A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults With Oral Corticosteroid Dependent Asthma (SOURCE)
Phase: PHASE3
Conditions: Asthma
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Tezepelumab
Study Code
D5180C00009
Version
4
Date
14 May 2020
A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study 
to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral 
Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma 
(SOURCE)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s): 
IND number: 103031
EudraCT number: 2017-003079-69

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Section 4.1, Overall design;
Section 6.3, Measures to minimise bias: randomisation and blinding – Methods for assigning 
treatment groups – revised percentage of subjects targeted to have ≥ 300 eosinophils/μl at 
enrolment from at least 30% to approximately 35%.  This allows to better explore the effect of 
tezepelumab in both the ≥ 300 eosinophils/µL and < 300 eosinophils/µL groups.
Section 4.1, Overall design – Added “When the target percentage of subjects for the 
eosinophil subgroup in a region is reached, consideration will be given to closing the 
IWRS/IVRS randomization for that subgroup, which may be done either overall or within a 
specific region. Once a subgroup is closed, subjects in the screening/run-in period in the 
closed subgroup will not be allowed to be randomized and will be screen failed.” To describe 
the approach for subgroup closure per region. 
Section 5.1, Inclusion criteria, removed criterion #15 – “Non-sterilized males who are 
sexually active with a female partner of childbearing potential must use a condom plus 
spermicide from Day 1 through 16 weeks after receipt of the final dose of IP. In those 
countries where the above-mentioned method for contraception is not available, a condom can 
be used alone. Male subjects must not donate or bank sperm during this same time period.”  
To align with the revised IB.
Section 5.2, Exclusion criteria # 6 – revised criteria to add in restrictions related to the usage 
of vaping products “Current smokers or subjects with smoking history ≥10 pack-years and 
subjects using vaping products, including electronic cigarettes. Former smokers with a 
smoking history of <10 pack years and users of vaping or e-cigarette products must have 
stopped for at least 6 months prior to visit 1 to be eligible.” To clarify the required timeframe 
for stopping of e-cigarettes prior to screening since its use is prohibited during the study.
Section 5.2, Exclusion criteria # 17 – reduced the timeframe for subjects who have been 
treated with bronchial thermoplasty from 24 to 12 months prior to visit 1. This allows 
sufficient time for any safety issues related to performing this procedure, (for example asthma 
exacerbations which occur within 1-2 months after the procedure), to resolve and for efficacy 
related to the procedure to stabilize.
Section 5.4, Screen failures – Replaced “Incorrect Enrolment” with “Screen Failure” to align 
with the proper documentation of the disposition of the screen failed subjects within the 
eCRF.  
Section 5.5, Re-Screening – clarified the treatment by adding intravenous in front of 
antibiotics and systemic in front of antiviral medication. The revised text reads: “Subjects with 
clinically significant infection, including respiratory infections requiring intravenous 
antibiotics or systemic antiviral medication during run-in should be screen failed but may be 
re-screened 2 weeks after completion of the therapy.” To clarify the type of treatment for a 
clinically significant infection that would require the subject to be screen failed. 
Section 5.5, Re-Screening – Added “If the timeframe between Screening and re-screening is 
more than 30 days, then all Visit 1 assessments should be repeated.” To reduce the risk of not 

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identifying the status change in HIV 1, HIV 2, Hepatitis B, Hepatitis C and FSH prior to re-
screening, if initial screening visit 1 was more than 30 days ago.
Section 6.2, Preparation/handling/storage/accountability – Dose preparation steps – Added 
that a 2 mL sterile syringe can be attached to a 21G 1½ -inch sterile disposable needle during 
IP dose preparation and subsequently used for IP administration. This change allows for use of 
a 2 mL syringe in addition to 3 mL syringe because it meets the requirements for IP dose 
preparation and dosing.
Section 6.2, Preparation/handling/storage/accountability – Dose preparation steps – clarified 
that the vial labels along with the vials can be discarded immediately post IP preparation as 
per site’s SOP. 
Section 6.2, Preparation/handling/storage/accountability – Dose administration – Removed 
wording “The subject, in the opinion of the investigator, is experiencing an acute or emerging 
asthma exacerbation” from the list of scenarios when IP should not be administered. An 
exacerbation per se is not a contraindication for IP administration. Reasons for not 
administering IP are well covered by the remaining bullets.  
Section 6.3, Measures to minimise bias: randomisation and blinding – Ensuring blinding –
removed “biomarker” from the following laboratory personnel that will have access to the 
randomization list. The reason for this change is that the laboratory does not require the 
randomization list for performing biomarker sample analysis.
Section 6.3, Measures to minimise bias: randomisation and blinding – Ensuring blinding –
Clarified that no other members of the study team, other than those listed earlier within this 
section, will have access to the randomization list until after the primary database lock.
Section 6.3, Measures to minimise bias: randomisation and blinding – Methods for unblinding
– replaced “pharmacists” with “Study Coordinator(s)” to clarify that the Study Coordinators in 
addition to the Investigator will be provided access to unblinding the treatment. This change 
allows alignment with the IXRS setup for this study.
Section 6.3, Measures to minimise bias: randomisation and blinding – Methods for unblinding
– replaced “until database lock” with “until primary database lock after last subject completes 
week 48.” To accommodate a planned additional database lock once the last subject completes 
treatment phase (week 48).
Section 6.5, Table 6 – Restricted Medications - Short-acting beta-agonists (SABA) – Added 
“Only albuterol/salbutamol is allowed to be used as a rescue medication during the study, 
except during exacerbations.” Since OCS titration criteria and ePRO alerts are based on 
salbutamol use as rescue medication, the same type of SABA should be used in all subjects.
Section 6.5, Table 7 – Prohibited Medications – Added “Ephedrine (e.g. in antitussives or 
mucolytics) - Not allowed from visit 1, during run-in and optimization phase, throughout the 
entire treatment period (even if the subject has discontinued IP) until the follow up visit week 

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60.” The reason for this change is to ensure consistency in standard of care and GINA 
guidelines. 
Section 6.5, Table 7 – Prohibited Medications – Added “Opiates prn (e.g. in antitussives) -
Not allowed from visit 1, during run-in and optimization phase, throughout the entire 
treatment period (even if the subject has discontinued IP) until the follow up visit week 60.” 
The reason for this change is to ensure consistency with standard of care and GINA 
guidelines.
Section 6.5.2, Rescue medicine – Added “Regularly scheduled SABA use in the absence of 
any asthma symptoms is not allowed from enrolment (Visit 1) and throughout the study 
duration. Prophylactic use of SABA (e.g. prior to planned exercise) or any other use than to 
curb worsening of asthma symptoms should be documented in medical notes and entered in 
the eCRF. Any such use of SABA must not be recorded in the Asthma Daily Diary. ” This 
change further clarifies that regularly scheduled SABA use in the absence of any asthma 
symptoms is not allowed and that the occasional prophylactic use of SABA is not to be 
recorded in the eDiary.
Section 7.1, Discontinuation of study treatment – Under “Development of any study specific 
criteria for discontinuation, any malignancy”, added the following statement “except subjects 
who develop basal cell carcinoma or localized squamous cell carcinoma of the skin, provided 
that the malignancy is excised and determined to have clean margins.” This change allows 
subjects who have had excision of their lesions, which is considered curative, to continue 
study treatment. 
Section 7.1.1, Procedures for discontinuation of study treatment;
Section 8.3.10, Disease under study – Replaced “termination” with “Discontinuation of 
Investigational Product” to reflect the corresponding eCRF module title. This change allows 
alignment with eCRF design. 
Section 7.3.2, Discontinuation or suspension of entire study and site closure – Updated the 
title of this section and added additional comments about site closure. The rationale for this 
change is to specify the conditions for closure of sites during and after study completion.
Section 8.1.1.1, OCS Dose Titration – OCS dose titration in the optimization phase – Dosing 
interval corrected from “10-30 mg” to “>10-30 mg”.  To ensure consistency with Table 8.
Section 8.1.1.2, Criteria for OCS dose reduction during the optimization and reduction phase
– Added “It is at the discretion of the Investigator to continue with the OCS down-titration 
even if the criteria for OCS reduction have not been met. Such a decision must be justified and 
documented in the source notes and captured in the eCRF. This decision must be notified to 
the AstraZeneca study physician within 2 business days.” This allows the Investigator the 
opportunity to continue down titrating OCS, if clinically indicated. This change recognizes 
that the Investigator will balance their concern about side effects related to OCS use and the 
patient’s clinical status.

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Section 8.1.2.3, Exacerbation management – Maintenance phase – Replaced “induction” with 
“maintenance” to correct the typographical error in the CSP.
Section 8.1.5, Fractional exhaled nitric oxide (FENO) – Removed the wording “which will be 
recorded as “Yes or No” in the eCRF” from the sentence “Subjects will be asked whether they 
have had a respiratory infection in the 2 weeks prior to measurement.” This change aligns 
with the eCRF design.
Section 8.2.4, Vital Signs – Revised text to specify that the pulse rate will be obtained before 
blood pressure only if the manual measurement technique is used. This is to reflect that when 
the automated device is used the pulse and blood pressure measurements are taken 
simultaneously. 
Section 8.2.4, Vital Signs – Removed “in degrees Celsius” as the units of body temperature 
measurement. This is to accommodate the local guidelines as some regions may not be 
measuring in degrees Celsius.
Section 8.2.6, Glucocorticoid toxicity index – Revised the text to “Scoring should be 
performed as per SoA, using the randomisation assessment as the baseline.” This is to clarify 
that the first assessment of GTI is at the randomisation visit. 
Section 8.3.8, Adverse Events of Special Interest – Added “systemic” in front of antiviral 
medications. The revised text reads: “Requiring treatment with systemic antiviral medications, 
intravenous antibiotics or medications for helminth parasitic infection”. To clarify that 
infections treated with local antivirals are not considered as adverse events of special interest.
Section 8.4.2.2, Paternal exposure – Removed “Male subjects should refrain from fathering a 
child or donating sperm during the study and for 16 weeks (5 half-lives) following the last 
dose.” To align with the revised IB.
Section 8.4.2.2, Paternal exposure – Added “in the Pregnancy Report Form” to clarify where 
outcome of all pregnancies will be reported. This change aligns with eCRF design.
Section 8.4.2.2, Paternal exposure – Added “Consent from the partner must be obtained 
before the Pregnancy Report Form is completed.” To clarify that consent is being obtained 
from the pregnant partner prior to completing the Pregnancy Report Form.
Section 9.4, Statistical Analyses – Added “There will be two DBLs in this study. The primary 
DBL will be conducted after last subject completes Week 48, and the final DBL will be 
conducted once all patients have completed the last safety follow-up visit (Week 60). All 
analyses of the primary and secondary objectives will be performed based on the primary 
DBL data. Following the primary DBL, data summaries created will be presented as an 
addendum to the CSR.” This provides clarity around timing of database locks and primary 
analysis evaluation.
Section 9.4, Statistical Analyses;

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Section 1.2, Synopsis, Overall design – Added wording “Subjects that complete the 48-week 
study visit will complete a 12-week post treatment, follow-up period unless the subject is 
eligible and decides to enrol into a separate extension study.”
Section 1.2, Synopsis, Treatments and treatment duration – Added wording “Subjects 
completing the planned treatment period, may be eligible to enrol in a separate extension 
study and these subjects will not attend the follow up visit at Week 54 and Week 60”.
Section 1.2, Synopsis, Independent Adjudication Committee – Added the following wording 
in the first paragraph “that occur from randomization until the end of the follow-up period” in 
relation to MACE and investigator reported malignancies.
Section 1.2, Synopsis, Independent Adjudication Committee – Added the following in the 
second sentence “that occur from randomization up to the end of treatment period” in relation 
to cases of ER or urgent care visits and hospitalizations and “that occur from randomization 
until the end of the follow-up period” in relation to all deaths.
Section 4.1, Overall design – Added the following paragraph “Subjects remaining on IP for 
entire planned treatment period, may be eligible to enrol in the extension study. These subjects 
will transition to the extension study, after completing the EOT assessments at week 48 and 
thus they will not attend the follow-up visits at Week 54 and Week 60.”
Section 4.3, Justification for dose – Added the following: “Tezepelumab was well-tolerated at 
all doses and the safety profile was well balanced between the tezepelumab and placebo 
groups with no evidence of a dose relationship to TEAEs.”
Section 5.1, Inclusion criteria # 5 – Added the wording “as per GINA guideline (GINA 
2017)”.
Section 5.1, Inclusion criteria # 6 – Added the word “as” and removed the wording “will be 
based upon GINA guidelines (GINA 2017)”. As for this criterion sites should follow 
equivalent ICS doses mentioned in Appendix F and not GINA guidelines.
Section 5.1, Inclusion criteria # 8 – Added wording “The OCS dose may be administered 
every other day (or different doses every other day); Average dose over two days = The daily 
dose.” This is to clarify that OCS can be administered every alternate day as well.  
Section 5.2, Exclusion criteria # 3 – Added the wording “localized squamous cell carcinoma 
of the skin”.
Section 5.2, Exclusion criteria #12 – Removed “randomization” and added “visit 1”.
Section 5.2, Exclusion criteria #13 – Removed wording “randomization or any planned use 
during course of the study” and added “visit 1”.
Section 5.2, Exclusion criteria #24 – Added the word “twice” for upper limit values. This was 
a typo error thus clarified.

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Section 5.2, Exclusion criteria #24 – Removed the wording “Subjects with on-going liver 
disease or inexplicably elevated liver chemistry values should be excluded from the study”. 
This criterion is covered by exclusion criteria #2.
Section 5.2, Exclusion criteria #32 – Added “or >30mg” for OCS dose as a clarification. This 
was done to exclude subjects optimized at >30 mg prednisone/prednisolone dose as for such 
subjects it will not be possible to totally omit OCS during the duration of study.
Section 5.5, Re-screening – Removed the wording “finalized < 2 weeks prior to visit 1 or.” 
Also removed “subject that experiences an exacerbation during the screening period can also 
be re-screened 4 weeks after their OCS has been stabilized” as these subjects are not to be 
screen-failed and can continue in the study.
Section 5.5, Re-Screening – Added wording “Re-screening of a subject for any other reason 
will be allowed only upon approval of the AstraZeneca Study Physician. A documented 
approval for re-screening should be filed in the Investigator Study File (ISF)”.
Section 6.1.1, Investigational products, Table 4 – Added “m” and removed “n” as the unit of 
measure for L-proline.
Section 6.2, Preparation/handling/storage/accountability; Dose preparation – Added the 
wording “30 minutes to” in step #1 to update the equilibration time of vial. 
Section 6.2, Preparation/handling/storage/accountability; Dose preparation – Added the 
wording “If the opened and dispensed vials must be discarded immediately after dose 
preparation as per site’s SOP the vial labels along with the kit boxes must be retained for IP 
accountability.”
Section 6.2, Preparation/handling/storage/accountability – Table 5 – Added superscript “a” to 
210 mg in Dose column for clarification. 
Section 6.3, Measures to minimize bias: randomization and blinding, Bullet #2 – Added 
wording: “via the Interactive Web Response System/Interactive Voice Response System 
(IWRS/IVRS)” in relation to enrolment number.
Section 6.3, Procedures for handling incorrectly enrolled or randomized subject - Added 
wording “Study treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the subject. In those cases where continuation of the study 
therapy is judged not to present a concern related to safety and disease management, the 
rationale for continuing study therapy must be clearly documented. Regardless of what is 
decided about IP, all randomized subjects should remain in the study and the subjects should 
continue to be followed up in accordance with defined study procedures.” 
Section 6.5, paragraph 4, added “asthma” to clarify that no changes are allowed to background 
asthma medications.

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Section 6.5, Concomitant therapy – Added wording “As theophylline has a narrow therapeutic 
window, please note that subjects on maintenance treatment with theophylline should have 
blood concentration levels within therapeutic range documented before visit 1. If this is not 
documented before signing the informed consent, it can be obtained after informed consent 
has been given or as part of the visit 1 procedures. The sample can be analyzed at the central 
or local lab as applicable. Investigator can use their clinical judgement about the therapeutic 
range of theophylline levels on the basis of sampling time and other factors that may impact 
the results”.
Section 6.5, Concomitant therapy – Table 6 - Maintenance treatment with long-acting 
bronchodilators – Removed “unless there is a medical need as judged by the Investigator”.
Section 6.5, Concomitant therapy – Table 6 - Short-acting beta-agonists (SABA) – Removed 
“unless there is a medical need as judged by the Investigator”.
Section 6.5, Concomitant therapy – Table 6 - Additional maintenance controllers - Removed 
“unless there is a medical need as judged by the Investigator”.
Section 6.5, Concomitant therapy – Table 6 - Additional maintenance controllers – Added 
“However, if theophylline blood concentration is out of therapeutic range after visit 1, dose 
adjustments are allowed.
Section 6.5, Concomitant therapy – Table 6 - Short-acting anti-cholinergics – Removed 
“unless there is a medical need as judged by the Investigator”.
Section 6.5 – Table 7 – Prohibited medications - Long-acting beta-agonists as a reliever –
Removed “unless there is a medical need as judged by the Investigator”.
Section 6.5 – Table 7 – Prohibited medications - Suplatast tosilate – Removed “unless there is 
a medical need as judged by the Investigator”.
Section 6.5 – Table 7 – Prohibited medications – Live attenuated vaccines – Removed “the 
date of randomization” and added “visit 1”.
Section 6.5 – Table 7 – Prohibited medications - Live attenuated vaccines –Added the 
wording “an absolute” within the sentence.
Section 6.5 – Table 7 – Prohibited medications - Any immunomodulators or 
immunosuppressives – Added the wording “adrenal insufficiency and” within the 
Medication/class of drug section.
Section 6.5 – Table 7 – Prohibited medications - Any immunomodulators or 
immunosuppressives – Removed “unless there is a medical need as judged by investigator”.

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Section 6.5 – Table 7 – Prohibited medications - Blood products or immunoglobulin therapy –
Added the wording “an absolute” within the sentence.
Section 6.5, Concomitant therapy - Table 7 – Any marketed or Investigational biologic 
treatment – Removed “the date of randomization” and added “visit 1”. 
Section 6.5, Concomitant therapy – Table 7 – Any marketed or Investigational biologic 
treatment – Added “benralizumab” to the medication/class of drug section.
Section 6.5, Concomitant therapy – Table 7 - Herbal remedies for the treatment of allergic, 
inflammatory, or respiratory diseases – Removed “unless there is a medical need as judged by 
investigator”.
Section 6.5, Concomitant therapy – Table 7 - Medications not currently licensed for use in the 
treatment of asthma – Removed “unless there is a medical need as judged by the Investigator”.
Section 6.7, Treatment after end of study – Added wording “Subjects that are eligible and 
decide to enrol in a separate extension study will not attend the follow-up visits at week 54 
and week 60 and should comply with the requirements of the separate extension study 
protocol.”
Section 7.1, Discontinuation of study treatment –   Added the wording in bullet point 3 related 
to an adverse event “considered to jeopardize the safety of a subject participating in the 
study”.
Section 7.1, Discontinuation of study treatment – Added a new bullet point 4 to include 
“Pregnancy”.
Section 7.1.1, Procedures for discontinuation of study treatment – Removed the wording “do 
not apply after IPD” and added “can be performed at PI’s discretion and judgement”.
Section 7.1.1, Procedures for discontinuation of study treatment, Option 2 - Added “including 
the questionnaires that otherwise would have been completed at the site as per SoA” – to 
emphasize that the subjects will be completing the questionnaires that are marked in SoA as 
being completed at the site.
Section 8.1.1.1 – Table 9 – Added the following wording below the table “The OCS dose may 
be administered every other day (or different doses every other day) Average dose over two 
days = The daily dose”.
Section 8.1.1.2 – Table 10 – Criteria #1 – Added “mean” at the end of the criterion for a 
consistency.
Section 8.1.1.2 – Table 10 – Added a new footnote c with the following wording for criterion 
2: “Number of nights with awakenings due to asthma requiring rescue medication will be 
counted from the most recent 7 days of available data”.

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Section 8.1.1.2 – Table 10 – Criteria #2 – Wording has been changed to “An increase of no 
more than 2 nights with asthma-related awakenings (requiring rescue medication) over a 7-
day period compared with baseline.”
Section 8.1.1.2 – Table 10 – Criteria #3 – Removed “any one” and added “all days” as well as 
“/day”, so that the criterion reads: “Meana SABA rescue medication use not more than 4 
puffs/day above the baseline b mean and <12 puffs/day on all days in the prior 14 days”.
Section 8.1.1.2 – Table 10 – Criteria #4 – Added “or hospitalisation” within the wording.
Section 8.1.1.2 – Table 10 – renamed footnotes, previous footnote “c” became “d”, previous 
footnote “d” became “e” and previous footnote “e” became “f”.
Section 8.1.1.2, Criteria for OCS dose reduction during the optimization and reduction phase –
Added “Steroid” in paragraph that overviews sign and symptoms of AI.
Section 8.1.2 – Table 11 – Criteria # 2 – added “≥” within phrase “12 puffs/day” for the 
criterion to read: “An increase in rescue medication use of ≥ 4 puffs/day on at least 2 
consecutive days compared with the average use during baseline or use of ≥12 puffs/day on 
any one day”.
Section 8.1.2 – Table 11 – Criteria # 4 - Added the wording “or more” within phrase “2 nights 
with awakenings” for the criterion to read: “An increase of 2 or more nights with awakenings 
due to asthma requiring rescue medication over a 7-day period c compared with the average 
during baseline, and ≥6 out of previous 7 nights with awakenings due to asthma requiring 
rescue medication (this criterion should be met on 2 consecutive days).
Section 8.1.2 – Table 11 – Footnote b - Reworded to “Baseline values for alerts will be 
calculated from the most recent 7 days of available data prior to visit 2 for the optimization 
phase and prior to randomization visit 6 for the treatment period”.
Section 8.1.2 – Table 11 – Added footnote c with the following wording “Number of nights 
with awakenings due to asthma requiring rescue medication will be counted from most recent 
7 days of available data”.   
Section 8.1.5, FENO – Removed the wording “The standard single exhalation technique 
recommended by the ATS will be followed (Dweik et al 2011) and added “The single 
exhalation technique recommended by the manufacturer will be followed (Alving et al 2017)”.
Section 8.1.6.2, ACQ -6 – Removed the wording” decrease of at least 0.5 are considered to be 
clinically meaningful and is the responder” and added the wording “changes of at least 0.5 are 
considered to be clinically meaningful and a decrease of at least 0.5 is the responder”.
Section 8.1.6.2, ACQ-6 – Added “For IPD subjects ACQ-6 can be completed at home as 
well”.

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Section 8.1.6.3, AQLQ(S)+12 – Added “For IPD subjects AQLQ(S)+12 can be completed at 
home as well”.
Section 8.1.6.6, WPAI+CIQ – Added “For IPD subjects WPAI+CIQ can be completed at 
home as well”.
Section 8.2.1 – Table 12 – Removed “S-HbA1C from clinical chemistry and added “B-
HbA1C” to Haematology. 
Section 8.2.1 – Table 12 – Added a note* under the table “*Urine samples will be first 
analysed locally using dipsticks and sent to the central laboratory only for analysis when a 
positive dipstick result for any parameter is observed” referring to U-Microscopy and culture 
as required.
Section 8.2.5, Electrocardiograms – Removed the wording “post FENO and lung function 
assessments, after the subject has been resting for at least 15 minutes. The assessment should 
be performed prior to blood draw and IP administration.” Added the wording “after resting for 
at least 15 minutes, prior to blood draw, FeNO, spirometry, BD administration and IP 
administration”.
Section 8.2.5, Electrocardiograms – Removed “Two copies” and added “A copy”.
Section 8.3.7, Adverse events based on examinations and tests – Removed the wording 
“Deterioration of a laboratory value, which is unequivocally due to disease progression, 
should not be reported as an AE/SAE”.
Section 8.3.10, Disease under study – For point # 2 removed “the study” and added “IP”.
Section 8.4.6, Independent adjudication committee – Added the following wording in the first 
sentence “that occur from randomization until the end of the follow-up period” in relation to 
MACE and investigator reported malignancies. Added the following wording in the second 
sentence “that occur from randomization up to the end of treatment period” in relation to cases 
of ER or urgent care visits and hospitalization and “that occur from randomization until the 
end of the follow-up period” in relation to all deaths.
Section 8.7.1, Optional exploratory genetic sample – Corrected typo “collected form” to 
“collected from”.
Section 9.4.4, Safety Analyses – Removed the word “Study” and added the wording “of IP” in 
the 2nd paragraph.
Section 10, References – Added “Alving et al 2017” and removed “Dweik et al 2011”.
Appendix D – Subject Data Protection - Removed the wording “In exceptional circumstances, 
however, certain individuals might see both the genetic data and the personal identifiers of a 
subject. For example, in the case of a medical emergency, an AstraZeneca Physician or an 

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS ...................................................................................16
1.
PROTOCOL SUMMARY .................................................................................21
1.1
SoA....................................................................................................................21
1.2
Synopsis.............................................................................................................31
1.3
Schema ..............................................................................................................39
2.
INTRODUCTION .............................................................................................39
2.1
Study rationale ...................................................................................................39
2.2
Background........................................................................................................40
2.3
Benefit/risk assessment ......................................................................................41
3.
OBJECTIVES AND ENDPOINTS ....................................................................42
4.
STUDY DESIGN...............................................................................................46
4.1
Overall design....................................................................................................46
4.2
Scientific rationale for study design....................................................................47
4.3
Justification for dose ..........................................................................................48
4.4
End of study definition.......................................................................................48
5.
STUDY POPULATION.....................................................................................48
5.1
Inclusion criteria ................................................................................................49
5.2
Exclusion criteria ...............................................................................................52
5.3
Lifestyle restrictions...........................................................................................55
5.3.1
Meals and dietary restrictions.............................................................................55
5.3.2
Alcohol, tobacco and other.................................................................................55
5.3.3
Activity..............................................................................................................55
5.4
Screen failures....................................................................................................55
5.5
Re-screening ......................................................................................................56
6.
STUDY TREATMENTS ...................................................................................56
6.1
Treatments administered ....................................................................................57
6.1.1
Investigational products .....................................................................................57
6.2
Preparation/handling/storage/accountability .......................................................57
6.3
Measures to minimise bias: randomisation and blinding .....................................60
6.4
Treatment compliance ........................................................................................62

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6.5
Concomitant therapy..........................................................................................62
6.5.1
Other concomitant treatment ..............................................................................67
6.5.2
Rescue medicine ................................................................................................67
6.5.3
Bronchial thermoplasty ......................................................................................67
6.6
Dose modification..............................................................................................67
6.7
Treatment after the end of the study ...................................................................67
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL...68
7.1
Discontinuation of study treatment.....................................................................68
7.1.1
Procedures for discontinuation of study treatment ..............................................69
7.2
Lost to follow-up................................................................................................70
7.3
Withdrawal from the study.................................................................................70
7.3.1
Withdrawal due to recruitment completion.........................................................71
7.3.2
Discontinuation or suspension of entire study and Site Closure ..........................71
8.
STUDY ASSESSMENTS AND PROCEDURES...............................................71
8.1
Efficacy assessments..........................................................................................72
8.1.1
Overview of OCS dose management ..................................................................72
8.1.1.1
OCS dose titration..............................................................................................73
8.1.1.2
Criteria for OCS dose reduction during the optimization and reduction phase.....75
8.1.2
Asthma exacerbations – Assessment and management .......................................76
8.1.2.1
Exacerbation management during the run-in period............................................78
8.1.2.2
Exacerbation management during the optimization phase...................................78
8.1.2.3
Exacerbation management during the treatment period.......................................78
8.1.3
Spirometry .........................................................................................................79
8.1.3.1
General requirements .........................................................................................79
8.1.3.2
Spirometry technique .........................................................................................79
8.1.3.3
Post-BD spirometry and FEV1 reversibility assessment ......................................80
8.1.4
Home PEF testing ..............................................................................................80
8.1.5
Fractional exhaled nitric oxide (FENO)..............................................................80
8.1.6
Patient reported outcomes ..................................................................................81
8.1.6.1
Asthma Daily Diary ...........................................................................................81
8.1.6.2
Asthma Control Questionnaire (ACQ-6) ............................................................82
8.1.6.3
Standardised asthma quality of life questionnaire for 12 years and older 
(AQLQ(S)+12)...................................................................................................83
8.1.6.4
St George’s respiratory questionnaire (SGRQ) ...................................................83
8.1.6.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L)...............................83
8.1.6.6
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ) ..................................................................84
8.2
Safety assessments .............................................................................................84
8.2.1
Clinical safety laboratory assessments................................................................84
8.2.2
Weight and height ..............................................................................................85
8.2.3
Physical examinations ........................................................................................85
8.2.4
Vital signs..........................................................................................................86
8.2.5
Electrocardiograms ............................................................................................86

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8.2.6
Glucocorticoid toxicity index .............................................................................87
8.3
Collection of adverse events...............................................................................87
8.3.1
Method of detecting AEs and SAEs....................................................................87
8.3.2
Time period and frequency for collecting AE and SAE information ...................87
8.3.3
Follow-up of AEs and SAEs...............................................................................88
8.3.4
Adverse event data collection.............................................................................88
8.3.5
Causality collection............................................................................................89
8.3.6
Adverse events based on signs and symptoms ....................................................89
8.3.7
Adverse events based on examinations and tests.................................................89
8.3.8
Adverse Events of Special Interest .....................................................................90
8.3.9
Hy’s law.............................................................................................................90
8.3.10
Disease under study............................................................................................90
8.4
Safety reporting and medical management .........................................................91
8.4.1
Reporting of serious adverse events....................................................................91
8.4.2
Pregnancy ..........................................................................................................92
8.4.2.1
Maternal exposure..............................................................................................92
8.4.2.2
Paternal exposure ...............................................................................................92
8.4.3
Overdose............................................................................................................93
8.4.4
Medication error.................................................................................................93
8.4.5
Management of IP-related toxicities ...................................................................93
8.4.6
Independent adjudication committee ..................................................................94
8.4.7
Data safety monitoring board (DSMB)...............................................................94
8.5
Pharmacokinetics ...............................................................................................94
8.5.1
Collection of samples and drug concentration.....................................................94
8.5.2
Collection of sample to measure for the presence of ADAs ................................95
8.5.3
Storage and destruction of pharmacokinetic/ADA samples.................................95
8.6
Pharmacodynamics ............................................................................................95
8.7
Genetics .............................................................................................................95
8.7.1
Optional exploratory genetic sample ..................................................................95
8.7.2
Storage and destruction of genetic samples.........................................................95
8.8
Biomarkers.........................................................................................................96
8.8.1
Storage, re-use and destruction of biomarker samples.........................................96
8.8.2
Serum immunoglobulins ....................................................................................96
8.8.3
Transcriptomics..................................................................................................96
8.9
Healthcare Resource Utilization and Health Economics .....................................97
9.
STATISTICAL CONSIDERATIONS................................................................97
9.1
Statistical hypotheses .........................................................................................97
9.2
Sample size determination..................................................................................98
9.3
Populations for analyses.....................................................................................99
9.4
Statistical analyses .............................................................................................99
9.4.1
Multiple testing procedure................................................................................100

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9.4.2
Definition of baseline.......................................................................................101
9.4.3
Efficacy analyses..............................................................................................101
9.4.3.1
Analysis of the primary efficacy endpoint ........................................................101
9.4.3.2
Analysis of the key secondary efficacy endpoints.............................................102
9.4.3.3
Analysis of other efficacy endpoints.................................................................103
9.4.4
Safety analyses.................................................................................................104
9.4.5
Other analyses..................................................................................................104
9.5
Interim analyses ...............................................................................................105
9.5.1
Data safety monitoring board (DSMB).............................................................105
10.
REFERENCES ................................................................................................106
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .......................................................................................110
LIST OF TABLES
Table 1
Study Plan – Enrolment/Run-in period/OCS optimization phase............22
Table 2
Study plan – Treatment and follow-up period........................................25
Table 3
Study objectives ....................................................................................42
Table 4
Study Treatments ..................................................................................57
Table 5
Investigational product dose preparation................................................59
Table 6
Restricted medications ..........................................................................64
Table 7
Prohibited medications ..........................................................................65
Table 8
OCS dose titration schedule during the optimization phase....................73
Table 9
OCS dose titration schedule during the reduction phase (V7-V15) a ......74
Table 10
Criteria for following OCS dose reduction schedule ..............................75
Table 11
eDiary alert criteria................................................................................77
Table 12
Laboratory safety variables....................................................................85
LIST OF FIGURES
Figure 1
Study design..........................................................................................39
Figure 2
Rotation of injection sites......................................................................59

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LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations ........................110
Appendix B
Adverse event definitions and additional safety information................114
Appendix C
Handling of Human Biological Samples..............................................118
Appendix D
Genetics ..............................................................................................121
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law .......................................................................124
Appendix F
Maintenance therapy equivalence table................................................129
Appendix G
Anaphylaxis: signs and symptoms, management .................................130
Appendix H
Glucocorticoid toxicity index ..............................................................133
Appendix I
Prednisone/Prednisolone doses < 5 mg in relation to available tablet 
strengths (scored tablets) .....................................................................139
Appendix J
Abbreviations......................................................................................140
Appendix K
Changes Related to COVID-19 Pandemic ...........................................145

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1.
PROTOCOL SUMMARY
For detailed schedule of activities (SoA) please see section 1.1 below.
1.1
SoA

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Table 1
Study Plan – Enrolment/Run-in period/OCS optimization phase 
Assessment/ activity
Enrolment
/
Run-in
OCS optimization phase b
Refer Section / 
Appendix
V1a
V2
V3 
V4 
V5 
W -10
W -8
W -6
W -4
W -2
Visit window (days)
N/A
+3c
±3
±3
-3c
Informed consent
X
Appendix A 3
Inclusion/exclusion criteria
X
X
X
X
X
Section 5.1 and 5.2
Routine clinical procedures
Demographics
X
Medical/Surgical and asthma history
X
Safety assessments
Complete physical examination
X
Section 8.2.3
Weight, Height
X
Section 8.2.2
Vital Signs
X
Section 8.2.4
12-lead ECG
X
Section 8.2.5
Assessments of asthma exacerbations
X
X
X
X
X
Section 8.1.2
Adverse events
X
X
X
X
X
Section 8.3
Concomitant medications d
X
X
X
X
X
Section 6.5
Laboratory assessments
Safety laboratory assessments (Clinical chemistry and 
haematology)
X
Section 8.2.1
Urinalysis (dipstick) e
X
Section 8.2.1

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Assessment/ activity
Enrolment
/
Run-in
OCS optimization phase b
Refer Section / 
Appendix
V1a
V2
V3 
V4 
V5 
W -10
W -8
W -6
W -4
W -2
Visit window (days)
N/A
+3c
±3
±3
-3c
Serology (hepatitis B, C; HIV-1; HIV-2)
X
Serum pregnancy or FSH test f (Females only)
X
Patient reported outcome assessments
Dispense and train on eDiary g
X
Section 8.1.6.1
Daily diary
Completed twice daily at home on eDiary
Daily diary adherence check h
X
X
X
X
ACQ-6
X
X 
Section 8.1.6.2
Lung function assessments
Pre-BD spirometry i
X
X 
Section 8.1.3
Post-BD spirometry (Reversibility assessment) i
X
X 
Section 8.1.3
Home peak-flow monitor (PEF meter) training and 
distribution
X
Section 8.1.4
Check compliance with home PEF meter
X
X
X
X
Home assessment of PEF
Measurement every morning and evening 
Section 8.1.4
OCS optimization
OCS switch to prednisone or prednisolone if required
X
OCS dose reduction
X j
X
X
Section 8.1.1.1
OCS dose increase, if indicated k
X
Section 8.1.1.1

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a
Visit 1 can be performed over a period of 3-working days, with the exception of documentation of informed consent. All study assessments including withholding of 
asthma medications for required period for Pre-BD spirometry at visit 1 to be performed after the documentation of informed consent. 
b
Visit 2 and 5 will be on-site visits. Visits 3 and 4 can be performed as telephonic visits provided the subject and sites are confident to perform the visit remotely. 
Depending on clinical judgement, investigator may decide to call the subject on-site for visits 3 and 4 as well. Instructions for OCS dose titrations at visits 3 and 4 can be 
communicated to the subject on phone. The optimization phase may be extended to account for treatment of an exacerbation to allow for 2-week stable OCS dose prior to 
randomization. 
c
At a minimum there should be at least 14 days window (could be extended to 17 days) between visit 1 and 2 and also between visit 5 and 6 (randomization). 
d
All asthma medications taken in the 12 months prior to visit 1 must be recorded in the eCRF along with reason for treatment. All other medications taken for conditions 
other than asthma in the 3 months prior to visit 1 must be recorded in the eCRF along with reason for treatment.
e
Urinalysis analyzed centrally only if dipstick locally is positive.
f
Serum pregnancy (β-HCG) test only for WOCBP. FSH test done only in women < 50 years who have been amenorrheic for > 12months to confirm postmenopausal 
status.
g
eDiary should be dispensed after all other assessments have been performed.
h
Daily Diary: Asthma symptom diary (ASD), general asthma symptom severity item, rescue medication use, night time awakenings and adherence to maintenance 
medications.
i
If Pre-BD FEV1 is met and reversibility is not met or vice versa, at visit 1; only the criteria that was not met needs to be verified at visit 2. Post-BD spirometry should be 
performed 15-30 min after administration of 4 puffs of albuterol/salbutamol. Reversibility can be documented in the previous 12 months prior to or at visit 1 or visit 2.  
Note: Reversibility (both historical and during screening) is defined as FEV1 ≥12% and ≥200 mL.
j
At visit 2 OCS dose titration will be attempted without referring to the protocol-captured set of baseline eDiary data. At other optimization visits eDiary data preceding 
the visits, will be compared to the baseline eDiary data derived from the interval between visit 1 and 2 for OCS dose titration decisions. Refer section 8.1.1.2. 
k
If the subject does not meet the criteria for following OCS dose reduction schedule at visits 3 or 4, the OCS dose should preferentially be returned to one level higher, 
unless the judgment of the investigator is to maintain the subject on their current dose of OCS, and visit 5 should be activated instead of visit 3 or 4 on the same day. 
Subject must be maintained on the optimized OCS dose for at least 2 weeks before randomization. 

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Table 2
Study plan – Treatment and follow-up period 
In
du
cti
on
Reduction
phase
Mainte-
nance 
phase
E
O
To
F
U
F
U
I
P
D
U
  N
S b
Refer
Section / Appendix
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Wk
0
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
54
Wk 
60
Visit window (days) a
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
N/A
N/A
Verifying Inclusion/
exclusion criteria
X
Section 5.1,  5.2
Weight
X
X
X
X
Section 8.2.2
Randomization
X
Health resource 
utilization (HRU) c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.9
Complete physical 
examination
X
X
X
Section 8.2.3
Brief physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.3
Vital Signs d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3
Assessments of asthma 
exacerbation
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.2
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
12-lead ECG e
X
X
X
X
Section 8.2.5

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In
du
cti
on
Reduction
phase
Mainte-
nance 
phase
E
O
To
F
U
F
U
I
P
D
U
  N
S b
Refer
Section / Appendix
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Wk
0
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
54
Wk 
60
Visit window (days) a
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
N/A
N/A
Glucocorticoid toxicity 
index
X
X
X
X
Section 8.2.6
Safety laboratory 
assessments (Clinical 
chemistry and 
haematology) f
X
X
X
X
X
X
X
X
Section 8.2.1
Urinalysis (dipstick) g
X
X
X
X
X
X
Section 8.2.1
Urine pregnancy test 
(dipstick) h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgE (FEIA)
X
Section 8.8.2
Total serum IgE, IgA, 
IgG, IgM i
X
X
X
X
X
X
X 
Section 8.8.2
PK
X
X
X
X
X
X
X
X
Section 8.5.1
ADA/nAb
X
X
X
X
X
X
X
X
Section 8.5.2
Serum for other 
biomarker analysis 
X
X
X
X
X
X
X 
Section 8.8.1
Blood sample for RNA 
transcriptome profiling
X
X
X
X
X
X
X 
Section 8.8.3

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In
du
cti
on
Reduction
phase
Mainte-
nance 
phase
E
O
To
F
U
F
U
I
P
D
U
  N
S b
Refer
Section / Appendix
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Wk
0
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
54
Wk 
60
Visit window (days) a
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
N/A
N/A
Pharmacogenetics 
assessment j (Optional)
X
X
X
X
Section 8.7
Daily diary k
Completed twice daily at home on eDiary
Daily diary adherence 
check 
X
X
X
X
X
X
X
X
X
X
X
X
X
ACQ-6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.6.2
AQLQ(s)+12
X
X
X
X
X
X
Section 8.1.6.3
WPAI+CIQ
X
X
X
X
Section 8.1.6.6
EQ-5D-5L
X
Completed every 2 weeks on the eDiary
X
Section 8.1.6.5
SGRQ
X
X
X
Section 8.1.6.4
FENO l
X
X
X
X
X
X
X
X
Section 8.1.5
Pre-BD spirometry
X
X
X
X
X
X
X
X
Section 8.1.3
Post-BD spirometry
X
X
X
X
X
Section 8.1.3
Home assessment of 
PEF
Measurements every morning and evening throughout treatment period
PEF adherence check
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of IP m
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.2

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In
du
cti
on
Reduction
phase
Mainte-
nance 
phase
E
O
To
F
U
F
U
I
P
D
U
  N
S b
Refer
Section / Appendix
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
V20
Wk
0
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
40
Wk 
44
Wk 
48
Wk 
54
Wk 
60
Visit window (days) a
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
N/A
N/A
OCS dose titration 
X
X
X
X
X
X
X
X
X
Xn
Section 8.1.1.1
EOT – End of treatment; FU – Follow-up; IPD – Investigational product discontinuation; UNS – Unscheduled
a
All visits are to be scheduled from the date of randomization; not from the date of previous visit.
b
Unscheduled visits may be initiated as needed. At unscheduled visits for assessing an asthma exacerbation, at a minimum, these assessments need to be performed. At other 
unscheduled visits assessments may be performed as per investigator’s judgement.
c
Asthma specific resource utilization (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications).
d
Vital signs will be taken pre-dose prior to administration of IP. Subjects will be observed 2 hours post treatment for Visits 6 and 7.  For all other visits where IP is 
administered, subjects will be observed for a minimum of 1 hour.
e
ECG must be collected prior to any blood draws.
f
During treatment period all laboratory samples should be obtained prior to IP administration. Subjects should be fasting for at least 12 hours prior to blood collection. Blood 
eosinophil, basophils and monocyte numbers from the visits after randomization visit will be redacted from the central laboratory reports.
g
Urinalysis analyzed centrally only if dipstick locally is positive.
h
For WOCBP urine pregnancy test (dipstick) to be done at site at each treatment visit prior to IP administration. Positive urine pregnancy test must be confirmed by serum β-
HCG.
i
All immunoglobulin results will be redacted from laboratory reports from the visits after randomization.
j 
Blood sample for DNA is optional and will be collected from subjects who have consented to participate in the genetic analysis component of the study
k
Daily Diary: ASD, general asthma symptom severity item, rescue medication use, night time awakenings and adherence to maintenance medications.
l
FENO test needs to be completed prior to spirometry. FENO results will be redacted.
m IP should be administered after all other assessments have been completed at the visit.
n
Up-titration only. 
o
Subjects completing the EOT visit may be eligible to enrol in a separate extension study D5180C00018 and these subjects will not complete the follow-up visits at Week 54
and Week 60. During the Corona Virus Disease 2019 (COVID-19) pandemic, subjects enrolling in the separate extension study D5180C00018 will continue participation in 
the follow-up visit(s) (Week 54, Week 60) until the on-site (or alternate site) visit for extension study randomization and IP administration can be conducted.
CHANGES REQUIRED DURING THE COVID-19 PANDEMIC

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Please Note: Changes below should only be implemented during the COVID-19 pandemic.
During the COVID-19 pandemic, changes are being implemented in order to ensure the safety of study subjects, to maintain 
compliance with good clinical practices, and to minimize risks to data integrity. Where allowable by local health authorities, ethics 
committees and healthcare provider guidelines (e.g. hospital policies), these changes include:

The option of home visits including home administration of Investigational Product (IP) performed by a qualified Health 
Care Professional (HCP). Additional information related to the visit can be obtained remotely by phone call and/or video 
conference. The rationale for this change is to minimize the risk of subjects missing scheduled IP administration and visit 
assessments due to inability/unwillingness to visit the site during the COVID-19 pandemic.

Remote visits (phone call and/or video conference) to replace on-site visits, if subjects cannot attend the visits at the study 
site, at an alternate site or have home visits. The rationale for this change is to ensure that assessments and collection of
information continue for visits that cannot be done at the site, at an alternate site or at the subject’s home.  This will reduce 
the risk of subject exposure to COVID-19.

Decision on OCS dose based on remote interview of subject, eDiary data, and if applicable, home visit physical examination 
and vital signs. The rationale for this change is to ensure optimal OCS dose for asthma control and to reduce the subject risk 
of exposure to COVID-19.

Subjects aimed to transition to the extension study D5180C00018 to continue participation in the safety follow-up visit(s) 
(Week 54, Week 60) until the on-site (or alternate site) extension study randomization and IP administration can be 
conducted. The rationale for this change is to ensure randomization/first IP administration in the extension study 
D5180C00018 can be performed at the site (alternate site) and to increase the chances of subjects transitioning to the 
extension study.

Re-consent will be obtained remotely and/or verbally if allowed by local and regional guidelines. The rationale for this 
change is to ensure that the subject agrees to the changes implemented due to the COVID-19 pandemic while minimizing 
the subject risk of exposure to COVID-19.

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For further details, please refer to Appendix K.

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The phase 2b tezepelumab efficacy study (CD-RI-MEDI9929-1146) conducted in patients with 
inadequately controlled severe asthma demonstrated a considerable reduction in the annualized 
asthma exacerbation rate (AAER) in subjects using OCS maintenance treatment. 
Thus, it would be valuable to evaluate the ability of tezepelumab in reducing OCS use in severe 
asthma population.
Study objectives:
Primary objective:
Endpoint/variable:
To evaluate the effect of tezepelumab 
compared with placebo in reducing the 
prescribed OCS maintenance dose in 
subjects with asthma requiring chronic 
treatment with maintenance OCS in 
addition to high dose ICS plus LABA 
Primary outcome variable: Categorized percent 
reduction from baseline in the daily OCS dose at Week 
48 while not losing asthma control
The categories for percent change from baseline in daily 
OCS dose are defined as:
1. ≥90% to ≤100% reduction
2. ≥75% to <90% reduction
3. ≥50% to <75% reduction
4. >0% to <50% reduction
5. no change or any increase
Primary outcome measure: Cumulative odds ratio vs 
placebo at Week 48
Key Secondary objective:
Endpoint/variable:

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To evaluate the effect of tezepelumab 
compared with placebo on asthma 
exacerbations
Key secondary outcome variable: Annualised asthma 
exacerbation rate (AAER)
Outcome measure: AAER ratio vs placebo over 48 
weeks
Supportive outcome variable: Time to first asthma 
exacerbation 
Outcome measure: Asthma exacerbation hazard ratio vs 
placebo over 48 weeks
Supportive outcome variable: Rate of asthma 
exacerbation associated with ER visit, urgent care visit or 
hospitalisation
Outcome measure: AAER ratio vs placebo over 48 
weeks
Supportive outcome variable: Proportion of subjects 
who did not experience an asthma exacerbation
Outcome measure: Difference in proportions vs placebo 
at Week 48
Other Secondary objectives:
Endpoint/variable:
To evaluate the effect of tezepelumab 
compared with placebo on the prescribed 
OCS daily maintenance dose
Outcome variables: 

Proportion of subjects with 100% reduction from 
baseline in daily OCS dose at Week 48

Proportion of subjects with daily OCS dose ≤5 mg at 
Week 48

Proportion of subjects with ≥50% reduction from 
baseline in daily OCS dose at Week 48 
Outcome measure: Odds ratio vs placebo at Week 48
To evaluate the effect of tezepelumab 
compared with placebo on pre-
bronchodilator (BD) lung function
Outcome variables: Change from baseline in pre-BD 
forced expiratory volume in 1 second (FEV1) 
Outcome measure: Mean difference vs placebo at Week 
48

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To assess the effect of tezepelumab 
compared with placebo with regards to 
asthma symptoms and other asthma control 
metrics
Outcome variables:
Change from baseline in:

Weekly mean daily Asthma Symptom Score as 
captured in the daily Asthma Symptom Diary (ASD)

Weekly mean rescue medication use

Weekly mean home peak expiratory flow (PEF) 
(morning and evening)

Weekly mean number of night-time awakening due 
to asthma

Asthma Control Questionnaire 6 (ACQ-6) score
Outcome measure: Mean difference vs placebo at Week 
48
To assess the effect of tezepelumab 
compared with placebo with regards to 
asthma related and general health-related 
quality of life
Outcome variables:
Change from baseline in:

Standardized Asthma Quality of Life Questionnaire 
for 12 years and older (AQLQ(s)+12) total score

European Quality of Life – 5 Dimensions 5 Levels 
Questionnaire (EQ-5D-5L) score
Outcome measure: Mean difference vs placebo at Week 
48
To evaluate the efficacy of tezepelumab 
compared with placebo on health resource 
utilization and productivity loss due to 
asthma
Outcome variables:

Number of asthma specific resource utilizations (e.g. 
unscheduled physician visits, unscheduled phone 
calls to physicians, use of other asthma medications)

Work Productivity and Activity Impairment 
Questionnaire and Classroom Impairment 
Questionnaire (WPAI+CIQ) score
Outcome measures:

Difference in number of asthma specific resource 
utilizations vs placebo over 48 weeks

Difference in WPAI+CIQ score vs placebo at Week 
48
To assess the effect of tezepelumab on 
biomarkers
Outcome variable: Change from baseline in FENO, 
peripheral blood eosinophils and total IgE 
Outcome measure: Mean difference vs placebo at Week 
48

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To evaluate the pharmacokinetics (PK) and 
immunogenicity of tezepelumab

PK: Serum trough concentrations

Immunogenicity: Incidence of anti-drug antibodies 
(ADA) 
Safety objective:
Endpoint/variable:
To evaluate the safety and tolerability of 
tezepelumab

Adverse events/serious adverse events

Vital signs 

Clinical chemistry/haematology/urinalysis 
parameters 

Digital electrocardiograms
To evaluate the effect of tezepelumab on 
corticosteroid toxicity
Glucocorticoid toxicity index 
Exploratory objectives
Endpoint/variable:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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Overall design:
This is a multicentre, randomized, double-blind, parallel group, placebo-controlled Phase 3 study 
designed to demonstrate the efficacy and safety of 210 mg tezepelumab administered 
subcutaneously (SC) every 4 weeks (Q4W) versus placebo in reducing OCS use in subjects with 
asthma requiring treatment with maintenance OCS in combination with high-dose ICS plus 
LABA with or without other asthma controller therapy, while maintaining asthma control.
The study will consist of a screening/run in period for 2 weeks, an OCS optimization phase for 
up to 8 weeks, a treatment period of 48 weeks and a post-treatment follow-up period of 12 
weeks. The treatment period will consist of an induction phase for 4 weeks, an OCS reduction 
phase for 36 weeks and a maintenance phase for 8 weeks.  
Subjects that complete the 48-week study visit will complete a 12-week post treatment, follow-
up period unless the subject is eligible and decides to enrol into a separate extension study 
D5180C00018.
Study period:
Estimated date of first subject enrolled: Q1 2018
Estimated date of last subject completed: Q4 2020
Number of Subjects:
Approximately 152 subjects will be randomized to tezepelumab or placebo (1:1) globally from 
about 65-75 study sites. Randomization will be stratified by region.
Treatments and treatment duration:
After the initial enrolment and confirmation of entry criteria all subjects will enter a 2-week run-
in period plus an up to 8-week optimization phase to establish a minimum effective dose of the 
prescribed OCS. The optimization phase may be extended to account for treatment of an 
exacerbation to allow for 2-weeks of a stable OCS dose prior to randomization.
After the OCS optimization phase, subjects who fulfil the eligibility criteria will be randomized 
to a 48-week treatment period. 
There are 3 phases in the 48-week treatment period following randomization where subjects will 
be administered study drug.

Induction phase – from week 0 to week 4 when subjects should remain on their optimized 
OCS dose.

OCS reduction phase – from week 4 to week 40 when OCS dose reduction should be 
started at week 4 with the possibility of dose titration every 4 weeks. No down-titration 
after week 36.

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
Maintenance phase – from week 40 to week 48 when subjects should remain on the OCS 
dose reached at week 40 (or earlier if OCS dose reduction failed because of clinical 
deterioration) or remain on complete oral corticosteroid elimination if possible.
Post treatment safety follow-up visits will be performed at week 54 and at week 60.
Subjects completing the planned treatment period may be eligible to enrol in a separate extension 
study and these subjects will not attend the follow up visit at Week 54 and Week 60
Subjects should preferably be maintained on their currently prescribed ICS plus LABA with or 
without other asthma controller therapy, without change, from 3 months before screening until 
end of study.
Subjects who prematurely discontinue investigational product (IP) during the study will be 
encouraged to undergo scheduled study visits/procedures for the full 48-week period. Further 
information is provided in section 7.1.
Independent Adjudication Committee
An independent adjudication committee will be constituted to provide an external independent 
assessment of blinded data during the Phase 3 trials to confirm the diagnosis of major adverse 
cardiac events (MACE) (to be defined in the charter) and investigator reported malignancies that 
occur from randomization until the end of the follow-up period. 
This independent adjudication committee will also evaluate cases of ER or urgent care visits and 
hospitalizations that occur from randomization up to the end of treatment period, as well as all 
deaths, that occur from randomization until the end of the follow-up period to evaluate whether 
any such event is due to a worsening of asthma. The committee will operate in accordance with 
the dedicated adjudication committee charter/manual of operations.
Data Safety Monitoring Board
The Data Safety Monitoring Board (DSMB) is an independent expert advisory group 
commissioned and charged with the responsibility of evaluating cumulative safety and other 
clinical trial data at regular intervals.
DSMB will operate in accordance with a DSMB charter and periodically review unblinded 
safety summary tables and listings, evaluate for subject safety and make appropriate 
recommendations. The committee will function independently of all other individuals associated 
with the conduct of the studies, including the study sponsor AstraZeneca.
Statistical methods:
Approximately 152 subjects (76 per treatment group) are needed for this study based on the 
primary objective (with primary endpoint as defined above).
With 76 subjects per treatment group it is estimated that, using a 2-sided 5% significance level, 
the power to reject the null hypothesis for the primary endpoint will be at least 90%, assuming:

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
An odds ratio of 2.75 and the proportional odds assumption

The proportion of subjects in the 5 different dose reduction categories for placebo is as 
follows:

Category 1 (90% - 100% reduction): 10% of subjects

Category 2 (75% - <90% reduction): 10% of subjects

Category 3 (50% - <75% reduction): 15% of subjects

Category 4 (>0% - <50% reduction): 15% of subjects

Category 5 (no reduction or an increase): 50% of subjects
Subjects who meet the eligibility criteria will be randomized (1:1) to receive either tezepelumab 
210 mg Q4W SC or placebo. Efficacy analyses will be performed using the full analysis set 
(FAS), which consists of all subjects randomized and receiving any IP. All subjects in the FAS 
will be included in the main efficacy analyses, including subjects who discontinue IP prior to 
Week 48 (for which every attempt will be made to collect data after discontinuation of IP up 
until week 48). No need is envisaged to adjust the planned number of randomized subjects in 
order to obtain an appropriate number of evaluable subjects.
A hierarchical testing strategy will be implemented to test for superiority of tezepelumab over 
placebo in the primary and key secondary endpoints, whilst controlling the overall Type 1 error 
rate at 0.05 (2-sided), as follows:

Percentage reduction category from baseline in daily OCS dose at 48 weeks whilst not 
losing asthma control (primary endpoint)

AAER over 48 weeks (key secondary endpoint)
The primary endpoint in the tezepelumab group will be compared to that in the placebo group 
using a proportional odds (ordinal logistic regression) model. The response variable in the model 
will be the ordered category number (1-5) at Week 48 as defined above. Treatment and region 
will be included as factors in this model. Baseline OCS dose will be included in the model as a 
continuous (linear) covariate.
Analysis of the key secondary endpoint will compare the AAER over 48 weeks between 
treatment groups using a negative binomial model. The response variable will be the number of 
asthma exacerbations experienced by the subject over the study period. Treatment, region, and 
history of exacerbations (≤2, or >2 in previous 12 months) will be included as factors in the 
model. The logarithm of the time at risk for exacerbation in the study will be used as an offset 
variable.  
Additional sensitivity analyses will be performed on the primary and key secondary endpoints, 
including analyses to explore the impact of missing data and early discontinuation from IP.
All safety variables will be summarized descriptively. The safety analysis will be performed 
using the safety analysis set, which consists of all subjects receiving any IP.

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maintenance OCS treatment (Data on file). Other biologics (mepolizumab and benralizumab) 
have been shown to effectively reduce the AAER and have also been demonstrated to enable 
reduction in daily OCS dose in severe asthma patients requiring maintenance therapy with OCS 
(Bel et al 2014, Nair et al 2017). Thus, there is reason to believe that tezepelumab should be 
effective in reducing the daily OCS dose in severe asthma patients on maintenance OCS 
treatment.
The purpose of the present study is to demonstrate the ability of tezepelumab versus placebo to 
enable reductions of the daily maintenance OCS use in adults with asthma also using high-dose 
ICS plus LABA with or without other asthma controller therapy, while maintaining asthma 
control.
2.2
Background
Asthma is a chronic inflammatory airway disease characterized by bronchial hyperreactivity and 
reversible airflow limitation that causes wheezing, shortness of breath, cough, and chest 
tightness. Although several treatments are available (e.g. ICS, LABA and LAMA), there is a 
clear unmet medical need among patients with severe asthma.
Biologic therapies can provide additional asthma control for such patients. Omalizumab may be 
suitable for a subgroup of patients with proven reactivity to an aeroallergen and elevated serum 
immunoglobulin E (IgE) levels who remain inadequately controlled with ICS plus LABA 
(XOLAIR US PI 2016). Two additional biologics, mepolizumab and reslizumab, have recently 
been approved for severe asthma with an eosinophilic phenotype (NUCALA US PI 2015, 
CINQAIR US PI 2016). Biologics targeting IL-5 and IgE are now included in international 
treatment guidelines (GINA 2017) as an add-on treatment to patients uncontrolled with 
LABA/ICS treatment. 
However, even when using currently available biologics, substantial proportions of patients 
continue to experience exacerbations and may benefit from agents that target different molecular 
pathways (Wenzel 2016, Froidure et al 2016, Swedin et al 2017). Therefore, despite these 
additional therapeutic options, there is still a clear unmet medical need among patients with 
severe asthma, independent of IgE status or eosinophil level, who are unable to gain complete 
asthma control using currently available therapies.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that is produced in 
response to proinflammatory stimuli (e.g., infectious, allergic and environmental stimuli) and 
trauma. TSLP has an upstream and central role in the initiation of inflammatory responses, and 
can activate a broad range of cell types including eosinophils, mast cells, T cells, dendritic cells, 
type 2 innate lymphoid cells and basophils (Tedeschi SK et al 2017, Watson and Gauvreau, 
2014). Classically, TSLP may be a critical component in the initiation and perpetuation of the T 
helper 2 (Th2) response and the resulting cascade of cytokines associated with Th2 driven 
asthma (Kaur and Brightling 2012). Asthma is now recognized as a heterogenous disease with 
subsets of patients that do not exhibit Th2-associated disease (Wenzel 2012). There are emerging 
data that TSLP may also mediate non-allergic (non-T helper cell 2) inflammation (Tanaka et al 
2009; Ziegler et al 2013). Given that TSLP is an upstream and pleiotropic cytokine, the blockade 

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of TSLP is therefore anticipated to have broad impact on the spectrum of inflammatory 
responses seen in asthma.
Tezepelumab is a human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) directed 
against TSLP. Tezepelumab binds to human TSLP and prevents its interaction with TSLP 
receptor (TSLPR).
Results of a completed study in 31 adult subjects with mild atopic asthma (Study 20101183) 
demonstrated that administration of tezepelumab attenuated both the early and late phase allergic
response and suppressed the expected increase in FENO following inhalation allergen challenge 
(Gauvreau et al 2014). Multiple doses of 700 mg IV tezepelumab demonstrated an acceptable 
safety profile in subjects with mild atopic asthma. Based upon these data, MedImmune/AZ have 
conducted a randomized, double-blind, placebo-controlled, dose range finding study in 
asthmatics who were inadequately controlled with medium- or high-dose ICS/LABA, with or 
without other controller medications.
Study CD-RI-MEDI9929-1146 was a Phase 2b multicenter, multinational, dose-ranging, double-
blind, randomized, parallel-arm, placebo-controlled study to evaluate the effect of 3 dose levels 
of tezepelumab on the AAER in adult subjects with inadequately controlled, severe asthma 
(Corren et al 2017). Subjects were randomized in a 1:1:1:1 ratio to 1 of 3 dose levels of SC 
tezepelumab (280 mg every 2 weeks [Q2W], 210 mg Q4W, or 70 mg Q4W) or placebo (Q2W) 
for 52 weeks. A total of 584 subjects received at least 1 dose of IP (tezepelumab or placebo). 
Statistically significant AAERR of 61%, 72%, and 66% for the 70 mg Q4W, 210 mg Q4W, and 
280 mg Q2W tezepelumab groups, respectively, compared with placebo were observed in the 
intent-to-treat (ITT) population (p<0.001). Moreover, clinically significant benefits in lung 
function, ACQ-6 and AQLQ+12 were observed. In addition, blood eosinophil numbers and 
FENO were significantly suppressed. 
After repeated SC administration, mean serum tezepelumab trough concentration increased over 
time and achieved steady-state by week 12. Tezepelumab exhibited linear PK across the 3 doses. 
A total of 5 (4.1%) placebo subjects and 8 (1.8%) tezepelumab subjects who had no detectable 
ADA at baseline had detectable ADA post-treatment; no subjects developed neutralizing ADA in 
the study. The results of this study did not identify safety signals associated with tezepelumab for 
any dosing regimen. The frequencies of treatment emergent adverse events (TEAEs) were 
similar between the placebo (62.2%) and the total tezepelumab (64.2%) dose groups and a 
majority of subjects had TEAEs that were mild or moderate in severity and not related to 
investigational product. Few subjects had TEAEs that resulted in permanent discontinuation of 
investigational product. Overall, tezepelumab was well-tolerated with an acceptable safety 
profile and no safety signals were identified.
A detailed description of the chemistry, pharmacology, efficacy, and safety of tezepelumab is 
provided in the Investigator’s Brochure.
2.3
Benefit/risk assessment
In order to evaluate the clinical benefit-risk balance, preclinical and clinical data, as well as a 
review of the available information for monoclonal antibodies that are approved for and are in 

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development for the treatment of severe asthma, have been considered. Benefits for tezepelumab 
over placebo include a clinically meaningful AAERR, an increased FEV1 and an improvement in 
asthma control metrics.
Tezepelumab has been well tolerated with no safety signals identified in studies to date. No 
serious allergic reactions or anaphylactic reactions considered related to tezepelumab were 
reported in the Phase 2 program. Although TSLP suppression could theoretically have 
unanticipated immune-related side effects impairing host defense against certain infections, there 
is no clear preclinical or clinical evidence supporting such a role and no safety signals related to 
infections have been detected in the tezepelumab program. Potential risks with tezepelumab will 
be mitigated by the selected inclusion/exclusion criteria and continuous monitoring of safety data 
during the study. In the present study, measures are taken to mitigate the risk for embryonal, fetal 
and child exposure to tezepelumab.
The benefit/risk assessment for tezepelumab in severe asthma based on the development through 
Phase 2 is favourable. The future benefit / risk assessment will largely be defined by results from 
the Phase 3 program.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tezepelumab may be found in the Investigator’s Brochure.
See Section 8.4.7 for information regarding the DSMB.
3.
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary objective:
Endpoint/variable:
To evaluate the effect of tezepelumab 
compared with placebo in reducing the 
prescribed OCS maintenance dose in 
subjects with asthma requiring chronic 
treatment with maintenance OCS in 
addition to high dose ICS plus LABA
Primary outcome variable: Categorized percent 
reduction from baseline in the daily OCS dose at Week 
48 while not losing asthma control
The categories for percent change from baseline in daily 
OCS dose are defined as:
1. ≥90% to ≤100% reduction
2. ≥75% to <90% reduction
3. ≥50% to <75% reduction
4. >0% to <50% reduction
5. no change or any increase
Primary outcome measure: Cumulative odds ratio vs 
placebo at Week 48
Key Secondary objective:
Endpoint/variable:

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To evaluate the effect of tezepelumab 
compared with placebo on asthma 
exacerbations
Key secondary outcome variable: AAER
Outcome measure: AAER ratio vs placebo over 48 
weeks
Supportive outcome variable: Time to first asthma 
exacerbation 
Outcome measure: Asthma exacerbation hazard ratio vs 
placebo over 48 weeks
Supportive outcome variable: Rate of asthma 
exacerbation associated with ER visit, urgent care visit or 
hospitalisation
Outcome measure: Asthma exacerbation rate ratio vs 
placebo over 48 weeks
Supportive outcome variable: Proportion of subjects 
who did not experience an asthma exacerbation
Outcome measure: Difference in proportions vs placebo 
at Week 48
Other Secondary objectives:
Endpoint/variable:
To evaluate the effect of tezepelumab 
compared with placebo on the prescribed, 
OCS daily maintenance dose
Outcome variables: 

Proportion of subjects with 100% reduction from 
baseline in daily OCS dose at Week 48

Proportion of subjects with daily OCS dose ≤5 mg at 
Week 48

Proportion of subjects with ≥50% reduction from 
baseline in daily OCS dose at Week 48 
Outcome measure: Odds ratios vs placebo at Week 48
To evaluate the effect of tezepelumab 
compared with placebo on Pre-BD lung 
function
Outcome variables: Change from baseline in Pre-
bronchodilator forced expiratory volume in 1 second 
(FEV1) 
Outcome measure: Mean difference vs placebo at Week 
48

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To assess the effect of tezepelumab 
compared with placebo with regards to 
asthma symptoms and other asthma control 
metrics
Outcome variables:
Change from baseline in:

Weekly mean daily Asthma Symptom Score as 
captured in the daily Asthma Symptom Diary (ASD)

Weekly mean rescue medication use

Weekly mean home peak expiratory flow (morning 
and evening)

Weekly mean number of night-time awakening due 
to asthma

Asthma Control Questionnaire 6 (ACQ-6) score
Outcome measure: Mean difference vs placebo at Week 
48
To assess the effect of tezepelumab 
compared with placebo with regards to 
asthma related and general health-related 
quality of life
Outcome variables:
Change from baseline in:

Standardized Asthma Quality of Life Questionnaire 
for 12 years and older (AQLQ(s)+12) total score

European Quality of Life – 5 Dimensions 5 Levels 
Questionnaire (EQ-5D-5L) score
Outcome measure: Mean difference vs placebo at Week 
48
To evaluate the efficacy of tezepelumab 
compared with placebo on health resource 
utilization and productivity loss due to 
asthma
Outcome variables:

Number of asthma specific resource utilizations (e.g. 
unscheduled physician visits, unscheduled phone 
calls to physicians, use of other asthma medications)

Work Productivity and Activity Impairment 
Questionnaire and Classroom Impairment 
Questionnaire (WPAI+CIQ) score
Outcome measures:

Difference in number of asthma specific resource 
utilizations vs placebo over 48 weeks

Difference in WPAI+CIQ score vs placebo at Week 
48
To assess the effect of tezepelumab on 
biomarkers
Outcome variable: Change from baseline in FENO, 
peripheral blood eosinophils and total IgE 
Outcome measure: Mean difference vs placebo at Week 
48

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To evaluate the pharmacokinetics (PK) and 
immunogenicity of tezepelumab

PK: Serum trough concentrations

Immunogenicity: Incidence of ADA 
Safety objective:
Endpoint/variable:
To evaluate the safety and tolerability of 
tezepelumab

Adverse events/serious adverse events

Vital signs 

Clinical chemistry/haematology/urinalysis 
parameters 

Digital electrocardiograms
To evaluate the effect of tezepelumab on 
glucocorticoid toxicity
Glucocorticoid toxicity index 
Exploratory objectives
Endpoint/variable:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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4.
STUDY DESIGN
4.1
Overall design
For an overview of the study design see Figure 1, Section 1.3. For details on treatments given 
during the study, see Section 6.1 Treatments administered.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives and 
Endpoints.  
This is a Phase 3, multi-centre, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the effect of 210 mg Q4W SC of tezepelumab on OCS dose reduction in adult 
subjects with OCS dependent asthma. 
The study will randomize approximately 152 subjects globally in a 1:1 ratio to either 
tezepelumab or placebo. The subjects will be stratified by region.
All subjects must have received OCS for the treatment of asthma for at least 6 months prior to 
visit 1 and must have been on a stable dose of between ≥ 7.5 to ≤ 30mg (prednisone or 
prednisolone) daily or daily equivalent for at least 1 month prior to visit 1. Subjects must have 
been on a medium- to high- dose ICS for the past 12 months and LABA with high dose ICS for 
at least 3 months prior to visit 1. Additional maintenance asthma controller medications are 
allowed according to standard practice of care. Their use must be documented for at least 3 
months prior to visit 1. See inclusion criteria 4-7. 
Subjects in the study will be required to have had at least one asthma exacerbation in the past 12 
months. Details on acceptable historical documentation is specified in section 5.1.
Eosinophils will be assessed using central lab analyses. Approximately 35% of the subjects will 
be targeted to have ≥ 300 eosinophils/μl at enrolment. When the target percentage of subjects for 
the eosinophil subgroup in a region is reached, consideration will be given to closing the 
IWRS/IVRS randomization for that subgroup, which may be done either overall or within a 
specific region. Once a subgroup is closed, subjects in the screening/run-in period in the closed 
subgroup will not be allowed to be randomized and will be screen failed.
Section 6.5 (Table 6 and Table 7) provides a list of medication restrictions and prohibitions to be 
followed throughout the conduct of the clinical trial.
The study will consist of a screening/run in period of 2 weeks, an OCS optimization phase for up 
to 8 weeks and a treatment period of 48 weeks consisting of a 4-week induction phase, a 36-
week OCS reduction phase and an 8-week maintenance phase. The duration of the post-treatment 
follow-up period is 12 weeks (week 48-60). During the treatment period, IP will be administered 
SC starting at randomization and continue until week 44. IP will not be administered on week 48. 
There are up to 18 visits from screening to scheduled end of treatment, followed by two follow-
up visits. 
During the screening/run-in period, the subject must undergo all assessments per Table 1.

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Prior to randomization the subjects must meet all inclusion /exclusion criteria. If a subject does 
not meet all inclusion criteria or meets any exclusion criteria as per section 5.1 and section 5.2, 
the subject will be screen failed. Further details are specified in section 5.5. 
Subjects who are administered IP week 44 and complete the 48-week study visit will complete a 
12-week post-treatment follow-up period. 
Subjects who prematurely discontinue IP during the study will be encouraged to undergo 
appropriate study visits/procedures for the full 48-week period. Subjects should have an IPD visit 
at 4 weeks from the final dose of IP. A follow-up visit should then be scheduled 16 weeks after 
last IP administration. Further information is provided in section 7.1.1. Any new treatments that 
are initiated will be recorded in the electronic case report form (eCRF). 
Subjects remaining on IP for entire planned treatment period, may be eligible to enroll in the 
extension study. These subjects will transition to the extension study, after completing the EOT 
assessments at week 48 and thus they will not attend the follow-up visits at Week 54 and Week 
60.
4.2
Scientific rationale for study design
This is a global study designed to evaluate the efficacy and safety of a fixed 210 mg dose of 
tezepelumab administered Q4W SC in severe asthma subjects who are on maintenance OCS and 
ICS/LABA therapy, with or without additional asthma controller(s). The primary efficacy 
measure will be based on the percentage change from baseline in the prescribed, daily, average 
OCS dose at week 48 post randomization while not losing asthma control. 
This study is double blind to reduce the risk of bias. Tezepelumab is compared to placebo on top 
of standard of care to better assess the effect in the appropriate clinical context. This study is a 
randomized, parallel group, double-blinded study in which subjects are stratified by region. The 
asthma study population has been chosen as one in need of reduction of the daily OCS dose. 
Subjects should be on maintenance OCS, high dose ICS and LABA to ensure that a severe 
asthmatic population is included in the trial. 
In the optimization phase, the lowest OCS dose is defined as the OCS dose at which asthma 
control is maintained. The duration of the induction phase is defined by the time to reach effect 
in the phase 2b study. In the reduction phase, strict criteria will be followed for down titration of 
the OCS dose. The maintenance phase is to assess the effectiveness to maintain asthma control 
without exacerbations. This study has a similar design and endpoints as previous studies with 
mepolizumab (Bel et al 2014) and benralizumab (Nair et al 2017). A difference in this study 
design from previous OCS sparing studies is that the duration of the present study is longer; 48
weeks compared to 24 - 28 weeks in previous trials. The reduction phase in the present study has 
a longer duration to allow more subjects to reduce daily OCS dose to 0 mg. In addition, the 
maintenance phase is of longer duration as compared to the previous studies to better evaluate 
the sustainability of the treatment effect.

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This phase 3 study will evaluate the OCS reduction capacity of tezepelumab and the effect on the 
AAER and other aspects of lung function, asthma control, and safety to further characterize the 
benefit-risk profile of the drug and understand how best to position it in the treatment pathway.  
4.3
Justification for dose
A 210 mg Q4W dosing regimen was selected for the Phase 3 studies based on efficacy data and 
an exposure-response analysis from the Phase 2b Study CD-RI-MEDI9929-1146 using 
population PK/PD methodology. The population PK model of tezepelumab was developed based 
on all available data from 5 Phase 1 studies (Study 20070620, Study 20080390, Study 2010118, 
Study D5180C00003, Study D5180C00002), and 2 Phase 2 studies (Study D5240C00001 and 
Study CD-RI-MEDI9929-1146). The exposure-response analysis was based on the Phase 2b 
Study CD-RI-MEDI9929-1146.
Analysis of data from the phase 2b study identified a statistically significant exposure-response 
against the primary efficacy endpoint of AAER and the pharmaco-dynamic endpoint FENO. 
These relationships indicate that the dose of 70 mg Q4W is a sub-optimally effective dose and 
the dose of 210 mg Q4W is optimally effective. In summary, characterization of AAERR data 
from Study CD-RI-MEDI9929-1146 indicate the 210 mg Q4W dose provides improved efficacy 
over the 70 mg Q4W dose, whereas the 280 mg Q2W dose did not further reduce the AAER. 
Therefore, the dose of 210 mg Q4W has been selected for evaluation in this study. Tezepelumab 
was well-tolerated at all doses and the safety profile was well balanced between the tezepelumab 
and placebo groups with no evidence of a dose relationship to TEAEs.
4.4
End of study definition
The end of study is defined as when the last subject has completed his/her last scheduled contact.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled contact.
See Appendix A 6 for guidelines for the dissemination of study results. 
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known as 
protocol waivers or exemptions, is not permitted.
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to become assigned/randomised to a study intervention. Under no circumstances 
can there be exceptions to this rule. Subjects who do not meet the entry requirements are screen 
failures, refer to section 5.4.
In this protocol, “enrolled” subjects are defined as those who sign informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number.

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For procedures for withdrawal of incorrectly enrolled subjects see Section 6.3.
5.1
Inclusion criteria
Subjects are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply:
Informed consent
1.
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses. 
2.
Provision of signed and dated written optional Genetic informed consent prior to 
collection of sample for genetic analysis (refer to 0 for specific requirements for 
genetic sampling).
The ICF process is described in Appendix A 3.
Age
3.
Subject must be 18 to 80 years of age inclusive at the time of signing the informed 
consent form.
Type of subject and disease characteristics
4.
Documented physician-diagnosed asthma for at least 12 months prior to visit 1.
5.
Subjects must have received a physician-prescribed medium- or high-dose ICS as per 
GINA guideline (GINA 2017) for at least 12 months prior to visit 1.
6.
Subjects must have received physician prescribed LABA and high dose ICS (total 
daily dose >500μg fluticasone propionate dry powder formulation equivalent) for at 
least 3 months prior to visit 1. The ICS and LABA can be parts of a combination 
product, or given by separate inhalers.

Equivalent ICS doses as detailed in 0.
7.
Additional maintenance asthma controller medications are allowed according to 
standard practice of care i.e., leukotriene receptor antagonists (LTRAs), theophylline, 
long-acting muscarinic antagonists (LAMAs), secondary ICS and cromones. The use 
of these medications must be documented for at least 3 months prior to visit 1. 
8.
Subjects must have received OCS for the treatment of asthma for at least 6 months 
prior to visit 1 and on a stable dose of between ≥ 7.5 to ≤ 30mg (prednisone or 
prednisolone) daily or daily equivalent for at least 1 month prior to visit 1. The OCS 
dose may be administered every other day (or different doses every other day); 
Average dose over two days = The daily dose.
9.
Morning pre-bronchodilator (BD) FEV1 must be < 80% predicted normal at visit 1 or 
visit 2.

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10.
Subjects must have evidence of asthma as documented by post-BD 
(albuterol/salbutatomol) reversibility of FEV1 ≥12% and ≥200 mL (15-30 min after 
administration of 4 puffs of albuterol/salbutamol), documented either in the previous 
12 months prior to or at visit 1 or at visit 2.
11.
Subjects must have a history of at least 1 asthma exacerbation event within 12 months 
prior to visit 1. For the purpose of this study an asthma exacerbation is defined as a 
worsening of asthma that either:

required treatment with a burst of systemic corticosteroids for at least 3 days or a 
single depot- injectable corticosteroid dose OR

resulted in an emergency department visit (defined as evaluation and treatment for 
<24 hours in an ER or urgent care center) which required systemic corticosteroids 
(as per above) OR

An inpatient hospitalisation due to asthma (defined as admission to an inpatient 
facility and/or evaluation and treatment in a healthcare facility for ≥24 hours)
NOTE: For subjects receiving a stable maintenance dose of OCS, a temporary 
increase for at least 3 consecutive days over and above the stable existing 
maintenance dose qualifies as an exacerbation. 
The below defines acceptable documentation of an exacerbation:

Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a subject was hospitalized/treated with systemic steroids for an 
asthma exacerbation.

Signed and dated notes from a referring physician, including information 
regarding diagnosis and treatment of an exacerbation with systemic steroids.

Subjects can provide evidence of prescriptions for systemic steroids used during 
an exacerbation.

A documented conversation between the treating/referral physician or nurse/nurse 
practitioner certifying that a subject was treated for an exacerbation with steroids 
at their clinic or under their supervision. The dates (month/year) of the 
exacerbations and verbal confirmation that appropriate prescriptions were 
provided is necessary. This option should be used only if reasonable attempts to 
procure subject records have been unsuccessful.
Weight
12.
Body weight ≥ 40 kg at visit 1.

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Reproduction
13.
Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
14.
Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use a highly effective method of contraception from screening, and must 
agree to continue using such precautions for 16 weeks after the final dose of 
investigational product. Periodic abstinence, the rhythm method, and the withdrawal 
method are not acceptable methods of contraception.  

A highly effective method of contraception is defined as one that results in a low 
failure rate (i.e. less than 1% per year) when used consistently and correctly. 
Highly effective forms of birth control include: true sexual abstinence, a 
vasectomised sexual partner, Implanon, female sterilization by tubal occlusion, 
any effective intrauterine device/system (IUD/IUS), Depo-Provera™ injections, 
oral contraceptive, and Evra Patch ™ or Nuvaring™.
Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrheic for 12 months prior to the planned date 
of randomization without an alternative medical cause. The following age specific 
requirements apply:

Women <50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels in the postmenopausal 
range. 

Women ≥50 years old would be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment.
15.
Inclusion Criterion # 15 removed with version 3.0 of Clinical Study Protocol
Inclusion criteria at randomization
16.
Subject must have received the optimized OCS dose for at least 2 weeks prior to 
randomization.
17.
Minimum 10 days compliance with the morning and evening eDiary completion 
during the 14 days prior to randomization.
A compliant day requires completion of evening eDiary and subsequent morning 
eDiary such that an ASD daily score can be calculated.

The period for this criterion is the duration from the evening of the final OCS 
dose adjustment (defining the optimized dose) during the optimization phase until 
the morning of the randomization visit.

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18.
Minimum 10 days compliance with OCS, ICS, LABA and other asthma controller 
medications as captured in the eDiary during the 14 days prior to randomization.

Days with missing eDiary data treated as non-compliant for this criterion.
19.
Acceptable inhaler, peak flow meter, and spirometry techniques as judged by the 
investigator.
5.2
Exclusion criteria 
Medical conditions
1.
Any clinically important pulmonary disease other than asthma (e.g. active lung 
infection, Chronic Obstructive Pulmonary Disease (COPD), bronchiectasis, pulmonary 
fibrosis, cystic fibrosis, hypoventilation syndrome associated with obesity, lung 
cancer, alpha 1 anti-trypsin deficiency, and primary ciliary dyskinesia) or ever 
diagnosed with pulmonary or systemic disease, other than asthma, that are associated 
with elevated peripheral eosinophil counts (e.g. allergic bronchopulmonary 
aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome).
2.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, hematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator and could: 

Affect the safety of the subject throughout the study

Influence the findings of the study or the interpretation

Impede the subject's ability to complete the entire duration of study
3.
History of cancer: 

Subjects who have had basal cell carcinoma, localized squamous cell carcinoma 
of the skin or in situ carcinoma of the cervix are eligible to participate in the study 
provided that curative therapy was completed at least 12 months prior to visit 1. 

Subjects who have had other malignancies are eligible provided that curative 
therapy was completed at least 5 years prior to visit 1.
4.
History of a clinically significant infection, including upper or lower respiratory tract 
infection (URTI and LRTI, respectively), requiring treatment with antibiotics or 
antiviral medications finalized < 2 weeks before screening or during the run-in period.
5.
A helminth parasitic infection diagnosed within 6 months prior to visit 1 that has not 
been treated with, or has failed to respond to, standard of care therapy. 

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6.
Current smokers or subjects with smoking history ≥ 10 pack-years and subjects using 
vaping products, including electronic cigarettes. Former smokers with a smoking 
history of <10 pack years and users of vaping or e-cigarette products must have 
stopped for at least 6 months prior to visit 1 to be eligible.
7.
History of chronic alcohol or drug abuse within 12 months prior to visit 1. 
8.
Tuberculosis requiring treatment within the 12 months prior to visit 1.
9.
History of any known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test. 
10.
Major surgery within 8 weeks prior to visit 1 or planned surgical procedures requiring 
general anaesthesia or in-subject status for >1 day during the conduct of the study.
11.
Clinically significant asthma exacerbation, in the opinion of the Investigator, including 
those requiring use of systemic corticosteroids or increase in the maintenance dose of 
OCS finalized within 30 days prior to visit 1.
Prior/concomitant therapy
12.
Receipt of any marketed or investigational biologic agent within 4 months or 5 half-
lives (whichever is longer) prior to visit 1 or receipt of any investigational non-
biologic agent within 30 days or 5 half-lives (whichever is longest) prior to visit 1. 
Note: Subjects on previous biologics treatment are allowed to enter the study provided       
the appropriate washout period is fulfilled.
13.
Treatment with the following medications within the last 12 weeks prior to visit 1 : 
systemic immunosuppressive/immunomodulating drugs (e.g. methotrexate, 
cyclosporine, oral/parenteral/intra-articular corticosteroids for other use than treatment 
of asthma).
14.
Receipt of immunoglobulin or blood products within 30 days prior to visit 1.  
15.
Receipt of the T2 cytokine inhibitor Suplatast tosilate within 15 days prior to visit 1. 
16.
Receipt of live attenuated vaccines 30 days prior to the date of randomization and 
during the study including the follow-up period. 
17.
Subjects who have been treated with bronchial thermoplasty in 12 months prior to visit 
1.
Prior/concurrent clinical study experience 
18.
Known history of sensitivity to any component of the investigational product 
formulation or a history of drug or other allergy that, in the opinion of the investigator 
or medical monitor, contraindicates their participation (see section 6.1.1).

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19.
History of anaphylaxis or documented immune complex disease (Type III 
hypersensitivity reactions) following any biologic therapy. 
20.
Concurrent enrolment in another clinical study involving an IP.
21.
Subject randomized in the current study or previous tezepelumab studies.
22.
Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff 
and/or site staff), or subjects employed by or relatives of the employees of the site or 
sponsor.
Diagnostic assessments
23.
Any clinically meaningful abnormal findings in physical examination, vital signs, 
ECG, haematology, clinical chemistry, or urinalysis during the run-in period, which in 
the opinion of the Investigator, may put the subject at risk because of his/her 
participation in the study, or may influence the results of the study, or the subject's 
ability to complete entire duration of the study.
24.
Evidence of active liver disease, including jaundice or aspartate transaminase, alanine 
transaminase, or alkaline phosphatase beyond twice the upper limit of normal. 
25.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at 
screening, or a positive medical history for hepatitis B or C. Subjects with a history of 
hepatitis B vaccination without a history of hepatitis B are allowed to participate. 
26.
A positive human immunodeficiency virus (HIV) test at screening or subject taking 
antiretroviral medications, as determined by medical history and/or subject's verbal 
report.  
Other exclusions
27.
Pregnant, breastfeeding, or lactating women.  
A serum β-human chorionic gonadotropin (HCG) pregnancy test must be drawn for 
women of childbearing potential at the screening visit. If the results of the serum β-
HCG cannot be obtained prior to dosing of the investigational product, a subject may 
be enrolled on the basis of a negative urine pregnancy test, though serum β-HCG must 
still be obtained. If either test is positive, the subject should be excluded. Since urine 
and serum tests may miss a pregnancy in the first days after conception, relevant 
menstrual history and sexual history, including methods of contraception, should be 
considered. Any subject whose menstrual and/or sexual history suggests the possibility 
of early pregnancy should be excluded. 
28.
Unwillingness or inability to follow the study procedures in the opinion of the 
investigator.

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29.
Judgment by the investigator that the subject should not participate in the study if the 
subject is unlikely to comply with study procedures, restrictions and requirements. 
Genetic research exclusion criteria
30.
Previous allogeneic bone marrow transplant.
31.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
Exclusion criteria at randomization
32.
During the optimization period, asthma control reached at an OCS dose of <7.5 mg or 
>30mg and/or 3 consecutive dose reductions after which asthma control was still 
obtained.
33.
Evidence of clinically significant infection or subject receiving treatment with 
antibiotics or antiviral medications.
5.3
Lifestyle restrictions
Subjects must abstain from donating blood and plasma from the time of informed consent, and 
for 16 weeks (5 half-lives) after last dose of IP.
5.3.1
Meals and dietary restrictions
Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the study site. Subjects should not eat or drink 1 hour prior to having FENO 
assessment.
5.3.2
Alcohol, tobacco and other
Chronic alcohol or drug abuse within 12 months prior to visit 1 and throughout the conduct of 
the study is not allowed.
Current smokers or subjects with smoking history ≥ 10 pack-years at visit 1 are not allowed.  
Former smokers with a smoking history of <10 pack years must have stopped for at least 6 
months to be eligible. Smoking is not allowed throughout the course of the study. The use of e-
cigarettes is also not allowed during the course of the study.
5.3.3
Activity
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung 
function assessments at the study site.
5.4
Screen failures
Screen failures are defined as subjects who signed the informed consent form to participate in the 
clinical study but are not subsequently randomly assigned to Study treatment. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure subjects to 

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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 serious adverse event (SAE).
These subjects should have the reason for study withdrawal recorded as ‘Screen Failure’ (i.e. 
subject does not meet the required inclusion/exclusion criteria) in the eCRF. This reason for 
study withdrawal is only valid for screen failures, and not randomized subjects. 
5.5
Re-screening 
Subjects with clinically significant infection, including respiratory infections requiring 
intravenous antibiotics or systemic antiviral medication during run-in should be screen failed but 
may be re-screened 2 weeks after completion of the therapy. 
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed visits prior to 
randomization), subjects may potentially be re-screened. These cases should be discussed with 
the AstraZeneca Study Physician and documented approval for re-screening should be filed in 
the Investigator Study File (ISF).
Re-screening of a subject for any other reason will be allowed only upon approval of the 
AstraZeneca Study Physician. A documented approval for re-screening should be filed in the 
Investigator Study File (ISF).
Any re-screened subject will be re-enrolled and reassigned their originally assigned enrolment 
number after signing a new Informed Consent Form (ICF). All visit 1 assessments as listed in the 
SoA should be re-performed with the exception of testing for HIV1 and HIV2, hepatitis B and C, 
and FSH. If the timeframe between Screening and re-screening is more than 30 days, then all 
Visit 1 assessments should be repeated.
6.
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study participant 
according to the study protocol. Study treatment in this study refers to tezepelumab or placebo.

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Each vial should be visually inspected prior to dose preparation. The IP will be provided to the 
study sites as a colorless to slightly yellow clear solution contained in 5 cc single use glass vials 
to be stored at 2°C to 8°C until used. If there are any defects noted with the IP, the investigator 
and site monitor should be notified immediately. Preparation of IP must be performed by a 
qualified person (e.g., pharmacist or study nurse) at the site.
The IP product does not contain preservatives and any unused portion must be discarded. 
Preparation of the IP is to be performed aseptically. Total in-use storage time from needle 
puncture of the IP vial to start of administration should not exceed 4 hours at room temperature. 
If storage time exceeds this limit, a new dose must be prepared from new vials.
To prepare the subject’s dose, the IP manager will select IP for administration according to the 
kit identification numbers assigned by the IVRS. One vial of IP will be assigned by IVRS for 
each dose. 
Dose preparation steps:
1.
Allow the vial to equilibrate at room temperature (about 30 minutes to 1 hour). Ensure 
that the vial is adequately protected from light during the warming process. Gently 
swirl the vial to ensure the contents are mixed to a clear, homogeneous solution. Do 
not shake.
2.
To prepare the IP for administration, remove the tab portion of the vial cap and clean 
the stopper with 70% ethyl alcohol or equivalent. 
3.
Attach a 21G 1½ -inch sterile disposable needle to a 2 mL or 3 mL sterile syringe. 
4.
Withdraw 1.9 mL of the IP from the vial.
5.
Apply the appropriate label to the syringe.
6.
Remove and discard the 21G 1½ -inch sterile disposable needle from the syringe. 
7.
Attach a new 27G ½-inch sterile disposable needle to the same syringe in step 6. 
Assigned vial should be used at one time to prepare the dose required at each visit. Unused 
product in opened and dispensed vial should not be used for subsequent dosing and should be 
stored for IP accountability. If the opened and dispensed vials must be discarded immediately 
after dose preparation as per site’s SOP the kit boxes must be retained for IP accountability.
The IP will be administered by one SC injection (see Table 5 below) and must be prepared using 
disposable plastic syringes and aseptic technique.

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Table 5
Investigational product dose preparation
Dose
Number of vials 
required
Syringe size required
Total volume 
administered
210 mg a
1
3 mL
1.9 mL
Placebo
1
3 mL
1.9 mL
a
Due to gradations available on 3 mL disposable plastic syringe, dose based on 1.9 mL administered 
volume is 209 mg.
Dose administration
IP will be administered by a qualified healthcare professional (e.g., pharmacist or study nurse) at 
the site. The person administering the dose will wipe the skin surface of the upper arm, anterior 
thigh or abdomen with alcohol, and allow to air dry. The skin will be pinched to isolate the SC 
tissue from the muscle. The needle will be inserted at a 90-degree angle approximately halfway 
into the SC tissue. The IP will be slowly injected (at least 5 seconds duration is recommended) 
into the SC tissue using gentle pressure. The area should not be massaged after injection. It is 
advised that the site of injection of IP be rotated such that the subject receives IP at a different 
anatomical site at each treatment visit. Injection site must be documented on the eCRF and in the 
source documents at each treatment visit. In cases when rotation of the injection site is not 
feasible and/or the subject prefers not to rotate injection sites, the reason for not rotating the 
injection site should be documented in the source documents.
The suggested injection site rotation sequence is presented below in Figure 2. 
Figure 2
Rotation of injection sites
Subjects should be observed for a minimum of 2 hours after the first two IP administrations for
the appearance of any acute drug reactions. For the remaining doses, subjects will be observed 
for a minimum of 1 hour after IP administration for any such reaction.
If any of the following should occur, the IP should not be administered: 

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
The subject received allergen immunotherapy injection on the same day as scheduled IP 
administration. 

The subject has an intercurrent illness that in the opinion of the investigator and/or 
medical monitor may compromise the safety of the subject in the study (e.g., viral 
illnesses). 

The subject is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP administration. 
The visit should be rescheduled within the allowed visit window and IP should be administered 
at that visit. If this is not possible, the IP administration should be skipped. If a subject skips 2 
consecutive IP administrations, the AZ study physician should be contacted to discuss further 
participation.  
If the subject reports an injection site reaction, the investigator or qualified designee will 
complete the AE eCRF page and an additional eCRF page with questions about the injection site 
reaction.  
6.3
Measures to minimise bias: randomisation and blinding
Subject enrolment and randomization 
The Investigator(s) should keep a subject screening log listing of those who have entered pre-
study screening. The Investigator(s) will:
1.
Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2.
Assign the potential subject a unique enrolment number (which begins with an ‘E’) via 
the Interactive Web Response System/Interactive Voice Response System 
(IWRS/IVRS).
3.
Determine subject eligibility. 
4.
Assign the eligible subject unique randomization code via the Interactive Web 
Response System/Interactive Voice Response System (IWRS/IVRS).
5.
Subjects will be allocated to receive tezepelumab or placebo in a 1:1 ratio stratified by 
region. Randomization numbers will be grouped in blocks. If a subject withdraws from 
the study, then his/her enrolment/randomisation code cannot be reused. Withdrawn 
subjects will not be replaced 
Specific information concerning the use of the IWRS/IVRS will be provided in the separate 
manual.
Procedures for handling incorrectly enrolled or randomized subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Subjects who 

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are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
If a subject does not meet all the eligibility criteria but is randomized in error, or incorrectly 
started on treatment, the Investigator should inform the AstraZeneca study physician 
immediately. A discussion should occur between the AstraZeneca study physician and the 
investigator regarding whether to continue or discontinue the subject from treatment. Study 
treatment must be discontinued in all cases where continued treatment is deemed to pose a safety 
risk to the subject. In those cases where continuation of the study therapy is judged not to present 
a concern related to safety and disease management, the rationale for continuing study therapy 
must be clearly documented. Regardless of what is decided about IP, all randomized subjects 
should remain in the study and the subjects should continue to be followed up in accordance with 
defined study procedures. The AstraZeneca study physician must ensure all decisions are 
appropriately documented.
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially in each stratum as subjects become 
eligible for randomization.
The randomization code will be assigned from a randomization list prepared by a computerized 
system provided by Parexel Informatics on behalf of AstraZeneca (AZRand). All subjects will be 
stratified at randomization by region.
Approximately 35% of the subjects will be targeted to have ≥ 300 eosinophils/μl at enrolment. 
Therefore, further enrolment of subjects with < 300 eosinophils/μl may be halted to achieve the 
required percentage. 
Ensuring blinding 
This is a double-blind study in which tezepelumab and placebo are not visually distinct from 
each other. All packaging and labelling of IP will be done in such way as to ensure blinding for 
all sponsor and investigational site staff. Neither the subject nor any of the investigators or 
sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
subjects will be aware of the treatment received.
To further prevent unblinding, blood eosinophil, basophils and monocyte numbers from the visits 
after randomization visit will be redacted from the central laboratory reports. In addition, FENO 
results will also be blinded throughout the study. 
AstraZeneca site monitor will perform IP accountability. In the event that the treatment 
allocation for a subject becomes known to the investigator or other study staff involved in the 
management of study subjects, or needs to be known to treat an individual subject for an AE, the 
sponsor must be notified immediately by the investigator and if possible, before unblinding.
The following personnel will have access to the randomization list:

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
those carrying out the packaging and labelling of IP

those generating the randomization list

personnel at the IWRS/IVRS company

supply chain management department

patient safety department at AstraZeneca

bioanalytical lab performing the PK, ADA, and nab sample analysis

those involved in the reporting and reviewing the DSMB presentations
The information in the randomization list will be kept from other personnel involved in the 
conduct of the study and in a secure location until the end of the study.
No other member of the extended study team at AstraZeneca, or any CRO handling data, will 
have access to the randomization scheme during the conduct of the study until after the primary 
database lock.
Methods for unblinding
Individual treatment codes, indicating the treatment randomization for each randomized subject, 
will be available to the Investigator(s) and  Study Coordinator(s) at the study sites from the 
IVRS/IWRS. Routines for this will be described in the IVRS/IWRS user manual that will be 
provided to each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. The Investigator 
documents and reports the action to AstraZeneca, without revealing the treatment given to 
subject to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are suspected to 
be causally related to an IP and that potentially require expedited reporting to regulatory 
authorities. Treatment codes will not be broken for the planned analyses of data until all 
decisions on the evaluability of the data from each individual subject have been made and until 
primary database lock after last subject completes week 48 has been documented.
6.4
Treatment compliance
Any change from the dosing schedule or dose discontinuations should be recorded in eCRF.
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. The date and time of all IP administrations, as well as 
any missed doses, should be recorded in the appropriate section of the eCRF.
6.5
Concomitant therapy
Information about any asthma treatment in the 12 months prior to and all other concomitant 
treatments 3 months prior to the date of the visit 1 and given during the study, with reason for the 
treatment, will be collected by the Investigator/authorized delegate at each visit and recorded in 
the eCRF.

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To satisfy inclusion criteria 5 to 8, there should be a documented history of treatment with 
medium- or high-dose ICS for at least 12 months and LABA with high dose ICS for at least 3 
months prior to visit 1. Use of OCS for at least 6 months, with a dose stable for at least 1 month 
prior to visit 1, should also be documented in source. 
Medium dose ICS corresponds to 500 μg and high dose ICS corresponds to >500 μg fluticasone 
propionate dry powder formulation equivalents as outlined in 0. Subjects may also receive other 
physician prescribed asthma controller medications.
No changes are allowed to background asthma medications (except OCS) throughout the 
duration of the study except during the treatment of an asthma exacerbation. 
However, subjects prematurely discontinuing IP administration should be given locally available 
standard of care therapy, allowing changes to background medications at the discretion of the 
Investigator. However, treatment with marketed or investigational biologics is not allowed until 
week 60 even if the subject has discontinued IP. Interaction studies between tezepelumab and 
other biologics indicated for the treatment of asthma have not been conducted. Thus, the effects 
and side effects of concomitant treatment of tezepelumab and other biologics have not been 
evaluated. The time for elimination of tezepelumab (5 half-lives) is approximately 16 weeks. 
However, the duration of downstream pharmacodynamics effects of tezepelumab is unknown. 
For additional information regarding pharmacokinetic and phamacodynamic effects of 
tezepelumab, reference should be made to the investigator brochure.
OCS medication as well as maintenance asthma medications will be provided/reimbursed by 
AstraZeneca according to local regulations, in order to maintain appropriate oversight and access 
to this concomitant therapy. 
As theophylline has a narrow therapeutic window, please note that subjects on maintenance 
treatment with theophylline should have blood concentration levels within therapeutic range 
documented before visit 1. If this is not documented before signing the informed consent, it can 
be obtained after informed consent has been given or as part of the visit 1 procedures. The 
sample can be analyzed at the central or local lab as applicable. Investigator can use their clinical 
judgement about the therapeutic range of theophylline levels on the basis of sampling
time and other factors that may impact the results.
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency

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Table 6
Restricted medications
Medication/class of drug:
Usage 
Maintenance treatment with long-
acting bronchodilators (including 
ICS/LABA combinations)
No changes, in dose and regimen, are allowed from visit 1, during 
run-in and optimization phase, throughout IP treatment and 
preferably 4 weeks after last dose of IP.
ICS/LABA should not be taken prior to scheduled spirometry, 
FENO, ECG and home lung function assessments (to be 
administered once assessments are completed):

Twice daily bronchodilator should be withheld for at least 12 
hours prior to the scheduled FENO and spirometry at site. 

Once daily bronchodilators, should be withheld for at least 24 
hours prior to the scheduled FENO and spirometry at site.
Subjects will not need to washout of their asthma medications for 
unscheduled visits due to asthma worsening.
Short-acting beta-agonists 
(SABA)
Regular scheduled use not allowed from visit 1, during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP. PRN use is allowed; however, attention 
should be paid to the following restrictions:
If possible, SABA should be withheld for at least 6 hours prior to 
scheduled spirometry, FENO, ECG at site and home lung function 
assessments. Only albuterol/salbutamol is allowed to be used as a 
rescue medication during the study, except during exacerbations.

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Medication/class of drug:
Usage 
Additional maintenance 
controllers
No changes, in dose and regimen, are allowed from visit 1, during 
run-in and optimization phase, throughout IP treatment and 
preferably 4 weeks after last dose of IP.
Once daily LABA and LAMA should be withheld for at least 24 
hours prior to the scheduled spirometry and FeNO.
Twice daily LABA- or LAMA-containing therapies should be 
withheld for at least 12 hours prior to scheduled spirometry and 
FENO at site.
LTRA should be restricted for at least 24 hours prior to scheduled 
spirometry and FENO at site.
Subjects on theophylline should have blood concentration levels 
within therapeutic range documented before proceeding in the 
study. However, if theophylline blood concentration is out of 
therapeutic range after visit 1, dose adjustments are allowed.
Twice daily theophyllines should be withheld for at least 12 hours 
prior to scheduled spirometry and FENO at site.
Once daily theophyllines should be withheld for at least 24 hours 
prior to scheduled spirometry and FENO at site.
Short-acting anti-cholinergics 
(e.g. ipratropium)
Not allowed as a rescue treatment for worsening of asthma 
symptoms from visit 1, during run-in and optimization phase, 
throughout IP treatment and preferably 4 weeks after last dose of 
IP.
May be used for managing an asthma exacerbation event.
Inactive/killed vaccinations (e.g. 
inactive influenza)
Allowed provided they are not administered within 5 days before 
or after any study visit.
Allergen immunotherapy
Allowed if on stable therapy for at least 30 days prior to visit 1; no 
anticipated changed during treatment period.
Should not be administered on the same day as IP administration.
Table 7
Prohibited medications
Medication/class of drug:
Usage
Long-acting beta-agonists as a 
reliever (e.g. Symbicort 
Maintenance and Reliever 
Treatment)
Not allowed 15 days prior to visit 1, during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP.

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Medication/class of drug:
Usage
Suplatast tosilate (T2 cytokine 
inhibitor)
Not allowed 15 days prior to visit 1, during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP.
Live attenuated vaccines
Not allowed 30 days prior to visit 1; throughout IP treatment and 
preferably 4 weeks after last dose of IP (unless there is an absolute 
medical need as judged by the Investigator) and follow-up period.
Any immunomodulators or 
immunosuppressives 
(corticosteroids with systemic 
effects such as oral, parenteral, or 
intra-articular administration for 
reasons other than asthma are not 
allowed. However, corticosteroid 
treatment of adrenal insufficiency 
and acute anaphylaxis is 
allowed.)
Not allowed 3 Months or 5 Half Lives (whichever is longer) prior 
to visit 1; during run-in and optimization phase, throughout IP 
treatment and preferably 16 weeks after last dose of IP.
Blood products or 
immunoglobulin therapy
Not allowed 30 days prior to visit 1; during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP (unless there is an absolute medical 
need as judged by the Investigator).
Any marketed (e.g. benralizumab, 
omalizumab, mepolizumab, 
reslizumab) or investigational 
biologic treatment
Not allowed 4 months or 5 half-lives (whichever is longer) prior to 
visit 1 ; throughout the entire treatment period (even if the subject 
has discontinued IP) and until the follow up visit week 60.
Other IP (including 
investigational use of an approved 
drug)
Not allowed 30 Days or 5 Half Lives (whichever is longer) prior to 
visit 1; during run-in and optimization phase, throughout the entire 
treatment period (even if the subject has discontinued IP) until the 
follow up visit week 60.
Herbal remedies for the treatment 
of allergic, inflammatory, or 
respiratory diseases
Not allowed 30 days prior to visit 1; during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP.
Medications not currently 
licensed for use in the treatment 
of asthma, for example 
medications approved for Chronic 
Obstructive Pulmonary Disease 
and not part of current standard of 
care
Not allowed 30 days prior to visit 1, during run-in and 
optimization phase, throughout IP treatment and preferably 4 
weeks after last dose of IP.
Spironolactone 
Not allowed from visit 1, during run-in and optimization phase, 
throughout the entire treatment period (even if the subject has 
discontinued IP) until the follow up visit week 60.
Eplerenon
Not allowed from visit 1, during run-in and optimization phase, 
throughout the entire treatment period (even if the subject has 
discontinued IP) until the follow up visit week 60.

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Medication/class of drug:
Usage
Ephedrine (e.g. in antitussives or 
mucolytics)
Not allowed from visit 1, during run-in and optimization phase, 
throughout the entire treatment period (even if the subject has 
discontinued IP) until the follow up visit week 60.
Opiates prn (e.g. in antitussives)
Not allowed from visit 1, during run-in and optimization phase, 
throughout the entire treatment period (even if the subject has 
discontinued IP) until the follow up visit week 60.
6.5.1
Other concomitant treatment
Other medication than that described above, which is considered necessary for the subject’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case report form.
6.5.2
Rescue medicine
SABA should preferably be withheld for at least 6 hours prior to scheduled site visit spirometry, 
FENO, ECG at site and home lung function assessments with the exception of any unscheduled 
visits due to asthma worsening.
The study site will supply albuterol /salbutamol rescue medication that will be provided by the 
sponsor/obtained locally. 
Regularly scheduled SABA use in the absence of any asthma symptoms is not allowed from 
enrolment (Visit 1) and throughout the study duration.
Prophylactic use of SABA (e.g. prior to planned exercise) or any other use than to curb 
worsening of asthma symptoms should be documented in medical notes and entered in the eCRF. 
Any such use of SABA must not be recorded in the Asthma Daily Diary. 
Rescue use of SABA administered via nebulization is discouraged, except as urgent treatment 
during an asthma exacerbation. Occasions where SABA is administered via nebulization will be 
recorded separately from metered dose inhaler inhalations in the eDiary.
6.5.3
Bronchial thermoplasty
Subjects should not be treated with bronchial thermoplasty during the study.
6.6
Dose modification
N/A
6.7
Treatment after the end of the study
After the end of the study at week 60, subjects should be given standard of care at the discretion 
of the investigator. Subjects that are eligible and decide to enrol in a separate extension study 
will not attend the follow-up visits at week 54 and week 60 and should comply with the 
requirements of the separate extension study protocol. 

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NB There is a potential risk that spironolactone and eplerenon may aggravate adrenal 
insufficiency in this population
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Subjects may be discontinued from IP in the following circumstances. Note that discontinuation 
from study treatment is NOT the same as a complete withdrawal from the study.

Subject decision. The subject is free at any time to discontinue investigational product, 
without prejudice to further treatment 

Severe non-compliance with the clinical study-protocol

An adverse event considered to jeopardize the safety of a subject participating in the 
study

Pregnancy

Development of any study specific criteria for discontinuation, including:

An anaphylactic reaction to the IP requiring administration of epinephrine

A helminth parasitic infestation requiring hospitalization

An asthma-related event requiring intubation

Any malignancy except subjects who develop basal cell carcinoma or localized 
squamous cell carcinoma of the skin, provided that the malignancy is 
excised and determined to have clean margins

Development of one or more of the following:

Confirmed ALT or AST increase of ≥8 x ULN

Confirmed ALT or AST increase of ≥5 x ULN for more than 2 weeks

Confirmed ALT or AST increase of ≥3 x ULN and total bilirubin of ≥2 x ULN 

ALT or AST of ≥3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (≥5%)
See the SoA for data to be collected at the time of premature IP discontinuation and follow-up.

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7.1.1
Procedures for discontinuation of study treatment
Subjects are free to discontinue IP or withdraw from the study at any time without prejudice to 
further treatment. Discontinuing study treatment is not the same as study withdrawal. Procedures 
to follow for study withdrawal are detailed below in section 7.3. If the subject decides to 
withdraw consent, then the reason for this must be recorded separately in the eCRF. A subject 
that decides to prematurely discontinue IP should always be asked about the reason(s) and the 
presence of any adverse events. The reason for premature discontinuing treatment and the date of 
last IP administration should be recorded in the eCRF. Subjects permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of the 
Investigator. However, treatment with marketed or investigational biologics is not allowed until 
week 60 even if the subject has discontinued IP. 
All subjects who prematurely discontinue IP should return to the study center and 
complete the procedures described for the premature IP Discontinuation visit (IPD) at 4 
weeks (+/-5 days) post last IP administration and a follow-up visit at 16 weeks (+/-5 days) 
(refer to SoA, V20 – Week 60).
Subjects who discontinue treatment should be encouraged to return for all regularly scheduled 
visits as per SoA. Protocol specified OCS dose reductions according to schedule can be 
performed at PI’s discretion and judgement .
At the IPD visit the subject will be given three options as to how they will be followed as 
follows:
Option 1: Ideally the subject should continue all regular clinic visits and perform all assessments 
as per SoA until scheduled EOT visit at Week 48 (+/-5 days). 
Option 2: (If the subject cannot comply or does not wish to comply with option 1 above) To be 
followed up on a monthly basis via telephone calls while continuing at-home eDiary and ePEF 
completion including the questionnaires that otherwise would have been completed at the site as 
per SoA. Followed by an on-site EOT visit at Week 48 (+/-5 days).
Option 3: (If the subject cannot comply with option 1 or 2 above) To be only contacted on 
phone at the scheduled EOT visit at Week 48 weeks (+/-5 days).
The EOT visit will be completed immediately in the case of subsequent early withdrawal. 
Subjects who do not wish to have any follow-up contacts, will be discontinued from the study. 
All discontinued subjects must return the eDiary and ePEF devices at the EOT visit (and at IPD 
visit for subjects choosing option 3 above).
If the subject chooses option 2 or 3, the key information to be collected during the telephone 
calls are AEs/SAEs, changes in concomitant medication, health care utilization, and asthma 
exacerbation information. 
Subjects who initially choose options 1or 2 and subsequently cannot or do not wish to comply 
with the requirements of their option can continue with a less intensive option (i.e. subject 

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initially choosing option 1 can continue with options 2 or 3, subjects initially choosing option 2 
can continue with option 3).
If a subject discontinues IP due to a study specific discontinuation criterion, this should
always be recorded as ’Development of study specific withdrawal’ on the Discontinuation of 
Investigation Product form in the eCRF.
7.2
Lost to follow-up
A subject will be considered potentially lost to follow-up if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.

Before a subject is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the subject or next of kin by either repeated telephone 
calls, certified letter to the subject´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the subject’s medical record. 

Efforts to reach the subject should continue until the end of the study. Should the subject 
be unreachable at the end of the study the subject should be considered to be lost to 
follow up with unknown vital status at end of study and censored at latest follow up 
contact.
A subject is considered lost to follow-up when any of the following attempts of contact are 
failed: 3 attempts of either phone calls, faxes or emails; having sent 1 registered letter/certified 
mail; or one unsuccessful effort to check the status of the subject using publicly available 
sources, if allowed by local regulations.
7.3
Withdrawal from the study
A subject may withdraw from the study (e.g., withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. A subject who 
considers withdrawing from the study must be informed by the Investigator about modified 
follow-up options as per section 7.1.1. 
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow-up subjects as medically indicated. A 
withdrawal visit is essential to collect as much data as possible for the subject as per EOT visit 
described in SoA, Table 2. The subject will return all study supplied equipment including Home 
PEF meter and eDiary.
If the subject withdraws consent for disclosure of future information, the sponsor may retain and 
continue to use any data collected before such a withdrawal of consent.

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If a subject withdraws from the study, he/she may request destruction of any samples taken, and 
the investigator must document this in the site study records.  
If the subject only withdraws consent for the retention of blood samples for future exploratory 
use (e.g., DNA, study of markers of asthma, identifying potential new drug targets for asthma, or 
for assay development purposes), the subject will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF as well as in the ICF.
7.3.1
Withdrawal due to recruitment completion
When the required number of subjects are randomized in the study, ongoing subjects in run-in 
period or optimization phase may not be randomized and will be withdrawn from the study. The 
reason of the withdrawal should be documented in the source and eCRF. As with screen failures, 
no further study related follow-up of these subjects is required.
7.3.2
Discontinuation or suspension of entire study and Site Closure
If AstraZeneca decides to prematurely terminate or suspend the study, the PI, and regulatory 
authorities should receive written notification of the reasons for the premature termination or 
suspension. The PI will immediately notify the decision to the subjects and if relevant give 
appropriate medical treatment; take necessary measures and document these in the source notes.
The sponsor designee also reserves the right to close the study site 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
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA.  
The investigator will ensure that data are recorded on the eCRFs. The Web Based Data Capture 
(WBDC) system will be used for data collection and query handling.  

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The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The investigator will sign the completed eCRF. A copy of the completed eCRFs will 
be archived at the study site. Additional data to assess the impact of COVID-19 pandemic will be 
collected.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the subject should continue or discontinue Study treatment.
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 subjects 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
subjects screened and to confirm eligibility or record reasons for screening failure, as applicable.  
Procedures conducted as part of the subject’s routine clinical management (e.g., blood count) 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.
The maximum amount of blood collected from each subject over the duration of the study 
(excluding optional blood samples) will not exceed 220 mL. Repeat or unscheduled samples may 
be taken for safety reasons or for technical issues with the samples. The total amount of blood 
collected over the duration of study will not exceed 450 mL. 
8.1
Efficacy assessments 
8.1.1
Overview of OCS dose management
During the OCS optimization phase, the minimum OCS dose while maintaining asthma control 
(optimized dose) will be reached for all subjects. Asthma control and the criteria for OCS dose 
reduction are described in section 8.1.1.2. The optimized OCS dose will be kept stable for 2 
weeks prior to randomization and will be considered the baseline OCS dose. 
The baseline OCS dose should be maintained at the same level from visit 5 (two weeks prior to 
randomization) to visit 7 (end of induction phase).
OCS dose reduction will commence at visit 7 and continue at 4-week intervals until visit 15 in 
accordance with the OCS dose titration schedule described in section 8.1.1.1 (reduction phase). 
During the reduction phase a minimum stable OCS dose, or complete elimination of requirement 
for OCS, while maintaining asthma control, will be reached for each subject.
If possible, no adjustments should be made to the OCS dose at visit 16 and 17 (maintenance 
period) and until visit 18 (End of treatment).

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8.1.1.1
OCS dose titration
At visit 1 subjects will continue with or be switched to prednisone/prednisolone. For subjects not 
previously receiving prednisone/prednisolone as OCS, the conversion table shown in 0 will be 
used to calculate the equivalent prednisone/prednisolone dose for dose titrations. 
The OCS dose titration will follow the same approach for both the optimization and the 
reduction phase. The dose of OCS should be reduced if the subject meets the protocol defined 
criteria indicating that it is acceptable for the subject to reduce OCS, as described in section 
8.1.1.2. When a subject does not meet these criteria defining asthma control, the investigator 
should preferentially increase up one step unless the judgment of the investigator is to maintain 
the subject on their current dose of OCS, depending on the rationale for not reducing per 
schedule. The OCS dose changes and their reasons must be documented in the source 
documentation and recorded in the appropriate eCRF form.
OCS dose titration in the optimization phase
In the OCS dose optimization phase, dose titration should begin at visit 2. 
Baseline readings to be used for dose titrations in the optimization period will be the mean of
measures (morning PEFs, SABA use and night time awakenings) collected between visit 1 and 
visit 2. Dose reduction at visit 2 is the only titration visit during the optimization phase that will 
not be based upon a protocol-captured set of baseline data because determining a change from 
baseline will not be possible.
Visits 3 and 4 can be performed as telephonic visits provided the subject and sites are confident 
to perform the visit remotely. Depending on clinical judgement, investigator may instead decide 
to call the subject on-site for visits 3 and 4.  OCS dose reductions can occur at 2-week intervals 
according to the titration schedule (Table 8). In the dosing interval >10-30 mg prednisone or 
prednisolone per day, the change in daily dose is 5 mg, whereas in the interval 7.5-10 mg, the 
corresponding reduction is 2.5 mg. 
Table 8
OCS dose titration schedule during the optimization phase
Regimen
Starting dose of OCS 
(mg/day) at each visit of 
optimization period
Change by (mg/day) a
Daily regimen
>10-30
5.0
7.5-10
2.5
a During the Optimization phase the reductions should occur at 2-week intervals.
The optimized dose of OCS will be decided by using the criteria for the OCS dose reduction 
schedule, described in section 8.1.1.2, Table 9. In cases when the subject is optimized on their 
OCS dose at visit 3 or 4, visit 5 should be activated, instead of visit 3 or 4, on the same day and 
he/she should be maintained at the optimized dose of OCS for at least 2 weeks before being 
randomized. Conversely, the optimization phase may be extended to account for treatment of an 
exacerbation to allow for 2-week stable OCS dose prior to randomization. The optimized dose 

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reached during the OCS optimization phase becomes the subject’s baseline OCS dose for 
analysis purposes.
Subjects who are considered by Investigators not to be candidates for starting OCS dose 
reduction in the optimization phase, based upon asthma symptoms or other clinical reasons, 
should be screen-failed. Similarly, if the subject is non-compliant to eDiary completion and 
OCS, ICS/LABA or other asthma controller use and due to which the OCS dose cannot be 
optimized, then the subjects should be screen-failed. 
If a subject reaches asthma control at an OCS dose of <7.5 mg during this phase, or asthma 
control is still obtained after 3 consecutive OCS dose reductions, then the subject will be a screen 
failure and will not be randomized. 
OCS dose titration in the treatment period
No OCS titration should occur during the induction phase (visit 6-7). 
Dose titration during the treatment period will begin at visit 7 and end no later than at visit 15 
(reduction phase). It is performed at 4-week intervals according to the titration schedule in Table 
9. 
Table 9
OCS dose titration schedule during the reduction phase (V7-V15) a
Optimized 
dose at V-6
Wk0
V-7
Wk4
V-8
Wk8
V-9
Wk12
V-10
Wk16
V-11
Wk20
V-12
Wk24
V-13
Wk28
V-14
Wk32
V-15
Wk36
30
25
20
15
10
7.5
5
2.5
0
0
25
20
15
10
7.5
5
2.5
0
0
0
20
15
10
7.5
5
2.5
0
0
0
0
15
10
7.5
5
2.5
0
0
0
0
0
12.5
7.5
5
2.5
0
0
0
0
0
0
10
7.5
5
2.5
0
0
0
0
0
0
7.5
5
2.5
0
0
0 
0
0
0
0
The OCS dose may be administered every other day (or different doses every other day) Average dose over 
two days = The daily dose
a All doses expressed in mg/day of Prednisone/Prednisolone.
Unlike the optimization phase, for all subjects entering the dose reduction phase, the baseline 
values for titration will be the mean of measures (morning PEFs, SABA use and night time 
awakenings) collected daily two weeks prior to randomization (visit 6). Similar to optimization 
phase, though, is that dose reduction at visit 7 is the only titration visit during the reduction phase 
that will not be based upon a protocol-captured set of baseline data (because the OCS dose is the 
same as during baseline). At a minimum 10 days of completed morning and evening eDiary 
assessments should be available prior to randomization to consider the mean as baseline for the 
OCS reduction phase.

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All subjects will enter the OCS dose maintenance phase at visit 16 (week 40). No further dose 
reductions should be attempted after visit 15 (week 36).
8.1.1.2
Criteria for OCS dose reduction during the optimization and reduction phase
OCS dose titration (reduction) should be attempted at each visit as per the SoA. Subject should 
meet all of the criteria listed in Table 10 to follow the dose titration schedule. For OCS dose 
titrations at each visit subjects should have a minimum compliance of 10 of the last 14 days 
before the visit with morning and evening eDiary completion, OCS, ICS/LABA and other 
asthma controller use. Compliance is calculated from the data available from eDiary completion 
between visits. In the event of a lower eDiary compliance, using the visit window period the 
planned visit could be delayed to allow for 10 of the last 14 days compliance or study physician 
should be consulted to decide if the OCS dose reduction should follow as per schedule.   
Table 10
Criteria for following OCS dose reduction schedule
Criteria
Definition of asthma control
1
Morning PEF ≥80% of mean a morning measures as compared with baseline b mean
2c
An increase of no more than 2 nights with asthma-related awakenings (requiring rescue 
medication) over a 7-day period compared with baseline b
3
Mean a SABA rescue medication use not more than 4 puffs/day above the baseline b mean 
and <12 puffs/day on all days in the prior 14 days d
4
No asthma exacerbation requiring increased systemic corticosteroids or hospitalization 
since the previous visit
5
Investigator judges subject’s asthma control to be sufficient to allow OCS dose reduction e
6
No signs/symptoms of adrenal insufficiency (at OCS dose reductions below 5 mg) f
a
Mean values to be considered for each titration visit will be from completed eDiary records 14 days prior to the 
visit.
b
Baseline values for optimization phase are calculated from completed eDiary records of a minimum of 10 out 
of 14 days before visit 2. Similarly baseline values for the reduction phase will be calculated from a minimum 
of 10 out of 14 days before randomization visit.
c
Number of nights with awakenings due to asthma requiring rescue medication will be counted from the most 
recent 7 days of available data.  
d
Each nebulization used will be counted as 2 puffs.
e
Investigator will provide detailed rationale in eCRF for not reducing the OCS dose.
f
Investigator will provide detailed description, in the eCRF, of the signs/symptoms of AI for not reducing the 
OCS dose according to schedule. 
It is at the discretion of the Investigator to continue with the OCS down-titration even if the 
criteria for OCS reduction have not been met. Such a decision must be justified and documented 
in the source notes and captured in the eCRF. This decision must be notified to the AstraZeneca 
study physician within 2 business days.
When a decision is made to not reduce the OCS dose according to the reduction algorithm, the 
reason(s) for not reducing OCS must be documented in the source notes and captured in the 
eCRF. Depending on the rationale for not reducing per schedule, the investigator should 
preferentially increase up one step unless the judgment of the investigator is to maintain the 

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subject on their current dose of OCS. This will be defined as the optimized OCS dose for the 
optimization phase and the visit must be combined with Visit 5.Once the optimized OCS dose 
is reached, no further OCS dose reductions should be performed during the optimization 
phase. The subject should be maintained on that OCS dose until randomization (Visit 6). 
Subjects who do not meet all of the criteria for continuing OCS down titration specified in Table 
10during the reduction phase, should preferentially be returned to the previous effective OCS 
dose (i.e. the higher dose level prior to not meeting the down-titration criteria) after they have 
returned to their baseline level of asthma control established prior to the randomization visit. 
However, depending on the rationale for not reducing per schedule, the investigator may decide 
to maintain the subject on the OCS dose at which the down-titration criteria were not met. 
Further dose reductions, during the reduction phase, can be considered in the opinion of 
the Investigator (further reductions will follow the scheduled titration, see Table 9). The 
decision and reason must be captured in the eCRF.
Throughout the reduction phase, subjects should be monitored for the signs and symptoms of 
adrenal insufficiency (AI). When subjects reach a prednisone/prednisolone dose of 5 mg/day the 
investigator should inform them of the signs and symptoms of AI and provide them a steroid 
card informing health care providers that the subject may need additional corticosteroids in case 
of medical emergencies. In evaluating subjects for OCS dose reductions to below 5 mg/day the 
investigator should be vigilant for signs and symptoms of AI. The recommended initial dose 
reduction from 5 mg/day should be to 2.5 mg/day. After 4 weeks at this OCS dose another 
reduction to 0 mg/day should be considered. However, if, in the judgment of the investigator, 
OCS dose reduction should be more gradually tapered, dose reductions of 1 to 1.25 mg/day 
every 1-4 weeks may be considered. 
For doses below 5 mg if the exact dose strength is not available in the country the daily dose to 
be administered could be achieved by dosing every other day. Daily dose will be the average of 2 
days. See 0 for help dosing < 5 mg in relation to tablet strength. Subjects with a final daily OCS 
dose >0 and ≤5 mg who are unable to reduce their OCS dose further due to AI, should be 
specified in eCRF.
8.1.2
Asthma exacerbations – Assessment and management
During the study, an asthma exacerbation will be defined as a worsening of asthma symptoms 
(defined below) that leads to any of the following:
A temporary bolus/burst of systemic corticosteroids (at a dose at least 1 level higher than the 
current titration step) 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. Note: Per protocol up titration of OCS dose to 1 level 
higher (as described in Table 9) is not considered an exacerbation event per se.
An emergency room or urgent care visit (defined as evaluation and treatment for <24 hours in 
an emergency department or urgent care center) due to asthma that required systemic 
corticosteroids (as per the above).
An in-patient hospitalization (defined as admission to an inpatient facility and/or evaluation 
and treatment in a healthcare facility for ≥ 24 hours) due to asthma.

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For the purpose of the protocol, worsening of asthma is defined as new or increased symptoms 
and/or signs identified by physical examination/subject interview or by the subject asthma e-
Diary.
The ePRO device will be programmed to alert both the subject and study site when any of the 
pre-specified worsening thresholds as mentioned in Table 11 are crossed.
Table 11
eDiary alert criteria
Criteria a, b
Definition
1
Decrease in morning peak flow ≥20% on at least 2 consecutive days compared with 
baseline 
2
An increase in rescue medication use of ≥ 4 puffs/day on at least 2 consecutive days 
compared with the average use during baseline or use of ≥12 puffs/day on any one day
3
An additional nebulized β2 agonist use on at least 2 consecutive days compared with the 
average use during baseline
4
An increase of 2 or more nights with awakenings due to asthma requiring rescue 
medication over a 7-day period c compared with the average during baseline, and/or ≥6 
out of previous 7 nights with awakenings due to asthma requiring rescue medication (this 
criterion should be met on 2 consecutive days)
5
An increase in total asthma symptom score (the sum of single-item global assessment of 
day time symptoms [evening assessment] and night time symptoms [morning 
assessment]) of at least 2 units above the baseline average or the highest possible score 
(daily score of 6), on at least 2 consecutive days
When an alert is triggered as a result of the 2-consecutive day rule, the alert will be reset following activation 
such that alerts cannot be triggered on consecutive days.
a
An alert in itself will not qualify as a clinically significant exacerbation and the site should follow up with the 
subject as appropriate.
b
Baseline values for alerts will be calculated from the most recent 7 days of available data prior to visit 2 for the 
optimization phase and prior to randomization visit 6 for the treatment period.
c
Number of nights with awakenings due to asthma requiring rescue medication will be counted from most 
recent 7 days of available data.  
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the investigator will have to justify the decision for defining the event 
as an exacerbation and record it in the eCRF. Events that are not supported by any objective 
assessment will be deemed not to be a protocol-defined exacerbation.
For the protocol, the start of an exacerbation is defined as the start date of additional systemic 
corticosteroids or of a temporary increase in a stable OCS background dose, date of ER or urgent 
care visits requiring additional systemic corticosteroids, or date of hospital admission due to 
asthma, whichever occurs earlier.
The end date of an exacerbation is defined as the last date of additional systemic corticosteroids 
(a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course 
of systemic corticosteroids) or of a temporary increase in a stable OCS background dose, date of 
ER or urgent care visit, or date of hospital discharge, whichever occurs later.

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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 and both should be counted as one and the same exacerbation.
Reasonable attempts should be made by the Investigator to bring the subject into the study site 
for evaluation of a diary alert or subject initiated contact due to asthma worsening, particularly 
when it results in additional treatment being prescribed. Study site evaluations for asthma 
worsening may occur as an unscheduled (UNS) visit or as part of an ordinary site visit if the 
worsening happens to be coincident with a scheduled visit window. A copy of the medical record 
should be obtained for exacerbations evaluated and treated at non-study sites (e.g., by the 
primary care HCP or at an ER/hospital) and details entered into the specific eCRF (EXACATE) 
module in a timely fashion. Changes in concomitant medication due to exacerbation must be 
recorded in the appropriate module of the eCRF.
8.1.2.1
Exacerbation management during the run-in period
Subjects who experience an asthma exacerbation during the run-in period may remain in the 
study. After the treatment of exacerbation, the subject should preferentially be placed on an OCS 
dose one step (or more if considered necessary by the investigator) higher than the dose they 
were on when the exacerbation occurred, unless the judgment of the investigator is to maintain 
the subject on their current dose of OCS. They should be on a stable OCS dose for a period of 2-
weeks before beginning the optimization phase.
8.1.2.2
Exacerbation management during the optimization phase
If a subject experiences an asthma exacerbation during optimization phase, OCS dose reduction 
should stop. After the treatment of exacerbation, the subject should preferentially be placed on an 
OCS dose one step (or more if considered necessary by the investigator) higher than the dose 
they were on when the exacerbation occurred, unless the judgment of the investigator is to 
maintain the subject on their current dose of OCS. The optimization phase could be extended to 
allow for the subject to be on a stable OCS dose for 2 weeks prior to randomization.
8.1.2.3
Exacerbation management during the treatment period
Those who experience an exacerbation after randomization may remain on the IP at the 
Investigator’s discretion. 
Induction phase
If a subject experiences an exacerbation during the induction phase, start of OCS dose reductions 
may be delayed. After the OCS bolus/burst to treat an exacerbation is complete, the subject may 
be returned to one step (or more if considered necessary by the investigator) higher than the OCS 
dose they were on when the exacerbation occurred or the investigator may decide to maintain the 
same OCS dose. 
The subject’s OCS dose should be stable for at least two weeks before entering the OCS dose 
reduction phase. 
Reduction phase
If a subject experiences an exacerbation during the reduction phase, after the OCS bolus/burst is 

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complete, the subject may be returned to one step (or more if considered necessary by the 
investigator) higher than the OCS dose they were on when the exacerbation occurred or the 
investigator may decide to maintain the same OCS dose and kept stable for at least two weeks. 
Further dose reductions during the reduction phase can be considered in the opinion of the 
Investigator. However, no further dose reductions should be performed after week 36. 
Maintenance phase
If a subject experiences an exacerbation during the maintenance phase, after the OCS bolus/burst 
is complete, the subject may be returned to one step (or more if considered necessary by the 
investigator) higher than the OCS dose they were on when the exacerbation occurred or the 
investigator may decide to maintain the same OCS dose throughout the maintenance phase.
8.1.3
Spirometry
8.1.3.1
General requirements
Lung function (FEV1 and forced vital capacity [FVC]) will be measured by spirometry at the 
study site using equipment provided by a central vendor. Spirometry will be performed by the 
Investigator or authorized delegate according to ATS/ERS guidelines (Miller et al 2005).
The vendor providing central spirometry services will be responsible for assuring that the 
spirometer used by each site meets ATS/ERS recommendations, and that the study site personnel 
who will be performing the testing are properly certified. Spirometry calibration will be detailed 
in a separate spirometry procedure manual.
Subjects should be instructed to follow the required restrictions for performing spirometry as 
described in sections 5.3 and Table 6. If the required restrictions have not been adhered to, the 
investigator should reschedule the visit to the earliest opportunity within the allowed visit 
window.
Spirometry testing must be performed according to the schedule provided in SoA. All post-
randomization spirometry assessments should be performed within ± 1.5 hours of the time that 
the baseline Pre-BD spirometry was performed. 
8.1.3.2
Spirometry technique
Detailed procedure for performing spirometry will be described in a separate instruction manual. 
Details regarding assessment of the quality of spirometry and the best test report (BTR) process 
will also be detailed in the manual. A signed and dated copy of the spirogram printout must be 
kept at the study site for source data verification. 
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the predicted 
normal values (PNV) and are pre-programmed into the spirometer (Quanjer et al 2012). 
FEV1, expressed as percent of the PNV, will be calculated as follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100

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8.1.3.3
Post-BD spirometry and FEV1 reversibility assessment
Post-BD spirometry procedures will be performed according to the SoA and will be described in 
a separate spirometry procedure manual. Bronchodilatation can be induced using albuterol (90 
μg metered dose) or salbutamol (100 μg metered dose) up to a maximum of 4 inhalations. In rare 
cases where a subject has an adverse or allergic reaction to albuterol/salbutamol, levalbuterol (45 
μg metered dose; up to a maximum of 4 inhalations) can be used. Levalbuterol will not be 
supplied by the sponsor. It is highly recommended to use a spacer device for this procedure. 
Nebulizer should not be used. A lower total dose (e.g., 2 inhalations instead of 4 puffs), can be 
used if there is a concern about any effect on the subject’s heart rate, tremor or safety; the reason 
should be noted in the subject’s medical record. 
If FEV1 reversibility has not been documented in the previous 12 months prior to or at visit 1, 
further assessments to meet the reversibility criteria may be performed at visit 2. It is acceptable 
to stop further reversibility assessments once the criteria for reversibility are met.
The highest pre- and post-BD FEV1 will be used to determine reversibility.
Reversibility is calculated as follows:
% Reversibility = (post-BD FEV1- pre-BD FEV1) × 100/pre-BD FEV1
8.1.4
Home PEF testing
An electronic, hand-held spirometer (AM3G+™) to measure PEF (ePEF meter) will be provided 
to the subject at visit 1.
Subjects will be trained on at-home use of the ePEF meter at visit 1. Training will include 
explanation of device functionality and proper use of the ePEF meter. 
Home PEF testing will be performed by the subject in the morning upon awakening (and prior to 
taking their AM asthma controller) and in the evening at bedtime (and prior to taking their PM 
asthma controller). Recording of home PEF should start from the evening of visit 1 until the 
morning of visit 18 (week 48). When possible, ambulatory lung function measurements should 
be taken at least 6 hours after the last dose of SABA rescue medication.
Subjects should perform 3 successive peak flow manoeuvres while sitting or standing, but in the 
same position at every testing.
The Investigator/authorized delegate will check subject’s adherence to use of the PEF meter as 
shown in SoA.
8.1.5
Fractional exhaled nitric oxide (FENO)
Airway inflammation will be evaluated using a standardized single-breath FENO test in 
accordance with the SoA. The single exhalation technique recommended by the manufacturer 
will be followed (Alving et al 2017).

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Subjects will be asked whether they have had a respiratory infection in the 2 weeks prior to 
measurement. The FENO measurements will not be performed within 2 weeks of a respiratory 
infection. The FENO test will be performed prior to spirometry. Subjects should not eat or drink 
1 hour prior to having the FENO test. Subjects should not use their rescue SABA medication 
(e.g., albuterol/salbutamol) within 6 hours of the measurement. Inhaled BDs (including ICS-
LABA) should be withheld for the effect duration specific to the BD as described in the 
spirometry section. If not, the assessment should be postponed till after the required time has 
passed since the meal or drink or the visit must 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 users’ 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. 
All FENO measurements will be blinded for sites, subjects and sponsor throughout the study. 
All post-randomization FENO assessments should be performed within ± 1.5 hours of the time 
that the randomization FENO was performed.
8.1.6
Patient reported outcomes
Patient reported outcomes (PRO) data will be captured electronically using a handheld device 
(eDiary). Site personnel will be trained on using the eDiary. Detailed procedures for using 
eDiary and training the subjects will be described in a separate instruction manual. Subjects will 
be trained on at-home use of the eDiary at visit 1. Training will include explanation of device 
functionality and its proper use. The subject will also be asked to verify completion of training 
on the eDiary. The site staff will set assessment reminder alarms on the device. At-home PRO 
assessment will start the evening of visit 1 and continue thereafter at every morning and evening 
until study completion as per the SoA. Subjects will be asked to bring the device back at each 
study visit. At site PRO questionnaires should be completed prior to any other assessments. The 
Investigator/authorized delegate will check subject’s adherence to the completing PRO at each 
visit and even in between as shown in SoA.
8.1.6.1
Asthma Daily Diary
The daily diary will be completed each day from the evening of visit 1 to the morning of visit 18. 
The morning eDiary will include: Asthma Symptom Diary (ASD) morning items, questions 
about rescue medication, night time awakening, and use of maintenance medications. The 
evening eDiary will include: ASD evening items and questions about rescue medications. Upon 
completion of the morning and evening questions the subject will complete the peak expiratory 
flow assessment.
There will be triggers in the eDiary to alert the subjects to signs of worsening of asthma and to 
contact their physician, please refer to Table 11. The subject should contact the investigator (or 
vice versa) for evaluation after receiving a diary alert. 

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Asthma Symptom Diary
Asthma symptoms will be recorded using the ASD (Globe et al 2015). The ASD comprises 10 
items (5 items in the morning; 5 items in the evening). The morning items assess night time 
symptom severity in relation to wheezing, shortness of breath, cough, and chest tightness, and 
the frequency of night time awakening. The evening items assess symptom severity in relation to 
wheezing, shortness of breath, cough, and chest tightness, and activity limitation since waking. 
Items are scored from “0” (no symptom, no night time awakening, or no activity limitation) to 
“4” (very severe symptom, unable to sleep, or extreme activity limitation). A daily ASD score is 
the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD 
score; otherwise, it is treated as missing. Calculation of a daily ASD score requires data from the 
evening diary assessment and the subsequent morning diary assessment. For the 7-day average 
asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 
daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 
4.
Global asthma symptom items
In addition to the ASD, subjects will complete a single-item global assessment of asthma 
symptoms (0-3) each morning and evening. The sum of evening and subsequent morning single 
global item scores (0-6) will be used for the alerts system.
Rescue medication
The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be 
recorded by the subject in the eDiary twice daily (i.e., in the morning and evening) beginning the 
evening of visit 1 until the morning of visit 18. The number of inhalations taken between the 
morning and evening lung function assessments will be recorded in the evening. The number of 
inhalations taken between the evening and the morning will be recorded in the morning. 
Night time awakenings
Night time awakenings due to asthma symptoms will be recorded by the subject in the eDiary 
each morning, beginning in the morning after visit 1 until the morning of visit 18, by answering 
the question whether he/she woke up during the night due to asthma symptoms with a “yes” or 
“no” response.
Maintenance medication
Maintenance medication compliance will be recorded in the eDiary once daily in the morning, 
beginning in the morning after visit 1 until the morning of Visit 18. There will be separate 
questions for checking compliance with OCS. 
8.1.6.2
Asthma Control Questionnaire (ACQ-6)
The ACQ-6 captures asthma symptoms (night-time waking, symptoms on waking, activity 
limitation, shortness of breath, wheezing) and short-acting β2-agonist use via subject-report.

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Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤ 0.75 
indicate well-controlled asthma, scores between 0.75 and <1.5 indicate partly controlled asthma, 
and a score ≥1.5 indicates uncontrolled asthma (Juniper et al 2006). Individual changes of at 
least 0.5 are considered to be clinically meaningful and a decrease of at least 0.5 is the responder 
definition for ACQ-6. 
ACQ-6 will be completed at the beginning of site visits using eDiary in accordance with the 
SoA. For IPD subjects ACQ-6 can be completed at home as well.
8.1.6.3
Standardised asthma quality of life questionnaire for 12 years and older 
(AQLQ(S)+12)
The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced 
by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity 
limitations, emotional function, and environmental stimuli). Patients are asked to recall their 
experiences during the previous 2 weeks and to score each of the questions on a 7-point scale 
ranging from 7 (no impairment) to 1 (severe impairment). The overall score is calculated as the 
mean response to all questions. The 4 individual domain scores (symptoms, activity limitations, 
emotional function, and environmental stimuli) are the means of the responses to the questions in 
each of the domains. The responder definition for AQLQ(s)+12 is 0.5-point improvement from 
baseline. 
The AQLQ(s)+12 will be completed at the beginning of site visits using eDiary in accordance 
with the SoA. For IPD subjects AQLQ(S)+12 can be completed at home as well. 
8.1.6.4
St George’s respiratory questionnaire (SGRQ)
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 2 parts: part 1 
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 3 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. Based on empirical data and interviews with patients, a mean change score of 4 
units is associated with a minimum clinically important difference (MCID). Specific details on 
the scoring algorithms are provided by the developer in a user manual (Jones et al 2009).
SGRQ will be completed at the beginning of site visit using eDiary in accordance with the SoA.
8.1.6.5
European quality of life-5 dimensions-5 levels (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty.

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The subject will be asked to indicate his/her current health state by selecting the most
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual
analogue scale, where the subject will be asked to rate current health status on a scale of 0-
100, with 0 being the worst imaginable health state.
The EQ-5D-5L will be completed using eDiary in accordance with the SoA.
8.1.6.6
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ)
The WPAI+CIQ consists of questions about how asthma and asthma related issues impact
a subject’s ability to work, attend classes, and perform regular daily activities. The questionnaire 
relates to the subject’s experience over the previous 7 days. The WPAI+CIQ will be used to 
measure self-reported productivity loss. 
WPAI+CIQ will be completed at the beginning of site visits using eDiary in accordance with the 
SoA. For IPD subjects WPAI + CIQ can be completed at home as well. 
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical safety laboratory assessments
See Table 12 for the list of clinical safety laboratory tests to be performed and to the SoA for the 
timing and frequency. All protocol-required laboratory assessments (including serology, 
pregnancy and FSH test), must be conducted in accordance with the laboratory manual and the 
SoA. Subjects should be fasting for at least 12 hours prior to blood collection.  
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at site as 
source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will be 
recorded on the appropriate CRF.
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory. 

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Table 12
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S-Alkaline phosphatase (ALP)
B-Leukocyte count
S-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen
B-Mean corpuscular volume
S-Calcium, total
B-Red blood cell (RBC) count
S-Chloride
B-HbA1C
S-Creatinine
S-Creatinine kinase (CK)
Urinalysis (dipstick)
S-C Reactive Protein (CRP)
U-Hb/Erythrocytes/Blood 
S-Gamma-glutamyl transpeptidase (GGT)
U-Protein/Albumin 
S-Glucose
U-Glucose
S-Phosphorus
S-Potassium
S-Sodium
U-Microscopy and culture as required*
S-Total cholesterol
S-Low density lipoprotein (LDL)
S-Uric acid
*Urine samples will be first analysed locally using dipstick and sent to the central laboratory only for analysis 
when a positive dipstick result for any parameter is observed
NB. In case a subject shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to 0 ‘Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law’, for further instructions.
8.2.2
Weight and height
Weight and height will be measured in accordance with the SoA. The subject’s weight will be 
recorded in kilograms, and height will be recorded in centimetres. Weight and height 
measurements will be performed in light clothing and with shoes off.
8.2.3
Physical examinations
A complete physical examination will be performed and include an assessment of the following: 
general appearance, respiratory, cardiovascular, abdomen skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and extremities) 
and neurological systems. Brief physical examination will also be performed and include an 
assessment of the general appearance, abdomen, cardiovascular and respiratory system. For the 

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brief physical examination only, information on whether the assessment was performed or not 
will be recorded.
Physical examination (complete and brief) will be performed at timelines as specified in the 
SoA, Investigators should pay special attention to clinical signs related to previous serious 
illnesses, new or worsening abnormalities may qualify as adverse events, see section 8.3.7 for 
details.
8.2.4
Vital signs
Vital signs (i.e. pulse, blood pressure, respiration rate and body temperature) will be obtained in 
accordance with SoA. 
Vital signs will be taken prior to blood drawing, IP administration and, if possible, usual asthma 
controller medication. Subjects should be observed for a minimum of 2 hours after 
administration of the first two IP doses for the appearance of any acute drug reactions. For the 
remaining doses, subjects will be observed for a minimum of 1 hour after IP administration for 
any such reaction.
Blood pressure and pulse measurements will be assessed in a sitting position with a completely 
automated device. Manual techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
subject in a quiet setting without distractions (e.g., television, cell phones). 
Pulse rate will be obtained before blood pressure, if the manual measurement technique is used.
Respiration rate will be obtained after subject has been resting for at least 5 minutes, by counting 
number of breaths (i.e., how many times the chest rises) for one minute.
Body temperature will be measured prior to IP administration, in accordance with local 
standards.
8.2.5
Electrocardiograms
A 12-lead ECG will be taken in supine position after resting for at least 15 minutes, prior to 
blood draw, FeNO, spirometry, BD administration and IP administration. 
The investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the investigator's interpretation and that provided by the ECG machine (if applicable), 
the investigator's interpretation will take precedence and should be noted on the printout and 
recorded in the eCRF.  A copy of the ECG will be produced and quality checked and kept in case 
of further need for re-evaluation.
It is highly recommended that the same machine is used for assessment throughout the subject’s 
participation in the study.

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8.2.6
Glucocorticoid toxicity index
Glucocorticoid Toxicity Index (GTI) will be assessed as described by Miloslavsky et al 2016
(see Appendix H for details). The composite GTI captures common glucocorticoid (GC) 
toxicities that are sensitive to differing cumulative GC doses over the period of a typical clinical 
trial (6 months to 3 years). The individual items within the GTI are weighted relative to each 
other for severity, and the instrument has the capability of measuring not only worsening of GC 
toxicity over baseline, but also improvement.
The composite GTI measures change in GC toxicity rather than absolute GC toxicity in order to 
account for the effects of prior GC therapy. Scoring should be performed as per SoA, using  the 
randomisation assessment as the baseline. The GTI items were ranked in order of severity within 
each domain.  The relative weights for each toxicity item were derived using multicriteria 
decision analysis (MCDA).  MCDA has been used for the creation of multiple classification 
criteria sets in a variety of inflammatory diseases, including rheumatoid arthritis (Neogi T et al 
2010), systemic sclerosis (Johnson SR et al 2014), systemic lupus erythematosus (Tedeschi SK 
et al 2017). IgG4-Related Disease classification criteria is presently under development (JH 
Stone; personal communication).
The composite GTI will be assessed at the timepoints given in the SoA. The following items will 
be assessed: BMI, glucose tolerance (HbA1c), blood pressure, LDL, steroid myopathy, skin 
toxicity, neuropsychiatric toxicity and Infection.
8.3
Collection of adverse events
The Investigator 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 0.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs see 
section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events including SAEs will be collected from time of signature of informed consent 
form throughout the treatment period and including the follow-up periods.

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All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in 0. The investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, if 
the investigator learns of any SAE, including a death, at any time after a subject’s last visit and 
he/she considers the event to be reasonably related to the Study treatment or study participation, 
the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in 0.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAE/non-serious AEs/AEs of special interest, will be followed 
until resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up. 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF. AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
8.3.4
Adverse event data collection
'The following variables will be collected for each AE;

AE (verbatim)

The date when the AE started and stopped

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

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

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
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'
8.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B 7 to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study site staff: Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected and recorded in the CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values or vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).

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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, see section 8.3.10.
8.3.8
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an event of scientific and medical interest towards 
improving the understanding of the investigational product. An AESI may be serious or non-
serious. For this study, AESIs include:

Anaphylactic reactions 

Immune complex disease (Type III hypersensitivity reactions)

Malignancy

Helminth infections 

Severe infections which are defined as:

SAEs or

Requiring treatment with systemic antiviral medications, intravenous antibiotics 
or medications for helminth parasitic infection or

Requiring a permanent discontinuation of study drug

Injection site reactions 

Opportunistic infections

Guillain Barre Syndrome

Adrenal crisis
8.3.9
Hy’s law
Cases where a subject shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to be 
reported as SAEs. Please refer to 0 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
8.3.10
Disease under study
Symptoms of the disease under study
Asthma symptoms or signs, such as, wheeze, cough, chest tightness, dyspnoea, breathlessness 
and phlegm, will be recorded as AEs when:

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
the sign or symptom is serious according to definitions, see 0

the subject discontinues IP   due to the sign or symptom, and/or

the sign or symptom is new to the subject or not consistent with the subject’s pre-existing 
asthma history (defined as within 1 year of visit 1) as judged by the Investigator
Asthma exacerbations should not be recorded as AEs, unless it fulfils any of the above criteria.  
All asthma exacerbations should be recorded in the EXACATE module as per Section 8.1.2.
If a subject discontinues IP due to a study specific discontinuation criterion, this should always 
be recorded as ’Development of study specific withdrawal’ on the Discontinuation of 
Investigational Product eCRF. In addition, the Investigator must assess whether the asthma 
deterioration should also be reported as an AE leading to discontinuation of IP (DAE)/AE 
leading to withdrawal from study on the AE form.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs must be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within one day i.e., immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE within 
one calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 
of it.
Once the Investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative.
If the eCRF system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
Investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative.

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For further guidance on the definition of a SAE, see 0 of the Clinical Study Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study subject has received any study drug. If a pregnancy is 
reported, the investigator should inform the sponsor within 24 hours of learning of the 
pregnancy. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a contraceptive 
medication. Congenital abnormalities/birth defects and spontaneous miscarriages should be 
reported and handled as SAEs. Elective abortions without complications should not be handled 
as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented even 
if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used to 
report the outcome of the pregnancy.
8.4.2.2
Paternal exposure
Pregnancy of the subject’s partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) should be followed up and documented in the Pregnancy Report Form 
for conceptions occurring from the date of the first administration of IP until 16 weeks (5 half-
lives) after the last administration of IP. Consent from the partner must be obtained before the 
Pregnancy Report Form is completed. 

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8.4.3
Overdose
For this study, any dose greater than 280 mg within a 2-week period will be considered an 
overdose. There is currently no specific treatment in the event of overdose of IP, and possible 
symptom of overdose are not established. 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant AE 
modules in the CRF and on the Overdose CRF module. An overdose without associated 
symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 8.4.1.  
For other overdoses, reporting must occur within 30 days.
8.4.4
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 1 day i.e., immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow up Fatal/Life-
Threatening) or 5 (other serious initial and follow up) calendar days if there is an SAE associated 
with the medication error (see Section 8.4.1) and within 30 days for all other medication errors.
The definition of a Medication Error can be found in Appendix B 8.
8.4.5
Management of IP-related toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as well 
as medical equipment to treat acute anaphylactic reactions must be immediately available when 
IP is being administered. Study site personnel must be trained to recognize and treat anaphylaxis. 
Details on anaphylaxis management are provided in Appendix G.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios:
1.
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue or both and at least one of the following: a) respiratory compromise; or b) 
reduced blood pressure or symptoms of end-organ dysfunction. 

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2.
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms.
3.
Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration. At visits 6 and 7, subjects should be observed for a minimum of 2 hours after IP 
administration for the appearance of any acute drug reactions. For the remaining visits involving 
IP administration, subjects will be observed for a minimum of 1 hour after IP administration for 
any such reaction.
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for analysis 
of serum tryptase. The sample will be tested at the local lab or central lab where applicable.
8.4.6
Independent adjudication committee
An independent adjudication committee will provide an external independent assessment of 
blinded data to confirm the diagnosis of MACE (to be defined in the charter) and investigator 
reported malignancies that occur from randomization up to the end of the follow-up period. The 
committee, will also evaluate cases of ER or urgent care visits and hospitalizations that occur 
from randomization up to the end of treatment period, as well as all deaths, that occur from 
randomization until the end of the follow-up period to confirm that any such event is due to a 
worsening of asthma. The committee will operate in accordance with dedicated adjudication 
committee charter/manual of operations.
8.4.7
Data safety monitoring board (DSMB)
DSMB is an independent expert advisory group commissioned and charged with the 
responsibility of assessing safety aspects in the study. The DSMB will evaluate cumulative 
safety and other clinical trial data at regular intervals and make appropriate recommendations 
based on the available data. The DSMB will function independently of all other individuals 
associated with the conduct of the studies, including the study sponsor, AstraZeneca. The 
committee will operate in accordance with a DSMB charter.
The DSMB will have access to the individual treatment codes and will be able to merge these 
with the collected study data while the study is ongoing if and as required. The personnel 
involved in the clinical study at AstraZeneca will remain blinded to these analyses and will have 
no knowledge of the results presented to the DSMB.
8.5
Pharmacokinetics
8.5.1
Collection of samples and drug concentration
Serum samples for determination of tezepelumab will be collected pre-dose according to SoA, 
Table 2. Samples will be collected, labelled, stored, and shipped as detailed in the laboratory 
manual. Samples for determination of tezepelumab concentration in serum will be analysed by a 
designated third party on behalf of AstraZeneca using a validated bioanalytical method. Details 

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of the analytical method used will be described in a bioanalytical report. Full details of the 
analytical method used will be described in a separate bioanalytical validation report.
8.5.2
Collection of sample to measure for the presence of ADAs
The presence of Anti-drug antibodies (ADAs) will be assessed in serum samples according to the 
SoA, Table 2. Samples will be measured for the presence of ADAs and ADA-neutralizing 
antibodies for tezepelumab using validated assays. Samples with confirmed ADAs positive will 
be analysed for the presence of ADA-neutralizing antibodies.
8.5.3
Storage and destruction of pharmacokinetic/ADA samples
The PK and ADA samples will be retained for future use at AstraZeneca or designee for a 
maximum of 15 years following Last Subject’s Last Visit.
Pharmacokinetic and ADA samples may be disposed of or destroyed and anonymised by 
pooling. Additional analyses may be conducted on the anonymised, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the Clinical Study Report (CSR).
8.6
Pharmacodynamics
Pharmacodynamic parameters will be evaluated using biomarkers (section 8.8) 
8.7
Genetics  
8.7.1
Optional exploratory genetic sample
Whole blood will be collected from subjects that have been randomized into the study for 
extraction of DNA and genetic analyses including but not limited to genetic polymorphisms, 
epigenetic modifications and the microbiome associated with asthma, TSLP or response to 
tezepelumab.
Approximately 35 mL blood sample for DNA isolation will be collected from subjects who have 
consented to participate in the genetic analysis component of the study as per Table in SoA.  
Participation is optional. Subjects who do not wish to participate in the genetic research may still 
participate in the study.
See 0 for Information regarding genetic research. Details on processes for collection and 
shipment and destruction of these samples can be found in 0 or in the Laboratory Manual.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality. Samples may be stored for a maximum of 15 years or as per 
local regulations from the date of the Last Subject’s Last Visit, after which they will be 
destroyed. DNA is a finite resource that may be used up during analyses. The results of any 
further analyses will be reported either in the CSR itself or as an addendum, or separately in a 
scientific report or publication.

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No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
Biomarker analysis may include (but not limited to) serum biomarkers, analysis of blood 
eosinophils, FENO (section 8.1.4), IgE (FEIA), total IgE (section 8.8.2) and transcriptomics 
(section 8.8.3). 
Biomarker analysis will be performed to evaluate the pharmacology of tezepelumab and to 
evaluate changes in biomarkers related to asthma, Th2 high and Th2 low inflammation, TSLP 
pathway and various phases of OCS dose reduction. Biomarkers will also be used to explore for 
potential predictive biomarkers of response or exposure to tezepelumab.
Serum samples for biomarker analysis will be collected according to the schedule in Table 2. 
Specific serum biomarkers that may be analyzed are cytokines, chemokines and inflammatory 
mediators associated with asthma and the TSLP pathway, including but not limited to TSLP, IL-
33 and TARC.
Instructions for sample collection, processing, storage, and shipment can be found in a separate 
laboratory manual provided to the centers.
8.8.1
Storage, re-use and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the date of the Last Subject’s Last Visit, 
after which they will be disposed of or destroyed and anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled pharmacodynamic samples to further 
evaluate pharmacology of tezepelumab. The results of this biomarker research will not be 
reported in the CSR but in an addendum, or separately in a scientific report or publication. The 
results of this biomarker research may be pooled with biomarker data from other studies with the 
study drug to generate hypotheses to be tested in future research.
8.8.2
Serum immunoglobulins
The levels of total IgE, IgA, IgG and IgM (nephelometry/chemiluminescence) and seasonal and 
perennial allergen specific IgE (ImmunoCAP; FEIA) will be tested by a central laboratory in 
accordance with SoA. Instruction for sample collection, processing, storage and shipment will be 
provided in a separate laboratory manual.
8.8.3
Transcriptomics
Whole blood samples will be collected in PAXgene blood RNA tubes for ribonucleic acid 
(RNA) sample preparation in accordance with SoA. RNA may be used in the analyses of host 
gene expression and microbiome research using quantitative methods that may include but not be 
limited to RNA microarrays, RNA Seq and quantitative reverse-transcriptase polymerase chain 
reaction technologies and stored for future analyses. Instruction for sample collection, 
processing, storage and shipment will be provided in a separate laboratory manual.

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8.9
Healthcare Resource Utilization and Health Economics
Healthcare resource utilization (HRU) and health economics data, associated with medical 
encounters, will be collected in the CRF by the investigator and study-site personnel for all 
subjects throughout the study. At randomization, HRU information will be collected with a ‘one 
year’ recall period. All the subsequent visits will collect HRU information with a recall period of 
‘since the last scheduled visit’. The data may be used as input to health economic analysis for 
example cost utility analysis or cost effectiveness analysis. Protocol-mandated procedures, tests, 
and encounters are excluded. Any results from such analyses may be reported separately from
the Clinical Study Report (CSR).  
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The following two-sided hypotheses will be evaluated in this trial at the 0.05 significance level. 
All other hypothesis testing in this study will be considered exploratory.
Primary endpoint
H01: Cumulative odds ratio of percentage reduction category from baseline in daily OCS dose at 
48 weeks whilst not losing asthma control (tezepelumab/placebo) = 1
versus
H11: Cumulative odds ratio of percentage reduction category from baseline in daily OCS dose at 
48 weeks whilst not losing asthma control (tezepelumab/placebo) ≠ 1.
For 5 ordered categories, there are 4 possible cumulative odds for each treatment group, 
corresponding to the 4 different possible binary splits, which are defined as follows:
•
Category 1 versus categories (2,3,4,5)
•
Categories (1,2) versus categories (3,4,5)
•
Categories (1,2,3) versus categories (4,5)
•
Categories (1,2,3,4) versus category 5,
where the ordered categories for OCS daily dose reduction are in turn defined as:
•
Category 1: 90% - 100% reduction
•
Category 2: 75% - <90% reduction
•
Category 3: 50% - <75% reduction
•
Category 4: >0% - <50% reduction

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•
Category 5: no reduction or an increase.
The above hypothesis assumes that the 4 possible odds ratios between the 2 treatments as defined 
above are the same (this is the proportional odds assumption).   
The direction of superiority of tezepelumab is indicated by an odds ratio greater than 1.
Key secondary endpoints
H02: AAER ratio over 48 weeks (tezepelumab/placebo) = 1
versus
H12: AAER ratio over 48 weeks (tezepelumab/placebo) ≠ 1
The direction of superiority of tezepelumab is indicated by a rate ratio less than 1.
9.2
Sample size determination 
Approximately 152 subjects will be randomly assigned to study treatment using 1:1 allocation 
between the two treatments. Since the primary analysis of the primary endpoint will include all 
randomised subjects as far as possible, no need is envisaged to adjust the number of subjects 
planned to be randomised in order to obtain a number of evaluable subjects.
With 76 subjects per treatment group it is estimated that, using a 2-sided 5% significance level, 
the power to reject the null hypothesis for the primary endpoint will be at least 90%, assuming:
•
An odds ratio of 2.75 and the proportional odds assumption (see Section 9.1)
•
The proportion of subjects in the 5 different dose reduction categories is similar to what 
was observed in the Steroid Reduction with mepolizumab Study (SIRIUS) (Bel et al 2014). The 
following proportions have been assumed for placebo:

Category 1 (90% - 100% reduction): 10% of subjects

Category 2 (75% - <90% reduction): 10% of subjects

Category 3 (50% - <75% reduction): 15% of subjects

Category 4 (>0% - <50% reduction): 15% of subjects

Category 5 (no reduction or an increase): 50% of subjects
The minimal detectable odds ratio still being significant with the above assumptions is 1.86.
For the key secondary endpoint, 76 subjects per group has >80%  power to reject the null 
hypothesis for rate ratios up to 0.39, using a 2-sided 5% significance level, and assuming:

A placebo rate of 1.3 exacerbations/year in this study population

A conservative assumption on the dispersion parameter (2.4)

Uniform dropout of 10%

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9.3
Populations for analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign the ICF
Randomly Assigned to Study 
treatment
All subjects randomised to study treatment (irrespective of whether 
treatment is subsequently taken)
Full Analysis Set
All subjects randomised to study treatment who received at least one 
dose of IP, irrespective of their protocol adherence and continued 
participation in the study.
Safety Analysis Set
All subjects who received at least one dose of IP.
Pharmacokinetic analysis set 
(PK)
All subjects in the full analysis set who received tezepelumab; 
including PK blood samples that are assumed not to be affected by 
factors such as protocol deviations (e.g. disallowed medication or 
incorrect study medication received).
For analysis of efficacy variables, subjects will be assigned to the full analysis set (defined 
above) according to their randomized treatment.
Safety presentations and anti-drug antibodies (ADA) presentations will be based on the safety 
analysis set, with subjects assigned according to their actual treatment. Further details of how 
actual treatment will be determined for analysis in the event of treatment dispensing errors etc. 
will be specified in the SAP. Any important deviations from the randomized treatment 
assignment, and any subjects that have received investigational product without being 
randomized will be listed and considered when interpreting the safety data. 
All PK summaries will be based on the PK analysis set.
9.4
Statistical analyses
There will be two DBLs in this study. The primary DBL will be conducted after last subject 
completes Week 48, and the final DBL will be conducted once all patients have completed the 
last safety follow-up visit (Week 60). All analyses of the primary and secondary objectives will 
be performed based on the primary DBL data. Following the primary DBL, data summaries 
created will be presented as an addendum to the CSR.
All personnel involved with the analysis and conduct of the study will remain blinded until 
primary database lock and important protocol deviations identified. 
After primary database lock, treatment allocation for subjects will become known to the Sponsor 
staff and/or designated CRO. The blind will be maintained for the Investigator, investigational 
site staff, and for the subject.

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Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalised before primary database lock and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. 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 clinical 
study report.
Frequency and percentages of subject disposition and reasons for discontinuation of IP will be 
presented. Subjects who prematurely discontinue the IP will be listed along with the reason for 
discontinuation. In addition, frequency and percentages of withdrawal from the study together 
with reasons will be presented.
Demographics and subject characteristics will be summarized by treatment group using 
frequency and percentages (for categorical variables) and n, mean, standard deviation, minimum, 
median and maximum (for continuous variables) using the full analysis set.
Relevant medical history/current medical conditions will be summarized by treatment group, 
system organ class and preferred term of the MedDRA dictionary using frequency and 
percentage of subjects for each treatment group.
Prior and concomitant medications, categorized according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system, 
will be summarized by treatment group as frequency and percentage of subjects reporting usage. 
Prior medications are defined as those which stopped before first dose of IP. Concomitant 
medications are defined as those which either started or continued after first dose of IP.
Important protocol deviations will be defined prior to unblinding and summarised by treatment 
group. Subjects will not be excluded from analysis sets on the basis of any important protocol 
deviations. The definitions of each category of important protocol deviation will be fully
specified in the SAP, and may include (but not necessarily limited to): subjects who were 
randomised to study treatment without fulfilling key entry criteria; subjects who received 
prohibited or restricted concomitant medications while on IP, subjects who received the incorrect 
study treatment or study dose at any time during the 48-week double-blind treatment period. 
9.4.1
Multiple testing procedure
To account for multiplicity when testing the primary and the secondary endpoints, the following 
hierarchical testing procedure will be applied, with the hypotheses tested as defined in Section 
9.1:
1. First the null hypothesis H01 will be tested at a 2-sided 5% significance with regard to 
the primary endpoint (percentage reduction category from baseline in daily OCS dose at 
48 weeks whilst not losing asthma control)
2. If H01 is rejected, then the null hypothesis H02 will be tested at a 2-sided 5% 
significance level with regard to the key secondary endpoint (AAER ratio over 48 weeks)

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9.4.2
Definition of baseline
In general, the last measurement at or prior to randomization will serve as the baseline 
measurement. If there is no value at or prior to randomization, then the baseline value will not be 
imputed and will be set to missing.
The baseline OCS dose for the primary and secondary variables related to OCS reduction during 
the reduction and maintenance periods is defined as the most recent prescribed daily dose prior 
to randomization.
For weekly means derived from subject diaries, baseline is defined as the mean of the available 
data in the most recent week prior to randomization. If more than 3 days within that period is 
missing, then the baseline will be considered to be missing. For titration of the OCS dose 
baseline values for optimization phase are calculated from completed eDiary records of a 
minimum of 10 out of 14 days before visit 2. Similarly baseline values for the reduction phase 
will be calculated from a minimum of 10 out of 14 days before randomization visit.
Further details regarding baseline definitions will be provided in the SAP. 
9.4.3
Efficacy analyses
9.4.3.1
Analysis of the primary efficacy endpoint
The primary analysis of the primary efficacy endpoint will quantify the effect of the initially 
randomised treatment, regardless of the treatments that subjects actually received. This analysis 
will therefore include all available data after treatment discontinuation for subjects who continue 
to attend monthly visits either at site or by telephone. Subjects will be encouraged to continue to 
undergo applicable study related visits/procedures for the full 48-week period even after 
premature discontinuation of IP.
The primary endpoint is the percentage reduction from baseline in daily OCS dose at 48 weeks 
whilst not losing asthma control (as per Table 10), by defined categories, where percent change 
from baseline is defined as {(final dose-baseline dose}/baseline dose)*100. Percent change from 
baseline will then be categorized per the categories in Section 3. 
The final OCS dose is defined based on the prescribed dose, expressed as a dose per day, at week 
48. If the subject is on a fixed daily dose, then the OCS dose is defined as that prescribed dose. If 
the subject is on an every other day regimen, then the OCS dose is defined as the average amount 
prescribed to be taken each day. 
Further details on deriving the final OCS dose in specific situations including asthma 
deterioration, discontinuation from study, and premature discontinuation from IP (with different 
options for subject follow up), will be specified in the SAP.
The primary endpoint in the tezepelumab group will be compared to that in the placebo group 
using a proportional odds (ordinal logistic regression) model. This model will be used to perform 
the statistical test specified in Section 9.1, and to estimate the treatment effect and its 95% 
confidence interval. The response variable in the model will be the ordered category number (1-

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5) at Week 48 as defined in Section 9.1. Treatment and region will be included as factors in this 
model. Baseline OCS dose will also be included in the model as a continuous (linear) covariate.
Frequency tables of the number and proportion of subjects in each of the response categories will 
be presented. Cumulative responder (percentage reduction) plots will be presented to aid 
interpretation of the primary analysis. In addition, the number and proportion of subjects with 
final daily oral corticosteroid dose >0 and ≤5 mg, unable to reduce the OCS dose further due to 
adrenal insufficiency will be tabulated.
As further support to the primary analysis, the actual percentage reduction in daily OCS dose at 
Week 48 will be summarized descriptively and compared between treatments using a Wilcoxon 
rank sum test stratified by region (van Elteren test).
The consistency of treatment effect across baseline biomarkers and demographic variables will 
be evaluated descriptively, given the possible limitations of sample size on statistical modelling 
approaches in this trial. Any further requirements for subgroup analysis, and exact definition of 
all relevant categories where needed, will be pre-specified in the SAP.
Sensitivity analyses on the primary endpoint will be performed, and will be fully specified in the 
SAP. These may include, but not necessarily be limited to:
•
Analysis which makes provision for data to be missing-not-at-random (MNAR) and 
which makes different assumptions regarding those subjects who discontinue treatment or study 
prior to 48 weeks
•
The impact of different imputation strategies for the final OCS dose including switching 
to other asthma treatments
•
An investigation into the proportional odds assumption, and if necessary further analyses 
which make fewer restrictions with regards to this assumption and/or analyses using different 
response category definitions 
•
Analysis in which additional factors or covariates are included.
9.4.3.2
Analysis of the key secondary efficacy endpoints
The main analysis of the key secondary endpoint (AAER over 48 weeks) will quantify the effect 
of the initially randomised treatment, regardless of the treatments that subjects actually received. 
This analysis will therefore include all available data after treatment discontinuation. Subjects 
will be encouraged to continue to undergo applicable study related visits/procedures for the full 
48-week period even after premature discontinuation of IP.
AAER in the tezepelumab group will be compared to that seen in the placebo group using a 
negative binomial model. This model will be used to estimate the rate ratio and its 95% 
confidence interval. The response variable in the model will be the number of asthma 
exacerbations experienced by a subject over the 48-week treatment period (or shorter duration if 
not followed up for the full 48 weeks). Treatment, region and history of exacerbations (≤2 or >2 
in previous 12 months) will be included as factors in this model. The logarithm of the time at risk 

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for exacerbation in the study will be used as an offset variable in the model, to adjust for subjects 
having different follow-up times during which the events occur. Time during an exacerbation 
and the 7 days following an exacerbation in which a new exacerbation cannot occur, will not be 
included in the calculation of time at risk for exacerbation. 
Descriptive summaries of the AAER will also be presented.
Sensitivity analyses on the key secondary endpoint will be performed, and will be fully specified 
in the SAP. These may include, but not necessarily be limited to, similar items considered for the 
primary endpoint (where relevant).
Rates for the individual exacerbation criteria (emergency room or urgent care visits due to 
asthma that required systemic corticosteroids, hospitalization due to asthma, or use of systemic 
corticosteroids) will be summarized and analysed similarly.
A sensitivity analysis may be performed where adjudication outcome of the ER or urgent care 
visits, hospitalizations and all deaths will be considered.
9.4.3.3
Analysis of other efficacy endpoints
Binary (responder) endpoints which support the primary objective with regards to OCS dose 
reduction will be summarized using frequency tables. The odds ratio (tezepelumab/placebo) and 
its 95% confidence interval will be estimated for each endpoint from a logistic regression model 
with factors for treatment and region, and baseline OCS dose included as a continuous (linear) 
covariate.
Other binary endpoints will be summarized and analysed similarly; these analyses will be 
adjusted for region and baseline of the corresponding endpoint.
Changes from baseline in continuous variables will generally be analysed using a mixed model 
for repeated measures (MMRM) model for each endpoint. This model will be used to estimate 
the treatment effect at Week 48 and its 95% confidence interval. The response variable in the 
model will be the change from baseline at each scheduled post-randomisation visit up to and 
including Week 48, and irrespective of whether the subject remained on treatment and/or took 
other treatments. Treatment, visit, region and treatment by visit interaction will be included as 
factors in this model. The baseline of the corresponding endpoint will also be included in the 
model as a continuous covariate. Unstructured covariance will be assumed to model the 
relationship between pairs of response variables taken at different visits on the same subject. If 
the MMRM model fails to converge with unstructured covariance, the SAP will pre-specify the 
approach for selecting a simpler covariance structure. The Kenward-Roger approximation to 
estimating the degrees of freedom will be used for tests of fixed effects derived from the MMRM 
model.
Descriptive summaries of continuous endpoints will also be presented. Adjusted means from the 
MMRM model above will be displayed graphically over time.
Time to first asthma exacerbation will be summarised graphically using Kaplan-Meier estimates, 
and analysed using a Cox proportional hazards model with factors for treatment and region.

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9.4.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version in force at each database lock. The definition of on-treatment and on-study for adverse 
event analyses will be given in the SAP.
The number and percentage of subjects with on-treatment and on-study adverse events will be 
tabulated separately by preferred term and system organ class. An event that occurred one or 
more times during a period will contribute 1 observation to the numerator of the proportion. The 
denominator of the proportion will comprise all subjects in the full analysis set. On-treatment 
adverse events will also be summarized by intensity/severity and separately, by 
causality/relatedness (as determined by the investigator). Should a subject report the same 
preferred term/system organ class within multiple intensity/severity or causality/relatedness 
categories, the subject’s worst occurrence (most severe/most related) will be tabulated. Serious 
AEs, AEs leading to discontinuation from IP, and commonly occurring AEs will be summarized 
in a generally similar manner. Adverse events, SAEs, AEs leading to death, and AEs leading to 
discontinuation of IP will be summarized for each treatment group as applicable. 
An overall summary of on-treatment AEs will be presented by treatment group adjusted for 
subject exposure to treatment. 
AEs of Special Interest (AESIs) will also be summarised descriptively by treatment group.
Laboratory data will be summarized by presenting shift tables using normal ranges (baseline to 
most extreme post-baseline value) and by presenting summary statistics of observed and change 
from baseline values (means, medians, quartiles, ranges). The incidence of clinically notable 
laboratory abnormalities will be summarized. 
Vital signs data will be summarized by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital signs abnormalities will be 
summarized.
The composite glucocorticoid toxicity index will be presented descriptively using summary 
statistics.
9.4.5
Other analyses 
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the statistical 
analysis plan finalised before primary database lock.  The population PK analysis and 
pharmacodynamic analyses will be presented separately from the main clinical study report 
(CSR).  
The prevalence and incidence of ADA will be reported by treatment group. ADA data will be 
summarized using descriptive statistics at each visit by treatment group. Samples confirmed 
positive for ADA will be tested for neutralizing antibodies (nAb), and the nAb status will be 
summarized by treatment group. The potential effects of ADA status and ADA titer on 
pharmacokinetics of tezepelumab will be evaluated. The potential association of ADA status, 

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ADA titer, and nAb status with efficacy will be evaluated. The potential association of ADA 
status with safety may be evaluated.
Additional analyses assessing the impact of COVID-19 may be included in the SAP.
9.5
Interim analyses 
No interim analyses are planned in this trial.
9.5.1
Data safety monitoring board (DSMB)
Details regarding DSMB are provided in section 8.4.7.

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10.
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XOLAIR US PI 2016
XOLAIR (omalizumab). Prescribing information. Novartis Pharmaceuticals Corporation, East 
Hanover, NJ, USA; 2016. Available at: 
https://www.gene.com/download/pdf/xolair_prescribing.pdf
Zhou et al 2008
Zhou B, Headley MB, Aye T, Tocker J, Comeau MR, Ziegler SF. Reversal of thymic stromal 
lymphopoietin-induced airway inflammation through inhibition of Th2 responses. J Immunol. 
2008;181:6557-62.
Zhou et al 2005
Zhou B, Comeau MR, De Smedt T, Liggitt HD, Dahl ME, Lewis DB, et al. Thymic stromal 
lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat Immunol. 
2005;10:1047-53.
Zhu and Lakkis 2014
Zhu H, Lakkis H. Sample size calculation for comparing two negative binomial rates. Stat Med 
2014;33(3):376-87
Ziegler et al 2013
Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal 
lymphopoietin (TSLP). Adv Pharmacol. 2013;66:129-55.

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
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 for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., 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 approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.  
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and Human 
Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study.

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A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorised representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorised representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (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 subject was enrolled in the study and the date and time the written consent was obtained.  
The authorised person obtaining the informed consent must also sign the ICF.
Subjects 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 subject or the subject’s legally authorised 
representative.  
If a subject declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the subject and he/she will not be 
excluded from other aspects of the study.
Subjects who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional exploratory research.  The investigator or authorised designee will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. The subject will give a separate agreement to allow any remaining specimens to 
be used for exploratory research. Subjects who decline to participate in this optional research 
will indicate this in the ICF. If a subject withdraws consent to the use of donated biological 
samples, the samples will be disposed of/destroyed, and the action documented. If samples 
already have been analysed at the time of the request, AstraZeneca will not be obliged to destroy 
the results of this research.
During the COVID-19 pandemic, re-consent may be obtained remotely and/or verbally if 
local/regional guidelines allow in order to reduce the risk of subjects of COVID-19 exposure 
during clinic visits. For further details please refer to Appendix K. 
A 4
Data protection
Each subject will be assigned a unique identifier by the sponsor. Any subject records or data sets
transferred to the sponsor will contain only the identifier; subject names or any information 
which would make the subject identifiable will not be transferred.  

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The subject 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 must also be explained to 
the subject.  
The subject 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 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and letters 
to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on other 
websites according to the regulations of the countries in which the main study is conducted.
A 7
Data quality assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects 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 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 

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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 8
Source documents
Source documents provide evidence for the existence of the subject and substantiate the integrity 
of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF 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.
Definitions of what constitutes source data can be found in the monitoring plan.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments.  
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.

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Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject 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 
(e.g.  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
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.

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B 5
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 jeopardize the subject 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. Examples of such events are:

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 (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse

Adrenal crisis
B 6
Intensity rating scale:
1.
mild (awareness of sign or symptom, but easily tolerated)
2.
moderate (discomfort sufficient to cause interference with normal activities)
3.
severe (incapacitating, with inability to perform normal activities)
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 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.

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
Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of effect 
should be classified as no reasonable possibility.
B 8
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.

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Medication error includes situations where an error.  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. 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 e.g. tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - 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) e.g.  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 standard of care medication in 
open label studies, even if an AZ 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 of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca 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 AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire 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 subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Principal Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented

Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action 
documented and the signed document returned to the study site

Ensures that the subject and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.

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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes, the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient

temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.ht
m)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 

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containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity and 
progression of disease. Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease aetiology; and/or molecular subtype of the disease being treated. Therefore, where 
local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis from
consenting subjects.
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. 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.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e. the entire 
genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or 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 tezepelumab continues but no longer than 15 
years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and if 
a subject declines to participate there will be no penalty or loss of benefit. The subject will not be 
excluded from any aspect of the main study.
Inclusion criteria

For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed 
consent for the genetic sampling and analyses.

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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 in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary discontinuation will not 
prejudice further treatment. Procedures for discontinuation are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood samples for genetic research will be obtained from the subjects as per SoA. Although 
DNA is stable, early sample collection is preferred to avoid introducing bias through excluding 
subjects who may withdraw due to an adverse event (AE), such subjects would be important to 
include in any genetic analysis. Samples will be collected, labelled, stored, and shipped as 
detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject confidentiality. Samples will be stored for a maximum of 15 years, from the 
date of last subject last visit, 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 blood 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 subject 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 D.

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Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate in 
the genetic component of the study the subject must sign and date both the consent form for the 
main study and the genetic component of the study. Copies of both signed and dated consent 
forms must be given to the subject and the original filed at the study centre. The Principal 
Investigator(s) is responsible for ensuring that consent is given freely and that the subject 
understands that they may freely discontinue from the genetic aspect of the study at any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, 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 subject. Regulatory authorities may require access to the relevant files, though 
the subject’s medical information and the genetic files would remain physically separate.
Data management
Any genotype 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 subject 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.
Statistical methods and determination of sample size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.

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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 
Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. Specific guidance on 
managing liver abnormalities can be found in Section 7.1 of the Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
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 Adverse Event 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 Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the Investigational Medicinal 
Product (IMP).  
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
Adverse Events (AE) and Serious Adverse Events (SAE) according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of normal 
(ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the 
start of study medication irrespective of an increase in alkaline phosphatase (ALP).  
Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g. elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  

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For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified time frame 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 subject who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Central laboratories being used:
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 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

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section E 2 Definitions within 
this Appendix 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 subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

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
Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 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 subjects 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 subject’s condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study subjects’ follow-up (including any further laboratory testing) 
and the continuous review of data. 

Subsequent to this contact the Investigator will:

Monitor the subject 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 the tests available in the Hy’s law lab kit 
should be used.

Complete the three Liver CRF Modules as information becomes 
available 
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 CRF

If the alternative explanation is an AE/SAE:  update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

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:

Provide 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 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Laboratory tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended when using a central laboratory. For studies using a local laboratory, the list may 
be modified based on clinical judgement. If required, additional assistance on which tests could 
be used to evaluate other potential causes of liver dysfunction consult with the Hepatic Safety 

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Knowledge Group. Any test results need to be recorded.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
IgG, anti-HCV
HCV RNA*
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)**
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
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive 
** Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this list accordingly
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’

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Appendix F
Maintenance therapy equivalence table 
Estimated daily doses for inhaled corticosteroids
Asthma Therapy 
Total Daily Dose (μg/day)
Inhaled Corticosteroid
High
Beclomethasone dipropionate (non HFA)
>1000
Beclomethasone HFA
>400
Ciclesonide 
>320
Triamcinolone acetonide 
>2000
Flunisolide 
>2000
Fluticasone furoate (e.g. Arnuity® Ellipta®)
200
Fluticasone propionate 
>500
Fluticasone propionate HFA
>500
Budesonide
>800
Mometasone furoate 
>440
Inhaled Corticosteroid in ICS/LABA combinationa
High
Beclomethasone dipropionate (e.g. Fostair®)
>400
Fluticasone propionate HFA (e.g. Seretide®, Advair®)
>500
Fluticasone furoate (e.g. Relvar® Ellipta®, Breo® Ellipta®)
184-200
Budesonide, if as delivered dose (e.g. Symbicort®)
>640
Mometasone Furoate (e.g. Dulera®)
>400
a The ICS doses for the ICS/LABA combinations were derived from GINA 2017 and using prescribing information.
Estimated OCS dose therapy equivalence
Oral Corticosteroid
Approximate equivalence dose
Prednisone
10 mg
Prednisolone
10 mg
Cortisone
50 mg
Hydrocortisone
40 mg
Methylprednisolone
8 mg
Triamcinolone
8 mg
Betamethasone
1.2 mg
Dexamethasone
1.5 mg
Deflazacort
12 mg

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

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3.
Reduced BP after exposure to known allergen for that subject (minutes to several hours): 
Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
subject’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-
antibody or antigen-antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness and nephritis is common.
G 3
Signs and Symptoms and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or all 
of the following signs and symptoms occur: 

Diffuse erythema

Pruritus

Urticaria and/or angioedema

Bronchospasm

Laryngeal edema

Hypotension

Cardiac arrhythmias

Feeling of impending doom

Unconsciousness

Shock
Other earlier or concomitant signs and symptoms can include:

Itchy nose, eyes, pharynx, genitalia, palms, and soles

Rhinorrhea

Change in voice

Metallic taste

Nausea, vomiting, diarrhea, abdominal cramps and bloating

Lightheadedness

Headache

Uterine cramps

Generalized warmth
G 4
Management of Acute Anaphylaxis

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Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
(e)
Place subject in recumbent position and elevate lower extremities.
(f)
Establish and maintain airway.
(g)
Administer oxygen.
(h)
Establish venous access.
(i)
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(j)
Consider epinephrine infusion.
(k)
Consider H1 and H2 antihistamines.
(l)
Consider nebulized β2 agonist [e.g. albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(m)
Consider systemic corticosteroids.
(n)
Consider vasopressor (e.g. dopamine).
(o)
Consider glucagon for subject taking b-blocker.
(p)
Consider atropine for symptomatic bradycardia.
(q)
Consider transportation to an emergency department or an intensive care facility.
(r)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A 
statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.

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Appendix H
Glucocorticoid toxicity index
Any untoward medical occurrences captured as part of the GTI assessment should be reported as 
an adverse event. This includes but is not limited to any clinically significant worsening of a 
subject’s pre-existing condition (i.e. worsening of glucose tolerance, etc.).  
Eight domains and 28 items are included in the composite glucocorticoid toxicity index (GTI).
For item weights please see table below. Details for scoring each item is provided at the end of 
the table.  
Adapted from Miloslavsky EM, Naden RP, Bijlsma JWJ, et al. Ann Rheum Dis Published 
Online First:29 July 2016 doi:10.1136/annrheumdis-2016-210002
The Glucocorticoid Toxicity Index (GTI)
Composite GTI
Item weight
BMI

Improvement in BMI
–8

No change in BMI
0

Moderate increase in BMI
21

Major increase in BMI
36
Glucose tolerance

Improvement in glucose tolerance
–8

No change in glucose tolerance
0

Worsening of glucose tolerance 
32

Worsening of glucose tolerance despite treatment
44
Blood pressure

Improvement in blood pressure
−10

No change in blood pressure
0

Worsening hypertension
19

Worsening hypertension despite treatment
44
Lipids

Improvement in lipids
−9

No change in lipids
0

Worsening hyperlipidaemia
10

Worsening hyperlipidaemia despite treatment
30
Steroid myopathy

No steroid myopathy
0

Mild steroid myopathy
9

Moderate steroid myopathy or greater 
63
Skin toxicity

No skin toxicity
0

Mild skin toxicity
8

Moderate skin toxicity or greater 
26
Neuropsychiatric toxicity

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
No neuropsychiatric symptoms 
0

Mild neuropsychiatric symptoms 
11

Moderate neuropsychiatric symptoms or greater
74
Infection

No significant infection
0

Oral/vaginal candidiasis or uncomplicated zoster
19

Grade III infection or greater 
93
Total
−35 to 410
Copyright © 2016-2018. Massachusetts General Hospital. All rights reserved.
1. Body Mass Index (BMI) (compared to baseline)
a.
Improvement in the direction of the normal range by more than 2 BMI units (normal
range = 18.5-24.9 kg/m2)
b. No significant change (BMI remains within +/- 2 BMI units compared with baseline)
OR BMI remains within the normal range 
c.
Moderate increase in BMI (increase by more than 2 but less that 5 BMI units, to above 
the upper limit of normal BMI [24.9 kg/m2])
d. Major increase in BMI (increase by at least 5 but less than 8 BMI units above normal
BMI [24.9 kg/m2])
2. Glucose Tolerance (compared to baseline)
a.
Improvement in glucose tolerance:

HbA1c declined >10% from baseline without medication increase
OR

Decrease in diabetic medication without an increase in HbA1c of >10% or
HbA1c < 5.7%
b. No significant change in glucose tolerance:

HbA1c within 10% of baseline or HbA1c < 5.7% AND no change in medication
OR

HbA1c increased to > 10% of baseline with a decrease in medication
OR

HbA1c decreased by > 10% of baseline with an increase in medication
c.
Worsening of glucose tolerance or medication status:

HbA1c > 5.7% and increased to >10% of baseline without a change in 
medication
OR

Increase in diabetic medication with < 10% increase in HbA1c
d. Worsening of glucose tolerance despite increased treatment:

HbA1c > 5.7% AND increased to >10% of baseline AND an increase in diabetic
medication
3. Blood Pressure (BP) (compared to baseline)
a.
Improvement in BP:

Decrease in BP of >10% of baseline without medication increase, unless baseline
systolic BP ≤120 and diastolic BP ≤85

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OR

Decrease in medication without an increase in BP of >10%, unless baseline
systolic BP ≤120 and diastolic BP ≤85
b. No significant change in BP:

BP within 10% of baseline or systolic BP ≤120 and diastolic BP ≤85 AND no 
change in medication
OR

Increase in either systolic or diastolic BP >10% with a decrease in medication
OR

Improvement in systolic or diastolic BP of > 10% with an increase in medication
c.
Worsening of hypertension:

Increase in BP of >10% such that the systolic BP exceeds 120 mmHg or the
diastolic BP exceeds 85 mmHg without a change in medication
OR

An increase in anti-hypertensive medication accompanied by stability or no
significant change in both the systolic and diastolic BP
d. Worsening of hypertension despite treatment:

Increase in BP of >10% such that the systolic BP exceeds 120 mmHg or the
diastolic BP exceeds 85 mmHg AND an increase in medication
4. Lipid metabolism (low-density lipoprotein [LDL] compared to baseline)
a.
Improvement in lipids:

Decrease in LDL concentration >10% of baseline toward the target range without
medication increase
OR

Decrease in medication without an increase in LDL of >10% or LDL remains 
within target range
b. No significant change in LDL:

LDL within 10% of baseline or within the target range for patient AND no 
change in medication
OR

Increase in LDL > 10% with a decrease in medication
OR

Improvement in LDL of > 10% with an increase in medication
c.
Worsening of LDL or medication status:

Increase in LDL of >10% to above target range without a change in medication
OR

Increase in medication with <10% change in LDL
d. Worsening of LDL despite treatment:

Increase in LDL of >10% AND an increase in medication
5. Glucocorticoid-induced myopathy
a.
No steroid myopathy
b. Mild steroid myopathy (weakness WITHOUT functional limitation)
c.
Moderate steroid myopathy (weakness WITH functional limitation)
See Steroid Myopathy definitions, below
6. Skin
a.
No skin toxicity
b. Mild skin toxicity
c.
Moderate skin toxicity

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See Skin definitions, below
7. Neuropsychiatric toxicity
a.
No neuropsychiatric symptoms
b. Mild neuropsychiatric symptoms
c.
Moderate neuropsychiatric symptoms
See Neuropsychiatry definitions, below
8. Infection (since last assessment)
a.
No significant infection
b. Specific infections < Grade 3 (oral or vaginal candidiasis, uncomplicated zoster)
c.
Grade 3 or complicated herpes zoster
See Infection definitions, below
Glucocorticoid-induced myopathy definitions
Glucocorticoid-induced myopathy is defined as mild symmetrical weakness of the proximal 
muscles and/or neck flexors associated with steroid therapy, and NOT due to any other 
apparent cause. Muscle enzymes are typically within normal limits.
Mild and moderate severity of myopathy are defined by a muscle strength of 4 on the standard 
Medical Research Council rating scale. A 4 means weaker than normal but greater than 
antigravity strength against resistance.
“Mild” is mild weakness (Grade 4) that does NOT functionally limit the patient.
“Moderate” is mild weakness (Grade 4) that does impose functional limitations on the
patient enough to interfere with normal daily activities.
Note that a person may have muscle weakness consistent with glucocorticoid-induced myopathy
that detectable on physical examination but might not be aware of it or have any corresponding
functional limitation - this would be classified as mild.
Severity of glucocorticoid toxicity in the skin
Manifestations to be considered:

Acneiform rash

Atrophy/striae

Easy Bruising

Erosions/tears/ulcerations

Hirsutism
Skin 6b. Mild
Skin 6c. Moderate
Acneiform rash (Grades 1-2)
Acneiform rash (Grade 3)
Easy bruising (Grade 1)
Easy bruising (Grade 2)
Hirsutism (Grade 1)
Hirsutism (Grade 2)
Atrophy/Striae (Grade 1)
Atrophy/Striae (Grade 2)
Erosions/Tears/Ulcerations (Grade 1)
Erosions/Tears/Ulcerations (Grade 2)

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Skin Definitions (from National Cancer Institute Common Terminology Criteria for
Adverse Events):
Acneiform rash
- Grade 1 - Papules and/or pustules covering <10% body surface area (BSA), which may or
may not be associated with symptoms of pruritus or tenderness
- Grade 2 – Papules and/or pustules covering 10 - 30% BSA, which may or may not be
associated with symptoms of pruritus or tenderness; OR associated with psychosocial
impact; OR limiting instrumental Activity of Daily Living (ADL)
- Grade 3 - Papules and/or pustules covering >30% BSA, which may or may not be 
associated with symptoms of pruritus or tenderness; OR limiting self-care ADL; OR
associated with local superinfection with oral antibiotics indicated
Easy bruising
- Grade 1 – Localized or in a dependent area
- Grade 2 - Generalized
Hirsutism - In women, increase in length, thickness or density of hair in a male distribution
- Grade 1 - Hirsutism that the patient is able to camouflage by periodic shaving, bleaching, 
or removal of hair
- Grade 2 - Hirsutism that requires daily shaving or consistent destructive means of hair
removal to camouflage; OR associated with psychosocial impact
Atrophy / Striae
- Grade 1 - Covering <10% BSA; OR associated with telangiectasias or changes in skin 
color
- Grade 2 – Covering 10 - 30% BSA; OR associated with striae or adnexal structure loss
Erosions / Tears / Ulcerations
- Grade 1 – Combined area of ulcers <1 cm; OR non-blanchable erythema of intact skin 
associated with warmth or erythema
- Grade 2 – Combined area of ulcers 1 - 2 cm; OR partial thickness skin loss involving skin 
or subcutaneous fat
Severity of neuropsychiatric glucocorticoid toxicity
Manifestations to be considered:

Insomnia

Cognitive 
Impairment

Mania

Depression
7b. Mild
7c. Moderate
Insomnia – (Grade 1)
Insomnia – (Grade 2)
Mania (Grade 1)
Mania (Grade 2)
Cognitive impairment (Grade 1)
Cognitive impairment (Grade 2)
Depression (Grade 1)
Depression (Grade 2)
Definitions of severity within the neuropsychiatric domain
Insomnia - Dissatisfaction with sleep quality and difficulty initiating or maintaining sleep or
early morning awakening

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- Grade 1: not associated with functional impairment
-  Grade 2:  associated with functional impairment
Mania
- Grade 1: Slightly or occasionally elevated or irritable mood and 0-1 mild or occasional
additional symptoms of inflated self-esteem, decreased need for sleep, increased 
talkativeness, feeling that thoughts are faster than usual, distractibility, increased 
activity or agitation, and impulsive actions.
- Grade 2: Frequent or moderately elevated or irritable mood and 2-3 mild additional
symptoms of inflated self-esteem, decreased need for sleep, increased talkativeness, 
feeling that thoughts are faster than usual, distractibility, increased activity or agitation, 
and impulsive actions.
Cognitive impairment
- Grade 1: Minor cognitive complaints, no objective findings on mental status examination 
(i.e., not apparent to the examiner) that were not present before initiating steroids.
- Grade 2: New moderate cognitive deficits that were not present before initiating steroids.
Depression
- Grade 1: Feeling slightly down or depressed and 0-2 mild or occasional addition 
symptoms of loss of interest, low energy, guilt, poor concentration, insomnia, restlessness, 
or change in appetite.
- Grade 2: Frequent or moderate feelings of being down or depression and/or 3-4 
symptoms of loss of interest, low energy, guilt, poor concentration, insomnia, 
restlessness, or change in appetite.
Infection Definitions
No significant infection = No specific infections or serious infections, grade 3 or greater
Specific Infections – Oral or vaginal candidiasis or zoster infections without post-herpetic
neuralgia or eye involvement
Grade 3 – Intravenous antibiotic, antifungal, or antiviral intervention or
hospitalization indicated OR radiologic or operative intervention indicated OR 
herpes zoster complicated by post-herpetic neuralgia or eye involvement
Copyright © 2016-2018. Massachusetts General Hospital. All rights reserved.
References
Medical Research Council of the United Kingdom. Guide to Examination of the Peripheral
Nervous System: Memorandum No 45. Palo Alto, Calif: Pedragon House; 1978. National
Cancer Institute Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, DHHS.
May 29, 2009 NIH publication # 09-7473.

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Appendix I
Prednisone/Prednisolone doses < 5 mg in relation to available 
tablet strengths (scored tablets)
Daily dose
Available tablet 
strength
Administered # of tablets and frequency
1 mg
1 mg 
1 tablet each day
1.25 mg
2.5 mg
½ tablet every day or 1 tablet every 2nd day
1.25 mg
5 mg
½ tablet every 2nd day
1.875 mg
2.5 mg
1 tablet every 2nd day and ½ tablet every 2nd day
2 mg
1 mg
2 tablets each day
2.5 mg 
5 mg
½ tablet each day or 1 tablet every 2nd day
2.5 mg
1 mg
2 ½ tablets each day OR 2 tablets every 2nd day and 
3 tablets every 2nd day
2.5 mg
5 mg
½ tablet each day
3 mg
1 mg
3 tablets each day
3.125 mg
2.5 mg
1 ½ tablet every 2nd day and 1 tablet every 2nd day
3.75 mg
2.5 mg
1 tablet every 2nd day and 2 tablets every 2nd day
3.75 mg
5 mg
½ tablet every 2nd day and 1 tablet every 2nd day
4 mg
1 mg
4 tablets each day

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Appendix J
Abbreviations 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation 
or special term
Explanation
AAER
Annual Asthma Exacerbation Rate
AAERR
Annualized Asthma Exacerbation Reduction Rate
ACQ-6
Asthma Control Questionnaire 6
ADA
Anti-Drug Antibodies
ADL
Activities of Daily Living
AE
Adverse Event
AERR
Asthma Exacerbation Reduction Rate
AESI
Adverse Event of Special Interest
AI
Adrenal Insufficiency
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ATC
Anatomical Therapeutic Chemical
ATS
American Thoracic Society
AQLQ(S)+12
Standardised Asthma Quality of Life Questionnaire for 12 Years and
Older
ASD
Asthma Symptom Diary
AST
Aspartate Aminotransferase
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BMI
Body Mass Index
BP
Blood Pressure
BSA
Body Surface Area
BTR
Best Test Report
BUN
Blood urea nitrogen
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatinine Kinase
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease

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Abbreviation 
or special term
Explanation
COVID-19
Corona Virus Disease 2019 
CRF
Case Report Form (electronic/paper)
CRO
Contract Research Organization
CRP
C-Reactive Protein
CSR
Clinical Study Report
DAE
Discontinuation of Investigational Product due to Adverse Event
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid 
DSMB
Data and Safety Monitoring Board
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EOT
End of Treatment 
ePRO
Electronic Patient Reported Outcome device
EQ-5D-5L
European Quality of Life - 5 Dimensions 5 Level
ER
Emergency Room
ERS
European Respiratory Society
FAS
Full Analysis Set
FEIA
Fluorescent Enzyme Immunoassay
FENO
Fractional Exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle-Stimulating Hormone
FU
Follow Up
FVC
Forced Vital Capacity
GC
Glucocorticoid
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
GTI
Glucocorticoid Toxicity Index
Hb
Haemoglobin

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Abbreviation 
or special term
Explanation
HCP
Health Care Professional
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
HRU
Healthcare resource utilization
IATA
International Air Transport Association
ICH
International Conference on Harmonisation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or activities 
internationally. 
ICF 
Informed Consent Form 
ICS
Inhaled Corticosteroids
Ig
Immunoglobulin
IL
Interleukin
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
ITT
Intent-to-Treat
IUD/IUS
Intrauterine Device / Intrauterine System
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
IXRS
Interactive Voice/Web Response System
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonist
LAR
Late Asthmatic Response
LIMS
Laboratory Information Management System
LDL
Low-Density Lipoprotein 
LRTI
Low Respiratory Tract Infection
LSLV
Last Subject Last Visit
LTRA
Leukotriene Receptor Antagonists
MAb
Monoclonal Antibody

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Abbreviation 
or special term
Explanation
MACE
Major adverse cardiac events
MAR
Missing at Random
MCDA
Multicriteria Decision Analysis
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed Model for Repeat Measurements
MNAR
Missing-Not-at-Random
nAB
Neutralizing Antibodies
OCS
Oral Corticosteroids
PD
Pharmacodynamic
PEF
Peak Expiratory Flow
PHL
Potential Hy’s Law
PI
Prescribing information
PK
Pharmacokinetic(s)
PNV
Predicted Normal Value
ppb
Parts per billion
PRO
Patient Reported Outcome
Q4W
Every 4 Weeks
RNA
Ribonucleic Acid
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous
SDV
Source Data Verification
SGRQ
St. George’s Respiratory Questionnaire
SNP
Single Nucleotide Polymorphism
SoA
Schedule of Assessment 
SOC
System Organ Class
TBL
Total Bilirubin
TEAE
Treatment Emergent Adverse Event
Th2
T Helper 2 Cells
TSLP
Thymic Stromal Lymphopoietin

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Abbreviation 
or special term
Explanation
TSLPR
Thymic Stromal Derived Lymphopoietin Receptor
ULN
Upper Limit of Normal
UNS
Unscheduled
URTI
Upper Respiratory Tract Infection
WBDC
Web Based Data Capture
WHO
World Health Organization
WOCBP
Women of Childbearing Potential
WPAI+CIQ
Work Productivity and Activity Impairment Questionnaire and
Classroom Impairment Questionnaire

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Appendix K
Changes Related to COVID-19 Pandemic
Please Note: Changes below should only be implemented during the COVID-19 pandemic and 
if allowable by local/regional guidelines. 
K 1
Home Visits to Replace On-Site Visits (where applicable)
Due to local travel restrictions and/or site restrictions, subjects may not wish to or may not be 
able to go to the study site for study visits and related procedures. If an on-site visit is not 
possible, it is recommended to have a home visit with home administration of IP by a qualified 
HCP (up to Visit 17) or without administration of IP for EOT Visit and Visits 19 and 20, 
provided this is acceptable within local regulation/guidance. Additional information related to 
the visit can be obtained remotely by phone call and/or video conference. This is to ensure safety 
of the study subjects and minimum disruption to IP administration that may occur during the 
COVID-19 pandemic. 
Study assessments, where possible to be performed at home, should be conducted according to 
the SoA. At minimum, during home visit the qualified HCP is expected to:

Collect information on healthcare resources utilization

Perform a physical examination

Collect vital signs

Collect adverse events

Collect information on asthma exacerbation

Review concomitant medications

If possible, collect blood and urine sample according to the SoA 

Conduct urine pregnancy test (dipstick), prior to IP administration, if applicable

eDiary data review/completion

Evaluation of OCS dose (done by Investigator, can be done remotely after relevant data is 
reviewed)

Administer IP

Observe the subject for one hour after IP administration for the signs or symptoms of any 
acute drug reactions 

Document the visit
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for 
D5180C00009 Study Re: COVID-19 for more information.
K 2
Visits at an Alternate Location (where applicable)
Study visits including administration of IP and study assessments according to the SoA can take 
place at an alternative location away from infection risk zones, or closer to the subject’s home, 
provided this is acceptable within local regulation/guidance. 
Please refer to the separate IP Home (or Alternative Site) Administration Instructions for 
D5180C00009 Study Re: COVID-19 for more information.

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K 3
Remote Visits to Replace On-Site Visits (where applicable)
During the COVID-19 pandemic, on-site visits may be replaced by a remote visit (phone call 
and/or video conference) if subjects cannot attend the visits at the study site, at an alternate site 
or have home visits and if allowed by local/regional guidelines. 
Having a phone call and/or a video conference with the subject will allow conduct of study 
procedures including reporting of adverse events, concomitant medication, information on 
asthma control/exacerbation and healthcare resource utilization as well as assessment and 
adjustment of OCS dose based on available sources of information (see K 4) while minimizing 
the risk to subjects of COVID-19 exposure.
K 4
OCS Titration During the COVID-19 Pandemic
During the COVID-19 pandemic, the Investigator may make decisions on the OCS dose based 
on remote interview of subject, eDiary data and if applicable, home visit physical examination 
and vital signs. 
If COVID-19 in any way interferes with OCS titration (e.g. suspected or confirmed COVID-19 
infection or lack of sufficient information due to COVID-19 pandemic) and/or titration decision 
is influenced by anything else than described in CSP Section 8.1.1.2, it needs to be specified in 
the eCRF/OCSDOSE form by including “COVID-19” phrase in the justification for the decision.
K 5
End of Treatment Visit / Transition to the Extension Study 
D5180C00018
If the EOT visit at Week 48 cannot be performed on-site, at an alternate site, or at the subject’s 
home, the EOT visit should be conducted as a remote visit. 
Subjects aimed to transition to the extension study D5180C00018 will continue participation in 
the safety follow-up visit(s) (Week 54, Week 60) until the on-site (or alternate site) extension 
study randomization and IP administration can be conducted.
If on-site (or alternate site) randomisation / IP administration into the extension study 
D5180C00018 is not possible by the end of the study safety follow-up (Week 60), a subject will 
not transition to the extension study. These cases should be discussed with the AstraZeneca study 
physician.
K 6
Re-consenting of Subjects During the COVID-19 Pandemic
If a subject is unable to travel to the site due to the COVID-19 pandemic, it is necessary to obtain 
re-consent remotely and/or verbally for the implementation of the new urgent changes in the 
study during the COVID-19 pandemic. This will minimize the risk to the subject of COVID-19 
exposure with clinic visits.  Applicable local guidelines and regulations on re-consenting process 
should be followed.

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5180c00009-csp-v4
Document Title:
D5180C00009 Clinical Study Protocol version 4
Document ID:
Doc ID-003538797
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
20-May-2020 12:04 UTC
Content Approval
20-May-2020 11:55 UTC
Content Approval
20-May-2020 19:32 UTC
Content Approval
21-May-2020 09:57 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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