A Phase 2, Randomized, Double-blind, Parallel Group, Placebo Controlled Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in Adults With Inadequately Controlled Asthma on Inhaled Corticosteroids and at Least One Additional Asthma Controller (CASCADE)
Phase: PHASE2
Conditions: Asthma, Bronchial Diseases, Respiratory Tract Diseases, Lung Diseases, Obstructive, Lung Diseases, Respiratory Hypersensitivity, Hypersensitivity, Immediate, Hypersensitivity, Immune System Diseases
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Tezepelumab
Study Code
D5180C00013
Version
4.0
Date
30 Apr 2020
A Phase 2, Randomized, Double-blind, Parallel Group, Placebo Controlled 
Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in 
Adults with Inadequately Controlled Asthma on Inhaled Corticosteroids and 
at least one additional asthma controller (CASCADE)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
EudraCT number: 2018-002069-21

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VERSION HISTORY
Version 4.0, 30 Apr 2020 
Changes to the protocol are summarized below
For entire CSP - Updated “From baseline to Week 28” to “from baseline to end of treatment 
visit (EOT) due to the possibility of additional visits during COVID-19 pandemic
Secton 1.1, SoA, Table 1, footnote #3 – Added “During the COVID-19 pandemic 
unscheduled visits may occur so that sites may perform EOT assessments 4 weeks after last 
dose of IP at either week 28, 32, 36, 40, 44 or 48(as needed) until the sites are able to 
resume the EOT assessments." This change is to minimize the risk for subjects being 
exposed to SARS-CoV-2 with these visits during the pandemic
Section 1.1, SoA, Table 1, footnote # 8 – Added “During the COVID-19 pandemic, 
recording, collecting and dispensing will continue once administration of extra dosing is 
implemented” to accommodate for extra visits
Section 1.1, SoA, Table 1 – Added footnote ‘18’ – “During the COVID-19 pandemic an 
additional 1 to 6 IP doses may be administered to subjects during unscheduled visits at 
weeks 28, 32, 36, 40, 44 and 48(as needed) until the sites are able to resume performing all 
EOT study assessments, including bronchoscopies. All assessments during the unscheduled 
visit may not be necessarily completed. Please refer to appendix J.” This change is being 
made because some sites are not able to perform research related bronchoscopies during the 
COVID-19 pandemic.  The change will enable subjects to continue dosing with IP until 
sites are able to perform bronchoscopy for the EOT visit during the COVID-19 pandemic
Section 1.1, SoA, Table 1 – Added “Asterix *** During the COVID-19 pandemic 
unscheduled visits may occur so that sites may perform EOT assessments 4 weeks after last 
dose of IP at either week 28, 32, 36, 40, 44 or 48 (as needed) until the sites are able to 
resume the EOT assessments.” This change is also being made because sites are not able to 
perform research related bronchoscopies during the COVID-19 pandemic
Section 1.1, SoA, Table 1 – Added “X” to include healthcare resource utilization, Urine 
pregnancy test (dipstick) and distribution and collection of paper diary to the unscheduled 
visit column. This is to collect/distribute during additional visits during the COVID-19 
pandemic
Section 1.1, SoA, Table 1 – Under Table 1 added guidance on how to proceed with respect 
to Schedule of Activities during the Covid-19 pandemic to ensure the safety of the study 
subjects, to maintain compliance with GCP and to minimize risks to data integrity

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Section 1.2, Synopsis, Secondary Objective # 3 – Added “determined by RNAseq of 
bronchial brushings at baseline” to the end of the sentence under outcome variable to clarify 
the methodology for determining the T2 status
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Synopsis 1.2, Number of Subjects, - Changed the eosinophil count stratification criteria to 
match the program specified criteria: Changed the medium group to be 150 - < 300 cells/µL 
instead of 150 - 300 cells/µL and the high group to be ≥300 cells/µL instead of > 300 at 
Visit 1 to correct the typographical error and to align with IXRS
Section 1.2, Treatments and treatment duration – Added “(or later due to COVID-19 
pandemic)” near the end of the paragraph for clarity 
Section 1.2, Synopsis, Treatments and treatment duration, - Added “Please note: During the 
COVID-19 pandemic, the treatment period may be extended and therefore subjects may be 
given 1 to 6 doses (as needed) every 4 weeks for a longer period than initially planned 
(please refer to Appendix J). For the last follow up visit, a phone call visit can replace an 
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on-site visit. Please refer to Appendix J” This change is being made because sites are unable 
to perform research bronchoscopies during the COVID-19 pandemic.  Additional treatments 
will allow subjects to receive IP up until 4 weeks before the EOT visit and bronchoscopy
Section 1.2, Statistical methods, - Added “During the COVID-19 pandemic, all subjects 
with EOT assessments performed after unscheduled visits will be summarized and analyzed 
together with all subjects with EOT assessments performed during the scheduled EOT visit 
at week 28 and will be reported as having completed the EOT assessments” Please refer to 
Appendix J. This change is to accommodate for extra visits to minimize the risk for subjects 
during the COVID-19 pandemic
Section 1.2, Statistical methods, - Changed the eosinophil count stratification criteria to 
match the program specified criteria: Changed the medium group to be 150 - < 300 cells/µL 
instead of 150 - 300 cells/µL and the high group to be ≥300 cells/µL instead of > 300 at 
Visit 1 to correct the typographical error and to align with IXRS
Section 1.3, Schema, Figure 1, Study Design – Week 28 is now EOT and Week 40 is now 
EOS. Figure has been updated to align with implemented changes during COVID-19 (ie) 
extra dosing 
Section 3, Objectives and Endpoints, Secondary Objective #3 - Added “determined by 
RNAseq of bronchial brushings at baseline” to the end of the sentence under outcome 
variable to clarify the methodology for determining the T2 status
 
 
 
 
 
 
 
 
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Section 4.1, Overall Design – Added “Please note: During the COVID-19 pandemic, there 
is an option for patients to have an extra dose every 4 weeks up to 6 additional doses, as 
needed. (please refer to Appendix J). For the last follow up visit, a phone call visit can 
replace an on-site visit. Please refer to Appendix J
Section 4.1, Overall Design – Changed “activities” to “Spectrum” in the first sentence of 
the 6th paragraph to provide more clarity to the sentence 
Section 4.1, Overall Design - Changed the eosinophil count stratification criteria to match 
the program specified criteria: Changed the medium group to be 150 - < 300 cells/µL 
instead of 150 - 300 cells/µL and the high group to be ≥300 cells/µL instead of > 300 at 
Visit 1 to correct the typographical error and to align with IXRS
Section 5.1, Inclusion Criteria - Under Inclusion #2 added wording that outlines re-consenting 
of subjects during the COVID-19 pandemic to accommodate the changes made to the protocol
Section 6.2, Preparation/handling/storage/accountability, Dose Administration – Added 
“Please Note: During the COVID-19 pandemic, if allowed by local/regional guidelines, 
IP preparation and administration can be performed at the subject’s home by a 
qualified HCP. Please refer to Appendix J for further details” at the end of the section 
to accommodate for home visits
Section 6.2, Preparation/handling/storage/accountability, Dose Administration, Table 4 -
Investigational product dose preparation – Added “2 or” within footnote as pertaining to the 
syringe size
Section 6.3, Measure to minimize bias: randomization and blinding, Methods for assigning 
treatment groups - Changed the eosinophil count stratification criteria to match the program 
specified criteria: Changed the medium group to be 150 - < 300 cells/µL instead of 150 -
300 cells/µL and the high group to be ≥300 cells/µL instead of > 300 at Visit 1 to correct 
the typographical error and to align with IXRS
Section 6.6, Dose Modification - Added “During the COVID-19 pandemic an additional 1-6 
IP doses may be administered to subjects during unscheduled visits at weeks 28, 32, 36, 40, 
44 and 48 (as needed) until the sites are able to resume performing all study assessments, 
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including bronchoscopies, in accordance to local regulations/guidelines. Please refer to 
Appendix J”
Section 6.7, Treatment after the end of the study – Changed “Subjects who complete week 
40 should be given standard of care at the discretion of the Investigator” to “Subjects who 
complete the study should be given standard of care at the discretion of the Investigator” as 
there may be additional weeks during the COVID-19 Pandemic
Section 7.1.1, Procedures for discontinuation of study treatment – Point # 2 and # 3 –
Added “(or later due to COVID-19 pandemic)” near the end of the paragraph
Section 7.1.1, Procedures for discontinuation of study treatment – Added “(or later due to 
COVID-19 pandemic)” at the end of the sentence in the first paragraph
Section 7.1.1, Procedures for discontinuation of study treatment – Added “or had an EOT 
visit date greater than 12 weeks after date of last dose of IP” to paragraph as some patients 
will now be receiving additional doses beyond the dose of week 24 during COVID-19 
pandemic
Section 7.1.1, Procedures for discontinuation of study treatment – Added “For more 
information related to COVID-19 please refer to eCRF instructions” as the last sentence of 
the section for more clarity on instructions
Section 7.3, Withdrawal from the Study – Added “For more information related to COVID-
19 please refer to eCRF instructions” near the end of the section for more clarity on eCRF 
instructions
Section 8.0, Study Assessment and Procedures – Added “Additional data to assess the
impact of COVID-19 pandemic will be collected.” at the end of paragraph # 2 
Section 8.1.18.1, Paper Diary – Added “Please note: During the COVID-19 pandemic, 
once extra dosing and/or home IP administration is implemented, recording, collection, and 
dispensation of the subject's paper diaries will continue” to accommodate for extra visits
Section 8.8, Biomarkers, - Changed “ 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. 
To “Selected results of this biomarker research may be reported in the CSR (as per section 
8.1.6). Biomarkers not reported in the CSR may be reported in an addendum, or separately 
in a scientific report or publication.” since there are certain biomarkers that may be included 
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Section 8.8.3, Transcriptomics – Changed “preparation” to “collection” in second sentence 
to provide more clarity
Section 9.2, Populations for analyses, Table 8, Evaluable Analysis Set  - Changed the 
description from “All subjects randomized to study treatment and completed at least 20 
weeks of study treatment” to  “All subjects randomized to study treatment who completed 
at least 20 weeks of study treatment and had an EOT visit date not greater than 8 weeks 
after date of last dose of IP” This change is that some patients will now be receiving 
additional doses beyond the dose of week 24 during COVID-19 pandemic 
Section 9.3.2, Primary outcome measure, Removed “week 28 (Visit 11(V11)) i.e 
(V11/V3b)”  added “EOT/V3b” due to the possibility of additional visits 
Section 9.3.4.2, Effect on large airways remodeling – Added “structure and function” to the 
exploratory objective to provide more clarity and specificity
Section 9.3.4.2, Effect on large airways remodeling – Removed bullet point #2 “Large 
airway dimensions and estimated airway resistance determined from computed tomography 
(CT)” and bullet point # 4 “Airway resistance for airway generations 3, 4 and 5 estimated 
based on lumen area” to clarify the analysis and remove duplication
Section 9.3.4.2, Effect on large airways remodeling – Removed the following wording from 
bullet point # 3 “segmental, sub-segmental, sub sub-segmental” to simplify the explanation 
for analysis
Section 9.3.4.2, Effect on large airways remodeling - Added “wall thickness”,  “and 3 & 4 
combined” and “as evaluated by computed tomography (CT)”to bullet point # 3 to provide 
more clarity and specificity for these variables 
Section 9.3.4.2, Effect on large airways remodeling – added Bullet point # 4 “Mucus score 
as evaluated by CT” as another variable for analysis 
Section 9.3.4.3, Effect on small airways obstruction – Removed bullet point #2 “Regional 
matching of the inspiratory/expiratory CT scans to assess air trapping/small airway 
obstruction” as it will be replaced with fSAD 
Section 9.3.4.3, Effect on small airways obstruction – Added bullet point # 2 “Functional 
small airway disease (fSAD), air trapping index and expiratory-to-inspiratory (E/I) ratio as 
evaluated by CT” as another variable for analysis
Section 9.3.4.8, Pharmacokinetics and immunogenicity of tezepelumab – Changed first 
sentence in second paragraph from “ADA status (positive vs. negative) at each visit will be 
summarized by treatment group” to “ADA status(positive vs. negative) and titers at 

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specified  visits will be summarized by treatment group” because the ADA assessment is 
not done for every visit 
Section 9.4, Statistical Analyses – Added “EOT assessments done at either week 28 or later 
will be discussed in the Statistical Analysis Plan (SAP).” to specify how analyses will be 
conducted with subjects receiving extra doses
Section 9.4.1, Efficacy analyses – Removed “For the primary endpoints only, only those 
subjects who complete at least 20 weeks of treatment will be included in the analysis” from 
the second paragraph, as some subjects will have additional doses after week 28 during the 
COVID-19 pandemic 
Section 9.4.2, Analysis of the primary variable(s) - Changed the eosinophil count 
stratification criteria to match the program specified criteria: Changed the medium group to 
be 150 - < 300 cells/µL instead of 150 - 300 cells/µL and the high group to be ≥300 
cells/µL instead of > 300 at Visit 1 to correct the typographical error and to align with 
IXRS
Section 9.4.4, Supportive analysis – Updated second paragraph from “For the primary 
variables, the analysis may be repeated using the full analysis set, hence including 
assessments in subjects who complete between 16 and 20 weeks of treatment as a 
supportive analysis to “For the primary variables, the analysis may be repeated using the 
full analysis set, hence including assessments in subjects who complete at least 16 weeks of 
study treatment and had an EOT visit date not greater than 12 weeks after date of last dose 
of IP as a supportive analysis” Change has been made due to the COVID-19 pandemic 
Section 9.4.4, Supportive analysis – Added the following wording “Additional analyses 
assessing the impact of COVID-19 may be included in the SAP”
Section 9.4.7, Other Analyses - Removed “To assess consistency of treatment effect across 
T2 activity as a continuum, a similar model will be fitted as for the primary analysis with 
additional factors for the subgroup variable (i.e. T2 quartiles) and its interaction with 
treatment.” as this is a repeat of the analysis for one of the secondary variables 
Appendix A 3 – Added “During the COVID-19 pandemic, re-consenting remotely may be 
obtained if local/regional guidelines allow” to accommodate the changes made in the 
protocol
Appendix J, - Added Appendix J to describe in more detail the changes made during the 
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Various typographical and grammatical corrections have been made 
Version 3.0, 03 May 2019
Changes to the protocol are summarized below
Section 1.1, SoA, Table 1 – Added “” symbol and subsequent footnote to V4, V12, and 
V13 further clarifying these visits can be conducted via telephone. 
Section 1.1, SoA, Table 1 – Added “Blood for” prior to Tezepelumab PK clarifying 
tezepelumab PK will be assessed via blood sample analysis. 
Section 1.1, SoA, Table 1 – Added “Proposed order of assessments as follows: Visit 11 Day 
1 - ACQ-6, paper diary completion, vital signs, ECG, FeNO, AO, physical exam, and AHR; 
Visit 11 Day 2 - vitals signs, pre-BD spirometry, blood draw, and bronchoscopy (biopsy, 
brushing, then BAL). Pre-BD spirometry can be done 1 day prior to bronchoscopy if there 
is a safety concern” to footnote ‘3’ to provide recommended order of procedures if Visit 11 
is performed over more than one day.
Section 1.1, SoA, Table 1 – Updated footnote ‘6’ from “Blood samples for PK and blood 
samples for ADA/nAb, biomarker and transcriptomics evaluations will be collected before 
the administration of IP.” to “Blood and BAL samples for PK and blood samples for ADA 
and nAb, biomarker and transcriptomics evaluations will be collected before the 
administration of IP. Samples with confirmed positive ADAs will be archived for possible 
testing for nAb.” This change is to clarify that both blood and BAL PK samples are intended 
to be collected, not only PK blood and that nAb samples will be archived for possible future 
testing. 
Section 1.1, SoA, Table 1 – Added “The morning diary will include: questions about rescue 
medications, night-time awakening, and use of maintenance medications. The evening diary 
will include: questions about rescue medications.” to footnote ‘8’ and corrected the 
corresponding inclusion criteria referenced to 14 & 15 as opposed to 15 & 16. This change 
is to detail the information that is captured on the paper diaries.
Section 1.1, SoA, Table 1 – Updated footnote ‘9’ from “ACQ-6 will not be done at Visit 2 
except if the criterion was not met at Visit 1” to “ACQ-6 will be performed at Visit 2 only if 
the eligibility criterion is not met at Visit 1.” This change is to better clarify when it is 
acceptable to complete ACQ-6 at V2.
Section 1.1, SoA, Table 1 – Updated footnote ‘12’ from “At EOT visit, AO, BAL, brushing, 
CT, and AHR will be performed only if baseline assessment is performed successfully, as 
confirmed by investigator.” to “At EOT visit, AO, BAL, brushings, CT, and AHR will be 

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performed only if baseline assessment is performed successfully, as confirmed by 
investigator.” This change is to clarify that bronchial brushing will also not be completed if 
the baseline measurement is unsuccessful. 
Section 1.1, SoA, Table 1 – Updated footnote ‘13’ from “…All post-randomization 
spirometry assessments should be performed within ± 1.5 hours of the time that the baseline 
spirometry (Visit 3b) was performed.” to “…All post-randomization spirometry assessments 
should be performed within ± 1.5 hours of the time that the baseline spirometry (Visit 1  
and/or Visit 2) was performed.” in order to be in line with details in Table 1.
Section 1.1, SoA, Table 1 – Removed footnote ‘15’ and updated the numbering of 
subsequent footnotes as no longer required due to update to footnote #6 as described above.
 
 
 
 
 
 
Section 1.2, Synopsis, Treatments and treatment duration – Updated “After initial 
enrolment and confirmation of entry criteria (Visit 1) subjects will proceed to a run-in 
period of 4 weeks during which their suitability for randomization will be confirmed.” to 
“After initial enrolment and confirmation of entry criteria (Visit 1) subjects will proceed to 
a screening/run-in period of 4 weeks during which their suitability for randomization will 
be confirmed.”. This change was to clarify that the screening & run-in period together 
constitute 4 weeks as opposed to run-in alone. 
Section 1.2, Synopsis, Statistical Methods – Added “expressed as a ratio” when discussing 
change from baseline to week 28 in the number of airway submucosal inflammatory cells to 
clarify that the change is reported as a ratio.
Section 1.2, Synopsis, Statistical Methods – Updated “Covariates and factors included in 
the model will include at least treatment, and baseline number of airway submucosal 
eosinophils” to “Covariates and factors included in the model will include at least screening 
blood eosinophil strata (screening blood eosinophil count < 150 cells/µL, 150 - 300 
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cells/µL, and > 300 cells/µL at Visit 1), treatment, and baseline value” to specify the exact 
stratification factor. 
Section 1.2, Synopsis, Statistical Methods – Added “across the spectrum of T2 status” to 
clarify that this will be across the entire spectrum of T2 status as opposed to within the T2 
spectrum. 
Section 1.2, Synopsis, Statistical Methods – Updated “To account for this, 55 subjects will 
be randomized in each treatment arm” to “To account for this and subject dropouts, 55 
subjects will be randomized in each treatment arm” to clarify that the total number of 
randomized subjects per treatment arm has also taken subject dropouts into consideration.
Section 2.2, Background – Updated “We believe that tezepelumab will be efficacious in 
both T2 low and T2 high subjects (based on the Phase 2b data) so the effect of tezepelumab 
across the T2 continuum as determined by the three gene mean signature, will be explored” 
to “We believe that tezepelumab will be efficacious in both T2 low and T2 high subjects 
(based on the Phase 2b data) so the effect of tezepelumab across the T2 spectrum as 
determined by the three gene mean signature, will be explored” to indicate that this will be 
across the entire spectrum of T2 status. 
Section 2.2, Background – Updated “These results are similar to those observed in the 
overall ITT population (AERR of 61%...” to “These results are similar to those observed in 
the overall ITT population (AAERR of 61%...” This change was made to clarify that the 
results are of the Annual Asthma Exacerbation Reduction Rate. 
Section 2.3, Benefit/risk assessment – Updated “Risks of the study include those associated 
with invasive study assessments like the bronchoscopy, bronchial biopsy, and 
bronchoalveolar lavage (BAL).” to “Risks of the study include those associated with 
invasive study assessments such as bronchoscopy, bronchial biopsy, bronchial brushing
and bronchoalveolar lavage (BAL).” This change is to correct an oversight in the previous 
wording as bronchial brushing is also considered an invasive procedure with potential 
associated risks. 
 
 
 
 
  
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Section 4.1, Overall Design – Corrected “Table 4 and Table 5” to “Table 5 and Table 6” 
when reference the list of medication restrictions and prohibitions. 
Section 4.2, Scientific rationale for the study design – Updated “In the present study, to 
ensure recruitment of adequate numbers of T2 low and T2 high subjects for analysis, 
subjects will be enrolled based on baseline blood eosinophil counts.” to “In the present 
study, to ensure recruitment of adequate numbers of T2 low and T2 high subjects for 
analysis, subjects will be enrolled based on screening blood eosinophil counts.” This 
change was to clarify that the baseline blood eosinophil counts will be collected at the 
screening visit. 
Section 5.1, Inclusion criteria #13 – Further defined abstinence requirement and clarified 
that bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system are 
acceptable methods of female contraception.
Section 5.1, Inclusion criteria #15 – Added “with a minimum of 4 days of compliance 
during the last 7 days of the run-in period” to clarify the period within the background 
asthma medication compliance must be maintained. 
Section 5.1, Inclusion criteria #18 – Updated to indicate that “Successful BAL and 
brushings are not inclusionary.” to clarify that brushings are also not inclusionary as was 
inadvertently omitted from this inclusion criterion. 
Section 5.2, Exclusion criteria #7 and Section 5.3.2, Alcohol, tobacco, and other – Updated 
from “Current smokers or subjects with smoking history ≥ 10 pack-years. Former smokers 
with a smoking history of <10 pack years must have stopped for at least 6 months prior to 
Visit 1 to be eligible.” to “Current smokers or subjects with smoking history ≥ 10 pack-
years, including the use of vaping products, such as electronic cigarettes. Former smokers 
with a smoking history of <10 pack years, including vaping or e-cigarette users, must have 
stopped for at least 6 months prior to Visit 1 to be eligible.” to clarify that tobacco 
restrictions also apply to vaping and e-cigarette products. 
Section 5.4, Screen Failures – Added “If the timeframe between screening and re-screening 
exceeds 30 days, the subject will not be permitted to rescreen without repeating Visit 1 
assessments, as per PI discretion.” to reduce the risk of not identifying the status change in 
HIV 1, HIV 2, Hepatitis B, Hepatitis C and FSH prior to rescreening, if initial screening 
visit 1 was more than 30 days ago.
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Section 6.2, Preparation/handling/storage/accountability – Clarified that the acceptable 
syringe size can be 2 or 3mL as opposed to strictly 3mL, as it meets requirements for dose 
preparation and administration. 
Section 6.2, Preparation/handling/storage/accountability – Removed “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. Measure to minimize bias: randomization and blinding, Methods for assigning 
treatment groups – Updated “Randomization will be stratified by baseline blood eosinophil 
level.” to “Randomization will be stratified by screening blood eosinophil level.” to clarify 
that the baseline blood eosinophil counts will be collected at the screening visit.
Section 6.3, Measure to minimize bias: randomization and blinding, Ensuring blinding –
Added “Applicable DSMB members” and removed “ADA, nAb, and biomarker” at 
‘Ensuring blinding’ to clarify that the laboratory does not require the randomization list for 
performing biomarker, ADA and nAb sample analysis and that DSMB members may 
require access to the randomization list.  
Section 6.3. Measure to minimize bias: randomization and blinding, Ensuring blinding –
Updated “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” to “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 
and until database lock” to clarify that access to the randomization scheme will not be 
available until after database lock. 
Section 6.3, Measure to minimize bias: randomization and blinding, Methods for unblinding 
– Updated “Individual treatment codes, indicating the treatment randomization for each 
randomized subject, will be available to the Investigator(s) or pharmacist at the study sites 
from the IVRS/IWRS.” to “Individual treatment codes, indicating the treatment 
randomization for each randomized subject, will be available to the Investigator(s) or 
delegate at the study sites from the IVRS/IWRS.” to clarify that any individual properly 
delegated by the PI may have access to individual treatment codes. 
Section 6.5, Concomitant therapy, Table 5 – Updated “No changes in either dose or regimen 
are allowed from V1 and throughout the IP treatment and preferably 4 weeks after the last 
dose of IP” to “No changes in either dose or regimen are allowed from V1 and until at least 
the EOT visit, unless there is a medical need as judged by the Investigator.” for 
‘Maintenance treatment with ICS and long-acting bronchodilators (including ICS/LABA 
combinations)’, ‘Short-acting beta-agonists (SABA)’, ‘Additional maintenance controllers’, 

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and ‘Short-acting anticholinergics (e.g. ipratropium)’. This change is to further detail the 
restriction period and permit use of the aforementioned medication if needed medically.  
Section 6.5, Concomitant therapy, Table 6 – Updated “No changes in either dose or regimen 
are allowed from V1 and throughout the IP treatment and preferably 4 weeks after the last 
dose of IP” to “No changes in either dose or regimen are allowed from V1 and until at least 
the EOT visit, unless there is a medical need as judged by the Investigator.” for ‘Long-
acting beta-agonists as a reliever (e.g. Symbicort Maintenance and Reliever Treatment)’, 
‘Suplatast tosilate (T2 cytokine inhibitor)’, ‘Anticoagulants’, ‘Any immunomodulators or 
immunosuppressives (except for OCS used in the treatment of asthma/asthma 
exacerbations)’, ‘Immunoglobulin or blood products’, ‘Other IPs (including investigational 
use of an approved drug)’, ‘Herbal remedies for the treatment of allergic, inflammatory, or 
respiratory diseases’ and ‘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’. This change is to further detail the restriction period 
and permit use of the aforementioned medication if needed medically.  
Section 7.1, Discontinuation of study treatment – Added “except subjects who develop 
basal cell carcinoma or localized squamous cell carcinoma of the skin, provided the 
malignancy is excised and determined to have clean margins” when discussing 
discontinuation due to any malignancy to align with the updated IB version 4.2. 
Section 7.1.1, Procedures for discontinuation of study treatment – Updated “If the last IP 
administration was after week 16 for options 1 or 2, the subject will return to the clinic for 
an EOT visit at week 28 (+/- 3 days).” to “If the last IP administration was at or after week 
16 for options 1 or 2, the subject will return to the clinic for an EOT visit at week 28 (+/- 3 
days).” to clarify that the EOT visit will be completed for subjects who complete at least 
week 16 of IP administration. 
Section 7.1.1, Procedures for discontinuation of study treatment – Updated “Development 
of study specific discontinuation criteria’ on the termination form in the eCRF.” to 
“Development of study specific discontinuation criteria’ on the Discontinuation of 
Investigational Product form in the eCRF.” to be in line with eCRF guidelines. 
Section 8.1.2, Bronchial brushing – Added “The brushings at the EOT Visit will be 
performed only if the baseline visit brushing is performed successfully, as judged by the 
Investigator.” to clarify that the bronchial brushing will only be collected if a successful 
baseline brushing is obtained. 
Section 8.1.4, Airwave Oscillometry – Removed “AO evaluation will be performed in 
accordance with the schedule provided in Table 1. Assessment at week -1 will be a training 
maneuver for the subjects.”, as training is not conducted and there is no week -1 visit. 

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Section 8.1.5, Airway hyper-responsiveness – Clarified that the mannitol challenge will also 
be performed in accordance to the vendor’s manual and added “Medication washouts 
should be followed as per the mannitol vendor's manual detailed in Appendix I”
Section 8.1.13, Computed tomography – Removed “of procedures” and “Principal” and 
updated “EOT CT will be performed only if baseline CT is performed successfully, as 
judged by the investigator.” to “EOT CT will be performed only if baseline CT is 
performed successfully, as confirmed by imaging QC review by the imaging vendor.” This 
change is to clarify that the imaging vendor will confirm proper baseline CT scan 
assessment.
Section 8.1.18, Patient reported outcomes – Replaced “The questionnaires will be 
administered at home in the following order…” to “The questionnaires will be completed at 
home in the following order…” and corrected the corresponding inclusion criteria 
referenced to 14 & 15 as opposed to 15 & 16, due to typographical error.
Section 8.2.2, Weight and height – Added “Body Mass Index (BMI) will be automatically 
calculated in the eCRF.”
Section 8.2.4, Vital signs – Replaced “Pulse rate will be obtained before blood pressure.” 
with “Pulse rate will be obtained before blood pressure only if the manual measuring 
technique is used”. to specify that the order of measurements is only applicable when 
manually measurement occurs. 
Section 8.2.5, Electrocardiograms – Updated “A 12-lead ECG will be taken in supine 
position, prior to blood draw, spirometry, BD administration, and IP administration” to “A 
12- or 15-lead ECG will be taken in supine position, prior to blood draw, spirometry, and 
BD administration” to be in line with the ECG timepoints detailed in the SoA and to clarify 
that either 12- or 15-lead ECGs are acceptable. 
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 updated IB version 4.2.
Section 8.5.1, Collection of samples and drug concentration – Added “Urea concentration 
will be measured in blood and BAL samples to correct for the dilution factor of the BAL 
samples” to clarify that correction for the dilution factor for PK measurements in BAL will 
occur. 
Section 8.5.2, Collection of samples to measure the presence of ADAs – Removed “and 
ADA-neutralizing antibodies” and updated “Samples with confirmed positive ADAs will be 
analyzed for the presence of neutralizing antibodies (nAb).” to “Samples with confirmed 

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positive ADAs will be archived for possible testing for neutralizing antibodies (nAb).” as 
nAb samples will be archived for possible future testing. 
Section 8.7.1, Optional exploratory genetic sample – Removed “Healthy volunteers and 
pediatric patient samples will not be collected for optional genetic research.” as no healthy 
volunteers or pediatric patients are permitted on this study.
Section 9, Statistical considerations – Updated “The null hypothesis H0: The ratio 
(tezepelumab/placebo) equals 1 and will be tested vs. H1: The ratio is not equal to 1.” to 
“The null hypothesis H0: The ratio (tezepelumab/placebo) of the change, expressed as a 
ratio, from baseline to week 28 for each primary and secondary endpoint between 
tezepelumab and placebo equals 1 and will be tested versus the alternative hypothesis H1: 
The ratio (tezepelumab/placebo) of the change, expressed as a ratio, from baseline to week 
28 for each primary and secondary endpoint between tezepelumab and placebo is not equal 
to 1.” and removed “For the primary endpoints only, one-sided tests will be conducted 
against the alternative hypothesis H1: The ratio tezepelumab/placebo is < 1”. This change is 
to clarify the hypotheses definitions. 
Section 9.1, Sample size determination – Updated “It is estimated that 50 subjects in each 
treatment arm will provide (using a nominal 10% significance level for each endpoint)” to 
“It is estimated that 50 subjects in each treatment arm will provide (using a 2-sided test with 
a nominal 10% significance level for each endpoint)” to clarify that all results will be 
presented as 2-sided tests. 
Section 9.2, Populations for analyses, Table 8 – Defined additional analysis population set 
“Evaluable analysis set” to account for subjects in the full analysis set with at least 20 
weeks of treatment. 
Section 9.2, Populations for analyses – Replaced “For analysis of efficacy variables, 
subjects will be assigned to the full analysis set (defined above) according to their 
randomized treatment. For consistency, demographic and baseline characteristics will be 
presented using the full analysis set.” with “For analysis of efficacy variables, subjects will 
be assigned to the evaluable analysis set (defined above) according to their randomized 
treatment. For consistency, demographic and baseline characteristics will be confirmed by 
presenting using both the evaluable analysis set (to correspond to the primary efficacy 
analysis population) and full analysis set.” This change was made to be consistent with 
safety and efficacy analysis populations. 
Section 9.3.3, Secondary outcome measures – Updated “The change, expressed as a ratio, in 
airway inflammatory cells/mm2 from baseline up to week 28 within T2 spectrum” to “The 
change, expressed as a ratio, in airway inflammatory cells/mm2 from baseline up to week 28 
across the spectrum of T2 status” to clarify that this will be across the entire spectrum of T2 
status as opposed to within the T2 spectrum. 

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Section 9.3.4.5, Rescue use – Removed “Total rescue medication use defined as the average 
number of inhalations (puffs) per day will be calculated as the outcome variable. The 
number of inhalations (puffs) per day will be calculated as follows: Number of night inhaler 
puffs + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number 
of day nebulizer times]. Biweekly mean number of inhalations (puffs) per day will be 
calculated as the outcome variable” as this information is captured via paper diaries and 
outcome variable analysis will not be possible. 
Section 9.3.4.6, Nights with awakening due to asthma – Removed sub-section and 
subsequent subsection numbering adjusted accordingly as this information is captured via 
paper diaries and outcome variable analysis will not be possible.
Section 9.3.4.7, Effect on lung function and bronchial hyper-responsiveness – Removed 
“…and post-BD” when discussing the change in baseline to week 28 for FEV1, FVC, 
FEF25-75% as post-BD spirometry measurement is not performed at EOT.
Section 9.3.4.8, Calculation or derivation of pharmacokinetics and immunogenicity 
variables – Removed “These validated methods are conducted using a bridging assay 
format and statistically determined floating screening assay cut point factor and 
confirmatory assay cut point. The minimal sample dilution is 1:13. Titer values are reported 
as the reciprocal of the highest dilution that yields a value above the cut point.” and added 
“Details of the method will be provided in validation reports as well as in bioanalytical 
reports.”. This change was made to clarify where the details of the method will be 
maintained.
Section 9.3.4.8, Calculation or derivation of pharmacokinetics and immunogenicity 
variables – Updated “Samples that confirm positive for ADA will also be tested for nAb 
activity.” to “Samples with confirmed positive ADAs will be archived for possible testing 
for nAb.”. This change was to clarify that nAb samples will be archived for possible future 
testing. 
Section 9.3.4.8, Calculation or derivation of pharmacokinetics and immunogenicity 
variables – Added “The prevalence and incidence of ADA over the course of the study will 
be calculated and tabulated by treatment group.” and removed “Neutralizing antibody 
evaluations will be conducted on those serum samples that test positive for ADA at end of 
treatment and also during the study follow up period. The test sample is deemed positive or 
negative for the presence of nAb to tezepelumab relative to a predetermined (in assay 
validation), statistically derived cut point. Samples positive for nAb to tezepelumab are then 
titered to determine relative amounts of nAb present in each test sample.” This change was 

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made to clarify how ADA results will be presented and that nAb samples will be archived 
for possible future testing.
Section 9.3.5, Calculation or derivation of safety variables – Updated “The following safety 
data will be collected: vital signs, physical examination, 12-lead ECG, hematology, clinical 
chemistry, urinalysis, and reported AEs.” to “The following safety data will be collected: 
vital signs, physical examination, 12- or 15-lead ECG, hematology, clinical chemistry, 
urinalysis, and reported AEs.” to clarify that either 12- or 15-lead ECGs are acceptable.
Section 9.3.5.3, Laboratory variables – Corrected “Table 3” to “Table 7” when referencing 
the lab parameters to be collected. 
Section 9.4.1, Efficacy analyses – Replaced “Efficacy analyses will be based on the full 
analysis set (FAS) population, and subjects will be classified according to their randomized 
treatment.” with “Efficacy analyses will be primarily based on the evaluable analysis set, 
and subjects will be classified according to their randomized treatment.” to account for 
subjects in the full analysis set with at least 20 weeks of treatment. 
Section 9.4.1, Efficacy analyses – Removed “%change” when discussing outcome measure 
for primary/secondary outcomes as this will only be presented as a ratio. 
Section 9.4.1, Efficacy analyses – Updated “All hypothesis testing will be reported using 2-
sided tests at the nominal 10% significance level. For the primary endpoints only, 
hypothesis tests with a nominal 5% significance level using 1-sided tests will also be 
reported. The alternative hypothesis for the 1-sided tests is that the ratio 
tezepelumab/placebo is lower than 1.” to “All hypothesis testing will be reported using 2-
sided tests with a nominal 10% significance level and 90% confidence intervals (CIs). For
the primary endpoints only, 2-sided 95% CIs will also be reported. The direction of interest
for each of the primary endpoints is that the ratio tezepelumab/placebo is lower than 1.” 
This change is to clarify the method of reporting the testing of the hypotheses.  
Section 9.4.2, Analysis of the primary variable(s) – Added “expressed as a ratio” when 
discussing change from baseline to week 28 and updated “The primary variable of within 
subject change from baseline to week 28 (expressed as a ratio) in numbers of each of the 
airway submucosal inflammatory cells will be analyzed using an analysis of covariance 
(ANCOVA) including at least baseline value and treatment as covariates.” to "The primary 
variable of within subject change from baseline to week 28 (expressed as a ratio) in 
numbers of each of the airway submucosal inflammatory cells will be analyzed using an 
analysis of covariance (ANCOVA) including at least screening blood eosinophil strata 
(screening blood eosinophil count < 150 cells/µL, 150 - 300 cells/µL, and > 300 cells/µL at 

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Visit 1), baseline value, and treatment as covariates.” to clarify that the change is expressed 
as a ratio change and to specify the exact stratification factor.
Section 9.4.2, Analysis of primary variable(s) – Removed “Patients that discontinue IP prior 
to week 20 visit will be excluded from the primary analyses.” as contained in the evaluable 
analysis set definition. 
Section 9.4.3, Analysis of the secondary variable(s) - Added “expressed as a ratio” when 
discussing change from baseline to week 28 to clarify that the change is expressed as a ratio 
change. 
Section 9.4.4, Supportive analysis – Updated “For the primary and secondary variables, 
non-parametric analysis methods will be applied as supportive analyses. For the primary 
analysis, the same method will be used including subjects who complete at least 16 weeks 
of treatment as a supportive analysis.” to “For the primary and secondary variables,
alternative transformations or non-parametric analysis methods may be applied as
supportive analyses if substantial deviations from the parametric assumptions are observed.  
This will be assessed and documented prior to unblinding. For the primary variables, the 
analysis may be repeated using the full analysis set, hence including assessments in subjects 
who complete between 16 and 20 weeks of treatment as a supportive analysis.” This change 
was made to further clarify the supportive analysis, including the definition of the 
supportive analysis set. 
Appendix A, Regulatory, ethical and study oversight considerations – Added details 
regarding the sponsor’s right to close a study site or terminate the study and potential 
reasons for early closure of a study site to A9 and Publication Policy shifted to A10. This 
change was made as per new AstraZeneca guidelines.  
Appendix E, Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law – Added “All sources of laboratory data are appropriate for the determination of 
PHL and HL events; this includes samples taken at scheduled study visits and other visits 
including central and all local laboratory evaluations even if collected outside of the study 
visits; for example, PHL criteria could be met by an elevated ALT from a central laboratory 
and/or elevated TBL from a local laboratory. The Investigator will also review AE data (for 
example, for AEs that may indicate elevations in liver biochemistry) for possible PHL 
events.” to E1. The appendix has been updated in conjunction with sponsor's routine 
pharmacovigilance activities/processes. 
Appendix E, Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law – Removed “Determine whether PHL criteria were met at any study visit prior to 
starting Study treatment (See Section E 6 Actions Required When Potential Hy’s Law 

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Criteria are Met Before and After Starting Study Treatment) from E4.2. The appendix has 
been updated in conjunction with sponsor's routine pharmacovigilance activities/processes.  
Appendix E, Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law – Updated “Once the necessary supplementary information is obtained, repeat the 
review and assessment to determine whether HL criteria are met. Update the SAE report 
according to the outcome of the review amending the reported term if an alternative 
explanation for the liver biochemistry elevations is determined.” to “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.” at E5. The appendix has been updated in conjunction with the sponsor's 
routine pharmacovigilance activities/processes.   
Appendix E, - Updated “Update the previously submitted PHL SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.” to “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.” at E5.The appendix has been updated in conjunction with 
sponsor's routine pharmacovigilance activities/processes. .  
Appendix E, Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law – Removed subsection E6 and E7 and renumbered subsequent subsections. The 
appendix has been updated in conjunction with the sponsor's routine pharmacovigilance 
activities/processes.   
Appendix F, Maintenance therapy equivalence table – Updated to include ICS/LABA 
combination therapies and changed footnote ‘a’ to confirm the source of the ICS/LABA 
combination therapy dose details. This change was made to provide Investigators additional 
information when assessing eligibility. 
Appendix F, Maintenance therapy equivalence table – removed the low dose references for 
ICS-LABA medication as low dose is not applicable to this study. 
Added Appendix I, Medication washout period for airway hyper-responsiveness, as these 
restrictions are more stringent than the medication washout for the study and are required to 
be withheld for safety and pharmacokinetic purposes. 
Various typographical and grammatical corrections have been made.

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Version 2.0, 12 Nov 2018
Changes to the protocol are summarized below
Section 1.1, SoA, Table 1 – Removed Pre-BD spirometry from V3a.
Section 1.1, SoA, Table 1 – Added Safety Spirometry (optional) to V3b.
Section 1.1, SoA, Table 1 –Removed FeNO from V3b and added to V3a.
Section 1.1, SoA, Table 1 –Removed AO from V3b and added to V3a.
Section 1.1, SoA, Table 1 – Updated footnote ‘*’ from “Order of assessments at V3a would 
be ACQ-6, vital signs, spirometry, physical exam.” to “Order of assessments at V3a would 
be ACQ-6, vital signs, FeNO, AO, physical exam.” and added “A compliance check for 
background medication and paper diary completion to be completed.”.
Section 1.1, SoA, Table 1 – Updated footnote ‘**’ from “Order of assessments at V3b 
would be FeNO, AO, vital signs, blood draw, bronchoscopy, then IP administration. Visit 3a 
and 3b should be performed within 7 days of each other.” to “Order of assessments at V3b 
would be vital signs, spirometry, blood draw, bronchoscopy (biopsy, brushing, then BAL),
then IP administration. Per PI discretion, the IP can be administered on the day after V3b if 
there is any safety concern. Visit 3a and 3b should be performed within 7 days of each 
other.”
Section 1.1, SoA, Table 1 – Updated footnote ‘8’ from “Paper diary will capture rescue 
medication, night time awakening, and use of maintenance medications from the evening of 
V2 to the morning of V14. Paper diary will be distributed at V2 to V11 (sufficient paper 
diaries will be distributed at V11) and collected at V3 to V11 and V14.” to “Paper diary will 
capture rescue medication, night time awakening, and use of maintenance medications from 
the evening of V2 to the morning of V14. Paper diary will be distributed at V2 to V11 
(sufficient paper diaries will be distributed at V11 for follow-up phase) and collected at V3 
to V11 and V14. The diary dispensed at V2 will be re-used for both V3a and V3b. Diary 
and background medications compliance for inclusion criteria numbers 15 and 16 will be 
performed at V3a.” to indicate that the diary dispensed at V2 will be re-used for both V3a 
and V3b. Diary and background medications compliance for inclusion criteria 15 and 16 
will be performed at V3a.
Section 1.1, SoA, Table 1 – Changed “baseline spirometry (Visit 3b)” to “baseline 
spirometry (Visit 1 or 2)”.

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Section 1.1, SoA, Table 1 – Added footnote ‘16’ to indicate that CT is to be performed 
between V3a and V3b.
Section 1.1, SoA, Table 1 – Added footnote ‘17’ to indicate that “In case of repeat of 
spirometry at V2, the AHR will be rescheduled to be done within 3 days of V2.”
Section 1.1, SoA, Table 1 – Added ADA testing at Unscheduled along with footnote ‘18’ to 
indicate that “ADA sample should be collected in case of any suspected immunologically-
related AEs.”
Section 1.1, SoA, Table 1 – Updated “Tezepelumab PK” to “Blood for Tezepelumab PK”
Section 1.1, SoA, Table 1 – Added “(except for spirometry which should be done pre-BD at 
V11)” to footnote ‘3’.
 
 
 
 
 
 
 
 
 
Section 1.2, Synopsis – Added information regarding the Data Safety Monitoring Board
Section 2.2, Background – Updated with additional published information regarding Study 
CD-RI-MEDI9929-1146.
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Section 5.1, Inclusion criteria #7 – Replaced “Subjects on OCS are allowed in the study, 
provided they are on a stable dose for at least 6 months before V1.” with “Subjects on OCS 
are allowed in the study, provided they are on a stable maintenance dose for at least 6 
months before V1.”
Section 5.1, Inclusion #9 – Replaced “15-30 min” with “15-60 min”
Section 5.1 - Removed Inclusion #14 which stated “Non-sterilized males who are sexually 
active with a female partner of childbearing potential must use a male condom plus 
spermicide from enrolment through 16 weeks after receipt of the final dose of IP. In the 
countries where the abovementioned method of contraception is not available a condom can 
be used alone. Male subjects must not donate or bank sperm during this same time period”
Section 5.1, Inclusion criteria #16 – Corrected “Subjects must have demonstrated a 
minimum 70% compliance with background asthma medication the during run-in period.” 
to read as “Subjects must have demonstrated a minimum 70% compliance with background 
asthma medication during the run-in period.”
Section 5.1, Inclusion #19 – Added “at Visit 3b”
Section 5.2, Exclusion #21 – Removed “the current study or”
Section 5.4, Screen failures – Added “Subjects who experience an asthma exacerbation 
during run-in period may be re-screened after 14 days of complete resolution of the asthma 
exacerbation, and when the subjects return to their baseline, at Investigator discretion.” and 
removed typo “X`”
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Section 6.4, Treatment Compliances – Removed “as well as any missed doses”
Section 6.5, Table 5 – Updated “Use of SABA should be avoided within 6 hours before 
ECG assessments.” to “Use of SABA or SAMA should be avoided within 6 hours before 
ECG assessments.”
Section 6.5.2, Rescue medication – Added “or SAMA” and removed “When possible, home 
lung function should be taken at least 6 hours after the last dose of SABA rescue 
medication.”
Section 7.1.1, Procedures for discontinuation of study medication – Corrected “…post last 
IP administration for the EOT visit at Week 28 (+/-3 days).” to “…post last IP 
administration and for the EOT visit at Week 28 (+/-3 days).”
Section 7.3, Withdrawal from the study – Added “AstraZeneca reserves the right to 
discontinue a subject’s participation in the study for any safety reasons.”
Section 8.1.1, Bronchial biopsy – Updated “Subjects will receive a sedative and local 
anesthetic to reduce any discomfort.” to “Subjects will receive a sedative and local 
anesthetic to reduce any discomfort, local guidelines to be followed.”
Section 8.1.1, Bronchial biopsy – Added “Bronchial biopsy, being the primary endpoint, 
will be conducted first followed by bronchial brushing then BAL.” to clarify the order of 
assessments. 
Section 8.1.5, Airway hyper-responsiveness – Added “In case of repeat spirometry at V2, 
AHR will be rescheduled within 3 days of Visit 2.”
Section 8.1.6, Biomarkers – Updated “Blood samples should be collected pre-dose at the 
pre-specified scheduled visit in the SoA” to “All biomarker samples should be collected 
pre-dose at the pre-specified scheduled visit in the SoA”
Section 8.1.7, Blood eosinophils and neutrophils – Added “All blood eosinophils and 
neutrophils results will be redacted from the laboratory reports except for Visit 1 and Visit 
3.” and removed “Results will be blinded after randomization.”
Section 8.1.9, Serum IgE – Added “All total serum IgE results will be redacted from the 
laboratory reports except for Visit 3.”
Section 8.1.11, DNA for genetics – Added “This data will be reported separately from the 
CSR in an addendum or in a scientific report or publication.”

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Section 8.1.12, Urine Biomarkers – Removed “which may include, but not limited to, lipids 
such as thromboxane.” 
Section 8.1.16.1, General requirements – Updated “SABAs should be withheld at least 6 
hours prior to scheduled spirometry at site.” to “SABAs and SAMAs should be withheld at 
least 6 hours prior to scheduled spirometry at site.”
Section 8.1.16.1, General requirements – Removed “and at randomization visits (Visit 3b 
(V3b))” and replaced “randomization spirometry” with “enrolment spirometry”.
Section 8.1.16.2, Figure 3 – Replaced “Wait 15-30 min” with “Wait 15-60 min”
Section 8.1.16.2, FeNO – Moved to new section 8.1.17
Section 8.1.17 (formerly section 8.1.16.2), FeNO – Updated “Subjects should not use their 
rescue SABA medication (e.g. albuterol/salbutamol) within 6 hours of the measurement.” to 
“Subjects should not use their rescue SABA medication (e.g. albuterol/salbutamol) or 
SAMA medications within 6 hours of the measurement.”
Section 8.1.17 (formerly section 8.1.16.2), FeNO – Updated “All FeNO measurements will 
be blinded for sites and subjects throughout.” to “All post-randomization FeNO 
measurements will be blinded for sites and subjects throughout the study.”
Section 8.1.17, Patient Reported Outcomes – Updated to section 8.1.18
Section 8.2.2, Weight and height – Removed “BMI will be automatically calculated in the 
eCRF.”
Section 8.2.5, Electrocardiograms – Removed “overall data and”
Section 8.3.2, Time period and frequency for collecting AE and SAE information – Added 
“AEs and SAEs should still be collected after IP discontinuation for subjects that 
prematurely discontinue from IP and will be encouraged to undergo appropriate study 
visits/procedures for the full 40-week period.”
Section 8.3.3, Follow-up of AEs and SAEs – Updated “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.” to “All SAE/non-serious AEs/AEs of special 
interest, AEs leading to premature discontinuation will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up.”
Section 8.3.7, Adverse events based on examinations and tests – Updated to include ECG 
and removed “unless unequivocally related to the disease under study”.
Section 8.4.2, Pregnancy – Added “Any cases of pregnancy during the study period or 
follow up will be recorded in the specific CRF module.”

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Section 8.4.2.1, Maternal Exposure – Updated “The PREGREP module in the CRF is used 
to report the pregnancy and PREGOUT is used to report the outcome of the pregnancy.” to 
“The PREGREP module in the CRF is used to report the pregnancy and the paper-based 
pregnancy outcome report is used to report the outcome of the pregnancy.”
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.”
Section 8.4.6, Data Safety Monitoring Board – section was added with details regarding the 
scope of the DSMB
Section 8.5.1 Collection of samples and drug concentrations – Removed “and BAL” and 
added "Samples for determination of tezepelumab concentration in BAL will be analyzed 
by a designated third party on behalf of AstraZeneca using a qualified bioanalytical method. 
Samples for determination of urea will be analyzed by a designated third party on behalf of 
AstraZeneca using qualified bioanalytical methods."
Section 8.5.2, Collection of samples to measure the presence of ADAs – Added “ADA 
sample should be collected in case of any suspected immunologically-related AEs.”
Section 8.8.2, Serum IgE – Added “All total serum IgE results will be redacted from the 
laboratory reports except for Visit 3.”
Section 9.2, Populations for analyses – Added “and PK BAL”
Section 9.3.4.4, Effect on restoring peripheral pulmonary vasculature – Removed 
“Exploratory biomarker of tissue vascularity in bronchial biopsy specimens assessed by 
histology, IHC, or ISH.”
Appendix E, Actions required in cases of increases in liver biochemistry and evaluation of 
Hy’s Law – Appendix has been updated including addition of section E6, E7, and E8.
Appendix F, Maintenance Therapy Equivalence Table – Updated as per GINA 2018 
guidelines. 
Appendix F, Maintenance Therapy Equivalence Table – Added “Breo®” as example of 
Fluticasone furoate. 
Various typographical and grammatical corrections have been made. 
Version 1.0, 20 Jul 2018
Initial Creation

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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................1
VERSION HISTORY ...........................................................................................................2
TABLE OF CONTENTS....................................................................................................28
1.
PROTOCOL SUMMARY ................................................................................33
1.1
SoA ..................................................................................................................33
1.2
Synopsis ...........................................................................................................38
1.3
Schema .............................................................................................................46
2.
INTRODUCTION ............................................................................................47
2.1
Study rationale..................................................................................................47
2.2
Background.......................................................................................................48
2.3
Benefit/risk assessment .....................................................................................50
3.
OBJECTIVES AND ENDPOINTS...................................................................51
4.
STUDY DESIGN .............................................................................................55
4.1
Overall design...................................................................................................55
4.2
Scientific rationale for the study design.............................................................56
4.3
Justification for dose.........................................................................................57
4.4
End of study definition......................................................................................57
5.
STUDY POPULATION ...................................................................................58
5.1
Inclusion criteria ...............................................................................................58
5.2
Exclusion criteria ..............................................................................................61
5.3
Lifestyle restrictions..........................................................................................65
5.3.1
Meals and dietary restrictions............................................................................65
5.3.2
Alcohol, tobacco and other................................................................................65
5.3.3
Activity.............................................................................................................65
5.4
Screen failures ..................................................................................................66
6.
STUDY TREATMENTS..................................................................................67
6.1
Treatments administered ...................................................................................67
6.1.1
Investigational products ....................................................................................67
6.2
Preparation/handling/storage/accountability......................................................68
6.3
Measure to minimize bias: randomization and blinding.....................................71
6.4
Treatment compliance.......................................................................................74
6.5
Concomitant therapy.........................................................................................74
6.5.1
Other concomitant treatment .............................................................................78
6.5.2
Rescue medication ............................................................................................78
6.6
Dose modification.............................................................................................79
6.7
Treatment after the end of the study ..................................................................79

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7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL .79
7.1
Discontinuation of study treatment....................................................................79
7.1.1
Procedures for discontinuation of study treatment .............................................80
7.2
Lost to follow-up ..............................................................................................81
7.3
Withdrawal from the study................................................................................82
7.3.1
Withdrawal due to recruitment completion........................................................83
7.3.2
Discontinuation or suspension of the whole study program ...............................83
8.
STUDY ASSESSMENTS AND PROCEDURES..............................................83
8.1
Efficacy assessments.........................................................................................84
8.1.1
Bronchial biopsy...............................................................................................84
8.1.2
Bronchial brushing............................................................................................84
8.1.3
Bronchoalveolar lavage.....................................................................................85
8.1.4
Airwave oscillometry........................................................................................85
8.1.5
Airway hyper-responsiveness............................................................................85
8.1.6
Biomarkers .......................................................................................................86
8.1.7
Blood eosinophils and neutrophils.....................................................................86
8.1.8
Airway inflammatory cells................................................................................86
8.1.9
Serum IgE.........................................................................................................86
8.1.10
RNA transcriptomics.........................................................................................87
8.1.11
DNA for genetics..............................................................................................87
8.1.12
Urine biomarkers ..............................................................................................87
8.1.13
Computed tomography......................................................................................87
8.1.14
Assessment of asthma exacerbation...................................................................88
8.1.15
Allergen specific IgE (FEIA) ............................................................................90
8.1.16
Spirometry........................................................................................................90
8.1.16.1
General requirements ........................................................................................90
8.1.16.2
Post-BD spirometry and FEV1 reversibility assessment .....................................91
8.1.17
Fractional exhaled nitric oxide ..........................................................................93
8.1.18
Patient reported outcomes .................................................................................94
8.1.18.1
Paper Diary.......................................................................................................94
8.1.18.2
Asthma control questionnaire (ACQ-6).............................................................95
8.2
Safety assessments............................................................................................95
8.2.1
Clinical safety laboratory assessments...............................................................95
8.2.1.1
Pregnancy Test .................................................................................................96
8.2.2
Weight and height.............................................................................................97
8.2.3
Physical examinations.......................................................................................97
8.2.4
Vital signs.........................................................................................................97
8.2.5
Electrocardiograms ...........................................................................................98
8.2.6
Other safety assessments...................................................................................98
8.2.6.1
Serology ...........................................................................................................98
8.3
Collection of adverse events..............................................................................98
8.3.1
Method of detecting AEs and SAEs ..................................................................99
8.3.2
Time period and frequency for collecting AE and SAE information..................99
8.3.3
Follow-up of AEs and SAEs .............................................................................99
8.3.4
Adverse event data collection.......................................................................... 100

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8.3.5
Causality collection......................................................................................... 100
8.3.6
Adverse events based on signs and symptoms................................................. 101
8.3.7
Adverse events based on examinations and tests ............................................. 101
8.3.8
Adverse events of special interest.................................................................... 102
8.3.9
Hy’s law ......................................................................................................... 102
8.4
Safety reporting and medical management ...................................................... 103
8.4.1
Reporting of serious adverse events ................................................................ 103
8.4.2
Pregnancy....................................................................................................... 103
8.4.2.1
Maternal exposure........................................................................................... 104
8.4.2.2
Paternal exposure............................................................................................ 104
8.4.3
Overdose......................................................................................................... 104
8.4.4
Medication error ............................................................................................. 105
8.4.5
Management of IP-related toxicities................................................................ 105
8.4.6
Data safety monitoring board .......................................................................... 106
8.5
Pharmacokinetics............................................................................................ 106
8.5.1
Collection of samples and drug concentration ................................................. 106
8.5.2
Collection of samples to measure the presence of ADAs.................................107
8.5.3
Storage and destruction of pharmacokinetic/ADA samples.............................. 107
8.6
Pharmacodynamics ......................................................................................... 107
8.7
Genetics.......................................................................................................... 107
8.7.1
Optional exploratory genetic sample ............................................................... 107
8.7.2
Storage and destruction of genetic samples ..................................................... 108
8.8
Biomarkers ..................................................................................................... 108
8.8.1
Storage, re-use and destruction of biomarker samples ..................................... 109
8.8.2
Serum IgE....................................................................................................... 109
8.8.3
Transcriptomics .............................................................................................. 109
8.8.4
Storage, re-use and destruction of transcriptomics samples.............................. 109
8.9
Healthcare Resource Utilization and Health Economics .................................. 110
9.
STATISTICAL CONSIDERATIONS............................................................. 110
9.1
Sample size determination............................................................................... 110
9.2
Populations for analyses.................................................................................. 111
9.3
Outcome measures for analyses....................................................................... 112
9.3.1
Definition of baseline and subject baseline analyses........................................ 112
9.3.2
Primary outcome measure............................................................................... 112
9.3.3
Secondary outcome measures.......................................................................... 113
9.3.4
Exploratory outcome measures ....................................................................... 113
9.3.4.1
Other biomarkers of airway inflammation....................................................... 113
9.3.4.2
Effect on large airways remodeling .................................................................114
9.3.4.3
Effect on small airways obstruction.................................................................114
9.3.4.4
Effect on restoring peripheral pulmonary vasculature...................................... 114
9.3.4.5
Rescue Use ..................................................................................................... 114
9.3.4.6
Asthma control questionnaire (ACQ-6)........................................................... 115
9.3.4.7
Effect on lung function and bronchial hyper-responsiveness ........................... 115
9.3.4.8
Calculation or derivation of pharmacokinetics and immunogenicity variables.116

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9.3.5
Calculation or derivation of safety variables.................................................... 116
9.3.5.1
Adverse events................................................................................................ 116
9.3.5.2
Other significant adverse events...................................................................... 117
9.3.5.3
Laboratory variables ....................................................................................... 117
9.3.5.4
ECGs .............................................................................................................. 118
9.3.5.5
Physical Examination...................................................................................... 118
9.3.5.6
Vital signs....................................................................................................... 119
9.4
Statistical analyses .......................................................................................... 119
9.4.1
Efficacy analyses ............................................................................................ 119
9.4.2
Analysis of the primary variable(s) .................................................................120
9.4.3
Analysis of the secondary variable(s) .............................................................. 121
9.4.4
Supportive analysis......................................................................................... 121
9.4.5
Exploratory analysis........................................................................................ 121
9.4.6
Safety analyses ............................................................................................... 122
9.4.7
Other analyses.................................................................................................122
9.5
Interim analyses.............................................................................................. 122
10.
REFERENCES ............................................................................................... 123
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 130
LIST OF TABLES
Table 1 – Schedule of Activities..........................................................................................33
Table 2 – Objectives and Endpoints ....................................................................................51
Table 3 – Study treatments..................................................................................................67
Table 4 – Investigational product dose preparation..............................................................69
Table 5 – Restricted medications.........................................................................................75
Table 6 – Prohibited medications ........................................................................................77
Table 7 – Laboratory safety variables..................................................................................96
Table 8 – Population descriptions...................................................................................... 111
LIST OF FIGURES
Figure 1
Study design ............................................................................................46
Figure 2
Suggested schema of rotation of injection sites ........................................70
Figure 3
Reversibility algorithm ............................................................................92

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LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations........................... 131
Appendix B
Adverse event definitions and additional safety information................... 136
Appendix C
Handling of human biological samples................................................... 141
Appendix D
Genetics.................................................................................................144
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law.......................................................................... 148
Appendix F
Maintenance therapy equivalence table .................................................. 154
Appendix G
Anaphylaxis: signs and symptoms, management.................................... 155
Appendix H
Abbreviations ........................................................................................ 159
Appendix I
Medication washout periods for airway hyper-responsiveness................ 164
Appendix J
Changes related to COVID 19 Pandemic................................................ 165

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1.
PROTOCOL SUMMARY
For detailed schedule of activities (SoA) please see section 1.1 below.
1.1
SoA
Table 1 – Schedule of Activities
Assessment/ activity
Screening
Run
-in
Randomization
Treatment period
EOT
***/ 
IPD
FU
UNS 
visit1
Details in CSP Section 
or Appendix 
Visits
Visit number
1
2
3a*
3b**
42
5
6
7
8
9
10
113
122

132

14
Details in CSP Section or 
Appendix
Weeks
Visit week
-4
-2
0
2
4
8
12
16
20
24
28
32
36
40
Visit window (days)4
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Routine Clinical Procedures
Informed consent
X
See Section 5.1
Inclusion/exclusion criteria
X
X
X
X
See Section 5.1& 5.2
Demographics
X
See Section 5.1& 5.2
Medical/surgical and asthma history
X
X
See Section 5.1
Height
X
See Section 8.2.2
Weight
X
X
X
X
See Section 5.1 & 8.2.2
Hematology
X
X
X
X
X
X
See Section 8.2.1
Serology (Hepatitis B, C; HIV-1,2)
X
See Section 8.2.6
Serum pregnancy test
X
X
See Section 8.2.1
Urine pregnancy test (dipstick)
X
X
X
X
X
X
X
X
See Section 5.1
FSH
X5
See Section 8.2.1
Blood for Tezepelumab ADA and nAb6
X
X
X
X
X17
See Section 8.5.2 & 
9.3.4.8
Serum IgE
X
X
X
X
See Section 8.1.9
IgE (FEIA)
X
See Section 8.1.15
Healthcare resource utilization7
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.9

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Assessment/ activity
Screening
Run
-in
Randomization
Treatment period
EOT
***/ 
IPD
FU
UNS 
visit1
Details in CSP Section 
or Appendix 
Visits
Visit number
1
2
3a*
3b**
42
5
6
7
8
9
10
113
122

132

14
Details in CSP Section or 
Appendix
Weeks
Visit week
-4
-2
0
2
4
8
12
16
20
24
28
32
36
40
Visit window (days)4
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Routine Safety Procedures
Distribution and collection of paper diary8
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.1.18.1
Clinical chemistry
X
X
X
X
X
X
See Section 8.2.1
Urinalysis (dipstick)
X
X
X
X
X
See Section 8.2.1
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.3
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 5.2 & 6.5
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.2.4 & 
9.3.5.6
Local ECG
X
X
See Section 5.2 & 8.2.5
Complete physical examination
X
X
X
See Section 9.3.5.5
Brief physical exam
X
X
X
See Section 9.3.5.5
Efficacy Measurements
ACQ-6
X
X9
X
X
X
See Section 8.1.18.2 & 
9.3.4.6
Urine for biomarker 
X
X
X
X
See Section 8.1.12
Asthma exacerbation reporting10
X
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.1.14
Blood for serum and plasma biomarkers6
X
X
X
X
See Section 8.1.6
Blood for RNA transcriptomics6,11
X
X
X
X
See Section 8.8.3
Fractional exhaled nitric oxide (FeNO)
X
X
X
X
See Section 8.1.17
Computed tomography (CT)
X15
X12
See Section 8.1.13
Pre- BD, spirometry
X
X13
X
X
X
See Section 8.1.16
Post-BD, spirometry
X
X13
See Section 8.1.16.2
Safety spirometry, optional
X
See Section 8.1.16.1
Airwave oscillometry (AO)
X
X12
See Section 8.1.4
Airway hyperresponsiveness (AHR)
X16
X12
See Section 8.1.5
Bronchoscopy/biopsy/brushing and 
bronchoalveolar lavage (BAL) 6, 11
X
X12
See Section 8.1
Pharmacokinetic Measurements

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Assessment/ activity
Screening
Run
-in
Randomization
Treatment period
EOT
***/ 
IPD
FU
UNS 
visit1
Details in CSP Section 
or Appendix 
Visits
Visit number
1
2
3a*
3b**
42
5
6
7
8
9
10
113
122

132

14
Details in CSP Section or 
Appendix
Weeks
Visit week
-4
-2
0
2
4
8
12
16
20
24
28
32
36
40
Visit window (days)4
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Blood for Tezepelumab PK6
X
X
X
X
See Section 8.5
Pharmacogenetic Sampling
Blood for DNA (optional)
X
See Section 8.7.1
Study Treatment Administration
Randomization
X
See Section 6.3
IP administration14
X
X
X
X
X
X
X
X18
See Section 6.2
* Order of assessments at V3a would be ACQ-6, vital signs, FeNO, AO, physical exam. A compliance check for background medication and paper diary completion to be completed. 
** Order of assessments at V3b would be vital signs, spirometry (if performed), blood draw, bronchoscopy (biopsy, brushing then BAL), then IP administration. Per PI discretion, the IP can be 
administered on the day after V3b if there is any safety concern. Visit 3a and 3b should be performed within 7 days of each other. 
*** During the COVID-19 pandemic unscheduled visits may occur so that sites may perform EOT assessments 4 weeks after last dose of IP at either week 28, 32, 36, 40, 44 or 48 (as needed) until 
the sites are able to resume the EOT assessments.
Telephone Visit
1
PI can add more assessments as needed to unscheduled visits.
2
Visits 4, 12 and 13 are phone visits. 
3
Based on investigator’s judgement and site resources, EOT assessments (V11) will be performed over more than one day, within a 7-day window. The sequence of assessments during Visit 11 
should be performed in the same order as completed at Visits 3a, 3b (except for spirometry which should be done pre-BD at V11). Proposed order of assessments as follows: Visit 11 Day 1 -
ACQ-6, paper diary completion, vital signs, ECG, FeNO, AO, physical exam, and AHR; Visit 11 Day 2 - vitals signs, pre-BD spirometry, blood draw, and bronchoscopy (biopsy, brushing, 
then BAL). Pre-BD spirometry can be done 1 day prior to bronchoscopy if there is a safety concern. During the COVID-19 pandemic unscheduled visits may occur so that sites may perform 
EOT assessments 4 weeks after last dose of IP at either week 28, 32, 36, 40, 44 or 48(as needed) until the sites are able to resume the EOT assessments.
4
All visits are to be scheduled from the date of randomization, not from the date of the previous visit. 
5
FSH will be done only for women < 50 years old, if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment.
6
Blood and BAL samples for PK and blood samples for ADA and nAb, biomarker and transcriptomics evaluations will be collected before the administration of IP. Samples with confirmed 
positive ADAs will be archived for possible testing for nAb.
7
Asthma specific resource utilization (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications).
8
Paper diary will capture rescue medication, night time awakening, and use of maintenance medications from the evening of V2 to the morning of V14. The morning diary will include: 
questions about rescue medications, night-time awakening, and use of maintenance medications. The evening diary will include: questions about rescue medications. Paper diary will be 
distributed at V2 to V11 (sufficient paper diaries will be distributed at V11) and collected at V3 to V11 and V14. The diary dispensed at V2 will be re-used for both V3a and V3b. Diary and 
background medications compliance for inclusion criteria numbers 14 and 15 will be performed at V3a. During the COVID-19 pandemic, recording, collecting and dispensing will continue 
once administration of extra dosing is implemented.
9
ACQ-6 will be performed at Visit 2 only if the eligibility criterion is not met at Visit 1.

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10
Any asthma exacerbation before randomization will be reported as an AE/SAE. Any asthma exacerbation that will occur during treatment and FU will be reported in the exacerbation page in 
the eCRF.
11
RNA samples will be obtained from the peripheral blood and bronchial brushings. RNA may also be collected from lung biopsies and BAL cells if sufficient sample remains after the other 
assessments on these cells are completed. 
12
At EOT visit, AO, BAL, brushings, CT, and AHR will be performed only if baseline assessment is performed successfully, as confirmed by investigator. EOT biopsy will only be performed if 
baseline biopsy meets pathology QC.
13
Pre- and post-BD spirometry to assess FEV1 and its reversibility will be performed at Visit 2 only if eligibility criteria is not met at Visit 1. The spirometry will be rescheduled if the subject did 
not withhold their BD at V1. Pre-BD spirometry testing must be initiated in the morning between 6:00 AM and 11:00 AM.  All post-randomization spirometry assessments should be 
performed within ± 1.5 hours of the time that the baseline spirometry (Visit 1 and/or Visit 2) was performed. 
14
IP will be administered after performing all the visit-specific assessments. 
15
CT to be performed during the period between V3a and V3b.
16
In case of repeat of spirometry at V2, the AHR will be rescheduled to be done within 3 days of V2.
17
ADA sample should be collected in case of any suspected immunologically-related AEs
18
During the COVID-19 pandemic an additional 1 to 6 IP doses may be administered to subjects during unscheduled visits at weeks 28, 32, 36, 40, 44 and 48 (as needed) until the sites are able to 
resume performing all EOT study assessments, including bronchoscopies. All assessments during the unscheduled visit may not be necessarily be completed. Please refer to Appendix J.
CHANGES REQUIRED DURING COVID-19 PANDEMIC
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 trial integrity. Where allowable by local health authorities, ethics 
committees and healthcare provider guidelines (e.g. hospital policies), these changes include:
● The option of providing home-administration of Investigational Product (IP) performed by a site qualified Health Care Professional 
(HCP) or HCP provided by a third-party vendor (TPV), if possible. More information related to the visit can be obtained via phone 
call and/or virtual visits. The rationale for this change is to ensure that subjects are not missing any scheduled visits due to 
inability/unwillingness to visit the site during COVID-19 pandemic. 
●Adding 1-6 extra IP doses every 4 weeks after week 24 (possibly through weeks 28, 32, 36, 40, 44 and 48)   The rationale for this 
change is to ensure that the duration between the last IP dose and end of treatment assessments is within the protocol specified 
duration. Adding additional doses will give the subject a chance to resume bronchoscopies and other assessments when the pandemic 
is over. 

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●Phone call and/or virtual visits to replace the last on-site follow up visit, if subjects cannot attend the visits at the study site where 
necessary. The rationale for this change is to ensure that we collect the safety information if the last follow up cannot be done at the 
site. 
●Re-consent will be obtained verbally if allowed by local and regional guidelines. The rationale is to ensure that the subject agrees to 
the changes implemented to the COVID-19 pandemic. 
For further details, please refer to Appendix J

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1.2
Synopsis
International Co-ordinating Investigator: 
Professor Chris Brightling
NIHR Senior Investigator
University of Leicester
Leicester, United Kingdom
LE3 9QP
Protocol Title: A Phase 2, Randomized, Double-Blind, Parallel Group, Placebo Controlled 
Study to Evaluate the Effect of Tezepelumab on Airway Inflammation in Adults with 
Inadequately Controlled Asthma on Inhaled Corticosteroids and at least One Additional 
Asthma Controller (CASCADE)
Short Title: 
Bronchoscopy Mechanistic Study
Rationale: 
Tezepelumab has been shown to significantly reduce exacerbation rates in severe asthma.  It is 
assumed that this effect was achieved by tezepelumab effectively controlling airway 
inflammation, but this has not been previously confirmed. This study is intended to explore 
the mechanism of a tezepelumab airway anti-inflammatory effect in improving asthma 
outcomes. Of particular interest in this study, is the action of tezepelumab across the spectrum 
of Type 2 (T2) activity, including the effect of tezepelumab in the T2 low population. The 
primary objective of this study is to directly explore the airway anti-inflammatory effect of 
tezepelumab. The secondary objectives will explore whether tezepelumab treatment (1) 
reduces reticular basement membrane (RBM) thickness, (2) improves airway epithelial 
integrity, (3) benefits subjects across the spectrum of T2 airway inflammation. In addition, 
this study will address several exploratory questions. First, it will explore the effect of 
tezepelumab on large airway remodeling and small airway obstruction. Second, it will explore 
the effect of tezepelumab on various biomarkers in the lung, bronchoalveolar lavage (BAL), 
blood, and urine. Third, the relationship between improvement in airway inflammation, lung 
function and bronchial hyper-responsiveness will also be assessed. Fourth, the relationship 
between tezepelumab and the effect on different inflammatory cells in the blood will be 
explored. Finally, the effect of tezepelumab on the pulmonary vasculature will be assessed.

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Objectives and Endpoints
Primary Objective
Outcome Measure:
To explore the airway anti-
inflammatory effect of tezepelumab
Outcome Variable: The change, expressed as a ratio, in the 
number of airway submucosal inflammatory cells/mm2 of 
bronchoscopic biopsies from baseline to end of treatment 
(EOT). Airway submucosal inflammatory cells will 
include eosinophils, neutrophils, T cells and mast cells
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
Secondary Objective:
Outcome Measure:
To explore the effect of tezepelumab 
on RBM thickening   
Outcome Variable: The change, expressed as a ratio, in 
RBM thickness determined by microscopic evaluation of 
bronchoscopic biopsies from baseline to EOT 
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
To explore the effect of tezepelumab 
on airway epithelial integrity   
Outcome Variable: The change, expressed as a ratio, in % 
airway epithelial integrity determined by microscopic 
evaluation of bronchoscopic biopsies from baseline to EOT 
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
To explore the airway anti-
inflammatory effect of tezepelumab 
across the spectrum of T2 status by 
three gene mean derived from 
bronchial brushing RNA 
transcriptomics
Outcome Variable: The change, expressed as a ratio, in 
number of airway submucosal inflammatory cells per mm2
determined by microscopic evaluation of bronchoscopic 
biopsies from baseline to EOT in subjects across the 
spectrum of T2 status determining by RNAseq of bronchial 
brushings at baseline 
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT across the spectrum of T2 status.
Safety Objectives:
Outcome Measures:
To evaluate the safety and 
tolerability of tezepelumab 
Adverse events (AEs)/serious adverse events 
(SAEs)/adverse events of special interest (AESIs)
Clinical chemistry/hematology/urinalysis
Vital signs
Electrocardiograms (ECG)
Exploratory Objectives:
Outcome Measure:

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Objectives and Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
Overall design:
This is a Phase 2, multicentre, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the effect of tezepelumab on airway inflammation in adults with 
inadequately controlled moderate-to-severe asthma. Patients will have background asthma 
therapy of medium- or high dose ICS plus at least one additional asthma controller 
medication, such as a long-acting β2 agonist (LABA), leukotriene receptor antagonist 
CCI

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(LTRA), long-acting anti-muscarinic (LAMA), cromone, and theophylline, with or without 
maintenance oral corticosteroids (OCS) from screening and throughout the study including the 
follow-up period.
The study will consist of a screening/run-in period of up to 4 weeks, a treatment period of 28 
weeks and a post-treatment follow-up period of 12 weeks. One dose level of tezepelumab, 210 
mg will be compared with placebo administered subcutaneously (SC) every 4 weeks (Q4W) 
over the treatment period. Subjects who discontinue investigational product (IP) during the 
study will be encouraged to undergo appropriate study visits/procedures for the full 40-week 
period. Any new treatments that are initiated will be recorded.
Subjects who complete the 28-week study visit will complete a 12 week off-treatment follow-
up period.
Study period:
Estimated date of first patient enrolled: Q4 2018
Estimated date of last patient completed: Q1 2021
Number of subjects:
Approximately 110 subjects will be randomized 1:1 to the following groups: 
Tezepelumab 210 mg administered SC Q4W or
Matching placebo administered SC Q4W
The study aims to randomize subjects across the spectrum of T2 low and high activation. 
Approximately 30% of randomized subjects will have < 150 blood eosinophils/μL, 
approximately 30% of subjects with 150 – <300 blood eosinophils/μL and approximately 40% 
of subjects with ≥ 300 blood eosinophils/μL. When the target percentage of subjects for each 
eosinophil subgroup in the study is reached, consideration will be given to closing the 
IWRS/IVRS randomization for that subgroup, which may be done on the study level 
irrespective of the 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.
Treatments and treatment duration:
After initial enrolment and confirmation of entry criteria (Visit 1) subjects will proceed to a 
screening/run-in period of 4 weeks during which their suitability for randomization will be 
confirmed. The subjects’ currently prescribed ICS and additional asthma controller medication 
will remain unchanged during the run-in and treatment period. Subjects who meet the 
eligibility criteria at week -2 and randomization criteria at day 0 will be randomized to a 28-
week treatment period and will receive either tezepelumab or placebo as an IP in addition to 

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their existing asthma controller medications. IP will be administered at weeks 0, 4, 8, 12, 16, 
20 and 24. End of treatment (EOT) visit will be at week 28 (or later due to COVID-19 
pandemic). A safety follow-up period for all subjects will be for 12 weeks from EOT. 
Please note: During the COVID-19 pandemic, the treatment period may be extended and 
therefore subjects may be given 1 to 6 doses (as needed) every 4 weeks for a longer period 
than initially planned (please refer to Appendix J). For the last follow up visit, a phone call 
visit can replace an on-site visit. Please refer to Appendix J
Data safety monitoring board:
A Data Safety Monitoring Board (DSMB) is an external independent expert advisory group 
commissioned and charged with the responsibility of evaluating cumulative safety data at 
regular intervals and making appropriate recommendations based on the available data. The 
DSMB will periodically review unblinded safety summary tables and listings and evaluate for 
subject safety and make appropriate recommendations. 
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. The committee will operate in accordance 
with a DSMB Charter.
Statistical methods:
During the COVID-19 pandemic, all subjects with EOT assessments performed after 
unscheduled visits will be summarized and analyzed together with all subjects with EOT 
assessments performed during the scheduled EOT visit at week 28 and will be reported as 
having completed the EOT assessments” Please refer to Appendix J. 
The primary analysis of the efficacy endpoints will include all data captured during the double 
blind, treatment period (intent-to-treat approach).  However, only subjects with complete data 
for an endpoint will be included in the primary analysis of that endpoint.
The primary efficacy objective will be evaluated through statistical testing of the within 
subject change, expressed as a ratio, from baseline to EOT in number of airway submucosal 
inflammatory cells. The null hypothesis test H0 will be: The ratio tezepelumab/placebo equals 
1 and will be tested vs. H1: The ratio is not equal to 1. The test will be based on an analysis of 
covariance model. Covariates and factors included in the model will include at least screening 

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blood eosinophil strata (screening blood eosinophil count <150 cells/μL, 150 – <300 cells/μL, 
and ≥300 cells/μL at Visit 1), treatment, and baseline value. 
The secondary variables of within subject change from baseline up to EOT in the RBM 
thickness and epithelial integrity will be analysed using a similar model as for the primary 
variable. The secondary variable of within subject change from baseline up to EOT across the 
spectrum of T2 status in airway submucosal inflammatory cells will be assessed by using a 
similar model as for the primary variable with additional terms for T2 quartiles and their 
interactions with treatment and by visual data displays. 
The analyses will be performed by using log-transformed data and estimated geometric means 
and the ratio of geometric means with 90% confidence intervals will be presented. 
The study is sized to explore reductions in airway submucosal inflammation, from baseline to 
EOT, for tezepelumab versus placebo in the overall study population and across the T2 
continuum. 
The sample size is based on the primary endpoint: change from baseline to EOT in number of 
airway submucosal inflammatory cells. Given the assumed standard deviation of the log 
values of change in number of eosinophils in the two treatment groups are 1.87 and 2.06, it is 
estimated that 50 subjects in each treatment arm will be sufficient to achieve 80% power to 
detect a 2.7-fold difference in number of eosinophils versus placebo using a two-sided test at 
10% significance level. Given the assumed standard deviation of the log values of change in 
number of neutrophils in the two treatment groups are 0.71 and 0.97, it is estimated that 50 
subjects in each treatment arm will be sufficient to achieve > 90% power to detect a 2.7-fold 
difference in number of neutrophils versus placebo using a two-sided test at 10% significance 
level. 
It is assumed that a non-neglectable proportion of the subjects will not have an evaluable 
primary endpoint value due to failed biopsies. To account for this and subject dropouts, 55 
subjects will be randomized in each treatment arm.
The results for the exploratory variables will be summarized using descriptive statistics and 
graphical displays by treatment group. All safety parameters will be analyzed descriptively. 
The safety analyses will be based on the safety analysis data set, defined as all subjects who 
received at least one dose of IP.

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1.3
Schema
The general study design is summarized in Figure 1
Figure 1
Study design
  

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2.
INTRODUCTION
Asthma is a chronic inflammatory airway disorder caused by the interaction of genetic and 
environmental factors. It is characterized by widespread, variable reversible airflow 
obstruction, airway inflammation, excessive mucus production, and airway 
hyperresponsiveness that lead to recurrent episodes of wheezing, breathlessness, chest 
tightness, and coughing (The Collaborative Study on the Genetics of Asthma (CSGA) 1997, 
GINA 2018).
Progressive pathologic airway remodeling and scarring may occur in persistent asthma 
resulting in only partially reversible or irreversible airway obstruction (Pascual and Peters 
2005). The etiology of asthma is thought to be multi-factorial, influenced by both genetic and 
environmental mechanisms. The majority of cases arise when a person becomes 
hypersensitive to allergens. Despite the availability of multiple therapeutic options, asthma 
continues to be a major health problem. Worldwide, asthma currently affects approximately 
300 million people and by 2020, it is predicted to affect 400 million people (Partridge 2007). 
Each year in the US, asthma accounts for an estimated 8.9 million outpatient visits, 1.9 million 
emergency room visits, 479,000 hospitalizations (Corren et al 2017), and 3,400 deaths 
(Centers for Disease Control and Prevention 2017). 
Approximately 5% to 10% of asthma patients have severe asthma, which may be inadequately 
controlled by ICS and LABA combinations together with additional controller therapies 
(Brightling et al 2008). These patients are at risk of asthma exacerbations (Tough et al 1998, 
Turner et al 1998) and have the greatest medical need among the asthmatic population today. 
Patients with severe asthma represent the greatest economic cost (>50% of total asthma-
related health care costs) (Antonicelli et al 2004, Serra Batlles et al 1998, Barnes and Kuitert 
1996).
2.1
Study rationale
Tezepelumab is a human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) directed 
against thymic stromal lymphopoietin (TSLP). It binds to human TSLP and prevents its 
interaction with thymic stromal lymphopoietin receptor (TSLPR). A Phase 1b study 
(Gauvreau et al 2014) provided indirect evidence that tezepelumab acts as an airway anti-
inflammatory by showing attenuation of both the late asthmatic response (LAR) and the early 
asthmatic response (EAR) after allergen challenge; tezepelumab also reduced the expected 
increases in blood and sputum eosinophilia after this allergen challenge. A Phase 2b study 
(CD-RI-MEDI9929-1146) showed doses of 70 mg and 210 mg administered every 4 weeks 
(Q4W) and 280 mg of tezepelumab administered every 2 weeks resulted in reduction of 
annualized asthma exacerbation rates (AAER) by 61%, 71% and 66% respectively in the all-
comer population (Corren et al 2017).  Analysis of subgroups in the Phase 2b study also 
showed that tezepelumab benefited subjects with low and high baseline eosinophil counts and 

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a low and high T2 profile. These analyses suggest that tezepelumab, unlike other currently 
available biologics on the market used to treat severe asthma, is effective in subjects with T2 
high and T2 low airway inflammation. It is assumed that tezepelumab reduces the AAER by 
acting as an airway anti-inflammatory. However, information directly supporting this 
assumption is currently not available and this study will investigate this further. 
2.2
Background
Biologic therapies used to treat asthma have been shown to reduce the AAER in severe 
asthma patients who are uncontrolled with medium-to-high dose ICS and additional asthma 
controller medications. Omalizumab provided benefit 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). Three additional 
biologics, mepolizumab, reslizumab, and benralizumab have recently been approved for 
severe asthma with an eosinophilic phenotype (XOLAIR US PI 2016; CINQAIR US PI 2016; 
FASENRA US PI 2017). Benralizumab is indicated for the add-on maintenance treatment of 
patients with severe asthma aged 12 years and older, and with an eosinophilic phenotype 
(FASENRA US PI 2017).  Biologics targeting IL-5 and IgE are now included in international 
treatment guidelines (GINA 2018) as an add-on treatment to patients uncontrolled with 
ICS/LABA treatment. However, when using the 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). 
These approved biologic therapies show efficacy mainly in the T2 high subpopulation, but 
there are no current biologic therapies that address the need of the T2 low patients.
Tezepelumab is the first biologic that has shown promising data in a Phase 2b study for both 
T2 high and T2 low population (Corren et al 2017). This mechanistic study is designed to 
understand how tezepelumab works in the T2 low population. Therefore, despite these 
additional therapeutic options, there is still a clear unmet medical need among patients with 
severe asthma, independently 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 acts as a 
danger signal and is produced in response to numerous proinflammatory stimuli (e.g., 
infectious, allergic and environmental agents) and trauma. TSLP has a central role in the 
initiation of immune responses and can activate a broad range of cell types including 
eosinophils, mast cells, T cells, dendritic cells, ILC-2 cells and basophils (Watson and 
Gauvreau 2014). Classically, TSLP is believed to be a critical component in the initiation and 
perpetuation of the T2 response and the resulting cascade of cytokines associated with T2 
driven asthma (Kaur and Brightling 2012). Asthma is recognized as a heterogeneous disease. 
There are subsets of patients that do not exhibit T2-associated disease (Wenzel 2012), and 
there is existing data that TSLP may also mediate non-allergic (non-T helper cell 2) 

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inflammation (Tanaka et al 2009, Ziegler et al 2013). The three gene mean, derived from 
epithelial expression levels of periostin (POSTN), chloride channel accessory 1 (CLCA1), and 
serpin family B member 2 (SERPINB2), has been demonstrated as a surrogate marker of T2-
driven inflammation in mild to moderate asthmatics (Woodruff et al 2009, Choy et al 2011, 
Bhakta et al 2013). This epithelial gene expression signature will be used to retrospectively 
determine the degree of T2 activity of each individual at randomization (Visit 3b). We believe 
that tezepelumab will be efficacious in both T2 low and T2 high subjects (based on the Phase
2b data) so the effect of tezeplumab across the T2 spectrum as determined by the three gene 
mean signature, will be explored.
Tezepelumab is a fully human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) 
directed against TSLP. Tezepelumab binds to human TSLP and prevents its interaction with 
TSLP receptor (TSLPR). Owing to the central role of TSLP in initiating and maintaining a T2 
response, anti-TSLP therapy may provide an opportunity to treat the upstream underlying
mechanisms of asthma by reversing the established inflammatory responses to asthma 
triggers.
Results of a completed inhaled allergen challenge study in 31 adult subjects with mild atopic
asthma (Study 20101183) demonstrated that tezepelumab attenuated the LAR and EAR to 
allergen challenge, as measured by the Area Under the Curve (AUC) for the percent fall in 
FEV1 and the maximum percent fall in FEV1. Tezepelumab also attenuated the expected 
increase in FeNO value as well as sputum and blood eosinophils on the post-allergen day 
compared with the pre-allergen day. Multiple doses of 700 mg IV tezepelumab demonstrated
an acceptable safety profile in subjects with mild atopic asthma. No subjects developed ADA 
after receiving tezepelumab in this exploratory study. 
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. Subjects were randomized in a 1:1:1:1 ratio to 1 of 3 dose levels of SC 
tezepelumab (280 mg Q2W, 210 mg Q4W, 70 mg Q4W) or placebo (Q2W) for 52 weeks. A 
total of 584 subjects received at least 1 dose of tezepelumab or placebo. One site was excluded 
from all analysis due to GCP noncompliance making the total number of subjects analyzed to 
550. A post-hoc sensitivity analysis excluding these subjects (38 subjects in the active 
treatment arms and 13 subjects in placebo arm) was performed for the primary and selected 
secondary endpoints. Results from the post-hoc analysis showed that reductions in AAER at 
Week 52 of 62% (p<0.001), 71% (p<0.001), and 66% (p<0.001) for the 70 mg Q4W, 210 mg 
Q4W, and 280 mg Q2W doses, respectively, compared with placebo were observed. These 
results are similar to those observed in the overall ITT population (AAERR of 61%, 71%, and 
66% for the 70 mg Q4W, 210 mg Q4W, and 280 mg Q2W tezepelumab groups, respectively, 
compared with placebo. After repeated SC administration, mean serum trough concentration 

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increased over time and achieved steady-state by week 12. Tezepelumab exhibited linear 
pharmacokinetics (PK) across 3 doses. A low incidence of ADA was observed across all 
treatment subjects. The ADA incidences were 9.4%, 3.7%, 0.8%, and 2.3% for placebo, 70 
mg Q4W, 210 mg Q4W, and 280 mg Q2W, respectively and no subjects tested positive for 
neutralizing antibodies. There was no impact of ADA on tezepelumab PK. The results of this 
study did not identify safety concerns associated with tezepelumab for any dosing regimen. 
The overall incidence of TEAEs were similar between the placebo (65.9%) and the 
tezepelumab (66.0%) dose groups. A majority of subjects had TEAEs that were Grade 1 
(mild) or Grade 2 (moderate) in severity and not related to IP. TEAEs that resulted in 
permanent discontinuation of IP occurred in few subjects, and at a similar incidence between 
the tezepelumab (5 subjects [1.2%] overall) and placebo (1 subject [0.7%]) groups. Overall, 
tezepelumab was well-tolerated with an acceptable safety profile and no identified safety risks 
were noted.
2.3
Benefit/risk assessment
In order to evaluate the clinical benefit-risk balance for tezepelumab, preclinical and clinical 
data have been taken into consideration, as well as a review of the available information for
monoclonal antibodies that are approved for and are in development for the treatment of 
severe asthma. Benefits for tezepelumab over placebo include a clinically meaningful 
reduction in asthma exacerbations, as well as improvements in lung function and asthma 
control metrics.
Tezepelumab has been well tolerated with no identified risks in the clinical 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 to date in the tezepelumab program.
The potential benefits of the study are expected to be Category IIB as described in the 
guidance document aimed directly at the diagnosis, cure, or prevention of disease.
Biopsies will be performed by qualified pulmonologists experienced in research 
bronchoscopies, and all due precautions will be taken to minimize the risk to subjects. Risks 
of the study include those associated with invasive study assessments such as bronchoscopy, 
bronchial biopsy, bronchial brushing and bronchoalveolar lavage (BAL).  Although rare, 
complications of bronchoscopy and biopsy include pneumothorax and the risks associated 
with anesthesia. BAL has some possible complications like cough, transient fever, transient 
chills and myalgias, bronchospasm, or transient decrease of lung function. Also, there is a 
minor risk of exposure to radiation by the CT scans, the use of CT may cause an increase in 
the risk of radiogenic tumors in subjects.

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The benefit/risk assessment for tezepelumab in severe asthma based on the development 
through Phase 2 is favorable. The future benefit/risk assessment will be defined by the results 
of the Phase 3 program.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of tezepelumab may be found in the Investigator’s Brochure. 
3.
OBJECTIVES AND ENDPOINTS
Table 2 – Objectives and Endpoints
Objectives and Endpoints
Primary Objective
Outcome Measure:
To explore the airway anti-
inflammatory effect of tezepelumab
Outcome Variable: The change, expressed as a ratio, in the 
number of airway submucosal inflammatory cells/mm2 of 
bronchoscopic biopsies from baseline to EOT. Airway 
submucosal inflammatory cells will include eosinophils, 
neutrophils, T cells and mast cells
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
Secondary Objective:
Outcome Measure:
To explore the effect of tezepelumab 
on RBM thickening   
Outcome Variable: The change, expressed as a ratio, in 
RBM thickness determined by microscopic evaluation of 
bronchoscopic biopsies from baseline toEOT 
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
To explore the effect of tezepelumab 
on airway epithelial integrity   
Outcome Variable: The change, expressed as a ratio, in % 
airway epithelial integrity determined by microscopic 
evaluation of bronchoscopic biopsies from baseline to EOT  
Outcome Measure: Ratio of tezepelumab to placebo at 
EOT 
To explore the airway anti-
inflammatory effect of tezepelumab 
across the spectrum of T2 status by 
three gene mean derived from 
bronchial brushing RNA 
transcriptomics
Outcome Variable: The change, expressed as a ratio, in 
number of airway submucosal inflammatory cells per mm2
determined by microscopic evaluation of bronchoscopic 
biopsies from baseline to EOT in subjects across the 
spectrum of T2 status determined by RNAseq of bronchial 
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Objectives and Endpoints
Outcome Measure: Ratio of tezepelumab to placebo at
EOT across the spectrum of T2.
Safety Objectives:
Outcome Measures:
To evaluate the safety and 
tolerability of tezepelumab 
AEs/SAEs/AESIs
Clinical chemistry/hematology/urinalysis
Vital signs
ECG
Exploratory Objectives:
Outcome Measure:
 
 
 
 
 
  
 
 
CCI

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Objectives and Endpoints
 
 
 
 
 
 
 
 
 
 
 
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 2, multicentre, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the effect of tezepelumab on airway inflammation in approximately 110 
adults with inadequately controlled moderate-to-severe asthma. Patients will have background 
asthma therapy of medium- or high dose ICS plus at least one additional asthma controller 
medication, such as a long-acting β2 agonist (LABA), leukotriene receptor antagonist 
(LTRA), long-acting anti-muscarinic (LAMA), cromone, and theophylline, with or without 
maintenance oral corticosteroids (OCS) from screening and throughout the study including the 
follow-up period.
The study will consist of a screening/run-in period of up to 4 weeks, a treatment period of 28 
weeks and a post-treatment follow-up period of 12 weeks. One dose level of tezepelumab, 210 
mg will be compared with placebo administered SC Q4W over the treatment period. Subjects 
who discontinue IP during the study will be encouraged to undergo appropriate study 
visits/procedures for the full 40-week period. Any new treatments that are initiated will be 
recorded. Subjects who complete the 28-week study visit will complete a 12-week post-
treatment follow-up period.
Please note: During the COVID-19 pandemic, there is an option for patients to have an extra 
dose every 4 weeks up to 6 additional doses, as needed. (please refer to Appendix J). For the 
last follow up visit, a phone call visit can replace an on-site visit. Please refer to Appendix J
The study aims to randomize subjects across the T2 spectrum. To ensure this, the study will 
randomize approximately 30% of subjects with < 150 blood eosinophils/μL, approximately 
30% of subjects with 150 - <300 blood eosinophils/μL and approximately 40% of subjects 
with ≥ 300 blood eosinophils/μL. 
When the target percentage of subjects for each blood eosinophil subgroup in the study is 
reached, consideration will be given to closing the IWRS/IVRS randomization for that 
subgroup, which may be done on the study level irrespective of 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.

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Section 6.5 (Table 5 and Table 6) provides a list of medication restrictions and prohibitions to 
be followed throughout the conduct of the clinical trial.
4.2
Scientific rationale for the study design
Given that TSLP is an upstream and pleiotropic cytokine, TSLP blockade is anticipated to 
have broad impact on the spectrum of inflammatory responses observed in asthma. Due to the 
mechanism of action it is expected that severe asthmatics, irrespective of their phenotype of 
asthma, would benefit from treatment with tezepelumab.
To better understand the effect of tezepelumab on airway inflammation, the study will assess 
multiple airway anti-inflammatory cells (eosinophils, neutrophils, T cells and mast cells) by 
microscopic evaluation of bronchoscopic biopsies. 
These cells have been chosen as they are the typical airway inflammatory cells of asthma and 
represent both T2 and non-T2 driven inflammatory cell types. Published literature supports a 
potential role for TSLP, and therefore tezepelumab, on all of these cell types; eosinophils 
(Wong et al 2010, Cook et al 2012), neutrophils (Li et al 2018), T cells (Soumelis et al 2002, 
Torii et al 2008, Tanaka et al 2009, Rochman et al 2007) and mast cells (Allakhverdi et al 
2007). This mechanistic study is designed to investigate the efficacy of tezepelumab in T2 
high and T2 low subjects, hence we will examine the anti-inflammatory effects of 
tezepelumab on a broad array of airway inflammatory cells. Bronchoscopic biopsies will be 
also used to assess the effect of tezepelumab on airway epithelial integrity and reticular 
basement membrane thickness. As an epithelial barrier alarmin, TSLP is predicted to be 
involved in epithelial homeostasis and wound healing. TSLP has also been reported to play a 
role in airway smooth muscle proliferation (Redhu et al 2013). Therefore, we believe the 
remodeling end points of airway epithelial integrity and reticular basement membrane 
thickness may be impacted by tezepelumab and this will be explored in this study.
The BAL will be used to assess different biomarkers and tezepelumab PK. The study is also 
assessing the effect of tezepelumab on large airways using CT and the effect of tezepelumab 
on the small airways using AO and CT. 
Bronchial epithelial brushings will be used to assess the T2 status of the subjects using the 
three gene mean. In addition, exploratory biomarkers in blood and urine will also be assessed.
The treatment period of 28 weeks allows ample time for tezepelumab to show effect on airway 
epithelial integrity and RBM thickness. 
In the Phase 2b trial subgroups, those with low and high baseline blood eosinophil counts and 
low and high T2 profile, clearly improved with tezepelumab treatment (CD-RI-MEDI9929-
1146). In the present study, to ensure recruitment of adequate numbers of T2 low and T2 high 

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subjects for analysis, subjects will be enrolled based on screening blood eosinophil 
counts. Blood eosinophils are not sufficient to determine T2 status, but are a convenient 
approach to use during the screening process. At study end, epithelial expression of periostin 
(POSTN), chloride channel accessory 1 (CLCA1), and serpin family B member 2 
(SERPINB2); a gene signature demonstrated as a surrogate marker of T2-driven inflammation 
in mild to moderate asthmatics (Woodruff et al 2009, Choy et al 2011, Bhakta et al 2013), will 
be assessed to confirm that a range of subjects spanning the T2 continuum was included in 
this study. 
In order to avoid bias, this study will be randomized and double-blinded. A placebo group will 
be included to ensure a control for comparison effects.
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 pharmacodynamic (PD) 
endpoint of 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 AAER 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 AAER. 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 in the adult population.
This study will use the same dose as the Phase 3 studies.
  
4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last subject undergoing the 
study.
A subject is considered to have completed the study when he/she has completed his/her last 
scheduled contact.

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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 be assigned/randomized 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 the informed consent.
“Randomized” subjects are defined as those who undergo randomization and receive a
randomization number.
For procedures for withdrawal of incorrectly enrolled subjects see Section 7.3.
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 genetic informed consent prior to collection 
of optional sample for genetic analysis. 
The ICF process is described in Appendix A 3.
Please note: During COVID-19 pandemic, ongoing patients in the study may need to be 
re-consented. Local/regional guidelines must be followed with regard to informed 
consent. Please refer to Appendix J . 
Age
3.
Subject must be 18 to 75 years of age inclusive, at the time of signing the informed 
consent form.
Type of subject and disease characteristics

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4.
Documented physician-diagnosed asthma for at least 12 months prior to Visit 1 
(V1).
5.
Subjects who have received a physician-prescribed asthma controller medication 
with medium or high dose ICS as per GINA guideline (GINA 2018) for at least 12 
months prior to V1. 
6.
Subjects who have received a physician-prescribed asthma controller medication 
with medium- or high-dose ICS must have been on a stable dose for at least 
3 months prior to V1.

High-dose ICS is defined as total daily dose of >500 μg fluticasone dry powder 
inhaler or a total daily dose of 440 μg fluticasone metered dose inhaler or equivalent

Medium-dose ICS is defined as a total daily dose of >250-500 μg fluticasone dry 
powder inhaler or a total daily dose of >220-440 μg fluticasone metered dose 
inhaler or equivalent 

Equivalent ICS doses will be based upon GINA guidelines (GINA 2018), as 
detailed in Appendix F.
7.
At least 1 additional maintenance asthma controller medication is required 
according to standard practice of care; e.g. LABA, LTRA, theophylline, LAMA, 
cromone etc. Use of additional asthma controller medications must be documented 
for at least 3 months prior to V1. 
Notes: 

Patients who are on triple background medication, e.g. ICS plus LABA plus 
LAMA, will be eligible for enrolment. 

The ICS and LABA can be parts of a combination product or given by separate 
inhalers.

Subjects on OCS are allowed in the study, provided they are on a stable 
maintenance dose for at least 6 months before V1.
8.
The subject must have a predicted normal value (PNV) for the morning pre-
bronchodilator (BD) FEV1 >50% and more than 1 L at V1. If this is not met at V1, 
this criterion must be met at V2. 
NB: If the subject did not withhold their morning BD dose, all other V1 study 
assessments may be completed, except for the spirometry procedure, which should 
be scheduled within 3 days of V1.  

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9.
Subjects must have evidence of asthma as documented by post-BD 
(albuterol/salbutamol) reversibility of FEV1 ≥12% and ≥200 mL (15-60 min after 
administration of 4 puffs of albuterol/salbutamol), documented either in the 
previous 12 months prior to V1, at V1, or at V2. 
10.
ACQ-6 score ≥ 1.5 at V1. If patient does not meet criterion at V1, ACQ-6 score ≥ 
1.5 must be met at V2. 
Weight 
11.
Weight ≥ 40 kg at V1.
Reproduction
12.
Negative serum pregnancy test for female subjects of childbearing potential at V1.
13.
Females of childbearing potential who are sexually active 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 IP. Cessation of contraception 
after this point should be discussed with a responsible physician. 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 methods include: true sexual abstinence 
[periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) is not permitted], a vasectomized sexual partner, Etonogestrel (e.g. 
Implanon™), bilateral tubal occlusion, intrauterine device/levonorgestrel 
intrauterine system,, Medroxyprogesterone (e.g. Depo-Provera™) injections, oral 
contraceptive, Norelgestromin/ Ethinyl Estradiol patch (e.g. Evra Patch ™) or 
etonogestrel/ethinyl estradiol vaginal ring (e.g. 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.

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
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.
Inclusion criteria at randomization: 
14.
Subjects must have demonstrated a minimum 70% compliance with diary 
completion during the run-in period with a minimum of 4 days of compliance 
during the last 7 days of the run-in period
A compliant day requires completion of evening diary and subsequent morning diary 

The run-in period for this criterion is defined as the period between diary assignment 
(evening assessment) of Visit 2 (V2) and Visit 3a (morning assessment).
15.
Subjects must have demonstrated a minimum 70% compliance with background 
asthma medication during the run-in period with a minimum of 4 days of 
compliance during the last 7 days of the run-in period. 
16.
For WOCBP only: have a negative urine pregnancy test prior to administration of 
the IP.
17.
Subjects must have the ability to perform acceptable inhaler and spirometry
techniques as judged by the Investigator. 
18.
Subjects must have a successful bronchial biopsy procedure at Visit 3b as judged by 
the Investigator. Successful BAL and bronchial brushing are not inclusionary.
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, history or planned lung lobectomy, alpha 1 anti-trypsin 
deficiency, and primary ciliary dyskinesia) or pulmonary or systemic diseases, 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: 

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
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 V1. 
Subjects who have had other malignancies are eligible provided that curative therapy was 
completed at least 5 years prior to V1.
4.
Subjects who had been hospitalized or required OCS for an asthma exacerbation 
event within 6 weeks of enrolment or who had more than 3 asthma exacerbations 
requiring OCS or hospitalization in the year prior to V1 or who had either been 
intubated or admitted to the ICU for an asthma exacerbation in the year prior to 
enrolment will be excluded. For 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 IM depo-injectable dose of corticosteroids will be considered equivalent to a 
3-day burst of systemic corticosteroids 
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 hospitalization 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.
5.
History of a clinically significant infection, including upper (URTI) or lower 
respiratory tract infection (LRTI), requiring treatment with antibiotics or antiviral 
medications finalized < 2 weeks before V1 or during the run-in period.

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6.
A helminth parasitic infection diagnosed within 6 months prior to V1 that has not 
been treated with, or has failed to respond to, standard of care therapy. 
7.
Current smokers or subjects with smoking history ≥ 10 pack-years including the use 
of vaping products, such as electronic cigarettes. Former smokers with a smoking 
history of <10 pack years, including former vaping or e-cigarette users, must have 
stopped for at least 6 months prior to Visit 1 to be eligible.
8.
History of chronic alcohol or drug abuse within 12 months prior to V1. 
9.
Tuberculosis requiring treatment within the 12 months prior to V1.
10.
History of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test at V1, or the subject taking antiretroviral 
medications as determined by medical history and/or subject’s verbal report.
11.
Major surgery within 8 weeks prior to V1 or planned surgical procedures requiring 
general anesthesia or in-patient status for > 1 day during the conduct of the study.
Prior/concomitant therapy
12.
Receipt of any marketed or investigational biologic agent within 4 months or 5 half-
lives (whichever is longer) prior to V1 or receipt of any investigational non-biologic 
agent within 30 days or 5 half-lives (whichever is longest) prior to V1.  
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 
randomization: Systemic immunosuppressive/immunomodulating drugs (e.g. 
methotrexate, cyclosporine, etc.) except for OCS used in the treatment of 
asthma/asthma exacerbations or receipt of the T2 cytokine inhibitor suplatast 
tosilate within 15 days prior to V1. 
14.
Receipt of immunoglobulin or blood products within 30 days prior to V1.  
15.
Receipt of live attenuated vaccines 30 days prior to the date of randomization 
16.
Subjects that have been treated with bronchial thermoplasty in the last 24 months 
prior to V1.
17.
Known or suspected history of immunosuppression, immune dysfunction or 
immune dysregulation which may include but is not limited to conditions such as: 
Guillain-Barré syndrome, invasive opportunistic infections (e.g. histoplasmosis, 

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listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis), or unusually 
frequent, recurrent, or prolonged infections, per Investigator judgment
Prior/concurrent clinical study experience 
18.
Known history of sensitivity to any component of the IP 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) 
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 randomization in 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 finding in physical examination, vital signs,
ECG, hematology, 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 the entire duration of the study.
24.
Evidence of active liver disease, including jaundice or aspartate transaminase, 
alanine transaminase, or alkaline phosphatase > 2 times the upper limit of normal 
(ULN) at V1. 
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 and subjects with hepatitis 
C who have been cured are allowed to participate.   
Other exclusions
26.
Pregnant, breastfeeding, or lactating women.  
A serum β-HCG pregnancy test must be drawn for women of childbearing potential
at the screening visit. If test result is positive, the subject should be excluded. Since 
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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. 
27.
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 or for safety reasons.
Genetic Research exclusion criteria
28.
Previous allogeneic bone marrow transplant.
29.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
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 center.
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 is restricted prior to V1 and throughout the 
conduct of the study is restricted.
Current smokers or subjects with smoking history ≥ 10 pack-years, including the use of 
vaping products such as electronic cigarettes at V1 are not allowed.
Former smokers with a smoking history of <10 pack years, including former vaping or e-
cigarette users, 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 center.

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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 randomized. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events (AEs) or serious adverse 
events (SAEs).
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. 
Re-screening is allowed only once under the following circumstances:

Subjects with respiratory infections requiring antibiotics or antiviral medication within 
14 days prior to the screening/run-in period may be re-screened 14 days after recovery, 
i.e., completion of the therapy. 

Subjects who experience an asthma exacerbation during run-in period may be re-
screened after 14 days of complete resolution of the asthma exacerbation, and when 
the subjects return to their baseline at Investigator discretion.
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, etc.), then
subjects may potentially be re-screened. These cases should be discussed with the 
AstraZeneca study physician and documented in the Investigator Study File (ISF).
Any re-screened subject will be re-enrolled and reassigned their originally assigned enrolment
number after signing a new Informed Consent Form (ICF) and after all V1 assessments have 
been performed as listed in SoA, Table 1 (with the exception of testing for HIV1 and HIV2, 
hepatitis B and C, and FSH). If the timeframe between screening and re-screening exceeds 30 
days, the subject will not be permitted to re-screen without repeating Visit 1 assessments, as 
per PI discretion. 
Subjects who experience an asthma exacerbation before the EOT assessments should have 
their EOT visit rescheduled to be after 14 days after the complete resolution of the asthma 
exacerbation, and when the subjects return to their baseline, provided that the Investigator has 
no safety concerns.
Rescreening should be documented so that its effect on study results, if any, can be assessed.
IMPORTANT: Re-screening for subjects who have screen-failed due to PRO criteria (e.g.

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ACQ-6 score <1.5 or did not report adequate compliance with maintenance medications) is 
not allowed.
Re-screening of a subject for any other reason (transient reasons including, but not limited to 
study supplies, equipment failures, unforeseen personal event, missed visits, etc.) 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).
6.
STUDY TREATMENTS
Study treatment is defined as an IP (including placebo) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to tezepelumab 
or placebo.
6.1
Treatments administered
6.1.1
Investigational products
Table 3 – Study treatments
Treatment 1
Treatment 2
Study treatment name:
Tezepelumab 
Placebo
Dosage formulation:
0.7% (w/v) sodium
carboxy methyl
cellulose in 10 mM
acetate, 250 mM L-
proline,
0.01% (w/v)
polysorbate 80, pH 5.0
Route of administration 
Subcutaneous
Subcutaneous
Dosing instructions:
Refer to section 6.2
Refer to section 6.2
CCI

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Packaging and labelling
Study treatment will be
provided in 5cc vial. Each
vial will be labelled in
accordance with Good
Manufacturing Practice
(GMP) Annex 13 and per
country regulatory
requirement.
Study treatment will be
provided in 5cc vial.
Each vial will be
labelled in accordance
with Good
Manufacturing Practice
(GMP) Annex 13 and
per country regulatory
requirement.
6.2
Preparation/handling/storage/accountability
The IP will be supplied to the site in a kit with one vial of either tezepelumab or placebo. Each 
kit has a unique number that is printed on all labels within the kit (i.e. the outer carton label 
and the label of each container within the carton).
The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the IP.
Only subjects enrolled in the study may receive study treatment and only authorized site staff
may supply or administer study treatment. All study treatments must be stored in a secure,
environmentally controlled, and monitored (manual or automated) area in accordance with the
labelled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study treatment accountability, reconciliation, and record maintenance (i.e.,
receipt, reconciliation, and final disposition records).
Please Note: During the COVID-19 pandemic, if allowed by local/regional guidelines, IP 
preparation and administration can be performed at the subject’s home by a qualified 
HCP. Please refer to Appendix J for further details 
Dose preparation
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 a 5-mL single use glass 
vial to be stored at 2°C to 8°C until used. If defects are 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, Investigator or qualified designee) at the site.

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The IP 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 will be selected 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 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 or 3-mL sterile syringe. 
4.
Withdraw 1.9 mL of the IP from the vial.
5.
Remove and discard the 21G 1½-inch sterile disposable needle from the syringe. 
6.
Attach a new 27G ½-inch sterile disposable needle to the same syringe in step 5. 
7.
Apply the appropriate label to the syringe.
The assigned vial should be used at one time to prepare the dose required at each visit. Unused 
product in opened and dispensed vials 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 vial labels along with the kit boxes must be 
retained for IP accountability.
The IP will be administered by one SC injection (see Table 4) and must be prepared using 
disposable plastic syringes and aseptic technique.
Table 4 – Investigational product dose preparation
Dose
Number of vial (s) 
required
Syringe size 
required
Total Volume 
administered
210 mg a
1
2 or 3 mL
1.9 mL

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Placebo
1
2 or 3 mL
1.9 mL
a Due to the gradations available on 2 or 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, Investigator or 
qualified designee) at the site. The injection site must be recorded in the source documents at 
each treatment visit and in the eCRF. The person administering the dose will wipe the skin 
surface of the upper arm, anterior thigh or abdomen with alcohol and allow to air dry. The 
skin will be pinched to isolate the SC tissue from the muscle. The needle will be inserted at a 
90-degree angle approximately halfway into the SC tissue. The IP will be slowly injected (at 
least 5 second duration is recommended) into the SC tissue using gentle pressure. The area 
should not be massaged after injection. It is advised that the site of injection of IP be rotated 
such that the subject receives IP at a different anatomical site at each treatment visit. 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. 
Note: Time of dispense of IP from IVRS, time IP taken out of the fridge and time of IP 
administration should be logged in a specific log. This log must be a part of the subject’s 
source documents. 
Figure 2
Suggested schema of rotation of injection sites 
Subjects should be observed for a minimum of 2 hours after administration of the first two IP

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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:

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 
subject skips 2 consecutive IP administrations, the AstraZeneca 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 questions about the injection site 
reaction.
6.3
Measure to minimize bias: randomization and blinding
The Investigator(s) will:
1.
Obtain signed informed consent or assent from the potential subject, or their 
guardian/legal representative, before any study specific procedures are performed.
2.
Assign the potential subject a unique enrolment number (which begins with an ‘E’) 
via the interactive web response system/interactive voice response system 
(IWRS/IVRS).
3.
Determine subject eligibility. 
4.
Assign the eligible subject unique randomization code via IWRS/IVRS.
5.
Subjects will be allocated to receive tezepelumab or placebo in a 1:1 ratio and 
stratified by baseline eosinophil level (< 150, 150 - 300, > 300). Randomization 
numbers will be grouped in blocks. If a subject withdraws from the study, then 
his/her enrolment/randomization code cannot be reused. Withdrawn subjects will 
not be replaced.

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Specific information concerning the use of the IWRS/IVRS will be provided in a 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 
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, and 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 patient. 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 patients should remain in the study and the subjects should continue to be 
followed up in accordance with defined study procedures.
Methods for assigning treatment groups
Randomization will be stratified by screening blood eosinophil level. Approximately 30% of 
subjects with < 150 blood eosinophils/μL, approximately 30% of subjects with 150 - <300 
blood eosinophils/μL, and approximately 40% of subjects with ≥300 blood eosinophils/μL. 
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 AZ (AZRand). 
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. Since tezepelumab and placebo are not 
visually distinct, IP will be handled by a qualified person (e.g. pharmacist, Investigator or 
qualified designee) at the site.

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An 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:

Those carrying out the packaging and labelling of IP

Those generating the randomization list

Personnel at the IXRS company

Supply Chain Management department

Bioanalytical lab performing PK sample analysis.

Patient Safety department at AstraZeneca

Applicable DSMB members
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 and until database 
lock.
Methods for unblinding
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) or delegate 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 should document and report 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 

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until all decisions on the evaluability of the data from each individual subject have been made 
and documented.
6.4
Treatment compliance
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 should be 
recorded in the appropriate section of the eCRF.
6.5
Concomitant therapy
All ICS asthma medications taken in the 12 months prior to V1 must be recorded in the eCRF 
along with reason for treatment.
To satisfy inclusion criterion 6, a history of continuous treatment with medium or high dose 
ICS plus a second controller medication for at least 3 months prior to V1 should be 
documented in source and recorded in the eCRF prior to the date of randomization. 
In order to satisfy inclusion criterion 7, a history of all asthma controller medications for the 3 
months prior to V1 until the end of the study should be documented in source and recorded in 
the eCRF. No changes are allowed to background asthma medications throughout the duration 
of the study except during the treatment of an asthma exacerbation.
All other medications taken for conditions other than asthma in the 3 months prior to V1 must 
be recorded in the eCRF along with reason for treatment by the Investigator/authorized 
delegate at each visit (as shown in Table 1). 
Maintenance asthma medication is not regarded as an IP, but will be provided/reimbursed by 
AstraZeneca according to local regulations in order to maintain appropriate oversight and 
access to this concomitant therapy.
As theophylline has a narrow therapeutic window, please note that subjects on maintenance 
treatment with theophylline should have blood concentration levels within therapeutic range. 
documented before V1. 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 V1 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:

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
Reason for use

Dates of administration including start and end dates
Table 5 – Restricted medications
Medication/class of drug:
Usage 
Maintenance treatment with ICS and long-
acting bronchodilators (including
ICS/LABA combinations)
No changes in either dose or regimen are allowed 
from V1 and until at least the EOT visit, unless there 
is a medical need as judged by the Investigator. 
The patients should be instructed not to take their 
usual asthma controller medication (i.e., LABA) prior 
to scheduled ECG assessment (please refer below for 
long-acting bronchodilator restrictions). Use of 
SABA or SAMA should be avoided within 6 hours 
before ECG assessments. The medication restrictions 
are waived for the screening ECG at V1.
Twice daily bronchodilators 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 a washout of their asthma 
medications for unscheduled visits due to asthma 
worsening.
Short-acting beta-agonists
(SABA)
Regular scheduled use of SABA is not allowed from 
V1 and until at least the EOT visit, unless there is a 
medical need as judged by the Investigator. 
PRN use is allowed if needed, however attention 
should be paid to the following restrictions.
SABA should be withheld for at least 6 hours prior to 
scheduled spirometry, FeNO, ECG at site with the 
exception of any unscheduled visits due to asthma 
worsening. 

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Medication/class of drug:
Usage 
Additional maintenance
controllers
No changes in either dose or regimen are allowed 
from V1 and until at least the EOT visit, unless there 
is a medical need as judged by the Investigator. 
Once daily LABA and LAMA should be withheld for 
at least 24 hours prior scheduled spirometry and 
FeNO at site visits with the exception of any 
unscheduled visits due to asthma worsening.
Twice daily LABA or LAMA containing therapies 
should be withheld for at least 12 hours prior to 
scheduled spirometry and FeNO at site with the 
exception of any unscheduled visits due to asthma 
worsening.
LTRA should be restricted for at least 24 hours prior 
to scheduled spirometry and FeNO at site with the 
exception of any unscheduled visits due to asthma 
worsening.
Subjects on theophylline should have blood 
concentration levels within therapeutic range 
documented before proceeding in the study.
Twice daily theophyllines should be withheld for at 
least 12 hours prior to scheduled spirometry and 
FeNO at site with the exception of any unscheduled 
visits due to asthma worsening.
Once daily theophyllines should be withheld for at 
least 24 hours prior to scheduled spirometry and 
FeNO at site with the exception of any unscheduled 
visits due to asthma worsening.
Short-acting anticholinergics (e.g. ipratropium)
These are not allowed as a rescue treatment for 
worsening asthma symptoms from V1 and until at 
least the EOT visit, unless there is a medical need as 
judged by the Investigator. They 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.

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Medication/class of drug:
Usage 
Allergen immunotherapy
Allowed, if on stable therapy for at least 2 months 
prior to date of V1 with no anticipated change during 
the treatment period. 
These should not be administered on the same day as 
IP administration.
Table 6 – Prohibited medications
Prohibited 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 V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator. 
Suplatast tosilate (T2 cytokine inhibitor) 
Not allowed within 15 days prior to V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator.
Live attenuated vaccines
Not allowed 30 days prior to the date of 
randomization, and during the study including the 
follow-up period.
Anticoagulants
Not allowed 15 days prior to V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator. 
Any immunomodulators or
immunosuppressives (except for OCS used in 
the treatment of asthma/asthma exacerbations)
Not allowed 12 weeks prior to randomization, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator. 
Immunoglobulin or blood products
Not allowed 30 days prior to V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator.

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Prohibited medication/class of drug:
Usage
Any marketed (e.g. omalizumab, 
mepolizumab, reslizumab, benralizumab) or to 
be marketed or investigational biologic 
treatment
Not allowed 4 months or 5 half-lives (whichever is 
longer) prior to the date of V1, throughout the entire, 
screening run in period, treatment period (even if the 
subject has discontinued IP) and until the follow up 
visit at week 40.  
Other IPs
(including investigational use of an approved 
drug)
Not allowed 30 days or 5 half-lives (whichever is 
longer) prior to V1, during screening/run-in and until 
at least the EOT visit, unless there is a medical need 
as judged by the Investigator.
Herbal remedies for the treatment of allergic, 
inflammatory, or respiratory diseases
Not allowed 30 days prior to V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator.
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 V1, during 
screening/run-in and until at least the EOT visit, 
unless there is a medical need as judged by the 
Investigator. 
6.5.1
Other concomitant treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the Case Report Form.
6.5.2
Rescue medication
SABA should be withheld for at least 6 hours prior to scheduled site visit spirometry, FeNO,
and ECG at site with the exception of any unscheduled visits due to asthma worsening. 
Albuterol (US)/salbutamol (ex US) rescue medication will be provided by the sponsor and
obtained locally. 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 paper 
diary.
The date and time of rescue medication administration as well as the name and dosage
regimen of the rescue medication must be recorded.

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6.6
Dose modification
During the COVID-19 pandemic an additional 1-6 IP doses may be administered to subjects 
during unscheduled visits at weeks 28, 32, 36, 40, 44 and 48 (as needed) until the sites are 
able to resume performing all study assessments, including bronchoscopies, in accordance to 
local regulations/guidelines. Please refer to Appendix J
6.7
Treatment after the end of the study
Subjects who complete the study should be given standard of care at the discretion of the 
Investigator.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
Subject may be discontinued from IP in the following situations. 
Note that discontinuation from study treatment does NOT mean complete withdrawal from the 
study. 
Subject decision.  The subject is at any time free to discontinue IP, without 
prejudice to further treatment 
An adverse event considered to jeopardize the safety of a subject participating in the 
study
Pregnancy or breastfeeding
Severe non-compliance with the CSP. 
Development of any study specific criteria for discontinuation, including:

An anaphylactic reaction to the IP 

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 the 
malignancy is excised and determined to have clean margins

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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 IP discontinuation and follow-up and for 
any further evaluations that need to be completed.
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. If the subject decides to 
withdraw consent, then the reason for this must be recorded separately in the eCRF. A subject 
that decides to discontinue IP should always be asked about the reason(s) and the presence of 
any adverse events. The reason for 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 40 even if the subject has discontinued IP. Interaction studies between tezepelumab 
and other biologics indicated for the treatment of asthma have not been conducted. For 
additional information regarding pharmacokinetic and pharmacodynamic effects of 
tezepelumab reference should be made to the Investigator brochure. 
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 (+/-7 days) post last IP administration. Subjects who discontinue treatment should be 
encouraged to return for all regularly scheduled visits for safety and efficacy assessments.
At the IPD visit the subject will be given three options as to how they will be followed as 
follows:
1.
The subject should be encouraged to return for all regular clinic visits and perform 
all scheduled assessments until he/she completes a total of 28 weeks treatment 
period.  

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2.
The subject will be offered follow-up on a monthly basis via telephone calls until 
the subject completes 28 weeks in the study. The subject should return for a follow-
up visit 16 weeks (+/- 3 days) post last IP administration and for the EOT visit at 
Week 28 (or later due to COVID-19 pandemic) (+/-3 days). 
3.
If the subject cannot or does not wish to comply with any of the options above, (or 
any component of them such as only telephone based visits without completion of 
the diary, they will complete a follow-up visit at 16 weeks (+/-7 days) (refer to SoA, 
Visit 14 – week 40) post last IP administration. After this visit the Investigator will 
only contact the subject at 28 weeks post-randomization (or later due to COVID-19 
pandemic) No other study assessments will be performed prior to this contact.
If the last IP administration was at or after week 16 for options 1 or 2, the subject will return 
to the clinic for an EOT visit at week 28 (or later due to COVID-19 pandemic) (+/- 3 days). 
The PI will not perform the EOT bronchoscopy assessment unless the subject has had IP 
administered at least through the week 16 dose. Any subjects who discontinues IP before 
week 16 (V8) or had an EOT visit date greater than 12 weeks after date of last dose of IP will 
not have the EOT bronchoscopy assessment performed. For option 3, the Investigator will 
contact the subject at 28 weeks post randomization. For all options 1, 2 and 3, subjects will 
then return for a follow-up Visit 16 weeks (+/- 7 days) post-last IP administration (refer to 
SoA, V14 – Week 40). The EOT visit will be completed immediately in the case of 
subsequent early withdrawal from option 1 or 2. Subjects who do not wish to have any follow-
up contacts will be discontinued from the study. All discontinued subjects must return the 
paper diaries at the EOT visit. If the subject chooses option 1, all assessments will be 
completed as per the SoA as indicated in Section 1.1. If the subject chooses 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 1 or 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 
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 discontinuation criteria’ on the 
Discontinuation of Investigational Product form in the eCRF. For more information related to 
COVID-19 please refer to eCRF instructions. 
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.  

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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 (e.g. telephone contacts, contacts with a relative or treating physician, or 
information from medical records) as per section 7.1.1. 
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs.  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, Section 1.1.
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.
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.  

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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. For more information related to COVID-19 please refer to eCRF 
instructions. 
AstraZeneca reserves the right to discontinue a subject’s participation in the study for any 
safety reasons.
7.3.1
Withdrawal due to recruitment completion
When the required number of subjects are randomized in the study, ongoing subjects in run-in 
will 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 patients is required.
7.3.2
Discontinuation or suspension of the whole study program
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.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1).  
The Investigator will ensure that data are recorded on the electronic Case Report Forms 
(CRFs). The Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  
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 electronic CRFs.  A copy of the 
completed electronic CRFs will be archived at the study site. Additional data to assess the 
impact of COVID-19 pandemic will be collected.

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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.  
The amount of blood collected from each subject over the duration of the study (excluding 
optional blood samples) will be approximately 220 mL, including any extra assessments that 
may be required, and will not exceed 450 mL. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples.
8.1
Efficacy assessments 
8.1.1
Bronchial biopsy
Facilities for the management of medical emergencies and cardiopulmonary resuscitation will 
be available. Biopsies will be performed by qualified pulmonologists experienced in research
bronchoscopies, and all due precautions will be taken to minimize the risk to subjects.
Subjects will receive a sedative and local anesthetic to reduce any discomfort and local 
guidelines to be followed. Subjects will be informed of the risks associated with bronchoscopy 
and bronchial biopsy procedure before participating in the study.
The biopsy at the EOT Visit will be performed only if the baseline biopsy tissue passes quality 
control, as judged by the study pathologist. QC criteria include tissue area, quality and 
architecture which must all be sufficient to allow quantification of inflammatory cells, RBM 
and epithelium to enable primary and secondary endpoints to be quantified.
Details for conducting bronchial biopsies will be described in a separate manual. Samples will 
be analyzed at a central facility designated by AstraZeneca. Details of assessment and analysis 
parameters will be described in a separate manual.
Bronchial biopsy, being the primary endpoint will be conducted first followed by bronchial 
brushing then the BAL.
8.1.2
Bronchial brushing
During bronchoscopy, bronchial brushings will be obtained. Details for sample collection, 
handling, processing, storage and transportation will be described in a separate manual. 
Samples will be analyzed at a central facility designated by AstraZeneca. Details of 

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assessment and analysis parameters and transporting samples will be described in a separate 
manual. The periostin (POSTN), chloride channel accessory 1 (CLCA1), and serpin family B 
member 2 (SERPINB2) three gene mean gene signature for each subject will be reported in 
the CSR, but additional transcriptomics data will be analyzed separately and will be reported 
separately from the CSR in a scientific report or publication.
The brushings at the EOT Visit will be performed only if the baseline visit brushing is 
performed successfully, as judged by the Investigator.
8.1.3
Bronchoalveolar lavage
Bronchoalveolar lavage (BAL) will be obtained during bronchoscopy. BAL will be mandatory 
for all subjects (unless if there is any safety concern by the Investigator), but it is not an 
inclusion criterion for patients to be randomized in the study. BAL samples should be 
collected pre-dose at the pre-specified scheduled visit in the SoA. Details for sample 
collection, handling, processing, storage and transportation will be described in a separate 
manual. The results of the exploratory BAL biomarker analyses may be reported separately 
from the CSR in a scientific report or publication.
The BAL at the EOT Visit will be performed only if the baseline visit BAL is performed 
successfully, as judged by the Investigator. 
8.1.4
Airwave oscillometry
AO is a non-invasive lung function test included in this study to evaluate treatment effect on 
small airway physiology. AZ will provide the equipment for testing.
A calibrated system will be used for measurements. Detailed procedures for performing, 
recording and analyzing AO data will be described in a separate manual. 
By measuring subject’s airflow and response to sound waves, frequency-dependent resistance 
and reactance will be calculated by the AO system software. A signed and dated copy of the 
results printout from the equipment must be kept at the study site for source data verification 
(SDV). The printout must be marked with the study code, subject enrolment code, date and 
time of measurement, and visit number. Number of parameters including (but not limited to) 
R5, R20 and AX for each trial will be recorded and analyzed.
The AO assessment at EOT Visit will be performed only if the baseline visit AO is performed 
successfully, as judged by the Investigator. 
8.1.5
Airway hyper-responsiveness
AHR measured by mannitol challenge testing (MCT) will be assessed in a subgroup of 
patients according to the schedule provided in Table 1. MCT will be performed in accordance 

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to GINA guidelines (GINA 2006), vendor’s manual, and applicable SOP and clinical 
standards of care at investigational sites. Medication washouts should be followed as per the 
mannitol vendor’s manual detailed in Appendix I.
Signed and dated worksheets from the measurements will be kept in the ISF for SDV. If a 
worksheet cannot be printed, required measurements will be recorded in the subject’s medical 
records for SDV. Sponsor will provide the mannitol kits to the sites.
The AHR assessment at EOT Visit will be performed only if Visit 2 AHR is performed 
successfully, as judged by the Investigator. 
In case of repeat spirometry at V2, AHR will be rescheduled within 3 days of Visit 2.
8.1.6
Biomarkers
Multiple sample types (blood, plasma, serum, BAL, bronchoscopic biopsies, bronchial 
brushings and urine) will be collected according to the Table 1 for exploratory analyses to 
investigate the effect of tezepelumab on biomarkers of inflammation, asthma, remodeling, 
pharmacology of tezepelumab and for potential predictors of response. All biomarker samples 
should be collected pre-dose at the pre-specified scheduled visit in the SoA. Instructions for 
sample collection, processing, storage, and shipment can be found in the separate manual 
provided to the sites. Samples may be analyzed separately. The results of the exploratory 
biomarker analyses may be reported separately from the CSR in an addendum, in a scientific 
report or publication.
8.1.7
Blood eosinophils and neutrophils
Samples for assessment of blood eosinophils and neutrophils will be collected as hematology 
samples according to the schedule in Table 1. Blood eosinophil and neutrophil counts will be 
obtained from the total and differential white blood cell (WBC) counts. All blood eosinophil 
and neutrophil results will be redacted from the laboratory reports except for Visit 1 and Visit 
3. Instructions for sample collection, processing, storage, shipment and analysis will be 
provided in a separate laboratory manual provided to the sites. 
8.1.8
Airway inflammatory cells
Lung biopsy tissue will be collected by bronchial biopsy at baseline and EOT to evaluate the 
effect of tezepelumab on inflammatory cell infiltrate. 
8.1.9
Serum IgE
Testing for Serum IgE will be performed as per schedule in Table 1. The analysis for this test 
will be managed by the central laboratory. All total serum IgE results will be redacted from 

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the laboratory reports except for Visit 3. Instructions for sample collection, processing, 
storage, and shipment will be provided in a separate laboratory manual provided to the sites. 
8.1.10
RNA transcriptomics
Transcriptomic analysis will be performed on the RNA sample obtained from bronchial 
brushing as per schedule in Table 1. Details for bronchial brushing collection will be as 
described above (8.1.2). Three gene mean gene signature will be reported in the CSR but 
additional transcriptomics data from bronchoscopic brushings will be reported separately from 
the CSR in an addendum, scientific report or publication.
In addition, other samples including whole blood, BAL cells and bronchial biopsies will be 
collected, stored and may be processed for RNA transcriptomics. Instructions for sample 
collection, processing, storage, shipment and analyses will be provided in a separate manual 
of procedures provided to the sites. Samples may be analyzed separately.  Any exploratory 
transcriptomics analyses on BAL cells, whole blood and biopsy tissue, will be reported 
separately from the CSR in an addendum, in a scientific report or publication.
8.1.11
DNA for genetics
An optional blood sample will be collected as per schedule in Table 1 for genetic analysis. 
Instructions for sample collection, processing, storage, shipment and analyses will be provided 
in a separate manual of procedures provided to the sites. This data will be reported separately 
from the CSR in an addendum, in a scientific report or publication.
8.1.12
Urine biomarkers
Urine will be collected and stored as per schedule in Table 1 for exploratory biomarker 
analysis of inflammatory markers. Instructions for sample collection, processing, storage, 
shipment and analyses will be provided in a separate manual of procedures provided to the 
sites. Samples may be analyzed separately. The results of the exploratory biomarker analyses 
will be reported separately from the CSR in an addendum, in a scientific report or publication.
8.1.13
Computed tomography
Chest CT will be performed in accordance with the schedule provided in Table 1. Prior to CT 
scan, subject will be asked to inhale 100 µg of salbutamol using a metered dose inhaler and a 
valve spacer device. This procedure will be repeated 4 times. CT scan procedure should be 
within 10-60 minutes post-bronchodilation. Scans will be performed in both full inspiration 
and full expiration. Detailed procedures for the acquisition, storage, anonymization and 
transfer of the CT image data will be described in a separate manual. 
Details for the analysis of the CT image data to obtain parameters for large airway 
morphometry, air trapping, vascular pruning and functional imaging will be described in a 

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separate imaging biomarker document. The CT scans will be assessed clinically at each site, 
and the Investigator is responsible for the clinical reporting of findings and its subsequent 
management. Clinically significant findings not related to asthma will be reported as medical 
history or AEs by the Investigator.
EOT CT will be performed only if baseline CT is performed successfully, as confirmed by 
imaging QC review by the imaging vendor. 
8.1.14
Assessment of asthma exacerbation 
The list below defines what is acceptable documentation for historical exacerbations:

Discharge summaries from a hospital, emergency room, or an urgent care 
facility indicating that a 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.

Evidence of prescriptions for systemic steroids used during an 
exacerbation.

A documented conversation that is recorded in a timely manner between 
the Investigator/nurse or nurse practitioner and a subject who is already on 
an OCS action plan, detailing the diagnosis and treatment of an asthma 
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.
During the study, an asthma exacerbation will be defined as a worsening of asthma that leads 
to any of the following:

A temporary bolus/burst of systemic corticosteroids (or a temporary 
increase in stable OCS background dose) for at least 3 consecutive days to 
treat symptoms of asthma worsening; a single depo-injectable dose of 
corticosteroids will be considered equivalent to a 3-day bolus/burst of 
systemic corticosteroids.

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
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.
Subjects are required to report any of the following in the paper diary:

An increase in rescue medication use of 4 or more puffs on at least 2 
consecutive days compared with the average use during baseline or use of 
12 puffs/day on any one day, and/or

An additional nebulized β2 agonist use on at least 2 consecutive days 
compared with the average use during baseline, and/or

An increase of 2 or more nights with awakenings due to asthma requiring 
rescue medication over a 7-day period compared with the average during 
baseline, and/or ≥ 6 out of previous 7 nights with awakenings due to 
asthma requiring rescue medication (this criterion should be met on 2 
consecutive days)
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the Investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. Events that are not supported by any 
objective assessment will be deemed not to be a protocol-defined exacerbation.
The start of an exacerbation is defined as the start date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visits 
requiring 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 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.
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.
All asthma exacerbations that occur during the treatment period and follow up, must be 
recorded in the exacerbation eCRF.  See section 8.3.7 for additional information on recording 
asthma exacerbations as an AE/SAE during the study.

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8.1.15
Allergen specific IgE (FEIA)
Testing for Phadiatop in blood (allergy screening test) will be performed as per schedule in 
Table 1. The analyses for these tests will be managed by the central laboratory. Instructions 
for sample collection, processing, storage, and shipment will be provided in a separate 
laboratory manual provided to the sites.
8.1.16
Spirometry
8.1.16.1
General requirements
Lung function (FEV1 and FEF25-75%) will be measured by spirometry using equipment 
provided by a central vendor. Spirometry will be performed by the Investigator or authorized 
delegate according to American Thoracic Society/European Respiratory Society (ATS/ERS) 
guidelines (Miller et al 2005).
The vendor providing central spirometry is responsible for assuring that the spirometer meets
ATS/ERS recommendations and that the study center personnel who will be performing the
testing is properly certified. Spirometry calibration will be detailed in a separate spirometry
procedures manual.
Important!

Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the center.

Subjects should avoid eating a large meal for at least 2 hours prior to all lung 
function assessments at the center. 

Subjects should withhold their usual maintenance therapies on the day(s) when lung 
function testing is being performed as below:

SABAs and SAMAs should be withheld at least 6 hours prior to scheduled 
spirometry at site. 

Twice daily LABA or LAMA-containing therapies should be withheld for at 
least 12 hours prior to scheduled spirometry at site.

Once daily LABA or LAMA-containing therapies should be withheld for at 
least 24 hours prior to scheduled spirometry at site.

LTRA should be restricted for at least 24 hours prior to scheduled spirometry 
at site.

Twice daily theophyllines should be withheld for at least 12 hours prior to 
scheduled spirometry at site.

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
Once daily theophyllines for at least 24 hours prior to scheduled spirometry 
at site. 
Note: If any of the above restrictions are not met, the spirometry assessment should be 
rescheduled within the allowed visit window.
Time of day for scheduled center visit spirometry
Spirometry testing should be done according to the SoA. For all subjects, spirometry testing 
must be initiated in the morning between 6:00 AM and 11:00 AM during the screening or re-
screening period. 
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the enrolment spirometry was performed. For example, if the enrolment spirometry 
was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated between 
6:30 AM and 9:30 AM.
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.
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
8.1.16.2
Post-BD spirometry and FEV1 reversibility assessment 
All subjects must meet inclusion criteria 9 either by having documented historical reversibility 
or by demonstrating reversibility either at V1 or V2. 
Even if documented historical reversibility is available, the post-BD spirometry procedures 
must be performed at V1 to categorize subjects (establish baseline characteristic) prior to 
randomization. The documented historical reversibility must be recorded in the 
eCRF/spirometer prior to randomization.  Further details will be provided in a separate 
instruction manual.

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Reversibility is calculated as follows:
% Reversibility = (post-BD FEV1- pre-BD FEV1) × 100/pre-BD FEV1
Record keeping
A signed and dated copy of the pre- and post-BD printout must be kept at study center for 
source data verification. The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number. If a printout cannot be printed, the mean value of 
the measurements will be recorded in the subject’s charts. 
8.1.17
Fractional exhaled nitric oxide
Airway inflammation will be evaluated using a standardized single-breath FeNO test in 
accordance with the SoA. A single exhalation technique recommended by the manufacturer 
will be followed (Allakhverdi et al 2007, Alving et al 2017).
Subjects will be asked whether they have had a respiratory infection in the 2 weeks prior to 
the 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) or SAMA medications 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 measured FeNO. 
Instructions for use of this monitor will be provided in a separate user’s manual.  
NIOX VERO® sensors will be replaced as recommended by the manufacturer. The vendor 
supplying the equipment will be responsible for ensuring that the equipment and procedures 
for the measurement of FeNO are validated prior to the start of the study. 
All post-randomization FeNO assessments should be performed within ± 1.5 hours of the time 
that the randomization FeNO was performed.
All post-randomization FeNO measurements will be blinded for sites and subjects throughout 
the study. The sponsor will be unblinded to the FeNO values prior to randomization and 
blinded to the FeNO values post randomization.

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8.1.18
Patient reported outcomes
Patient reported outcomes (PRO) data will be captured by paper diaries at home and at the 
site. Subjects will be trained on at-home use of the diary at V2. Training will emphasize the 
importance of completing the paper diary assessments as scheduled to capture the subject's 
experience and meet the objectives of the study. The questionnaires will be completed at home 
in the following order: Rescue medication, nocturnal awakening, maintenance medication. At 
every visit, subjects will be asked to return their paper diaries to be filed with the source 
documents. Site will give the subject a new diary booklet every visit, as specified in the SoA.
At-home paper diary assessments will start the evening of V2. Subjects will complete 
assessments twice daily at timepoints specified in the SoA. 
The Investigator/authorized delegate will check subject’s adherence to the paper diary 
completion to minimize missing data at each study visit. Frequent compliance checks between 
visits will be necessary to ensure sufficient data is available to meet inclusion criteria 14 and 
15.
8.1.18.1
Paper Diary
The paper diary will be completed each day from the evening of V2 to the morning of Visit 14 
(V14). The morning diary will include: questions about rescue medication, night-time 
awakening, and use of maintenance medications. The evening diary will include: questions 
about rescue medications. Only the occurrence of worsening or new asthma symptoms will be 
reported on the paper diary. 
Please note: During the COVID-19 pandemic, once extra dosing and/or home IP 
administration is implemented, recording, collection, and dispensation of the subject's paper 
diaries will continue. 
Rescue medication
The number of rescue medication inhalations (puffs) and nebulizer treatments taken will be 
recorded by the subject in the paper diary twice daily (i.e., in the morning and evening) 
beginning the evening of V2 until the morning of V14. The number of inhalations taken 
between the morning and evening lung function assessments will be recorded in the evening. 
The number of inhalations taken between the evening and the morning will be recorded in the 
morning.
Nocturnal awakenings

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Nocturnal awakenings due to asthma symptoms will be recorded by the subject in the paper 
diary each morning, beginning in the morning after V2 until the morning of V14, by 
answering a question as to whether he/she woke up during the night due to asthma symptoms 
by a “yes” or “no” response. 
Maintenance medication
Maintenance medication administration will be recorded daily in the paper diary in the 
morning, beginning in the morning after V2 until the morning of V14.
8.1.18.2
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 paper subject 
report.
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.
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 7 for the list of clinical safety laboratory tests to be performed, and the SoA for the 
timing and frequency. All protocol-required laboratory assessments, as defined in the Table 7, 
must be conducted in accordance with the laboratory manual and the SoA. 
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 
center 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.
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory.

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Table 7 – Laboratory safety variables
Hematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (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
S-Creatinine
Urinalysis (dipstick)*
S-Creatinine kinase (CK)
U-Blood 
S-CRP
U-Protein 
S-Gamma-glutamyl transpeptidase (GGT)
U-Glucose 
S-Glucose
S-Phosphorus
U-Microscopy and culture as required**
S-Potassium
S-Sodium
S-Total cholesterol
S-Uric acid
*The urine dipstick test is not only limited to Blood, Protein and Glucose, but also additional test analytes as defined by 
central lab.
**Urine samples will be analyzed locally with the urine dipstick test and sent to the central laboratory only for further 
microscopy and culture 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 Appendix E for further instructions.
8.2.1.1
Pregnancy Test 
The following tests are applicable to female subjects only and will be conducted in accordance 
with the schedule provided in section 1.1.

Serum ß-human chorionic gonadotropin (ß-HCG) – the test will be mandatory 
at enrolment (V1) and at EOT visit, for women of child-bearing potential 
(WOCBP).

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
FSH – the test done at enrolment (V1) only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrheic for 
>12 months.

Urine HCG – the test will be performed at the study site for WOCBP at each 
treatment visit before IP administration using a dipstick. Positive urine test 
result must be confirmed with serum β-HCG.
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 centimeters. Weight and height 
measurements will be performed in light clothing and with shoes off. Body Mass Index (BMI) 
will be automatically calculated in the eCRF. 
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, musculoskeletal (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 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, as 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. 
Blood pressure and pulse measurements will be assessed in 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). 

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Pulse rate will be obtained before blood pressure only if the manual measuring 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 in degrees Celsius prior to IP administration, in 
accordance with local standards.
8.2.5
Electrocardiograms
A 12- or 15-lead ECG will be taken in supine position, prior to blood draw, spirometry, and 
BD 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.
ECG evaluation will be recorded in the eCRF.
8.2.6
Other safety assessments
8.2.6.1
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be 
assessed at enrolment (V1) only.  All testing for these will be performed at a central 
laboratory.
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites.
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 Appendix A.

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AEs 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 
All AEs, including SAEs will be collected from time of signature of informed consent form 
throughout the treatment period and the follow-up periods. AEs and SAEs should still be 
collected after IP discontinuation for subjects that prematurely discontinue from IP and will be 
encouraged to undergo appropriate study visits/procedures for the full 40-week period.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. 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 AEs or SAEs 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 must notify the sponsor.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B. 
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 SAEs/non-serious AEs/AEs of special interest, AEs leading 
to premature discontinuation 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.

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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 IP(s) (yes or no)

Action taken with regard to IP(s)

Select the appropriate as required: AE caused subject’s withdrawal from study (yes 
or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to 

Date of hospitalization

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 IP and each Adverse Event, and
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the IP?’

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For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
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 CSP mandated laboratory tests, vital signs and ECG will be summarized 
in the CSR. Deterioration as compared to baseline in protocol-mandated laboratory 
values/vital signs/ECG should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign/ECG 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. anemia versus low 
hemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 
deteriorations in non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms. Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnea, breathlessness and phlegm, will be recorded as AEs only when:

The sign or symptom is serious according to definitions, see Appendix B

The patient discontinues IP due to the sign or symptom

The sign or symptom is new to the patient or not consistent with the patient’s pre-
existing asthma history (defined as within 1 year of V1) as judged by the Investigator.

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Asthma exacerbation should be recorded as an AE or SAE only if it fulfils any of the above 
criteria.
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 IP. 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 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
8.3.9
Hy’s law
Cases where a subject shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.

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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 IP, 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 must 
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 will work 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 will be undertaken immediately. Investigators or other site personnel will 
inform AstraZeneca representatives of any follow-up information on a previously reported 
SAE within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative(s).
If the WBDC system is not available, then the Investigator or other study site staff must report 
a SAE to the appropriate AstraZeneca representative(s) by telephone.
The AstraZeneca representative(s) will advise the Investigator/study site staff how to proceed.  
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca IP.
For further guidance on the definition of a SAE, see Appendix B.
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. Any cases of pregnancy during the study period or follow up will be recorded in 
the specific CRF module.

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Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal 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, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive medication.  
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs.  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca 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 paper-based 
pregnancy outcome report 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 for conceptions 
occurring from the date of the first administration of IP until 16 weeks (5 half-lives) after the 
last administration of IP.
8.4.3
Overdose
A dose in excess of 280 mg administered within a 2-week period is considered an overdose.
There is currently no specific treatment in the event of overdose of IP and possible symptoms 
of an overdose are not established.

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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 
8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If a medication error occurs during 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 8.3.2) 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 (Lieberman et al 2010). 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 manifests 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 3 and 5, 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
Data safety monitoring board
The DSMB is an external independent expert advisory group commissioned and charged with 
the responsibility of evaluating cumulative safety data at regular intervals and making 
appropriate recommendations based on the available data. The DSMB will function 
independently of all other individuals associated with the conduct of the study, including the 
study sponsor, AstraZeneca, and 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 and BAL samples for determination of tezepelumab will be collected pre-dose 
according to the SoA (Section 1.1, Table 1)
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual. 
Samples for determination of tezepelumab concentration in serum will be analyzed by a 
designated third party on behalf of AstraZeneca using a validated bioanalytical method. 
Samples for determination of tezepelumab concentration in BAL will be analyzed by a 
designated third party on behalf of AstraZeneca using a qualified bioanalytical method. 

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Samples for determination of urea will be analyzed by a designated third party on behalf of 
AstraZeneca using qualified bioanalytical methods. Urea concentration will be measured in 
blood and BAL samples to correct for the dilution factor of the BAL samples. Details 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 samples to measure the presence of ADAs
The presence of ADA will be assessed in serum samples according to the SoA (section 1.1).
Samples will be measured for the presence of ADAs for tezepelumab using validated assays. 
Tiered analysis will be performed to include screening, confirmatory, and titer assay 
components, and positive-negative cut points previously statistically determined from drug-
naïve validation samples will be employed. Samples with confirmed positive ADAs will be 
archived for possible testing for neutralizing antibodies (nAb).
ADA sample should be collected in case of any suspected immunologically-related AEs.
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 Last Visit (LSLV).
Pharmacokinetic and ADA samples may be disposed of or destroyed and anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method.  Any results from such 
analyses may be reported separately from the CSR.
8.6
Pharmacodynamics
Pharmacodynamic parameters will be evaluated using biomarkers (see section 8.8).
8.7
Genetics
8.7.1
Optional exploratory genetic sample
The blood sample for DNA isolation will be collected from subjects who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Patients 
who do not wish to participate in the genetic research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.

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See Appendix D for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D or in 
the separate Laboratory Manual provided to the sites.
The results of the analyses will be reported separately from the CSR in a scientific report or 
publication.
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 LSLV, 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.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
Mandatory collection of samples for biomarker research is also part of this study. The patient's 
consent to the use of the donated biological samples is mandatory. 
Biological samples will be collected for exploratory analyses to investigate the effect of 
tezepelumab on biomarkers of inflammation, asthma, pharmacology of tezepleumab and for 
potential predictors of response. 
The following samples for biomarker research are required and will be collected from all 
subjects in this study as specified in the SoA: Blood, plasma, serum, BAL, bronchial 
brushings, bronchoscopic biopsy and urine samples will be collected according to the SoA in 
order to evaluate changes in biomarkers related to asthma, inflammation and the TSLP 
pathway. Biomarkers that may be analyzed include, but are not limited to, cytokines, 
chemokines and inflammatory mediators associated with asthma and the TSLP pathway.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the centers. 
Selected results of this biomarker research may be reported in the CSR (as per section 8.1.6). 
Biomarkers not reported in the CSR may be reported in an addendum, or separately in a 
scientific report or publication.

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8.8.1
Storage, re-use and destruction of biomarker samples
AstraZeneca or a designee will retain biomarker samples for investigation of research on 
asthma, the pharmacology of tezepelumab, and potential predictors of response for a 
maximum of 15 years from the date of the LSLV, after which they will be destroyed.
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. Any residual 
samples may be retained for up to 15 years and used for the purpose of investigating asthma, 
the pharmacology of tezepelumab, predictors of response or assay validation work. If a subject 
does not allow samples to be used for future biomarker research they may continue with their 
samples being used for the main study.
8.8.2
Serum IgE
The levels of serum IgE may be tested by a central laboratory in accordance with the SoA.  
All total serum IgE results will be redacted from the laboratory reports except for Visit 3. 
Instructions for sample collection, processing, storage and shipment will be provided in a 
separate laboratory manual.
8.8.3
Transcriptomics
RNA will be isolated from bronchial brushings. Sample collection will be in accordance with 
SoA. In addition, other samples including whole blood samples for RNA will be collected in 
PAX gene blood RNA tubes for ribonucleic acid (RNA), BAL cells and bronchial biopsies 
will be collected, stored and may be processed for RNA transcriptomics if sufficient material 
is collected. RNA may be used in the analyses of host gene expression and microbiome 
research using quantitative methods that may include but are 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. The epithelial three 
gene mean signature (POSTN, CLCA1, SERPINB2) will be reported in the CSR. Any 
additional transcriptomics data from bronchoscopic brushings will be reported separately from 
the CSR in an addendum or in a scientific report or publication. Any exploratory 
transcriptomics analyses on BAL cells, whole blood and biopsy tissue, will be reported 
separately from the CSR in an addendum or in a scientific report or publication
8.8.4
Storage, re-use and destruction of transcriptomics samples
Transcriptomics samples are considered biomarker samples so all storage, re-use and 
destruction instructions defined in section 8.8.1 also applies to any samples collected for 
transcriptomics.

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8.9
Healthcare Resource Utilization and Health Economics
Healthcare resource utilization 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, Healthcare Resource Utilization (HRU) 
information will be collected with a ‘one year’ recall period. All the subsequent visits will 
collect HRU information with a recall period of ‘since the last scheduled visit’. 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 CSR.
9.
STATISTICAL CONSIDERATIONS
Statistical hypotheses: The null hypothesis H0: The ratio (tezepelumab/placebo) of the 
change, expressed as a ratio, from baseline to EOT for each primary and secondary endpoint 
between tezepelumab and placebo equals 1 and will be tested versus the alternative hypothesis 
H1: The ratio (tezepelumab/placebo) of the change, expressed as a ratio, from baseline to EOT 
for each primary and secondary endpoint between tezepelumab and placebo is not equal to 1. 
Improvement under treatment is characterized by a reduction in the number of inflammatory 
cells, so ratios of tezepelumab/placebo less than 1 correspond to beneficial treatment effect of 
tezepelumab over placebo.  
9.1
Sample size determination 
The study is sized to explore reductions in airway submucosal inflammation, from baseline to 
EOT for tezepelumab, versus placebo in the overall study population and across the T2 
continuum. 
The sample size chosen is based on the change from baseline to EOT in number of airway 
submucosal eosinophils and in number of airway submucosal neutrophils (ratio of 
tezepelumab to placebo). 
It is estimated that 50 subjects in each treatment arm will provide (using a 2-sided test with a 
nominal 10% significance level for each endpoint); 

80% power to observe a reduction in number of airway submucosal eosinophils if 
the true effect is a 2.7-fold difference versus placebo (assuming standard deviation 
on log scale of 1.87 and 2.06 for placebo and tezepelumab respectively based on 
tralokinumab study D2210C00014). 

>90% power to observe a reduction in number of airway submucosal neutrophils if 
the true effect is a 2.7-fold difference versus placebo (assuming standard deviation 

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on log scale of 0.71 and 0.97 for placebo and tezepelumab respectively based on 
tralokinumab study D2210C00014)
This sample size allows exploratory assessment of the effect of tezepelumab on airway 
inflammation within quartiles across the T2 continuum and within other subgroups of interest. 
It is assumed that a small proportion of subjects will not have an evaluable primary endpoint 
value due to failed biopsies. To account for this and subject dropouts, 55 subjects will be 
randomized in each treatment arm. A 2.7-fold change has been chosen because it is within the 
range of effect sizes observed with Nucala (Haldar et al 2009) and Fasenra (Laviolette et al 
2013)
9.2
Populations for analyses
For purposes of analysis, the following populations are defined: 
Table 8 – Population descriptions
Population
Description
Enrolled 
All subjects who sign the ICF
Randomized
All subjects randomized to study treatment 
(irrespective of or whether treatment is 
subsequently taken)
Full analysis set
All subjects randomized to study treatment who 
received at least one dose of IP, irrespective of 
their protocol adherence and continued 
participation in the study
Evaluable analysis set
All subjects randomized to study treatment who 
completed at least 20 weeks of study treatment 
and had an EOT visit date not greater than 8 
weeks after date of last dose of IP
Safety analysis set 
All subjects who received at least one dose of IP
PK analysis set 
All subjects in the full analysis set who received 
tezepelumab and from whom PK blood and PK 
BAL samples are assumed not to be affected by 
factors such as
protocol deviations (e.g. disallowed medication or 
incorrect study medication received).
Efficacy analyses will be based on the evaluable analysis set unless otherwise stated, with 
patients classified by their randomized treatment, in line with the Intention to Treat (ITT) 

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principle. Demographic and baseline characteristics will be presented using both the evaluable 
analysis set and full analysis set.  
Safety presentations and anti-drug antibodies (ADA) presentations will be based on the safety
analysis set, with subjects assigned according to the treatment they received. A subject who 
has on one or several occasions received active treatment will be classified as active. Any 
important deviations from the randomized treatment assignment, and any subjects that have 
received IP without being randomized, will be listed and considered when interpreting the 
safety data.
All PK summaries will be based on the PK analysis set.
9.3
Outcome measures for analyses
9.3.1
Definition of baseline and subject baseline analyses
In general, the last measurement on or prior to the date of randomization will serve as the 
baseline measurement. If there is no value on or prior to the date of randomization, then the 
baseline value will not be imputed and will be set to missing. The baseline for outcome 
variables based on efficacy biomarkers is defined as value recorded at the V3 (a or b); if a 
measurement is not scheduled to be measured at V3 or if the V3 measurement is missing, the 
last non-missing value before V3 will be used as baseline instead.
The baseline for ACQ-6 will be captured using paper questionnaire at Visit 3b. 
For laboratory data and physical examination, baseline will be defined as the latest non-
missing assessment prior to first dose (V3b).
Absolute change from baseline outcome variables is computed as (post-randomization value –
baseline value).
Percent change from baseline is computed as 100 x 1((post-randomization value – baseline 
value) / baseline value) %. If either the post-randomization value or the baseline value is 
missing, then the absolute or percent change from baseline value will also be set to missing.
The ratio post-randomization value / baseline value will also be computed when stated below.
9.3.2
Primary outcome measure
The change, expressed as a ratio, in number of airway inflammatory cells per mm2 determined 
by microscopic evaluation of bronchoscopic biopsies from baseline (V3b) to EOT/V3b will be 
compared between treatments. This will be done separately for eosinophils, neutrophils, T 
cells, and mast cells. 

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9.3.4.6
 
 
 
 
CCI

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
AEs occurring during run-in (onset date ≥ V1 and before the first dose of study 
treatment)

AEs occurring during treatment (onset date ≥ the first day of study treatment and ≤ 
the last day of study treatment + 4 weeks)

AEs occurring during follow-up (onset date > the last day of study treatment + 4 
weeks and ≤ the last day of study treatment + 16 weeks)
The timing of AEs will be assigned to the period in which they first occurred. If an AE has a 
missing onset date, then unless the stop date of the AE indicates otherwise, this will be 
considered an on-treatment event. Similarly, if an AE has a partial onset date, then unless the 
partial onset date or the stop date indicates otherwise, this will be considered an on-treatment 
AE.
9.3.5.2
Other significant adverse events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations due to AEs.
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OSAEs) and reported as such in the CSR.
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
9.3.5.3
Laboratory variables
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis 
parameters will be taken at the times detailed in the CSP and will be assessed in a central 
laboratory. The parameters outlined in Table 7 in Section 8.2.1, will be collected. Laboratory 
data will be reported in SI units.
Changes in hematology and clinical chemistry variables between baseline and each 
subsequent on treatment assessment will be calculated as described in Section 9.3.1. There 
will be no imputation for missing values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The AstraZeneca extended 
reference ranges will be used for laboratory variables (where they exist). All values (absolute 
and change) falling outside the reference ranges will be flagged.

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Urinalysis data will be categorized as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each time-point.
For the purposes of hematology, clinical chemistry and urinalysis shift tables, baseline will be 
defined as the latest non-missing assessment prior to first dose, and on-treatment will be 
defined as the latest non-missing assessment whilst the subject is ongoing on treatment.
For the liver function tests: AST, ALT, ALP, GGT and total bilirubin, the multiple of the 
AstraZeneca ULN (not extended) range will be calculated for each data point.
Multiple = Value / ULN
i.e. if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2.
Subjects who meet any of the following criteria at any point during the study will be flagged:

AST ≥ 3x ULN

ALT ≥ 3x ULN

TBL ≥ 2xULN
9.3.5.4
ECGs
Twelve-lead ECG measurements will be recorded in accordance with the protocol, with the 
baseline visit being defined as V1.
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant.
9.3.5.5
Physical Examination
Complete and brief physical examinations will be performed at time points specified in 
Table 1.
What is included in the assessment will be dependent on whether the examination is complete 
or brief, as described in Section 8.2.3. For the brief physical examination, only information on 
whether the assessment was performed or not will be recorded.
Each component of the complete physical examination at baseline visit (i.e., V3a) will be 
recorded as normal or abnormal. Each component of the physical examinations at follow-up 
will be recorded as normal, same as baseline, or new/aggravated.
Any new finding(s), or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE.

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9.3.5.6
Vital signs
Pre-dose vital signs (pulse, systolic blood pressure, diastolic blood pressure, respiration rate 
and body temperature) will be obtained in accordance with the schedule provided in Table 1.
Changes in vital sign variables between baseline and each subsequent scheduled assessment 
will be calculated as described in 9.3.1. There will be no imputation for missing values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). All values (absolute and 
change) falling outside the reference ranges will be flagged.
BMI will be calculated from the height (in meters) and weight (in kilograms) as BMI = kg/m2
9.4
Statistical analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive 
statistical analysis plan (SAP) will be developed and finalized before 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.
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violators identified.
EOT assessments done at either week 28 or later will be discussed in the Statistical Analysis 
Plan (SAP).
9.4.1
Efficacy analyses
Efficacy analyses will be based on the evaluable analysis set, and subjects will be classified 
according to their randomized treatment.
The analysis of study endpoints will include all data captured during the double-blind 
treatment period. This includes data regardless of whether study treatment was prematurely 
discontinued or delayed, and/or irrespective of protocol adherence, unless the subject 
withdraws consent to study participation. 
Summary data will be presented in tabular format by treatment. Categorical data will be 
summarized by the number and percentage of subjects in each category. Continuous variables 
for parametric data will be summarized by descriptive statistics including N, mean, standard 
deviation (SD), geometric mean, SD of log values, median, and range. All data will be listed 
and data listings will be sorted by treatment and subject number.

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The primary and secondary variables will be analyzed using geometric means. Geometric 
mean is often used to evaluate data covering several orders of magnitude, and for evaluating 
ratios, percentages, or other data sets bounded by zero. A geometric mean, unlike an 
arithmetic mean, tends to dampen the effect of very high values, which might bias the mean if 
an arithmetic mean was calculated. The geometric mean is also a log-transformation of data to 
enable meaningful statistical evaluations; it accounts for some of the expected skewness in the 
data, but with the possibility to use a parametric analysis with a p-value directly linked to the 
confidence interval for the treatment effect. Both the difference in number of cells and the 
ratio will be reported, but the statistical analysis will only be based on the ratio. 
Nonparametric analyses will be applied as sensitivity analyses.
All hypothesis testing will be reported using 2-sided tests with a nominal 10% significance 
level and 90% confidence intervals (CIs). For the primary endpoints only, 2-sided 95% CIs 
will also be reported. The direction of interest for each of the primary endpoints is that the 
ratio tezepelumab/placebo is lower than 1. Nominal p-values will be reported for primary and 
secondary variables i.e., no adjustment of multiplicity will be performed. P-values will be 
rounded to 3 decimal places.
9.4.2
Analysis of the primary variable(s)
The primary efficacy objective will be evaluated through statistical testing of the within 
subject change from baseline to (EOT), expressed as a ratio, in number of airway submucosal 
inflammatory cells (separately eosinophils, neutrophils, T cells, and Mast cells). 
The primary variable of within subject change from baseline to EOT (expressed as a ratio) in 
numbers of each of the airway submucosal inflammatory cells will be analyzed using an 
analysis of covariance (ANCOVA) including at least screening blood eosinophil strata 
(screening blood eosinophil count <150 cells/µL, 150 - <300 cells/µL, and ≥ 300 cells/µL at 
Visit 1), baseline value, and treatment as covariates. The analysis will be performed by using 
log-transformed data and estimated geometric means and the ratio of geometric means with 
both 95% and 90% two-sided confidence intervals will be presented.
If the change from baseline for a subject, expressed as a ratio, is zero, the value will be 
replaced by half the smallest observed value among the subjects with non-zero values, before 
doing the logarithmic transformation.  If the baseline value for a subject is zero, the baseline 
value will be replaced by half the smallest observed value among subjects with non-zero 
values, before calculating the change from baseline.  If both baseline and on-treatment for a 
subject is zero, the value for the ratio is defined to be 1.  
Available values at both baseline and (EOT) are required for a subject to be included in the 
analysis and it is unlikely that a subject with a missing baseline value will undergo a second 
biopsy.  

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9.4.3
Analysis of the secondary variable(s)
The secondary variables of within subject change, expressed as a ratio, from baseline up to 
EOT in RBM thickness and % airway epithelial integrity will be analysed using the same 
ANCOVA model described for the primary variable. The secondary analysis of inflammatory 
cells across the spectrum of T2 status will be assessed by using the same ANCOVA model 
described for the primary variable with the addition of elements in the ANCOVA model for 
T2 quartile (categorical) and interactions between T2 quartile and treatment as well as visual 
data displays. 
The analyses of inflammatory cells will be performed by using log-transformed data.  The 
scale (i.e. ratio, percent change, or absolute change) and possible log transformation for the 
other secondary endpoints will be determined using blinded data prior to database lock.   
9.4.4
Supportive analysis
For the primary and secondary variables, alternative transformations or non-parametric 
analysis methods may be applied as supportive analyses if substantial deviations from the 
parametric assumptions are observed.  This will be assessed and documented prior to 
unblinding.  
For the primary variables, the analysis may be repeated using the full analysis set, hence 
including assessments in subjects who complete at least 16 weeks of study treatment and had 
an EOT visit date not greater than 12 weeks after date of last dose of IP as a supportive 
analysis. 
It is likely that some biopsy specimens will not be evaluable. Also, due to the invasive 
procedures performed, it is likely that some subjects will withdraw from the study. We cannot 
rule out that there is a relationship between unobserved values and the likelihood of data being 
missing and therefore the effect of missing data may be assessed using multiple imputations 
and a range of assumptions for the missing data.
Additional analyses assessing the impact of COVID-19 may be included in the SAP.
Full details of the supportive analyses will be pre-specified in SAP and documented prior to 
database lock of the study. 
9.4.5
Exploratory analysis
Exploratory variables will be summarized using descriptive statistics and graphical displays. 
How changes in biomarkers correlate with changes in airway inflammation and remodeling 
will be explored graphically.

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9.4.6
Safety analyses
Safety analyses will be based on the Safety Analysis Set, and subjects will be classified 
according to the treatment they received. A subject who has on one or several occasions 
received active treatment will be classified as active.
9.4.7
Other analyses 
PK, immunogenicity, pharmacodynamic analyses will be described in the statistical analysis 
plan finalized before database lock. Details of the biomarker analyses will be described in the 
exploratory analyses plan, which will be finalized before the database lock. The results will be 
reported outside the CSR.
Three gene mean from epithelial brushings transcriptomics will be used to determine T2 
activity. Analysis for any other transcriptomic data, if generated, will be described in the 
exploratory analysis plan (EAP), which will be finalized before the database lock. The results 
from the EAP will be reported outside the CSR.
9.5
Interim analyses

No interim analyses are planned in this trial.

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council 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 

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are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
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 authorized representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized 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 
center.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  
The authorized 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 authorized 
representative.  
If 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 authorized 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 analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.

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During the COVID-19 pandemic, re-consenting remotely may be obtained if local/regional 
guidelines allow.
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.  
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 authorized 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 CSP 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.  

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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 authorized 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 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
Site and Study Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to:

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•
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
A 10
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 
multicenter 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 unfavorable 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 hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity.  

Is a congenital abnormality or birth defect.

Is an important medical event that may jeopardize 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
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g. bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 

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existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
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, hospitalization, 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 anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
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

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When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another etiology 
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

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For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the participant 
or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were 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 

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
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 keeps full traceability of collected biological samples from the 
subjects while in storage at the center 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 analyzed,
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 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.

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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.
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.htm)

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

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
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 
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 etiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, blood samples 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 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

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
For inclusion in this genetic research, subjects must fulfil all of the 
inclusion criteria described in the main body of the CSP and: Provide 
informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion 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 withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7.3 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
Blood samples for genetic research will be obtained from subjects at any time after the 
consent is signed. 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. Only one sample should 
be collected per subject for genetics during the study. 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 LSLV, 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 

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organization.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the subject enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations.  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.
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 center.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely withdraw 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 analyze the samples.
AstraZeneca and its designated organizations 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 organizations or health insurance companies.  This 

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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) 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 PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met.  
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than 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 AE and 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)

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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.  
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 (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory without 
delay

Complete the appropriate unscheduled laboratory 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:

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
Determine whether the subject meets PHL criteria (See Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results)
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the subject meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
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.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the CSP.
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 and the continuous review of 
data.  

Subsequent to this contact the Investigator will:

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
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 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 calendar days from the 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.  
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 PHL 
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

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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 but not mandatory when using a central laboratory. 
If required, additional assistance on which tests could be used to evaluate other potential 
causes of liver dysfunction consult with the Hepatic Safety Knowledge Group. Any test 
results need to be recorded. 

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Hy’s Law lab kit for central laboratories
*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’.
Additional standard 
chemistry and coagulation 
tests
GGT 
LDH 
Prothrombin time 
INR
Viral hepatitis
IgM anti-HAV 
IgG anti-HBc 
HBsAg 
HBV DNA 
IgM and 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 Antibody 
(AntiLKM) 
Anti-Smooth Muscle Antibody (ASMA)
Metabolic diseases
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation

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Appendix F
Maintenance therapy equivalence table
Estimated daily doses for inhaled corticosteroids
Asthma Therapy 
Total Daily Dose (μg/day)
Inhaled Corticosteroida
Medium
High
Beclomethasone dipropionate (CFC)b
>500–1000
>1000
Beclomethasone dipropionate (HFA)c
>200–400
>400
Budesonide
>400–800
>800
Ciclesonide 
>160–320
>320
Fluticasone furoate (e.g. Arnuity® Ellipta® Breo®)
n.a.
200
Fluticasone propionate 
>250–500
>500
Fluticasone propionate HFA
>250–500
>500
Mometasone furoate 
>220–440
>440
Triamcinolone acetonide 
>1000–2000
>2000
Inhaled Corticosteroid in ICS/LABA combinationa
Medium 
High
Beclomethasone dipropionate (e.g. Fostair®)
>200–400
>400
Fluticasone propionate HFA (e.g. Seretide®, Advair®)
>250–500
>500
Fluticasone furoate (e.g. Relvar® Ellipta®, Breo® Ellipta®)
n.a.
184-200
Budesonide, if as delivered dose (e.g. Symbicort®)
>400–640
>640
Mometasone Furoate (e.g. Dulera®)
>220–400
>400
a The ICS doses were derived from GINA 2018 and the ICS/LABA combinations were derived from GINA 2017 and 2018 
and using prescribing information
b CFC: Chlorofluorocarbon propellant
c HFA: hydrofluoroalkane propellant 

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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 Appendix G 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in Appendix G 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, 
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):
(c)
Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, 
swollen lips-tongue-uvula).
(d)
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, 
hypoxemia).

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(e)
Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence).
(f)
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting).
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

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
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
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, 
as necessary, depending on the presenting signs and symptoms of anaphylaxis, to 
control signs and symptoms and prevent progression to more severe symptoms such 
as respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
(a)
Place subject in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(a)
Consider epinephrine infusion.
(b)
Consider H1 and H2 antihistamines.

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(c)
Consider nebulized β2 agonist [e.g. albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.
(d)
Consider systemic corticosteroids.
(e)
Consider vasopressor (e.g. dopamine).
(f)
Consider glucagon for subject taking β-blocker.
(g)
Consider atropine for symptomatic bradycardia.
(h)
Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and 
prolonged resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp SF, Lockey RF, Simons FE; World Allergy Organization Ad hoc 
Committee on Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. 
A statement of the World Allergy Organization. Allergy. 2008; 63(8):1061-70.

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Appendix H
Abbreviations
The following abbreviations and special terms are used in this study CSP.
Abbreviation or special 
term
Explanation
AAER
Annualized Asthma Exacerbation Rate
ACQ-6
Asthma Control Questionnaire-6
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
AHR
Airway Hyperresponsiveness
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibody
AntiLKM
Anti-Liver/Kidney Microsomal Antibody
AO
Airwave Oscillometry
ASMA
Anti-Smooth Muscle Antibody
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AX
Area under the reactance curve
BAL
Bronchoalveolar Lavage
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BUN
Blood Urea Nitrogen
BV5
Blood Vessels less than 5mm2 in Cross-Sectional Area
BV10
Blood Vessels less than 10mm2 in Cross-Sectional Area
CLCA1
Chloride Channel Accessory 1
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form (paper)
CSA
Clinical Study Agreement

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Abbreviation or special 
term
Explanation
CSR
Clinical Study Report
CT
Computed Tomography
DNA
Deoxyribonucleic Acid 
DSMB
Data Safety Monitoring Board
DUS
Disease under Study
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
E/I 
Expiratory-to-Inspiratory
EDN
Eosinophil-derived Deurotoxin
ER
Emergency Room
EOT
End of Treatment 
PRO
Patient Reported Outcome 
EU
European Union
FAS
Full Analysis Set
FEIA
Fluorescent Enzyme Immunoassay
FEF25%-75%
Forced Expiratory Flow over 25-75% of the Vital Capacity
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FRI
Functional Respiratory Imaging
fSAD 
Functional Small Airway Disease 
FSH
Follicle-Stimulating Hormone
FU
Follow-Up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice

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Abbreviation or special 
term
Explanation
HCP
Health Care Professional 
HIV
Human Immunodeficiency Virus
IATA
International Air Transport Association
ICH
International Conference on Harmonization
ICI
International Co-ordinating Investigator (If a study is conducted in 
several countries the International Co-ordinating Investigator is the 
Investigator coordinating the Investigators and/or activities 
internationally). 
ICF 
Informed Consent Form 
ICS
Inhaled Corticosteroids
IgE
Immunoglobulin E
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IRB
Institutional Review Board
ISF
Investigator Study File
ISH
In-Situ Hybridization
ITT
Intent-to-Treat
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 Antagonists
LAR
Late Asthmatic Response
LIMS
Laboratory Information Management System
LRTI
Low Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonists
LSLV
Last Subject Last Visit

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Abbreviation or special 
term
Explanation
MAb
Monoclonal Antibody
MAR
Missing at Random
MedDRA
Medical Dictionary for Regulatory Activities
MCID
Minimum Clinically Important Difference
MCT
Mannitol Challenge Testing
MNAR
Missing-Not-at-Random
nAB
Neutralizing Antibodies
OCS
Oral Corticosteroids
OSAE
Other Significant Adverse Event
PD
Pharmacodynamic
PGx
Genetic research
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PI
Principal Investigator 
PK
Pharmacokinetic(s)
PNV
Predicted Normal Value
PRO
Patient Reported Outcome
POSTN
Periostin
PT
Preferred Term
Q4W
Every 4 Weeks
R5-R20
Peripheral airway resistance defined as the difference in resistance 
between 5 Hz (R5, total respiratory system resistance) and 20 Hz (R20, 
central resistance)
RBM
Reticular Basement Membrane
RNA
Ribonucleic Acid
SABA
Short-Acting β2-Agonist
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SC
Subcutaneous

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Abbreviation or special 
term
Explanation
SERPINB2
Serpin Family B Member 2
SGRQ
St. George’s Respiratory Questionnaire
SoA
Schedule of Activities
SOC
System Organ Class
SDV
Source Data Verification
TLC
Total Lung Capacity
TPV
Third Party Vendor
TSLP
Thymic Stromal Lymphopoietin
ULN
Upper Limit of Normal
UNS
Unscheduled
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential

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Appendix I
Medication washout periods for airway hyper-responsiveness
Medication 
Time to 
Withhold 
INHALED NON-STEROIDAL ANTI-INFLAMMATORY AGENTS 
(e.g. sodium cromoglycate, nedocromil sodium)
6-8 hours 
SHORT-ACTING BETA2 AGONISTS 
(e.g. salbutamol, terbutaline)
8 hours 
INHALED CORTICOSTEROIDS 
(e.g. beclomethasone dipropionate, budesonide, fluticasone propionate)
12 hours 
IPRATROPIUM BROMIDE 
12 hours 
LONG-ACTING BETA2 AGONISTS 
(e.g. salmeterol, formoterol)
24 hours 
INHALED CORTICOSTEROIDS PLUS LONG-ACTING BETA2 AGONISTS 
(e.g. fluticasone and salmeterol, budesonide and formoterol)
24 hours 
THEOPHYLLINE 
24 hours 
TIOTROPIUM BROMIDE 
72 hours 
ANTIHISTAMINES 
(e.g. cetirizine, fexofenadine and loratadine)
72 hours 
LEUKOTRIENE-RECEPTOR ANTAGONISTS 
(e.g. montelukast sodium)
4 days 
Food: Ingestion of significant quantities of coffee, tea, cola drinks, chocolate or other food 
containing caffeine may decrease bronchial responsiveness and should be totally avoided on 
the day of the test.

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Appendix J
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.
J 1 Home IP Administration Instructions
Due to local travel restrictions and/or site restrictions, patients 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 home administration of IP by a qualified HCP, provided this is 
acceptable within local regulation/guidance. This is to ensure safety of the study subjects and
minimum disruption to IP administration that may occur during the COVID-19 
pandemic. Minimum requirements for collection are listed below under the extra dose(s) 
instruction (J.3)
Please refer to the Transportation, Preparation, Administration by the Health Care 
Professional and Handling of Investigational Product (IP) for Home Administration (or 
alternative site) of the IP  working instructions for more information.
J 2 Phone Call visit to replace On-site visit (where applicable)
The last follow up visit is an on-site visit where safety assessments are performed including 
vital signs, blood and urine samples and physical examination. There are several currently 
enrolled subjects who are expected to have their last follow up visit on site. During the 
COVID-19 pandemic, on-site follow up visit may be replaced by a phone call and/or a virtual 
visit if allowed by local/regional guidelines. 
Having a phone call and/or a virtual visit with the subject will allow:

Adverse Events 

Concomitant Medication

Exacerbation history to be reported and documented for safety
J 3 Extra Dose(s)
During the COVID-19 pandemic, sites may administer 1-6 additional IP doses at weeks 28, 
32, 36, 40, 44 and 48 (as needed) until the sites may be able to resume performing the end of 
treatment (EOT) study assessments, mainly bronchoscopies, in accordance to local 
regulations/guidelines during COVID-19 pandemic. Once the bronchoscopy can be 
performed, the site should schedule the patient to have the EOT study assessments 4 weeks 
after the last dose. If the subjects have extra IP doses administered, at minimum, the following 
is expected:

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
Vital Signs

Urine pregnancy test (dipstick) prior to IP administration

Any worsening of underlying asthma symptoms/Asthma exacerbations since last 
contact with the subject

Adverse events reported since last contact with the subject

Collection of healthcare utilization data

New concomitant medications since last contact with the subject

Collection of paper diaries from previous visit and distribution of new paper diaries

Complete the appropriate eCRF pages related to COVID-19

Optional Safety lab samples and/or visit specific lab samples, as per the PI discretion
J 4 Reconsenting of subjects during the COVID-19 pandemic
It is critical that where a subject is unable to travel to the site, obtaining re-consent remotely 
necessary for the implementation of the new urgent changes in the Cascade study during the 
COVID-19 pandemic. Please ensure that applicable local guidelines and regulations are 
followed on re-consenting process.

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: d5180c00013-csp-v4
Document Title:
D5180C00013 Clinical Study Protocol version 4
Document ID:
Doc ID-003832814
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
06-May-2020 07:40 UTC
Content Approval
05-May-2020 16:22 UTC
Author Approval
05-May-2020 18:35 UTC
Content Approval
05-May-2020 19:43 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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