.5) for 
the ITT population. Additionally, descriptive statistics on the number of pack-years for former 
or current cigarettes smokers will be provided.  
4.2.3.6 
Other assessments at Screening 
Summary statistics for eDiary data at baseline such as 2-weekly mean PEF, 2-weekly mean 
FEV1, number of days with awakening and rescue medication use, number of days with 
rescue medication used during the night and number of days with rescue medication use 
during the day, will be provided by treatment and overall. 
4.2.4 
Analysis of primary efficacy endpoint 
4.2.4.1 
Primary analysis of the primary endpoint 
The primary efficacy endpoint is the change from baseline in pre-BD FEV1 to Week 16.  
The primary estimand is a ‘Treatment Policy’ estimand, as follows: The difference in mean 
change from baseline in pre-BD FEV1 at Week 16 (MEDI3506 – placebo) will be analysed 
using MMRM (see Section 4.1.2) for the ITT population. This will include all available data 
from all visits up to and including Week 16, irrespective of whether the participant 
discontinued study intervention or received rescue therapy. Graphical representations of the 
LSMean change from baseline and the two-sided 80% CI over time will be provided by 
treatment group using the ITT population. 
The observed values and change from baseline through Week 16 in pre-BD FEV1 (L) by 
treatment group and visit will be summarised using the ITT population. 
4.2.4.2 
Supportive analysis of the primary endpoint 
As a supportive analysis of the primary endpoint, the MMRM analysis (see Section 4.1.2) will 
be repeated on the ITT population using data from visits up to and including Week 16, but 
excluding the data from visits after IP discontinuation. Graphical representations of the 
LSMean change from baseline and the two-sided 80% CI over time will be provided by 
treatment group using the ITT population. 
4.2.4.3 
Subgroup analysis for the primary endpoint 
For each of the subgroup factors (see Section 3.1.7) a separate MMRM will be fitted using the 
same covariates as described for the primary analysis in Section 4.2.4.1. Geographical region 
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will not be a covariate if it is the subgroup; baseline ICS total daily dose will not be a 
covariate if it is the subgroup; background medication will not be a covariate if it is the 
subgroup. MMRM results from subgroup analysis will be displayed using forest plot.  
The observed values and change from baseline through Week16 pre-BD FEV1 (L) by 
treatment group, visit and subgroup will be summarised using the ITT population. 
4.2.4.4 
Exploratory analysis of the primary endpoint 
The exploratory analysis of the primary analyses will consist of the following. 
The primary analysis will be repeated on the ITT population using data from visits up to and 
including Week 16 by means of the MMRM as described in section 4.1.2, 
 
 
 
Additionally, the exploratory analysis of the primary endpoint will consist of repeating the 
MMRM analysis (see Section 4.1.2) on the ITT population from visits up to and including 
Week 24.  
Graphical representations of the LSMean change from baseline and the two-sided 80% CI up 
to and including Week 24 will be provided by treatment group using the ITT population. 
The observed values and absolute change from baseline though Week 24 will be summarised 
by treatment group using the ITT population. 
4.2.5 
Analysis of secondary endpoints 
4.2.5.1 
Analysis of lung function parameters measured in clinic 
The observed values and changes from baseline in lung function parameters measured in 
clinic such as pre-BD FEV1, post-BD FEV1 , FVC, FEV1/FVC, percent predicted FEV1, 
percent predicted FVC, PEF and FEF25-75% will be summarised by treatment group and visit 
for the ITT population. Observed values and changes from baseline in pre-BD FEV1 to 4-
hours post administration of IP at Day 1 will also be summarised. 
The difference in mean change from baseline in post-BD FEV1 to Weeks 8 and 16 will be 
estimated using a MMRM, similar to that described for the primary efficacy analysis 
(Section 4.1.2). The change from baseline through Week 16 will be included in the model. 
LSMean change from baseline and two-sided 80% CI through Week 16 in post-BD FEV1 will 
be presented in figures. 
All lung function parameters measured in clinic will be also reported in listing using the ITT 
population. 
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4.2.5.2 
Analysis of ACQ-6 
Change from baseline to Week 16 in ACQ-6 will be analysed using MMRM (see Section 
4.1.2). LSMean change from baseline and two-sided 80% CI through Week 24 in ACQ-6 
score will be presented in figures. 
Observed values and absolute change from baseline through Week 16 will be summarised by 
treatment group using the ITT population. 
As a part of exploratory analysis change from baseline through Week 24 in ACQ-6 will also 
be analysed. 
Number and proportion of participants with a decrease in ACQ-6 score of ≥ 0.5 from baseline 
to Week 16 and number and proportion of participants achieving ACQ-6 well controlled status 
at Week 16 (as defined in Section 3.4.3) will be summarised and analysed using chi-squared 
test as described in Section 4.1.4 for the ITT population. 
A listing including results from each of the questions and the ACQ-6 score will be produced 
for the ITT population. 
4.2.5.3 
Analysis of SGRQ 
Change from baseline to Week 16 in SGRQ total and domain scores will be analysed using 
MMRM (see Section 4.1.2). LSMean change from baseline and two-sided 80% CI through 
Week 16 in SGRQ total score will be presented in figures. 
Observed values and absolute change from baseline through Week 16 will be summarised. 
As a part of exploratory analysis change from baseline through Week 24 in SGRQ total score 
will also be analysed. 
Number and proportion of participants with a decrease in SGRQ total score of ≥ 4 points from 
baseline to Week 16 (as defined in Section 3.4.4) will be summarised and analysed using chi-
squared test as described in Section 4.1.4 for the ITT population. 
A listing including results from each of the question and the total SGRQ score will be 
produced for the ITT population. 
4.2.5.4 
Analysis of Asthma CompEx 
Time to first asthma CompEx event will be analysed using a Cox proportional hazard model, 
with group, background medication, geographic region and baseline ICS total daily dose as 
covariates (see Section 4.1.6). All available data from participants through Week 16 will be 
included. Additionally, the analysis of time to first asthma CompEx event will be repeated 
using all available data from participants through Week 24 (end of follow-up). 
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Time to first asthma CompEx will also be displayed in a Kaplan-Meier plot, including all data 
through to Week 24 (end of follow-up).  
The asthma CompEx event rate will be analysed using negative binomial regression, with the 
log(follow-up time) included as an offset term and treatment group, geographic region, 
baseline ICS total daily dose as covariates (see Section 4.1.5). The dependent variable will be 
the number of asthma CompEx events through Week 16. All available data from participants 
through to Week 16 will be included, irrespective of whether they discontinued study 
intervention. 
Additionally, the analyses of the asthma CompEx event rate will be repeated using all 
available data from participants through Week 24 (end of follow-up). 
Asthma CompEx events will be also reported in listing for the ITT population. 
4.2.5.5 
Analysis of FeNO 
Relative and percent change from baseline through Week 16 in concentration of FeNO will be 
analysed using a repeated measures analysis of covariance model, similar to that described for 
the primary efficacy analysis (Section 4.1.2 – reportable results for variables log-normally 
distributed). Estimates of the least square mean change from baseline for each treatment, and 
the difference between them, together with two-sided 80% confidence interval and one-sided 
p-values, will be obtained from the model for each visit. LSMean percent change from 
baseline through Week 16 in concentration of FeNO will be presented in figure. Observed 
concentration of FeNO and relative and percent change from baseline will be descriptively 
summarised for the ITT population. 
As a part of exploratory analysis change from baseline through Week 24 in concentration of 
FeNO will also be analysed. 
FeNO results will be also reported in listing for the ITT population. 
4.2.6 
Analysis of exploratory endpoints 
4.2.6.1 
Analysis of AO 
Change from baseline in AO parameters (R5, R20, R5-R20, AX) will be analysed using 
MMRM (see Section 4.1.2). LSMean change from baseline and two-sided 80% CI for each 
visit through Week 16 in AO parameters will be presented in figures.  
Observed values and change from baseline through Week 16 will be descriptively summarised 
for all AO parameters by treatment groups for the ITT population. 
AO parameters will be also reported in listing for the ITT population. 
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4.2.6.2 
Analysis of FEV1% reversibility and FEF25-75% 
The difference in mean change from baseline in FEV1 % reversibility (see Section 3.6.3) 
through Week 16 will be estimated using a MMRM, similar to that described for the primary 
efficacy analysis (Section 4.1.2). The change from baseline through Week 16 will be included 
in the model.  
The FEF25-75% will also be analysed in the same way. 
4.2.6.3 
Analysis of asthma exacerbation 
Time to first asthma exacerbation will be analysed using a Cox proportional hazard model, 
with treatment group, geographic region and baseline ICS total daily dose as covariates (see 
Section 4.1.6). The data will also be displayed in a Kaplan-Meier plot.  
Number of exacerbations, total follow-up time and annual exacerbation rate including the two-
sided 80% CI will be summarised by treatment group for the ITT population. Asthma 
exacerbations during the intervention period (baseline to last dose date +28 days) will be 
analysed using negative binomial model (see Section 4.1.5). Rate ratio from MEDI3506 
 
mg compared to placebo and from MEDI3506 
mg compared to placebo will be displayed. 
Similarly, the hospitalised asthma exacerbations will also be analysed. 
Asthma exacerbations and hospitalised asthma exacerbations will be also reported in listing 
for the ITT population. 
4.2.6.4 
Analysis of PGI-BR 
The results of the 5-item questionnaire of the PGI-BR will be descriptively summarised at 
Week 16 by treatment group for the ITT population. 
PGI-BR responses will be also reported in listing. 
4.2.6.5 
Analysis of SNOT-22 
The total SNOT-22 score and the change from baseline will be descriptively summarised by 
visit andby treatment group for the ITT population. 
Total SNOT-22 score as well as single questions will be also reported in listing for the ITT 
population. 
Change from baseline through Week 16 in SNOT-22 score will be analysed using MMRM 
(see Section 4.1.2). LSMean change from baseline and two-sided 80% CI through Week 16 in 
SNOT-22 score will be presented in figures. 
4.2.6.6 
Analysis of diary data and home spirometry 
2-weekly mean asthma symptom score, 2-weekly mean rescue medication usage, 2-weekly 
mean night time awakening due to asthma, 2-weekly mean home FEV1 and 2-weekly mean 
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home PEF as derived in Section 3.6.2 through Week 24 and the changes from baseline 
through Week 24 will be descriptively summarised using the ITT population. 
Additionally, change from baseline will be analysed using MMRM (see Section 4.1.2). The 
LSmean changes from baseline and two-sided 80% CI through Week 24 will be presented in 
figures.  
2-weekly means will be also reported in listing for the ITT population. 
4.2.7 
Analysis of safety endpoints 
Duration of exposure as calculated in Section 3.1.6 will be summarised by treatment groups 
for the As-treated population. 
 
Number and percentage of participants who received planned starting dose, who received 
different starting dose from planned, who had any interruption or 1, 2, 3, etc. interruption will 
be summarised by treatment group for the As-treated population. Reason for interruption will 
also be provided. 
Interruption will be defined as any administration where action taken is reported as ‘Drug 
interrupted’. 
A listing of the administration of investigational product together with the duration of 
exposure will be presented for all subjects belonging to the As-treated population. 
4.2.7.1 
Analysis of AEs 
All AE summary tables and listings will be created by treatment group and for total 
MEDI3506 for the As-treated population, unless otherwise specified. AEs occurred during 
study intervention (on-treatment phase as defined in section 3.1.4) and follow-up period 
(follow-up phase as defined in section 3.1.4) will be reported in summary tables. All AEs, 
including AEs for enrolled but not randomised participants and for participants who were not 
exposed to treatment, will be listed. 
An overall summary table will be produced by treatment group and for total MEDI3506 
showing the number and percentage of participants with at least one AE in any of the 
following categories:  
• 
AEs; 
• 
AEs with toxicity grade 4 or 5; 
• 
Serious adverse events (SAEs); 
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• 
Deaths due to AE; 
• 
AEs leading to discontinuation of IP; 
• 
AEs leading to dose interruption; 
• 
AEs leading to withdrawal from study; 
• 
AESI. 
 
The total number of AEs in the different AE categories in terms of AE counts (ie, accounting 
for multiple occurrences of the same event in a subject) will also be presented by treatment 
group and for total MEDI3506.  
Number and percentage of participants with at least one AE by SOC term will be produced by 
treatment group and for total MEDI3506. 
Number and percentage of participants with at least one AE by PT will be produced for AEs 
with a frequency of > 5% by treatment group and for total MEDI3506. Frequency will be 
defined according to percentage in total MEDI3506. 
Number and percentage of participants with AE by SOC and PT will be summarised by 
treatment group and for total MEDI3506. 
Number and percentage of participants with AE by PT and maximum reported toxicity grade 
will be summarised by treatment group and for total MEDI3506 in table and AEs with 
frequency of >5% per treatment group will be graphically displayed using bar graphs. Each 
participant is represented only for the maximum reported intensity of each PT. Frequency will 
be defined according to percentage in total MEDI3506. 
Number and percentage of participants with AEs by PT and investigator’s causality 
assessment will be summarised by treatment group and for total MEDI3506. 
Total number of AEs by SOC and PT will be summarised by treatment group and for total 
MEDI3506. Total number of SAEs by SOC and PT will be summarised by treatment group 
and for total MEDI3506. 
Number and percentage of participants with AE leading to dose interruption by SOC and PT 
will be summarised by treatment group and for total MEDI3506. 
Number and percentage of participants with non-serious AEs and number of non-serious 
events occurring in more than 5% of participants will be summarised by SOC and PT. 
Number and percentage of participants with AE with outcome of death by SOC and PT will 
be summarised by treatment group and for total MEDI3506. Key subject information for 
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participants experience AEs with outcome of death will be produced for each treatment group 
using following information: 
• 
Treatment group 
• 
Subject identifier 
• 
Sex 
• 
Age (years) 
• 
Event term as reported by the investigator 
• 
PT  
• 
Time from first IP administration to onset of AE (days) as derived in Section 3.1.6.6 
• 
Treatment period 
• 
Time from last IP administration to death (days) as derived in Section 3.1.6.9 
• 
Time from first IP administration to death (days) as derived in Section 3.1.6.8  
• 
Received treatment for AE 
• 
Reasonable possibility AE caused by IP 
 
Number and percentage of participants with SAE by SOC and PT will be summarised by 
treatment group and for total MEDI3506. Key subject information for participants experience 
SAEs will be produced using following information: 
• 
Treatment group 
• 
Subject identifier 
• 
Sex 
• 
Age (years) 
• 
Event term as reported by the investigator 
• 
PT  
• 
Time from first IP administration to onset of AE (days) as derived in Section 3.1.6.6 
• 
Time from last IP administration prior to AE start date, calculated for AEs starting after 
the discontinuation of the IP. 
• 
Time from start of IP administration to becoming serious 
• 
Outcome 
• 
Action taken with IP 
• 
Reasonable possibility AE caused by IP. 
 
Number and percentage of participants with AE leading to discontinuation of IP by SOC and 
PT will be summarised by treatment group and for total MEDI3506. Key subject information 
for participants experience AEs leading to discontinuation of IP will be produced using 
following information: 
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• 
Treatment group 
• 
Subject identifier  
• 
Sex 
• 
Age 
• 
AE as reported by the investigator 
• 
PT  
• 
Time from first IP administration to AE onset 
• 
Time from first IP administration to discontinuation of IP 
• 
Seriousness 
• 
Outcome 
• 
Reasonable possibility AE caused by IP. 
 
Number and percentage of participants with AESIs by maximum reported toxicity grade will 
be summarised by treatment group and for total MEDI3506. A list of PTs for AESIs 
experienced during the study will be produced. Number of participants with injection site 
reaction (ISR) by maximum reported toxicity grade will be summarised by treatment group 
and for total MEDI3506. 
Number of subjects with COVID-19 related AESIs  by maximum reported toxicity grade will 
be summarised by treatment group and for total MEDI3506. Similar table will be repeated for 
the number of subjects with COVID-19 related serious AESIs. 
All AEs will be listed as well as AEs among ADA positive participants. 
4.2.7.2 
Analysis of vital signs 
Observed values and change from baseline in vital signs will be summarised by treatment 
group and for total MEDI3506, and visit. Key subject information will be produced for vital 
sign parameters treatment-emergent changes outside predefined criteria (Table ). 
Individual vital sign results will be listed. 
4.2.7.3 
Analysis of laboratory measurements 
Laboratory evaluations (haematology, clinical chemistry and quantitative urinalysis 
parameters as per Table ) will be summarised with descriptive statistics at each visit and 
change from baseline summarised for each post-baseline visit by treatment group and for total 
MEDI3506. Categorical haematology, clinical chemistry and urinalysis results will be 
summarised in shift tables comparing maximum value during treatment with baseline value by 
treatment group and for total MEDI3506. Similarly, haematology and clinical chemistry 
results will also be summarised in shift tables comparing minimum value during treatment.  
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ALT or AST versus total bilirubin, expressed as multiples of ULN as well as liver 
biochemistry test results over time – participants with elevated ALT or AST, and elevated 
total bilirubin at any point during the study following the start of study medication will be 
presented in figures. 
In addition to the summaries above also the maximum on-treatment ALT and AST by 
maximum total bilirubin for assessing Hy’s law criteria will be presented by treatment group 
and for total MEDI3506. 
All laboratory results will be listed as well as any SARS-CoV-2 test results. 
4.2.7.4 
Analysis of ECG 
ECG variables will be summarised with descriptive statistics at each visit and change from 
baseline summarised for each post-baseline visit by treatment group and for total MEDI3506. 
Investigators’ ECG assessments at baseline versus last observation on treatment will be 
summarised in shift table by treatment group and for total MEDI3506. Key subject 
information will be produced for ECG parameter values outside predefined criteria (Table ).  
In addition, the number and percentage of participants with QTcF intervals (derived as 
described in Section 3.5.4) at any observation on treatment >450 ms, >480 ms, >500 ms and 
QTcF increase from baseline >30 ms, >60 ms, >90 ms, and combination of both, will be 
presented by treatment group and for total MEDI3506. 
Individual ECG results and abnormalities in ECG will be listed. 
4.2.7.5 
Analysis of echocardiogram 
Observed values and change from baseline in LVEF will be summarised by visit, by treatment 
group and for total MEDI3506 using descriptive summary statistics for the As-treated 
population. 
Individual echocardiogram results and abnormalities will be listed. 
4.2.7.6 
Other safety tests 
NT-proBNP results will be summarised with descriptive statistics at each visit and change 
from baseline summarised for each post-baseline visit for the As-treated population. NT-
proBNP results will be also summarised in shift tables comparing maximum value during 
treatment with baseline value for the As-treated population. 
The number of subjects tested positive for SARS-CoV-2 (by PCR or serology test) at end of 
study, but who were tested negative at baseline visit will also be presented.  
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Finally, the number of subjects tested positive for SARS-CoV-2 (by PCR or serology test) 
during the study (including both intervention and follow-up periods) who experienced or not 
at least one COVID-19 related AEs/SAEs will be provided. 
4.2.8 
Other analysis 
4.2.8.1 
Immunogenicity and PK 
Summary of ADA responses during the study with number and percentage of participants in 
each category (defined in Section 3.4.2.2) and ADA titres over time displaying min, Q1, 
median, Q3 and max, will be provided by treatment group. The impact of ADA on MEDI3506 
PK concentrations will be assessed.  Sumary of AEs by ADA status will be provided. The 
relationship between ADA and biomarkers or efficacy might be evaluated.  
MEDI3506 serum concentrations will be tabulated along with descriptive statistics.  
Geometric mean (together with gSD) serum MEDI3506 concentration over time will be 
plotted by treatment. Individual serum MEDI3506 concentration over time plots will be 
provided. Spaghetti plots of individual serum MEDI3506 concentrations over time by ADA 
category (TE-ADA negative, TE-ADA positive, ADA negative) will also be generated.  
All serum concentrations data will be listed for PK population. ADA results and participants 
key subject information for ADA positive participants will be provided for the As-treated 
population. 
Separately from the CSR, population PK modelling may be performed and reported, and 
potential correlation between PK exposure and pharmacodynamic biomarker, efficacy/safety 
response may be evaluated.  
4.2.8.2 
Analysis of blood biomarkers 
Analysis of blood eosinophils 
Blood eosinophils count will be summarised with descriptive statistics at each visit and 
change from baseline summarised for each post-baseline visit for the ITT population. Change 
from baseline in blood eosinophils will be analysed using MMRM as described in Section 
4.1.2 for the ITT population. Endpoints will be log transformed prior to analysis. Estimates of 
the least square mean change from baseline for each treatment, and the difference between 
them, together with two-sided 80% confidence interval and one-sided p-values, will be 
obtained from the model for each visit. LSMean change from baseline and two-sided 80% CI 
for each visit through Week 24 in blood eosinophils will be presented in figure. 
Blood eosinophils count will be also summarised in shift tables comparing maximum value 
during treatment to baseline value for the ITT population.  
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Other exploratory biomarkers 
The following serum and plasma biomarkers will be collected and summarised: 
• 
Total IgE, allergen-specific IgE, sST2 (serum); 
• 
Plasma EDN; 
• 
 
• 
Serum IL-5; 
• 
Serum IL-13; 
• 
Serum TSLP. 
 
Allergen-specific IgE status and Serum IL33:ST2 at baseline will be used for subgroup 
analysis of the primary endpoint (pre-BD FEV1) as described in Section 4.2.4.3. The subgroup 
cut-off for Serum IL33:ST2 is the Serum IL33:ST2 baseline median. 
 All the above biomarkers, except allergen specific IgE will be summarised with descriptive 
statistics at each visit and change from baseline summarised for each post-baseline visit. 
Change from baseline in all the above biomarkers, except allergen specific IgE and Serum 
IL33:ST2 will be analysed using a MMRM as described in Section 4.1.2. Endpoints will be 
log transformed prior to analysis. LSMean change from baseline and two-sided 80% CI for 
each analysed visit will be presented in figures.   
4.2.8.3 
Exploratory analyses 
Analysis of Objective Cough 
Observed values, percentage and relative change from baseline to Week 16 in objective cough 
measurements (see Section 3.6.2) will be summarised for ITT population. 
Percentage and relative changes from baseline in objective cough measures at Week 16 will 
be analysed using an analysis of covariance model as described in Section 4.1.3 (reportable 
results for variables log-normally distributed). Objective cough measurements will be log-
transformed prior to analysis. LSMean change from baseline to Week 16, together with the 
two-sided 80% CI, in objective cough parameters will be presented in figure.  
Cough VAS 
Observed values and absolute change from baseline to Week 16 in cough VAS score will be 
summarised by visit for ITT population. 
Change from baseline to Week 16 in cough VAS score will be analysed using an ANCOVA 
model as described in Section 4.1.3. LSMean change from baseline to Week 16, together with 
the two-sided 80% CI, in cough VAS score will be presented in figure. 
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A listing including cough VAS score results will be produced for the ITT population.  
5 
INTERIM ANALYSIS 
No formal interim analyses are planned for this study. 
The primary analysis (PA) will occur once all participants have either completed the SV10 
(Week 16) assessments or have withdrawn from the study. The sponsor staff will be fully 
unblinded following the PA data lock. Investigators, participants and site staff will not be 
made aware of unblinded treatment assignments for individual participants who are in the 
follow-up period until these participants have completed the study. The final analysis will 
occur when all participants have completed the follow-up period at SV12 (Week 24) or have 
withdrawn from the study. 
6 
CHANGES OF ANALYSIS FROM PROTOCOL 
This SAP is based on study protocol D9181C00001 Amendment V4.0 dated 08 March 2022. 
Any further amendment of the study protocol which can have an impact on the SAP will lead 
to an amendment of this document. Changes of analysis from D9181C00001 Amendment 
V4.0 dated 08 March 2022 are listed here below: 
Section 3 Objectives and endpoints 
• Time to first CompEx event based on the period from baseline to Week 16 is a 
secondary endpoint for this study. However, in this SAP, a supplementary analysis 
including events on the period from baseline to end of follow-up (Week 24) has been 
added. 
• An additional spirometry parameter not part of the main study endpoints (FEF25-75%) 
will be explored.  
 
Section 8.1.8.3 Asthma Control Questionnaire-6 
In this section is stated that “Mean scores of ≤ 0.75 indicate well-controlled asthma, scores 
between 0.75 and ≤ 1.5 indicate partly controlled asthma, and scores > 1.5 indicate not well-
controlled asthma”. In this SAP it is specified that “Mean scores of ≤ 0.75 indicate well-
controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and 
scores ≥1.5 indicate not well-controlled asthma”. 
Section 9.4.2.1 Primary Endpoint 
In this section it is stated that the MMRM will include “fixed effects for baseline, visit, 
treatment and the baseline by visit and treatment by visit interactions”. In this SAP it is 
mentioned that the MMRM will additionally include background medication, geographic 
region and baseline ICS total daily dose as fixed effects. The same variables will be added as 
covariates to ANCOVA, logistic regression, Cox proportional hazards and negative binomial 
models.
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7 
REFERENCES 
Fuhlbrigge et al 2017  
Fuhlbrigge AL, Bengtsson T, Peterson S, Jauhiainen A, Eriksson G, Da Silva CA et al. A novel 
endpoint for exacerbations in asthma to accelerate clinical development: a post-hoc analysis of 
randomised controlled trials. The Lancet Respiratory medicine. 2017;5(7):577-90. 
Jones et al 1991  
Jones PW, Quirk FH, Baveystock CM. The St George's Respiratory Questionnaire. Respir 
Med. 1991;85 Suppl B25-31; discussion 3-7. 
Jones and Forde 2009 
Jones PW, Forde Y. St George's Respiratory Questionnaire Manual. 2009; Version 2.3. 
Juniper et al 1999 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J. 1999;14(4):902-7. 
Juniper et al 2006 
Juniper EF, Bousquet J, Abetz L, Bateman ED, Committee G. Identifying 'well-controlled' 
and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med. 
2006;100(4):616-21. 
Hopkins et al 2009 
Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item 
Sinonasal Outcome Test. Clin Otolaryngol. 2009;34(5):447-54. 
NIH 2019 
NIH. Guidelines for the prevention and treatment of opportunistic infections in adults and 
adolescents with HIV. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 
Published 2019. Accessed 14 May 2020. 
Piccirillo et al 2002 
Piccirillo JF, Merritt MG, Jr., Richards ML. Psychometric and clinimetric validity of the 20-
Item Sino-Nasal Outcome Test (SNOT-20). Otolaryngol Head Neck Surg. 2002;126(1):41-7. 
Smith et al 2006 
Smith J, Owen E, Jones A, Dodd M, Webb A, Woodcock A. Objective measurement of cough 
during pulmonary exacerbations in adults with cystic fibrosis. Thorax. 2006;61(5):425-9. 
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8 
APPENDIX 
 
Appendix A  
Calculation of SGRQ scores 
Each questionnaire response has a unique empirically derived 'weight'. The lowest possible weight is zero and the highest is 100. 
Each component of the questionnaire is scored separately in three steps: 
1 
The weights for all items with positive responses are summed. 
2 
The weights for missed items are deducted from the maximum possible weight for each component. The weights for all missed 
items are deducted from the maximum possible weight for the Total score.  
3 
The score is calculated by dividing the summed weights by the adjusted maximum possible weight for that component and 
expressing the result as a percentage: 
Score =  100 × Summed weights from positive items in that component
Sum of weights for all items in that component
  
The Total score is calculated in similar way: 
Score =  100 × Summed weights from positive items in the questionnaire
Sum of weights for all items in the questionnaire
 
The Symptoms component is calculated from the summed weights for the positive responses to questions 1-8. 
The Activity component is calculated from the summed weights for the positive responses to questions 11 and 15. 
The Impacts component is calculated from the summed weights for the positive responses to questions 9-10, 12-14 and 16-17.  
The Total score is calculated by summing all positive responses in the questionnaire and expressing the result as a percentage of the 
total weight for the questionnaire. 
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Sum of maximum possible weights for each component and Total (for Step 2 in calculations):  
• 
Symptoms 662.5;  
• 
Activity 1209.1;  
• 
Impacts 2117.8;  
• 
Total 3989.4. 
Item weights 
The wording of the item may not correspond exactly with the wording in the current version of the questionnaire. 
PART 1 
Response 
Response weight 
1) Over the past 4 weeks, I have coughed: 
Almost every day  
80.6 
Several days a week  
63.2 
A few days a month 
29.3 
Only with respiratory infections 
28.1 
Not at all 
0.0 
2) Over the past 4 weeks, I have brought up phlegm (sputum): 
Almost every day  
76.8 
Several days a week  
60.0 
A few days a month 
34.0 
Only with respiratory infections 
30.2 
Not at all 
0.0 
3) Over the past 4 weeks, I have had shortness of breath: 
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Response 
Response weight 
Almost every day  
87.2 
Several days a week  
71.4 
A few days a month 
43.7 
Only with respiratory infections 
35.7 
Not at all 
0.0 
4) Over the past 4 weeks, I have had wheezing attacks:  
Almost every day  
86.2 
Several days a week  
71.0 
A few days a month 
45.6 
Only with respiratory infections 
36.4 
Not at all 
0.0 
5) How many times during the past 4 weeks have you suffered from severe or very unpleasant respiratory attacks? 
More than three  
86.7 
3 attacks  
73.5 
2 attacks  
60.3 
1 attack  
44.2 
None  
0.0 
6) How long did the worst respiratory attack last? 
a week or more  
89.7 
3 or more days  
73.5 
1 or 2 days  
58.8 
less than a day  
41.9 
7) Over the past 4 weeks, in a typical week, how many good days (with few respiratory problems) have you had? 
None  
93.3 
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Response 
Response weight 
1 or 2  
76.6 
3 or 4  
61.5 
nearly every day  
15.4 
every day  
0.0 
8) If you wheeze, is it worse when you get up in the morning? 
No  
0.0 
Yes  
62.0 
 
PART 2 
Response 
Response weight 
9) How would you describe your respiratory condition? 
The most important problem I have  
83.2 
Causes me quite a lot of problems  
82.5 
Causes me a few problems  
34.6 
Causes no problem  
0.0 
10) If you have ever held a job: 
My respiratory problems made me stop working altogether 
88.9 
My respiratory problems interfere with my job or 
made me change my job 
77.6 
My respiratory problems do not affect my job 
0.0 
Not applicable 
 
11) These are questions about what activities usually make you feel short of breath these days. 
Sitting or lying still 
90.6 
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Response 
Response weight 
Washing or dressing yourself 
82.8 
Walking around the house 
80.2 
Walking outside on level ground 
81.4 
Walking up a flight of stairs 
76.1 
Walking up hills 
75.1 
Playing sports or other physical activities 
72.1 
12) These are more questions about your cough and shortness of breath these days. 
Coughing hurts 
81.1 
Coughing makes me tired 
79.1 
I am short of breath when I talk 
84.5 
I am short of breath when I bend over 
76.8 
My coughing or breathing disturbs my sleep 
87.9 
I get exhausted easily 
84.0 
13) Questions about other effects your chest trouble may have on you. 
My cough or breathing is embarrassing in public 
74.1 
My respiratory problems are a nuisance to my family, friends or neighbours 
79.1 
I get afraid or panic when I cannot catch my breath 
87.7 
I feel that I am not in control of my respiratory problems 
90.1 
I do not expect my respiratory problems to get any better 
82.3 
I have become frail or an invalid because of my respiratory problems 
89.9 
Exercise is not safe for me 
75.7 
Everything seems too much of an effort 
84.5 
14) These are questions about your respiratory treatment. 
My treatment does not help me very much 
88.2 
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Response 
Response weight 
I get embarrassed using my medication in public 
53.9 
I have unpleasant side effects from my medication 
81.1 
My treatment interferes with my life a lot 
70.3 
15) These are questions about how your activities might be affected by your respiratory problems. 
I take a long time to get washed or dressed 
74.2 
I cannot take a bath or shower, or I take a long time to do it  
81.0 
I walk slower than other people my age, or I stop to rest 
71.7 
Jobs such as household chores take a long time, or I have to stop to rest 
70.6 
If I walk up one flight of stairs, I have to go slowly or stop 
71.6 
If I hurry or walk fast, I have to stop or slow down 
72.3 
My breathing makes it difficult to do things such as walk up hills, carry things up stairs, light 
gardening such as weeding, dance, bowl or play golf 
74.5 
My breathing makes it difficult to do things such as carry heavy loads, dig in the garden or 
shovel snow, jog or walk briskly (5 miles per hour), play tennis or swim 
71.4 
My breathing makes it difficult to do things such as very heavy manual work, ride a bike, run, 
swim fast, or play competitive sports 
63.5 
16) We would like to know how your respiratory problems usually affect your daily life. 
I cannot play sports or do other physical activities 
64.8 
I cannot go out for entertainment or recreation 
79.8 
I cannot go out of the house to do the shopping 
81.0 
I cannot do household chores 
79.1 
I cannot move far from my bed or chair 
94.0 
17) Now please select the response (one only) that you think best describes how your respiratory problems affect you: 
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Figure 14.2.1.2 
Change from baseline through Week 16 in pre-BD FEV1 measured in the clinic, 
LSMeans (80% CI) - supportive analysis 
ITT population 
Table 14.2.1.5 
Change from baseline to Week 16 in pre-BD FEV1 (as measured in the clinic) treatment 
comparisons by subgroups, MMRM  
ITT population 
Figure 14.2.1.3 
Change from baseline through Week 16 in pre-BD FEV1 measured in the clinic, 
LSMeans (80% CI) by subgroups 
ITT population 
Figure 14.2.1.4 
Change in pre-BD FEV1 measured in the clinic at Week 16, MMRM - forest plot by 
subgroups 
ITT population 
Table 14.2.1.6 
Change from baseline to Week 16 in pre-BD FEV1 (as measured in the clinic) treatment 
comparisons, MMRM - exploratory analysis 
ITT population 
Table 14.2.1.7 
Change from baseline through Week 24 in pre-BD FEV1 (as measured in the clinic) 
treatment comparisons, MMRM 
ITT population 
Figure 14.2.1.5 
Change from baseline through Week 24 in pre-BD FEV1 measured in the clinic, 
LSMeans (80% CI) 
ITT population 
Table 14.2.1.8 
Change from baseline through Week 16 in post-BD FEV1 (as measured in the clinic) 
treatment comparisons, MMRM 
ITT population 
Figure 14.2.1.6 
Change from baseline through Week 16 in post-BD FEV1 measured in the clinic, 
LSMeans (80% CI) 
ITT population 
Table 14.2.1.9 
Change from baseline through Week 16 in FEV1% reversibility (as measured in the 
clinic) treatment comparisons, MMRM 
ITT population 
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Table 
14.2.21.2 
Percent and relative change from baseline through Week 16 in serum IL-5 treatment 
comparisons, MMRM 
ITT population 
Figure 
14.2.21.1 
Percent change from baseline through Week 16 in serum IL-5, LSMeans (80% CI) 
ITT population 
Table 
14.2.22.1 
Serum IL13 by visit, summary statistics 
ITT population 
Table 
14.2.22.2 
Percent and relative change from baseline through Week 16 in serum IL13 treatment 
comparisons, MMRM 
ITT population 
Figure 
14.2.22.1 
Percent change from baseline through Week 16 in serum IL13, LSMeans (80% CI) 
ITT population 
Table 
14.2.23.1 
Serum IL33:ST2 by visit, summary statistics 
ITT population 
Table 
14.2.23.2 
Change from baseline through Week 16 in pre-BD FEV1(as measured in 
clinic)  treatment comparisons by IL33:ST2 subgroups, MMRM 
ITT population 
Figure 
14.2.23.1 
Change from baseline through Week 16 in pre-BD FEV1 measured in the clinic, 
LSMeans (80% CI) by IL33:ST2 subgroups 
ITT population 
Table 
14.2.24.1 
Serum TSLP by visit, summary statistics 
ITT population 
Table 
14.2.24.2 
Percent and relative change from baseline through Week 16 in serum TSLP treatment 
comparisons, MMRM 
ITT population 
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Redacted for Public Disclosure 


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Table 
14.3.7.2.2 
Clinical chemistry parameters, baseline to maximum value during treatment 
As-treated population 
Table 
14.3.7.2.3 
Clinical chemistry parameters, baseline to minimum value during treatment 
As-treated population 
Table 
14.3.7.2.4 
Subjects with potential Hy's Law - individual subject data  
As-treated population 
Figure 
14.3.7.2.1 
ALT versus total bilirubin, expressed as multiples of ULN 
As-treated population 
Figure 
14.3.7.2.2 
AST versus total bilirubin, expressed as multiples of ULN 
As-treated population 
Table 
14.3.7.2.5 
Maximum on-treatment ALT and AST by maximum total bilirubin for assessing Hy's 
Law criteria 
As-treated population 
Figure 
14.3.7.2.3 
Liver biochemistry test results over time - subjects with elevated ALT or AST, and 
elevated total bilirubin, at any point during the study following the start of study 
medication 
As-treated population 
Table 
14.3.7.3.1 
Urinalysis parameters over time 
As-treated population 
Table 
14.3.7.3.2 
Urinalysis parameters, baseline to maximum value during treatment 
As-treated population 
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Redacted for Public Disclosure 


Redacted for Public Disclosure 


Redacted for Public Disclosure 


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Appendix 
16.2.4.4 
Prior and concomitant treatments containing ICS and combination of products containing 
ICS 
ITT population 
Appendix 
16.2.5 
Administration of investigational product  
As-treated population 
Appendix 
16.2.6.1 
Individual efficacy response data 
ITT population 
Appendix 
16.2.6.2.1 
Clinic spirometry 
ITT population 
Appendix 
16.2.6.2.2 
Home spirometry 2-weekly means 
ITT population 
Appendix 
16.2.6.2.3 
ACQ-6 questions and score 
ITT population 
Appendix 
16.2.6.2.4 
SGRQ questions, domains and total score 
ITT population 
Appendix 
16.2.6.2.5 
Compex events 
ITT population 
Appendix 
16.2.6.2.6 
FeNO results 
ITT population 
Appendix 
16.2.6.2.7 
Airway oscillometry parameters 
ITT population 
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Statistical Analysis Plan  
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Appendix 
16.2.6.2.8 
PGI-PR responses 
ITT population 
Appendix 
16.2.6.2.9 
SNOT-22 questions and score 
ITT population 
Appendix 
16.2.6.2.10 
Diary data, 2-weekly means 
ITT population 
Appendix 
16.2.6.3 
Objective cough measures 
Exploratory cough sub-study 
population 
Appendix 
16.2.6.4 
Drug concentration data 
PK population 
Appendix 
16.2.6.5 
Anti-Drug Antibody results 
As-treated population 
Appendix 
16.2.6.6 
Listing of ADA positive subjects, key subject information 
As-treated population 
Appendix 
16.2.7.1 
Adverse events 
As-treated population 
Appendix 
16.2.7.2 
Listing of adverse events among Anti-Drug Antibody positive subjects 
As-treated population 
Appendix 
16.2.7.3 
Adverse events for enrolled but not randomised subjects and for subjects who were not 
exposed to treatment 
All subjects 
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Statistical Analysis Plan  
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Appendix 
16.2.8.1 
Individual laboratory measurement 
As-treated population 
Appendix 
16.2.8.2 
Other laboratory safety variables 
As-treated population 
Appendix 
16.2.9 
Individual vital signs data 
As-treated population 
Appendix 
16.2.10.1 
Electrocardiogram data 
As-treated population 
Appendix 
16.2.10.2 
Abnormalities in electrocardiogram 
As-treated population 
Appendix 
16.2.10.3 
Echocardiography data 
As-treated population 
Appendix 
16.2.10.4 
Abnormalities in echocardiography 
As-treated population 
 
 
 
Redacted for Public Disclosure