An Open-label Study to Evaluate the Pharmacokinetics and Pharmacodynamics and Long-term Safety of Benralizumab Administered Subcutaneously in Children With Severe Eosinophilic Asthma
Phase: PHASE3
Conditions: Severe Uncontrolled Asthma
Sponsor: AstraZeneca

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 1 
 
 
Clinical Study Protocol  
Drug Substance 
Benralizumab (MEDI-563) 
Study Code 
D3250C00025 
Version 
5.0 
Date 
22 February 2022  
An Open-label Study to Evaluate the Pharmacokinetics and 
Pharmacodynamics and Long-term Safety of Benralizumab 
Administered Subcutaneously in Children with Severe Eosinophilic 
Asthma 
Sponsor:  
AstraZeneca AB, 151 85 Södertälje, Sweden 
Local Sponsor in Japan:  
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan 
Regulatory Agency Identifying Number(s):  
EudraCT number: 2019-004638-40 
NCT number: 04305405 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 2 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Amendment 4 (Version 5.0) 
22 February 2022 
Amendment 3 (Version 4.0) 
01 July 2020 
Amendment 2 (Version 3.0) 
22 August 2019 
Amendment 1 (Version 2.0) 
22 July 2019 
Original Protocol (Version 1.0) 
22 June 2018 
 
Amendment 4 (22 February 2022) 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment: 
The primary rationale for this amendment is to update: the estimated study completion date; 
the benefit/risk assessment; storage of ECG readings; to add information regarding to medical 
device malfunctions; and to align with current CSP template requirements.  
Section # and Name 
Description of Change 
Brief Rationale 
Substantial/ 
Non-substantial 
Section 1.2, Synopsis 
Estimated date of last 
patient completed was 
changed from May 2022 
to September 2022. 
The last patient’s first 
dose was mid-September 
2021. If this patient 
completes the study, the 
estimated date of 
completion would be in 
September 2022. 
Non-substantial 
Section 2.3 Benefit/risk 
assessment 
The minimum 
observation period at the 
clinical site following IP 
administration was 
changed to 1-hour from 
2-hours.  
Typographical correction 
to align with 
Section 6.3.3 
Non-substantial 
Section 6.1.1, 
Investigational products, 
Table 3 Study treatments 
Aligned information 
presented with current 
CSP template. 
Clarification 
Non-substantial 
Section 8.2.4 
Electrocardiograms 
Clarification that ECG 
readings can be stored as 
physical copies in 
subject’s source files. 
Clarification 
Non-substantial 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5  
 
 
T a ble 1:  
•  
T he wi n d o w f or t he scree ni n g visit has bee n u p date d.  
•  
Wi n d o ws f or Visit 3, Visit 4, a n d Visit 5 ha ve bee n u p date d t o be c o nsiste nt wit h t he 
wi n d o w f or t he P K sa m ple at t hese visits.  
•  
I nter vie wer-a d mi nistere d A st h ma C o ntr ol Q uesti o n naire ( A C Q -I A) has bee n a d de d at 
Visit 2, Visit 4, Visit 5, Visit 1 1, Visit 1 2, a n d Visit 1 4.  
•  
I nter vie wer-a d mi nistere d P atie nt G l o bal Im pressi o n of C ha n ge ( P GI C -I A) has bee n 
a d de d at Visit 9, Visit 1 0, Visit 1 1, Visit 1 3 a n d at t he earl y disc o nti n uati o n  ( D X D)/earl y 
wit h dra wal ( W D) visit . 
•  
Cli nicia n G l o bal Im pressi o n of C ha n ge ( C GI C) has bee n a d de d a t Visit 9, Visit 1 0, Visit 
1 1, Visit 1 3 a n d at t he D X D/ W D visit.  
•  
F orce d e x pirat or y v ol u me i n 1 sec o n d ( F E V 1) has bee n a d de d at Visit 2.  
•  
Uri nal ysis has bee n a d de d at scree ni n g a n d at Visit 6, V isit 7, Visit 8, Visit 9, Visit 1 0, 
Visit 1 3, a n d at t he D X D  v isit, t o be c o nsiste nt wit h t he te xt of Secti o n 8. 2. 1. 
•  
Ast h ma ex acer bati o n has bee n a d de d t o all visits e xce pt Visit 1 a n d Visit 2.  
•  
Pre g na nc y test, p har mac o ki netic ( P K ) sa m pli n g a n d a nti-dr u g a nti b o d y ( A D A ) sa m pli n g 
assess me nts ha ve bee n u p date d wit h a c orr es p o n di n g f o ot n ote a d de d t o i n dicate w he n 
t hese assess me nts s h o ul d be perf or me d pre-d ose . 
•  
T he sc he d ule of A D A sa m pli n g has bee n u p date d  
•  
Sa m pli n g f or ne utrali zi n g a nti b o dies (n A b ) has bee n delete d fr o m t he A D A sa m pli n g 
r o w, a n d fr o m t he ta ble f o ot n otes. 
•  
T h e ta ble has bee n re or ga nise d t o f oll o w t he rec o m me n de d se q ue nce f or t he c o m pleti o n 
of assess me nts at eac h visit.  
S y n o psis  
•  
 has bee n a d de d as t he i nter nati o nal c o-or di nati n g i n vesti gat or.  
S y n o psis a n d Secti o n 2. 2, Secti o n 4. 1, Secti o n 4. 2, Secti o n 5. 1, a n d Secti o n 9. 5. 2  
•  
I ncl usi o n of patie nts a ge d 1 2 t o 1 4 years a n d wei g hi n g at least 3 5 k g i n Ja pa n has bee n 
a d de d.  
S y n o psis  a n d Secti o n 3 : 
•  
Prese nce of n e utralizi n g a nti b o dies has bee n delete d f r o m t he sec o n dar y o bjecti ves. 
•  
A C Q -I A has bee n a d de d at Wee ks 1, 2, 3 2, a n d 4 0 a n d at t he f oll o w -u p visit i n t he 
sec o n dar y e n d p oi nts . 
•  
P GI C -I A has bee n a d de d at Wee k 1 6 ( Part A), a n d Wee ks 2 4, 3 2 a n d 4 8 ( Part B) a n d at 
t he D X D/ W D visit. 
•  
C GI C has bee n a d de d at Wee k 1 6 ( Part A), a n d Wee ks 2 4, 3 2 a n d 4 8 ( Part B) a n d at t he 
D X D/ W D visit.  
•  
A n n ualize d ast h ma e xacer bati o n rate ( A A E R) has bee n a d de d as a n e x pl orat or y 
o bjecti ve.  
P P D

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6  
 
 
S y n o psis a n d Secti o n 4. 1, Secti o n 6. 1, Secti o n 6. 1. 1, a n d Secti o n 9. 5. 2:  
•  
Stratifica ti o n b y b o d y wei g ht < 4 0 k g / ≥4 0 k g has bee n c ha n ge d t o stratificati o n b y b o d y 
wei g ht < 3 5 k g / ≥3 5 k g.  
•  
T he d ose of 
 m g t o be a d mi nistere d t o patie nts i n t he l o wer wei g ht strat u m ( pre vi o usl y 
< 4 0 k g) has bee n c ha n ge d t o 
 m g f or t he u p date d l o wer wei g ht strat u m of < 3 5 k g.  
S y n o psis a n d Secti o n 4. 1:  
•  
A state me nt has bee n a d de d t o all o w t he scree ni n g peri o d t o be e xte n de d if necessar y.  
•  
T he state me nt t hat a n y of t he first 4 patie nts i n eac h c o h ort w ill be re place d if t he patie nt  
misses a d ose or a sc he d ule d assess me nt has bee n delete d.  
Secti o n 2. 3:  
•  
A state me nt has bee n a d de d c o ncer ni n g t he ris k relate d t o h y perse nsiti vit y reacti o ns.  
Secti o n 4. 1 : 
•  
A state me nt has bee n a d de d t o clarif y t he re q uire me nts f or patie nts i n Part A t o be 
e val ua ble, a n d t hat n o n -e val ua ble patie nts i n Part A will be re place d.  
Secti o n 4. 3:  
•  
T he j ustificati o n f or t he d ose of be nraliz u ma b has bee n u p date d t o pr o vi de a rati o nale f or 
t he use of 
 m g i n patie nts wei g hi n g < 3 5 k g.  
Secti o n 5. 1:  
•  
T he Ja pa nese Pe diatric Ast h ma G ui deli nes ha ve bee n a d de d t o incl usi o n criteri o n 3. 
•  
Defi niti o n of i n hale d c ortic oster oi d rele va nt t o Ja pa n has bee n a d de d t o incl usi o n 
criteri o n 6. 
Secti o n 6. 1. 2:  
•  
Secti o n 6. 1. 2 Me dical De vi ces has bee n delete d , as it is n ot a p plica ble t o t his st u d y. 
Secti o n 6. 2  
•  
F urt her i nf or mati o n has bee n a d de d relati n g t o st ora ge of t he i n vesti gati o nal pr o d uct (I P) 
a n d t o acti o ns t o be ta ke n i n case of te m perat ure e xc ursi o ns or da ma ge t o t he I P or I P 
pac ka gi n g . 
Secti o n 6. 6:  
•  
‘Fi ve -li p o x y ge nase i n hi bit ors’ has bee n delete d fr o m t he ta ble of pr o hi bite d me dicati o ns.  
Secti o n 8:  
•  
A rec o m me n de d se q ue nce f or t he c o m pleti o n of assess me nts at eac h visit has bee n 
a d de d.  
•  
Ta ble 7 has bee n u p date d t o i ncl u de detail of t he t y pe of sa m ples t o be ta ke n at eac h visit 
i n a d diti o n t o t he v ol u me of bl o o d t o be ta ke n at eac h visit. 
Secti o n 8. 1. 2:  
•  
A rati o nale has bee n a d de d f or t he c o m pleti o n of t he A C Q -I A at all visits d uri n g t he 
treat me nt a n d p ost-treat me nt peri o ds. 
C CI
C CI
C CI

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 8 
 
 
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. 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 9 
 
 
TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE...................................... 2 
TABLE OF CONTENTS .......................................................................................................... 9 
1 
PROTOCOL SUMMARY ................................................................................... 13 
1.1 
Schedule of Activities (SoA) ................................................................................ 13 
1.2 
Synopsis ................................................................................................................ 16 
1.3 
Schema .................................................................................................................. 20 
2 
INTRODUCTION ................................................................................................ 21 
2.1 
Study rationale ...................................................................................................... 21 
2.2 
Background ........................................................................................................... 21 
2.3 
Benefit/risk assessment ......................................................................................... 23 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 24 
4 
STUDY DESIGN ................................................................................................. 25 
4.1 
Overall design ....................................................................................................... 25 
4.1.1 
Study conduct mitigation during study disruptions due to cases of civil crisis, 
natural disaster, or public health crisis ................................................................. 27 
4.2 
Scientific rationale for study design ..................................................................... 28 
4.3 
Justification for dose ............................................................................................. 28 
4.4 
End of study definition ......................................................................................... 29 
5 
STUDY POPULATION ....................................................................................... 29 
5.1 
Inclusion criteria ................................................................................................... 29 
5.2 
Exclusion criteria .................................................................................................. 31 
5.3 
Lifestyle restrictions ............................................................................................. 33 
5.3.1 
Meals and dietary restrictions ............................................................................... 33 
5.3.2 
Caffeine, alcohol, and tobacco ............................................................................. 33 
5.3.3 
Activity ................................................................................................................. 33 
5.4 
Screen failures ...................................................................................................... 33 
6 
STUDY TREATMENTS ..................................................................................... 33 
6.1 
Treatments administered ....................................................................................... 33 
6.1.1 
Investigational products ........................................................................................ 34 
6.2 
Preparation/handling/storage/accountability ........................................................ 35 
6.3 
Investigational drug administration ...................................................................... 35 
6.3.1 
Before investigational product administration...................................................... 35 
6.3.2 
Investigational product administration ................................................................. 36 
6.3.3 
After investigational product administration ........................................................ 36 
6.3.4 
Conditions requiring investigational product administration rescheduling .......... 36 
6.4 
Measures to minimise bias: randomisation and blinding ..................................... 36 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 10 
 
 
6.5 
Treatment compliance .......................................................................................... 36 
6.6 
Concomitant therapy ............................................................................................. 36 
6.6.1 
Background medication ........................................................................................ 38 
6.6.2 
Other concomitant treatment ................................................................................ 38 
6.6.3 
Rescue medication ................................................................................................ 38 
6.7 
Dose modification ................................................................................................. 38 
6.8 
Treatment after the end of the study ..................................................................... 38 
7 
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 38 
7.1 
Discontinuation of study treatment ....................................................................... 38 
7.1.1 
Procedures for discontinuation of study treatment ............................................... 39 
7.2 
Lost to follow-up .................................................................................................. 39 
7.3 
Withdrawal from the study ................................................................................... 40 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 40 
8.1 
Efficacy assessments ............................................................................................ 43 
8.1.1 
Spirometry ............................................................................................................ 43 
8.1.1.1 
General requirements ............................................................................................ 43 
8.1.1.2 
Spirometry technique ............................................................................................ 43 
8.1.2 
Clinical outcome assessments .............................................................................. 44 
8.2 
Safety assessments ................................................................................................ 45 
8.2.1 
Clinical safety laboratory assessments ................................................................. 45 
8.2.2 
Physical examinations .......................................................................................... 47 
8.2.3 
Vital signs ............................................................................................................. 47 
8.2.4 
Electrocardiograms ............................................................................................... 47 
8.2.5 
Other safety assessments ...................................................................................... 48 
8.2.5.1 
Weight and height ................................................................................................. 48 
8.2.5.2 
Medical/surgical history ....................................................................................... 48 
8.2.5.3 
Pregnancy test ....................................................................................................... 48 
8.2.5.4 
Concomitant medications ..................................................................................... 48 
8.2.5.5 
Asthma exacerbation ............................................................................................ 48 
8.3 
Collection of adverse events ................................................................................. 49 
8.3.1 
Method of detecting AEs and SAEs ..................................................................... 49 
8.3.2 
Time period and frequency for collecting AE and SAE information ................... 49 
8.3.3 
Follow-up of AEs and SAEs ................................................................................ 50 
8.3.4 
Adverse event data collection ............................................................................... 50 
8.3.5 
Causality collection .............................................................................................. 50 
8.3.6 
Adverse events based on signs and symptoms ..................................................... 51 
8.3.7 
Adverse events based on examinations and tests ................................................. 51 
8.3.8 
Disease-under study (DUS) .................................................................................. 51 
8.4 
Safety reporting and medical management .......................................................... 51 
8.4.1 
Reporting of serious adverse events ..................................................................... 51 
8.4.2 
Pregnancy ............................................................................................................. 52 
8.4.2.1 
Maternal exposure ................................................................................................ 52 
8.4.2.2 
Paternal exposure .................................................................................................. 53 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 11 
 
 
8.4.3 
Overdose ............................................................................................................... 53 
8.4.4 
Management of investigational product-related reaction ..................................... 53 
8.4.5 
Medication error ................................................................................................... 54 
8.4.6 
Medical device deficiencies .................................................................................. 55 
8.4.6.1 
Time period for detecting medical device deficiencies ........................................ 55 
8.4.6.2 
Follow-up of medical device deficiencies ............................................................ 55 
8.4.6.3 
Prompt reporting of medical device deficiencies to sponsor ................................ 55 
8.4.6.4 
Regulatory reporting requirements for device deficiencies .................................. 55 
8.5 
Pharmacokinetics .................................................................................................. 56 
8.5.1 
Collection of samples ........................................................................................... 56 
8.5.2 
Determination of drug concentration .................................................................... 56 
8.5.3 
Storage and destruction of pharmacokinetic samples ........................................... 56 
8.6 
Pharmacodynamics ............................................................................................... 56 
8.6.1 
Collection of samples ........................................................................................... 56 
8.6.2 
Storage, re-use and destruction of pharmacodynamic samples ............................ 56 
8.7 
Genetics ................................................................................................................ 56 
8.8 
Biomarkers ............................................................................................................ 56 
8.9 
Health Economics ................................................................................................. 57 
8.10 
Immunogenicity .................................................................................................... 57 
8.10.1 
Collection of samples ........................................................................................... 57 
8.10.2 
Storage and destruction of immunogenicity samples ........................................... 57 
9 
STATISTICAL CONSIDERATIONS ................................................................. 57 
9.1 
Statistical hypotheses ............................................................................................ 57 
9.2 
Sample size determination .................................................................................... 57 
9.3 
Patient evaluability ............................................................................................... 57 
9.4 
Populations for analyses ....................................................................................... 58 
9.5 
Statistical analyses ................................................................................................ 58 
9.5.1 
Overview .............................................................................................................. 58 
9.5.2 
General statistical methodology ........................................................................... 58 
9.5.3 
Primary variables .................................................................................................. 59 
9.5.3.1 
Pharmacokinetics .................................................................................................. 59 
9.5.3.2 
Pharmacodynamics ............................................................................................... 59 
9.5.4 
Secondary variables .............................................................................................. 59 
9.5.4.1 
Pharmacokinetics .................................................................................................. 59 
9.5.4.2 
Immunogenicity .................................................................................................... 59 
9.5.4.3 
Spirometry ............................................................................................................ 59 
9.5.4.4 
Asthma Control Questionnaire ............................................................................. 59 
9.5.4.5 
Global Impression of Change Questionnaires ...................................................... 60 
9.5.5 
Safety variables ..................................................................................................... 60 
9.5.6 
Exploratory variables ............................................................................................ 60 
9.5.6.1 
Annualized asthma exacerbation rate ................................................................... 60 
9.6 
Interim analyses .................................................................................................... 60 
9.6.1 
Data Safety Monitoring Board ............................................................................. 61 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 12 
 
 
9.6.2 
Safety Review Committee .................................................................................... 61 
9.7 
Sensitivity analyses ............................................................................................... 61 
10 
REFERENCES ..................................................................................................... 62 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 69 
 
LIST OF TABLES 
Table 1 
Schedule of assessments ............................................................................. 13 
Table 2 
Study objectives and endpoints ................................................................... 25 
Table 3 
Study Treatments ........................................................................................ 34 
Table 4 
Restricted medications ................................................................................ 37 
Table 5 
Prohibited medications ................................................................................ 37 
Table 6 
Maximum volume of blood to be withdrawn from a patient ...................... 41 
Table 7 
Maximum volume of blood to be withdrawn from each patient ................. 42 
Table 8 
Laboratory safety variables ......................................................................... 46 
Table 9 
Analysis populations ................................................................................... 58 
 
LIST OF FIGURES 
Figure 1 
Study design ................................................................................................ 20 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, ethical and study oversight considerations .............................. 70 
Appendix B 
Changes related to mitigation of study disruptions due to cases of civil 
crisis, natural disaster, or public health crisis ............................................. 75 
Appendix C 
Adverse event definitions and additional safety information ..................... 77 
Appendix D 
Handling of human biological samples ....................................................... 82 
Appendix E 
Abbreviations .............................................................................................. 84 
Appendix F 
Anaphylaxis: signs and symptoms, management ........................................ 86 
Appendix G 
Medical device AEs, ADEs, SAEs, SADEs, USADEs and medical 
device deficiencies: definitions and procedures for recording, evaluating, 
follow-up, and reporting in medical device studies .................................... 89 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 13 
 
 
1 
PROTOCOL SUMMARY 
1.1 
Schedule of Activities (SoA) 
Table 1 
Schedule of assessments 
 
Part A – PK, PD, Safety 
Part B- Safety 
DXD/ 
WD 
 
Visit 
 
Visit windows 
1  
SCRN 
Days 
–28 
to -14 
2 
 
 
3 
 
+1 
day 
4 
 
±3 
day 
5 
 
±4 
day 
6 
 
±7 
day 
7 
 
±7 
day 
8 
 
±7 
day 
9 
 
±7 
day 
10 
 
±7 
day 
11 
 
±7 
days 
12 
 
±7 
days 
13 
EOT 
±7 
day 
14 
F/U 
±7 
day 
 
For 
details 
see 
Section 
Week 
- 
0 
0 
1 
2 
4 
8 
12 
16 
24 
32 
40 
48 
52 
- 
Section  
Day 
- 
0 
1 
7 
14 
28 
56 
84 
112 
168 
224 
280 
336 
362 
- 
- 
Written 
informed 
consent/assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 
A 3 
Inclusion/ 
exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.1, 5.2 
ACQ-IA 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.1.2 
PGIC-IA 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
8.1.2 
CGIC 
 
 
 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
8.1.2 
Body weight 
and height 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
X 
8.2.5.1 
Patient 
stratification  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.1 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.3 
Medical/surgica
l history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.5.2 
12-lead ECG 
X 
   
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
8.2.4 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 14 
 
 
Table 1 
Schedule of assessments 
 
Part A – PK, PD, Safety 
Part B- Safety 
DXD/ 
WD 
 
Visit 
 
Visit windows 
1  
SCRN 
Days 
–28 
to -14 
2 
 
 
3 
 
+1 
day 
4 
 
±3 
day 
5 
 
±4 
day 
6 
 
±7 
day 
7 
 
±7 
day 
8 
 
±7 
day 
9 
 
±7 
day 
10 
 
±7 
day 
11 
 
±7 
days 
12 
 
±7 
days 
13 
EOT 
±7 
day 
14 
F/U 
±7 
day 
 
For 
details 
see 
Section 
Week 
- 
0 
0 
1 
2 
4 
8 
12 
16 
24 
32 
40 
48 
52 
- 
Section  
Day 
- 
0 
1 
7 
14 
28 
56 
84 
112 
168 
224 
280 
336 
362 
- 
- 
Complete PE 
(pre-dose) 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
8.2.2 
Brief PE (pre-
dose) 
 
 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
8.2.2 
FEV1 
X 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
8.1.1 
Clinical 
chemistry 
assessments 
Xa 
a 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
8.2.1 
Haematology 
(CBC + 
differential) 
Xa 
a 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
8.2.1, 
8.6.1 
Serology 
(hepatitis B, C, 
HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.1 
Urinalysis 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
X 
 
X 
8.2.1 
Pregnancy test  
X 
Xb 
 
 
 
Xb 
Xb 
X 
Xb 
Xb 
Xb 
Xb 
X 
 
X 
8.2.5.3 
Concomitant 
medications 
X 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.5.4 
Asthma 
exacerbation 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.2.5.5 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8.3 
PK sampling   
 
Xb 
X 
X 
X 
Xb 
Xb 
X 
Xb 
Xb 
 
 
X 
  
X 
8.5 

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 15 
 
 
Table 1 
Schedule of assessments 
 
Part A – PK, PD, Safety 
Part B- Safety 
DXD/ 
WD 
 
Visit 
 
Visit windows 
1  
SCRN 
Days 
–28 
to -14 
2 
 
 
3 
 
+1 
day 
4 
 
±3 
day 
5 
 
±4 
day 
6 
 
±7 
day 
7 
 
±7 
day 
8 
 
±7 
day 
9 
 
±7 
day 
10 
 
±7 
day 
11 
 
±7 
days 
12 
 
±7 
days 
13 
EOT 
±7 
day 
14 
F/U 
±7 
day 
 
For 
details 
see 
Section 
Week 
- 
0 
0 
1 
2 
4 
8 
12 
16 
24 
32 
40 
48 
52 
- 
Section  
Day 
- 
0 
1 
7 
14 
28 
56 
84 
112 
168 
224 
280 
336 
362 
- 
- 
ADA sampling  
 
Xb 
 
 
 
 
Xb 
  
 Xb  
Xb 
 
 
X 
 
X 
8.10 
Single-dose IP 
injections 
 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
6.1 
a 
The screening clinical chemistry/haematology samples at Visit 1 (Day -28 to Day -14) will constitute baseline values provided that Visit 2 (Day 0) is done ≤ 
28 days after Visit 1.  If so, no safety laboratory samples will need to be collected at Visit 2. 
b 
To be performed before IP is administered at these visits. 
Abbreviations: ACQ-IA  interviewer-administered asthma control questionnaire, ADA anti-drug antibody(ies), CBC  complete blood count, CGIC clinician 
global impression of change,  DXD early discontinuation, ECG  electrocardiogram, exam  examination, EOT  end of treatment, FEV1  forced expiratory 
volume in 1 second, F/U  follow-up, HIV human immunodeficiency virus, IP  investigational product, PD  pharmacodynamics, PE  physical examination, 
PGIC-IA interviewer administered patient global impression of change, PK  pharmacokinetics, SCRN  screening, std  standard, WD early withdrawal. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 6  
 
 
1. 2  
S y n o psis  
I nter n ati o n al c o-or di n ati n g i n vesti g at or:  
 
St. L o uis, Miss o uri 6 3 1 1 0  
Pr ot oc ol Title:  
A n O pe n -la bel St u d y t o E val uate t he P har mac o ki netics a n d P har mac o d y na mics a n d L o n g-
ter m Safet y of Be nraliz u ma b A d mi nistere d S u bc uta ne o usl y i n C hil dre n wit h Se vere 
E osi n o p hilic Ast h ma  
R ati o n ale:  
Se vere ast h ma a p pears t o be relate d t o i ncrease d bl o o d c o nce ntrati o ns of e osi n o p hilic cells i n 
a d ults, a d olesce nts, a n d c hil dre n a ge d  6 t o 1 1 years  (Fitz patric k et al 2 0 1 1 ).  E osin o p hilic cells 
ha ve bee n s h o w n t o be a me diat or i n t he pat h o p h ysi ol o g y of ast h ma i n a d ults, a d olesce nts, a n d 
c hil dre n a ge d  6 t o 1 1 years.  Yet, it is u nclear w het her t he pat h o p h ysi ol o g y is i de ntical i n 
t hese t hree a ge gr o u ps.   
T he a bs ol ute e osi n o p hilic c ou nt  i n bl o o d ca n be relia bl y meas ure d i n all t he a ge gr o u ps 
c o ncer ne d, t h us a p har mac o ki netic ( P K )/p har mac o d y na mic ( P D ) relati o ns hi p ca n be 
e val uate d.  Pre vi o us cli nical st u dies of be nraliz u ma b i n a d ult ast h ma patie nts ha ve s h o w n a n 
ass ociati o n bet wee n de p leti o n of e osi n o p hilic cells i n bl o o d a n d i m pr o ve me nt of ast h ma 
e xacer bati o n rate, l u n g f u ncti o n, a n d ast h ma s y m pt o ms.  Alt h o u g h a n i m pr o ve me nt i n t hese 
ast h ma para meters was n ot de m o nstrate d i n t he a d olesce nt p o p ulati o n, a P K/ P D relati o ns hi p 
si milar t o a dults i n e osi n o p hil de pleti o n was o bser ve d.  H o we ver, t he sa m ple size was li mite d, 
a n d c o nsi dera ble efficac y was als o see n i n t he place b o gr o u p .  
T he p o p ulati o n P K a nal ysis of be nraliz u ma b i n ast h ma patie nts f o u n d t hat t he cleara nce of t he 
dr u g i ncrease d wi t h b o d y wei g ht (Astra Ze neca 2 0 1 6 , Astra Ze neca 2 0 1 7 ).  I n a d diti o n, a ge 
was n ot f o u n d t o be a si g nifica nt c o variate i n P K; t he P K of a d olesce nts was c o nsiste nt wit h 
t hat of a d ults after acc o u nti n g f or wei g ht differe nce.  T h us, be nraliz u ma b ca n be e x pecte d t o 
s h o w P K pr o perties pr o p orti o nal t o b o d y wei g ht i n c hil dre n a ged  6 t o 1 1 years, as well as i n 
a d olesce nts a n d i n a d ults, t h us ma ki n g a m o delli n g a p pr oac h base d o n a d olesce nt a n d a d ult 
data p ossi ble t o pr oject a n efficaci o us d ose i n c hil dre n b y matc hi n g t he e x p os ure of t he a d ult 
efficaci o us d ose.  M ore o ver, t here ha ve bee n n o safet y si g nals detecte d i n pre vi o us 
be nraliz u ma b cli nical st u dies t hat w o ul d precl u de a d mi nistrati o n t o c hil dre n a ge d  6 t o 1 1 
years.  
P P D

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 17 
 
 
This study will evaluate the PK, PD and long-term safety of benralizumab in 30 children aged 
6 to 11 years with severe eosinophilic asthma.  Up to 3 additional Japanese patients aged 12 to 
14 years will be enrolled. 
Objectives and endpoints 
 
Primary objectives: 
Endpoints/variables: 
To evaluate the pharmacokinetics (PK) of 
benralizumab administered subcutaneously (SC) in 
children from 6 to 11 years of age with severe 
eosinophilic asthma 
• 
Clearance 
• 
Area under concentration time curve to Day 28 
(AUC0-28) 
• 
Maximum serum concentration (Cmax) 
• 
Terminal phase elimination half-life (t1/2) 
• 
Time to reach Cmax (Tmax) 
To evaluate the pharmacodynamics (PD) of 
benralizumab administered SC in children from 6 to 
11 years of age with severe eosinophilic asthma 
Change from baseline in peripheral blood eosinophil 
count at Weeks 4, 8, 12 and 16 (Part A), and Weeks 
24 and 48 (Part B) 
Secondary objectives: 
Endpoints/variables: 
To characterize the PK of benralizumab 
Body weight-adjusted clearance 
To evaluate the immunogenicity of benralizumab 
Presence of anti-benralizumab antibodies 
To evaluate the effect of benralizumab on pulmonary 
function 
Change from baseline in pre-dose (when applicable), 
pre-bronchodilator, forced expiratory volume in 1 
second (FEV1) measured at Weeks 4, 8, 12, and 16 
(Part A), and Weeks 24 and 48 (Part B) 
To assess the effect of benralizumab on asthma 
symptoms and other asthma control metrics 
Change from baseline in Interviewer-administered 
Asthma Control Questionnaire (ACQ-IA) score, 
measured at screening and Weeks 1, 2, 4, 8, 12, and 
16 (Part A), and Weeks 24, 32, 40 and 48, and at 
follow-up (Part B)  
Interviewer-administered Patient Global Impression 
of Change (PGIC-IA), measured at Week 16 (Part A), 
Weeks 24, 32 and 48 (Part B), and at the DXD/WD 
visit 
Clinician Global Impression of Change (CGIC), 
measured at Week 16 (Part A), Weeks 24, 32 and 48 
(Part B), and at the DXD/WD visit 
Safety objective: 
Endpoints/variables: 
To assess the safety and tolerability of benralizumab 
Adverse events (AEs) 
Vital signs  
Collection of clinical chemistry/haematology 
parameters and urinalysis 
Exploratory objective: 
Endpoints/variables: 
To evaluate exacerbations experienced 
Annualized asthma exacerbation rate (AAER) 
 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 8  
 
 
O ver all desi g n:  
T his is a n o pe n -la bel, parallel gr o u p st u d y desi g ne d t o e val uate t he P K a n d P D , a n d l o n g-ter m 
safet y of be nraliz u ma b a d mi nistere d S C i n 3 0 c hil dre n fr o m 6 t o 1 1 years of a ge wit h se vere 
e osi n o p hilic ast h ma. U p t o 3 a d diti o nal Ja pa nese patie nts a ge d 1 2 t o 1 4 years will be e nr olle d.  
Patie nts a ge d 6 t o 1 1 years will be stratifie d b y b o d y wei g ht at scree ni n g ( < 3 5  k g / ≥3 5  k g) .  
Patie nts wit h a b o d y wei g ht < 3 5  k g at scree ni n g will recei ve t he f oll o wi n g re gi me n of 
be nraliz u ma b: 
 m g a d mi nistere d b y S C i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), 
f oll o we d b y 
 m g at W ee ks 2 4, 3 2, a n d 4 0 ( Part B) .  Patie nts wit h a b o d y wei g ht ≥3 5  k g at 
scree ni n g will recei ve t he f oll o wi n g re gi me n of be nraliz u ma b:  
m g a d mi nistere d b y S C 
i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), f oll o we d b y 
 m g at Wee ks 2 4, 3 2, a n d 
4 0 ( Part B).   Ja pa nese patie nts a ge d 1 2 t o 1 4 years will recei ve t he 
 m g d ose , a n d t heir visit 
sc he d ules will be t he sa me as patie nts a ge d 6 t o 1 1 years t hr o u g h o ut t he st u d y. 
T he st u d y will be c o n d ucte d i n 2 parts, Part A a n d Part B .  Part A will c o nsist of 1 6 wee ks of 
treat me nt t o e val uate t he P K/ P D , a n d safet y of be nraliz u ma b.  Part B will c o nsist of 3 2 wee ks 
of c o nti n ue d treat me nt t o e val uate t he safet y of be nraliz u m a b.  All st u d y data will be 
s u m marise d t o get her, n ot se paratel y b y st u d y part. 
After i nitial e nr ol me nt a n d c o nfir mati o n of e ntr y criteria, patie nts will pr ocee d t o a scree ni n g 
peri o d of u p t o 2 8 da ys t o all o w a de q uate ti me f or t he eli gi bilit y criteria t o b e e val uate d .  T he 
scree ni n g peri o d ma y be e xte n de d if necessar y after disc ussi o n wit h t he Astra Ze neca St u d y 
P h ysicia n.  Patie nts w h o meet t he eli gi bilit y criteria will e nter t he 4 8 -wee k treat me nt peri o d.  
Sta g gere d i ncl usi o n will occ ur f or patie nts a ge d 6 t o 1 1 years i n w hic h 4 patie nts wit h a b o d y 
wei g ht < 3 5  k g a n d 4 patie nts wit h a b o d y wei g ht ≥3 5  k g will c o m plete Part A t he n pr o gress 
directl y i nt o Part B .  Eac h treat me nt/wei g ht gr o u p will be assesse d se p aratel y b y t he S afet y 
R e vie w C o m mittee ( S R C ) i n acc or da nce wit h t he c harter, s o t he treat me nt/wei g ht gr o u ps ca n 
pr o gress i n de pe n de ntl y i nt o Part B .  After e val uati o n of all a vaila ble P K a n d safet y data fr o m 
t he i nitial 4 e val ua ble patie nts i n eac h treat me nt/wei g ht gr o u p, t he re mai ni n g e nr olle d patie nts 
will e nter t he treat me nt p hase .  T he 4 patie nts i n eac h treat me nt/ wei g ht gr o u p i n Part A m ust 
ha ve recei ve d at least 1 d ose of be nraliz u ma b a n d at least 3 p ost -first I P d ose P K ser u m 
sa m ples m ust ha ve bee n c ollecte d t o be e val ua ble.  If a n y of t he patie nts i n Part A d o n ot meet 
t hese criteria, t he n t hat patie nt will be re place d.  Ja pa nese patie nts a ge d 1 2 t o 1 4 years ma y be 
e nr olle d i n parallel wit h t he sta g gere d i ncl usi o n f or t he first 8 patie nts a ge d 6 t o 1 1  years.  
St u d y Peri o d:  
Esti mate d date of first patie nt e nr olle d : N o ve m ber 2 0 1 9 
Esti mate d date of last patie nt c o m plete d : Se pte m ber 2 0 2 2  
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 1 9  
 
 
N u m ber of S u bjects:  
A p pr o xi matel y 3 0 e val ua ble patie nts a ge d 6 t o 1 1 years will be treate d wit h be nraliz u ma b 
acr oss t he 2 c o m bi ne d wei g ht strata, wit h a mi ni m u m of 8 patie nts i n eac h strat u m.  U p t o 3 
a d diti o nal Ja pa nese patie nts a ge d 1 2 t o 1 4 years will be e nr olle d.  
Tre at me nts a n d tre at me nt d ur ati o n:  
Patie nts a ge d 6 t o 1 1 years will recei ve eit her 
 m g or 
 m g of be n raliz u ma b ( M E DI-5 6 3) 
base d o n baseli ne b o d y wei g ht f or S C i njecti o n a n d t he d ose f or eac h patie nt will n ot c ha n ge 
d uri n g t he st u d y .  Patie nts a ge d 1 2 t o 1 4 years will recei ve 
 m g of be nraliz u ma b ( M E DI -
5 6 3) f or S C i njecti o n d uri n g t he st u d y.  St u d y treat m e nt will be pr o vi de d i n a n access orise d 
pre -fille d s yri n ge.  Eac h  s yri n ge will be la belle d i n acc or da nce wit h G o o d Ma n ufact uri n g 
Practice ( G M P) A n ne x 1 3 a n d per c o u ntr y re g ulat or y re q uire me nt.  
I n Part A, patie nts will recei ve 4 d oses of st u d y treat me nt (t he first 3 d oses e ver y 4 wee ks a n d 
t he f o urt h d ose 8 wee ks after) de pe n di n g o n b o d y wei g ht.  I n Part B, 8 wee ks after c o m pleti n g 
Part A, patie nts will recei ve a n a d diti o nal 3 d oses of st u d y trea t me nt e ver y 8 wee ks  ( Q 8 W).  
T he t otal d urati o n of t he st u d y f or m ost  patie nt s will be u p t o 5 6 wee ks a n d will i ncl u de a 
scree ni n g peri o d of u p t o 2 8 da ys a n d a treat me nt peri o d of 4 8 wee ks, a n d a safet y f oll o w-u p 
visit at Wee k 5 2.  T he t otal d urati o n of t h e st u d y ma y be l o n ger if t he scree ni n g peri o d is 
e xte n de d. 
D at a S afet y M o nit ori n g B o ar d : 
A Data Safet y M o nit ori n g B oar d ( D S M B) will o versee s pecific as pects of t his st u d y.  
St atistic al met h o ds:  
T he sa m ple size is n ot base d o n a f or mal sa m ple size calc ulati o n.  A sa m ple size of 3 0 
e val ua ble patie nts  a ge d 6 t o 1 1 years , wit h a mi ni m u m of 8 patie nts i n eac h wei g ht strat u m , 
was c h ose n t o pr o vi de s ufficie nt data acr oss t he d osi n g a n d wei g ht cate g ories f or P K 
para meter esti mati o ns usi n g n o nc o m part me ntal a nal ysis ( N C A ) criteria ass u mi n g 3 0 % f or 
perce nt of c oefficie nt of variati o n ( C V %) .  E val ua ble patie nts are defi ne d as t h ose patie nts 
wit h at least 3  p ost -first i n vesti gati o nal pr o d uct (I P) d ose P K assess me nt s a b o ve t he l o wer 
li mit of q ua ntificati o n.  A c o h ort of u p t o 3 Ja pa nese patie nts a ge d 1 2  t o 1 4 years has bee n 
a d de d f oll o wi n g disc ussi o n wit h t he P M D A.  
P K para meters will be deri ve d usi n g eit her N C A or P K a nal ysis  set.  P K a nal ysis will, w here 
p ossi ble, be carrie d o ut usi n g act ual ti me  rec or de d i n t he ra w data.  If act ual ti mes are missi n g, 
n o mi nal ti mes will be use d .  A listi n g of P K bl o o d sa m ple c ollecti o n ti mes, as well as deri ve d 
sa m pli n g ti me de viati o ns will be pr o vi de d.  Ser u m c o nce ntrati o ns a n d P K para meters will be 
s u m marise d us i n g a p pr o priate descri pti ve statistics.  Fi g ures s h o wi n g i n di vi d ual a n d mea n of 
P K c o nce ntrati o n -ti me pr ofiles will be pr o d uce d o n b ot h se mi-l o g a n d li near scales.  Ser u m 
c o nce ntrati o n data ass ociate d wit h p ositi ve a nti-dr u g a nti b o d y ( A D A ) stat us will be fla g ge d i n 
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 0  
 
 
t he P K c o nce ntrati o n listi n gs a n d ma y be e xcl u de d fr o m t he s u m mar y statistics a n d/ or mea n 
pr ofiles.   T he o bser ve d pae diatric P K will be c o m pare d wit h t he pr ojecti o n fr o m t he 
p o p ulati o n P K m o del i n a d ult a n d a d olesce nt ast h ma pati e nts. 
Peri p heral bl o o d e osi n o p hils val ues a n d c ha n ges fr o m baseli ne at eac h visit will be 
s u m marise d usi n g descri pti ve statistics f or eac h treat me nt/ wei g ht gr o u p.  
Ot her varia bles will be s u m marise d, as a p pr o priate, usi n g descri pti ve statistics . 
1. 3  
Sc he m a  
T he  ge neral st u d y desi g n is s u m marise d i n Fi g ure 1 . 
Fi g ure 1  
St u d y desi g n  
 
 
 
( a) Aft er t h e fir st 4 p ati e nt s  i n e ac h w ei g ht gr o u p h a v e c o m pl et e d P art A ( aft er e v al u ati o n of t h e P K a n d s af et y fr o m P art A i n t h es e p ati e nt s  b y t h e 
s af et y r e vi e w c o m mitt e e ), t h e r e m ai ni n g p ati e nt s wi hi n t h e w ei g ht gr o u p will e nt er t h e tr e at m e nt p h as e .. 
P a e di atric p ati e nt s 
wit h s e v er e 
e o si n o p hilic as h m a 
a n d a  hi st or y of at 
l e a st 2 
e x a c er b ati o n s 
r e q uiri n g s y st e mic 
c ortic o st er oi d s , 
a n d/ or 
h o s pit alis ati o n.  
A g e d 6 t o 1 1 y e ar s; 
s tr atifi e d b a s e d o n 
b o d y w ei g ht 
(< 3 5  k g / ≥3 5  k g) . 
A g e d 1 2 t o 1 4 
y e ar s; n ot str atifi e d  
 
A g e d 6 t o 1 1 y e ar s 
< 3 5  k g:  
b e nr a 
 m g S C at 
D a y 0 & W e ek s 4 , 
8, 1 6  
A g e d 6 t o 1 1 y e ar s 
≥3 5  k g or a g e d 1 2 
t o 1 4 y e ar s: 
b e nr a 
 m g S C at 
D a y 0 & W e ek s 4 , 
8, 1 6  
A g e d 6 t o 1 1 y e ar s 
< 3 5  k g:  
b e nr a 
 m g S C at 
W e ek s 2 4 , 3 2 , 4 0 
 
F oll o w -u p Vi sit  
 
A g e d 6 t o 1 1 y e ar s 
≥3 5  k g or a g e d 1 2 
t o 1 4 y e ar s: 
b e nr a 
m g S C at 
W e ek s 2 4 , 3 2, 4 0  
S cr e e ni n g  (-2 8 t o -1 4  D a ys)  
 
P art A  
P K, P D, 
S af et y  
Tr e at m e nt P h a s e  ( 4 8 W e ek s) 
St a g g er e d I n cl u si o n a  
P art B  
S af et y  
F oll o w -u p  
( W e ek 5 2) 
 
be nra be nraliz u ma b; P K p har mac o ki netics; P D p har mac o d y na mics; S C s u bc uta ne o usl y
C CI
C CI
C CI
C CI

Clinical Study Protocol 
AstraZeneca 
Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 21 
 
 
2 
INTRODUCTION 
2.1 
Study rationale 
Severe asthma appears to be related to increased blood concentrations of eosinophilic cells in 
adults, adolescents, and children ages 6 to 11 years (Fitzpatrick et al 2011).  Eosinophilic cells 
have been shown to be a mediator in the pathophysiology of asthma in adults, adolescents, and 
children ages 6 to 11 years.  Yet, it is unclear whether the pathophysiology is identical in these 
three age groups.   
The absolute eosinophilic count in blood can be reliably measured in all the age groups 
concerned, thus a PK/PD relationship can be evaluated.  Previous clinical studies of 
benralizumab in adult asthma patients have shown an association between depletion of 
eosinophilic cells in blood and improvement of asthma exacerbation rate, lung function, and 
asthma symptoms.  Although an improvement in these asthma parameters was not 
demonstrated in the adolescent population, a PK/PD relationship similar to adults in 
eosinophil depletion was observed.  However, the sample size was limited, and considerable 
efficacy was also seen in the placebo group.  
The population PK analysis of benralizumab in asthma patients found that the clearance of the 
drug increased with body weight (AstraZeneca 2016, AstraZeneca 2017).  In addition, age 
was not found to be a significant covariate in PK; the PK of adolescents was consistent with 
that of adults after accounting for weight difference.  Thus, benralizumab can be expected to 
show PK properties proportional to body weight in children ages 6 to 11 years, as well as in 
adolescents and in adults, thus making a modelling approach based on adolescent and adult 
data possible to project an efficacious dose in children by matching the exposure of the adult 
efficacious dose. 
2.2 
Background 
Asthma is a syndrome characterized by airway inflammation, reversible airway obstruction, 
and airway hyper responsiveness.  Patients present clinically with recurrent wheezing, 
shortness of breath, cough, and chest tightness.  Asthma affects children and adults of all ages.  
Asthma is a major cause of chronic morbidity and mortality throughout the world, with a 
higher prevalence in children as compared to adults (Fitzpatrick et al 2011, GINA 2018).  
Asthma often starts during childhood and may persist into adulthood.  Current treatment 
strategies for controlling asthma are primarily aimed at reducing inflammation, with 
corticosteroids being the mainstay of treatment for patients with persistent asthma due to their 
powerful anti-inflammatory effects (GINA 2018, NAEPP 2007).  However, the suppression of 
inflammation is incomplete in a considerable proportion of adults and children with severe 
asthma, despite treatment with corticosteroids in addition to or in combination with other 
long-term controller medications (Davies and Holgate 2002).  This results in considerable 

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impact on quality of life, disproportionate use of healthcare resources, and adverse reactions 
from regular systemic steroid use.  Therefore, there remains an urgent unmet medical need for 
patients, particularly children, whose severe asthma is not controlled by existing therapies 
(Alonso and Saglani 2017). 
The observed variability in clinical response to currently available asthma therapies appears to 
be related, in part, to distinctive inflammatory phenotypes (Weiss and Ware 1996).  In 
particular, asthma associated with eosinophilic inflammation in the airway (often referred to 
as eosinophilic asthma) is common (approximately 40% to 60% of asthmatics) with the degree 
of eosinophilia associated with clinical severity including the risk of asthma exacerbations 
(Bousquet et al 1990, Di Franco et al 2003, Louis et al 2000, Sampson et al 2006, 
Scott and Wardlaw 2006, Zhang and Wenzel 2007).  
Interleukin-5 (IL-5) is a key cytokine essential for eosinophil trafficking and survival 
(Molfino et al 2011).  Benralizumab (MEDI-563) is a humanized, afucosylated, monoclonal 
antibody (mAb) that binds specifically to the human IL-5 receptor alpha subunit (IL-5Rα) on 
the target cell, which is expressed on the surface of eosinophils and basophils 
(Takatsu et al 1994, Toba et al 1999).  Afucosylation confers enhanced antibody-dependent 
cellular cytotoxicity, which results in highly efficient eosinophil depletion by apoptosis 
(Kolbeck et al 2012).  Single and repeated doses of benralizumab in mild to severe asthma 
patients has resulted in depletion of blood eosinophils; repeated doses of benralizumab 
administered SC also markedly reduced airway wall and sputum eosinophil levels 
(Busse et al 2010, Gossage et al 2012, Laviolette et al 2013, Pham et al 2016).  Since 
benralizumab has an anti-eosinophil mechanism of action with resultant tissue eosinophil 
depletion, it could reduce the disease burden in children with severe asthma. 
The clinical efficacy of benralizumab 30 mg SC in adults was confirmed in 2 large Phase 3 
global safety and efficacy studies in patients on high dose inhaled corticosteroids/long-acting 
β2 agonists (ICS/LABA) and blood eosinophil counts ≥300 cells/μL 
(Bleecker et al 2016, FitzGerald et al 2016).  In these studies, that included patients ≥12 years, 
benralizumab was dosed Q8W for approximately 1 year and produced significant decreases in 
asthma exacerbations (up to 51%), and improvements in FEV1 (up to 159 mL) and total daily 
asthma symptom scores in both studies.  Additionally, the Phase 3 program also studied the 
efficacy of benralizumab in patients with blood eosinophil counts <300 cells/μL and in an oral 
corticosteroid (OCS)-dependent asthma population (FitzGerald et al 2017, 
Goldman et al 2017, Nair et al 2017).  The results of these pre-specified and pooled analyses 
demonstrate broad efficacy in patients with blood eosinophil levels ≥150 cells/μL and support 
an enhanced response to benralizumab treatment when certain identifiable clinical features of 
the eosinophilic asthma phenotype are present, including OCS dependence and a history of 
frequent exacerbations.  

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To date, safety and tolerability has been evaluated in the paediatric population (≥12 years old) 
treated with benralizumab and patients (2 to 17 years old) treated with mepolizumab, a similar 
mAb that targets IL-5 and depletes eosinophils.  In Phase 3 studies conducted in patients aged 
12 years and older with severe uncontrolled asthma, benralizumab was generally well 
tolerated and depleted blood eosinophils, reduced exacerbation rates, and improved lung 
function in the overall population (Bleecker et al 2016, FitzGerald et al 2016).  In patients 
with severe eosinophilic asthma, exacerbations decreased following treatment with 
mepolizumab (Ortega et al 2014, Pavord et al 2012); however, only a very small number of 
adolescents were included.  A recently completed clinical study studying the pharmacological 
properties of SC administration of mepolizumab in children ages 6 to11 years with severe 
eosinophilic asthma further established the safety in younger children of mAbs that target 
eosinophils (NCT02377427).  Further, children as young as 2 years have been included in 
clinical studies with mepolizumab for eosinophilic esophagitis (NCT00358449, 
Assa’ad et al 2011).  Therefore, the PK/PD and safety profile of benralizumab in children is 
anticipated to be similar to adolescents and adults who demonstrate eosinophilic asthma. 
The goal of this open-label, parallel group study Phase 3 study is to evaluate the PK and PD, 
and long-term safety of benralizumab administered SC in children from 6 to 11 years of age 
(or 6 to 14 years of age in Japan) with severe eosinophilic asthma. 
2.3 
Benefit/risk assessment 
Benralizumab is currently approved for the treatment of severe eosinophilic asthma.  This 
antibody is specific for the IL-5Rα subunit expressed predominantly on eosinophils and acts 
to deplete eosinophils.  To date, trials of the efficacy of mAbs that deplete eosinophils either 
via targeting IL-5 (mepolizumab or reslizumab) or its receptor (benralizumab) have not been 
undertaken in children with severe asthma.  Although it should be noted that paediatric severe 
asthma is markedly heterogeneous, eosinophils are the predominant inflammatory cell types 
present in the airway lumen and airway wall in children with severe asthma 
(Bossley et al 2012, Saglani and Lloyd 2014, Alonso and Saglani 2017).  Benralizumab is 
beneficial for the treatment of adult severe asthma with an eosinophilic phenotype and thus 
there is a potential that benralizumab can be beneficial for the treatment of severe paediatric 
asthma at exposures that deplete eosinophils. 
Overall, the AE profile in adolescents was generally similar to the overall population in Phase 
3 studies conducted with benralizumab and mepolizumab.  Additionally, during the 
benralizumab Phase 3 asthma exacerbation studies, extensive evaluation of immunoglobulins 
and flow cytometric assessment of cell subtypes demonstrated no differences between 
adolescent patients receiving benralizumab compared with placebo.  Of note, mepolizumab 
had an acceptable AE profile in children with eosinophilic esophagitis as young as 2 years, 
and the PK in children was similar to adults (Assa’ad et al 2011).  In summary, there have 
been no safety signals detected in previous clinical trials with benralizumab or other mAbs 

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that deplete eosinophils (mepolizumab) that would preclude administration of benralizumab to 
children ages 6 to 11 years. 
Development of ADAs to benralizumab has been documented.  Theoretical risks of 
developing ADA include decreased drug efficacy and increased hypersensitivity reactions (eg, 
anaphylaxis or immune complex disease).  Anti-drug antibody development has not been 
associated with an increase in AEs. 
Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially associated 
with a positive prognosis in certain solid tumours.  Therefore, there is a theoretical risk that 
sustained eosinophil depletion may diminish the ability to defend against helminthic parasites, 
or negatively impact the natural history of certain malignant tumours.  Risk minimisation 
measures include exclusion of patients with untreated parasitic infection and active or recent 
malignancy. 
Serious hypersensitivity reactions (including anaphylaxis) are a risk of treatment with biologic 
therapy including benralizumab.  Anaphylaxis may be life-threatening.  Risk minimisation 
includes a minimum of a 1-hour observation period at the clinical site following IP 
administration for the appearance of any acute drug reactions. 
To date, benralizumab has exhibited a similar risk profile in adults and adolescents, one that is 
commensurate with placebo, and the important potential risks are manageable based on risk 
minimisation measures currently utilised in the clinical studies in conjunction with 
AstraZeneca routine pharmacovigilance activities. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of benralizumab may be found in the Investigator’s Brochure. 
See Section 9.6.1 and Appendix A for information regarding the DSMB. 
3 
OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints are shown in Table 2. 

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Table 2 
Study objectives and endpoints 
Primary objectives: 
Endpoints/variables: 
To evaluate the pharmacokinetics (PK) of 
benralizumab administered subcutaneously (SC) in 
children from 6 to 11 years of age with severe 
eosinophilic asthma 
• 
Clearance 
• 
Area under concentration time curve to Day 28 
(AUC0-28) 
• 
Maximum serum concentration (Cmax) 
• 
Terminal phase elimination half-life (t1/2) 
• 
Time to reach Cmax (Tmax) 
To evaluate the pharmacodynamics (PD) of 
benralizumab administered SC in children from 6 to 
11 years of age with severe eosinophilic asthma 
Change from baseline in peripheral blood eosinophil 
count at Weeks 4, 8, 12 and 16 (Part A), and Weeks 
24 and 48 (Part B) 
Secondary objectives: 
Endpoints/variables: 
To characterize the PK of benralizumab 
Body weight-adjusted clearance 
To evaluate the immunogenicity of benralizumab 
Presence of anti-benralizumab antibodies 
To evaluate the effect of benralizumab on pulmonary 
function 
Change from baseline in pre-dose (when applicable), 
pre-bronchodilator, FEV1 measured at Weeks 4, 8, 12, 
and 16 (Part A), and Weeks 24 and 48 (Part B) 
To assess the effect of benralizumab on asthma 
symptoms and other asthma control metrics 
Change from baseline in ACQ-IA score, measured at 
screening and Weeks 1, 2, 4, 8, 12, and 16 (Part A), 
and Weeks 24, 32, 40 and 48, and at follow-up (Part 
B)  
PGIC-IA, measured at Week 16 (Part A), Weeks 24, 
32 and 48 (Part B), and at the DXD/WD visit 
CGIC, measured at Week 16 (Part A), Weeks 24, 32 
and 48 (Part B), and at the DXD/WD visit 
Safety objective: 
Endpoints/variables: 
To assess the safety and tolerability of benralizumab 
AEs 
Vital signs  
Collection of clinical chemistry/haematology 
parameters and urinalysis 
Exploratory objective: 
Endpoints/variables: 
To evaluate exacerbations experienced 
Annualized asthma exacerbation rate (AAER) 
4 
STUDY DESIGN 
4.1 
Overall design 
This is an open-label, parallel group study designed to evaluate the PK and PD, and long-term 
safety of benralizumab administered SC in children from 6 to 11 years of age with severe 
eosinophilic asthma, with an additional cohort of up to 3 Japanese patients aged 12 to 
14 years. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 6  
 
 
A p pr o xi matel y 3 0 e val ua ble patie nts a ge d 6 t o 1 1 years will be treate d wit h be nraliz u ma b 
acr oss t he 2 c o m bi ne d wei g ht strata, wit h a mi ni m u m of 8 patie nts i n e ac h strat u m  
( Secti o n 9. 3 ).  U p t o 3 a d diti o nal Ja pa nese patie nts a ge d 1 2 t o 1 4 years will be e nr olle d.  
Patie nts a ge d 6 t o 1 1 years will be stratifi e d b y b o d y wei g ht at scree ni n g ( < 3 5  k g / ≥3 5  k g).  
Patie nts wit h a b o d y wei g ht < 3 5  k g at scree ni n g will recei ve t he f oll o wi n g re gi me n of 
be nraliz u ma b: 
 m g a d mi nistere d b y S C i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), 
f oll o we d b y 
 m g at Wee ks 2 4, 3 2, a n d 4 0 ( Part B).  Patie nts wit h a b o d y wei g ht ≥3 5  k g at 
scree ni n g will recei ve t he f oll o wi n g re gi me n of be nraliz u ma b: 
 m g a d mi nistere d b y S C 
i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), f oll o we d b y 
 m g at Wee ks 2 4, 3 2, a n d 
4 0 ( Part B).   Ja pa nese patie nts a ge d 1 2 t o 1 4 years will recei ve t he 
 m g d ose , a n d t heir visit 
sc he d ules will be t he sa me as patie nts a ge d 6 t o 1 1 years t hr o u g h o ut t he st u d y . 
T he st u d y will be c o n d ucte d i n 2 parts, Part A a n d Part B .  Part A will c o nsist of 1 6 wee ks  of 
treat me nt t o e val uate t he P K a n d P D , a n d safet y of be nraliz u ma b.  Part B will c o nsist of 3 2 
wee ks of c o nti n ue d treat me nt t o e val uate t he safet y of be nraliz u ma b .  All st u d y data will be 
s u m marise d t o get her, n ot se paratel y b y st u d y part. 
After i nitial e n r ol me nt a n d c o nfir mati o n of e ntr y criteria, patie nts will pr ocee d t o a scree ni n g 
peri o d of u p t o 2 8 da ys t o all o w a de q uate ti me f or t he eli gi bilit y criteria t o be e val uate d.  T he 
scree ni n g peri o d ma y be e xte n de d if necessar y after disc ussi o n wit h t he Astra Ze neca St u d y 
P h ysicia n.  Patie nts w h o meet eli gi bilit y criteria will e nter t he 4 8 -wee k treat me nt peri o d .  
Patie nts will be mai ntai ne d o n t heir c urre ntl y prescri be d ast h ma mai nte na nce t hera p y(ies) 
wit h o ut c ha n ge, fr o m e nr ol me nt t hr o u g h scree ni n g, a n d t hr o u gh t he treat me nt peri o d.  
Sta g gere d i ncl usi o n will occ ur f or patie nts a ge d 6 t o 1 1 years i n w hic h 4 patie nts wit h a b o d y 
wei g ht < 3 5  k g a n d 4 patie nts wit h a b o d y wei g ht ≥3 5  k g will c o m plete Part A t he n pr o gress 
directl y i nt o Part B .  Eac h treat me nt/wei g ht gr o u p will be assesse d se paratel y b y t he S R C  i n 
acc or da nce wit h t he c harter , s o t he treat me nt/wei g ht gr o u ps ca n pr o gress i n de pe n de ntl y i nt o 
Part B.   After e val uati o n of all a vaila ble P K a n d safet y data fr o m Part A i n t he first 4 
e val ua ble patie nt s wit hi n eac h treat me nt/wei g ht gr o u p , t he re mai ni n g e nr olle d patie nts will 
e nter t he treat me nt p hase  ( Secti o n 9. 6. 2 ).  T he  4 patie nts i n eac h treat me nt/ wei g ht gr o u p i n 
Part A m ust ha ve recei ve d at least 1 d ose of be nraliz u ma b a n d at least 3 p ost -first I P d ose P K 
ser u m sa m ples m ust ha ve bee n c ollecte d t o be e val ua ble.  If a n y of t he patie nts i n Part A d o 
n ot meet t hese criteri a, t he n t hat patie nt will be re place d.   Ja pa nese patie nts a ge d 1 2 t o 1 4 
years ma y be e nr olle d i n parallel wit h t he sta g gere d i ncl usi o n f or t he first 8 patie nts a ge d 6 t o 
1 1 years.  
T he t otal d urati o n of t he st u d y f or m ost patie nts will be  u p t o  5 6 wee ks a n d  will i ncl u de a 
scree ni n g peri o d of u p t o 2 8 da ys a n d a treat me nt peri o d of 4 8 wee ks, a n d a safet y f oll o w-u p 
visit at Wee k 5 2.  T he t otal d urati o n of t he st u d y ma y be l o n ger if t he scree ni n g peri o d is 
e xte n de d. 
C CI
C CI
C CI
C CI
C CI

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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.   
For details on what is included in the efficacy and safety endpoints, see Section 3.   
4.1.1 
Study conduct mitigation during study disruptions due to cases of civil 
crisis, natural disaster, or public health crisis 
The guidance given below supersedes instructions provided elsewhere in this Clinical Study 
Protocol (CSP) and should be implemented only during cases of civil crisis, natural disaster, 
or public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study patients become infected with 
SARS-CoV-2 or similar pandemic infection) which would prevent the conduct of 
study-related activities at study sites, thereby compromising the study site staff or the patient’s 
ability to conduct the study.  The investigator or designee should contact the study sponsor to 
discuss whether the mitigation plans below should be implemented.   
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice (GCP), and minimise risks to study integrity.  
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 
• 
Obtaining consent/reconsent and assent/reassent for the mitigation procedures (note, in 
the case of verbal consent/reconsent, the Informed Consent Form [ICF] should be signed 
at the patient’s next contact with the study site). 
• 
Rescreening: Additional rescreening for screen failure due to study disruption and to 
confirm eligibility to participate in the clinical study can be performed in previously 
screened patients.  The investigator should confirm this with the designated Study 
Physician.  
• 
Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).  
• 
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.  
• 
At-home IP administration: Performed by a site qualified HCP or HCP provided by a 
TPV. Additional information related to the visit can be obtained via telemedicine. 
 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix B. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 8  
 
 
4. 2  
Scie ntific r ati o n ale f or st u d y desi g n  
T he ai m of t his st u d y is t o e val uate t he P K a n d P D, a n d l o n g -ter m safet y of be nraliz u ma b 
a d mi nistere d S C as a n a d d -o n t hera p y i n c hil dre n ( 6 t o 1 1 years ol d , or 6 t o 1 4 years ol d i n 
Ja pa n) wit h se vere e osi n o p hilic ast h ma. 
T he sp o ns or c o nsi ders t he a p pr o priate tar get p o p ulati o n t o be c hil dre n a ges 6 t o 1 1 years wit h 
u nc o ntr olle d ast h ma des pite a de q uate use of esta blis he d ast h ma t hera pies (i ncl u di n g I C S a n d 
L A B A).  Si nce P K a n d P D are o bjecti ve meas ure me nts n ot assesse d directl y b y t he 
i n vesti gat or or patie nt, a n d as s uc h are n ot s usce pti ble t o i n vesti gat or or patie nt bias, t here is 
n o ne e d f or a d o u ble -bli n d c o ntr ol i n t his st u d y.  T he pri mar y a n d sec o n dar y e n d p oi nts f or t his 
st u d y ( Secti o n 3 ) are c o nsiste nt wit h t h ose i n pre vi o usly c o n d ucte d st u dies a n d s u p p ort t he 
o verall pae diatric cli nical de vel o p me nt pla n f or be nraliz u ma b.  
4. 3  
J ustific ati o n f or d ose  
C li nical ast h ma ma nifestati o ns a n d treat me nt res p o nses i n c hil dre n ( 6 t o 1 1 years of a ge) a n d 
a d olesce nts ( 1 2 t o 1 7 years of a ge) are si milar t o t he a d ult p o p ulati o n ( Weiss a n d Ware 1 9 9 6 ).  
F or se veral mar kete d or e mer gi n g t hera pe utic m A bs (a dali m u ma b, basili xi ma b, ca na ki n u ma b, 
ec uliz u ma b, a n d o maliz u ma b), c hil dre n t y picall y recei ve t he sa me fi xe d d ose as f or a d ults if 
t heir b o d y wei g ht is greater t ha n 3 0 t o 4 0 k g or t he sa me wei g ht -base d i ntra ve n o us d ose (ie, 
i nfli xi ma b a n d dacliz u ma b) as i n a d ults (X u  et al 2 0 1 3).  F or t he l o wer b o d y wei g ht strata, a 
d ose is t y picall y selecte d t o matc h P K e x p os ure of t he a d ult efficaci o us d ose usi n g, f or 
e xa m ple, a p o p ulati o n P K m o del.  
A p o p ul ati o n P K m o del f or be nraliz u ma b was pre vi o usl y de vel o pe d wit h data fr o m 8 cli nical 
st u dies ( SI R O C C O, C A LI M A, BI S E, MI-C P 1 5 8, MI -C P 1 6 6, MI -C P 1 8 6, MI -C P 1 9 7 a n d MI -
C P 2 2 0).  I n t his p o p ulati o n P K m o del, wei g ht was i de ntifie d as a si g nifica nt c o variate.  T he 
P K  pr ofile f or c hil dre n 6  t o 1 1 years of a ge wei g hi n g < 3 5 k g was si m ulate d usi n g t he wei g ht 
distri b uti o n i n t he C D C gr o wt h c hart ass u mi n g it was e q uall y li kel y t o recr uit fe males a n d 
males at a n y a ge wit hi n t he a ge gr o u p .  T he 
 m g d ose was selecte d f or c hi l dre n a ge d 6  t o 1 1 
years wei g hi n g < 3 5 k g as t he stea d y -state P K e x p os ure was pr ojecte d t o be c o m para ble t o t hat 
of t he a d ult efficaci o us d ose, 
 m g.  Base d o n t he P K/ P D relati o ns hi p, bl o o d e osi n o p hils 
were pre dicte d t o attai n near c o m plete de pleti o n.  
I n t he pi v otal P hase 3 st u dies, a d ult a n d a d olesce nt ( 1 2 t o 1 7 years ol d) patie nts were e nr olle d 
a n d ra n d o mise d t o recei ve place b o, 3 0 m g e ver y 4 wee ks ( Q 4 W), a n d 3 0 m g Q 8 W.  I n t hese 
st u dies, t here was n o a p pare nt a d va nta ge t o m ore fre q ue nt d osi n g ( Q 4 W).  T he safet y pr ofile 
i n a d olesce nts was c o nsiste nt wit h t he pr ofile i n a d ults a n d t he m ore fre q ue nt re gi me n of 3 0  
m g Q 4 W was well t olerate d i n b ot h p o p ulati o ns.  M ore o ver, n o e x p os ure -relate d i ncrease i n 
T E A Es was o bser ve d i n a d ult patie nts recei vi n g 1 0 0  m g Q 8 W ( m ore t ha n t hree ti mes t he 
rec o m me n de d cli nical d ose f or t he ast h ma i n dicati o n). 
C CI
C CI

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 2 9  
 
 
Patie nts a ge d 1 2 t o 1 4 years will recei ve 
 m g of be nraliz u ma b ( M E DI -5 6 3) f or S C i njecti o n 
d uri n g t he st u d y, irres pecti ve of t heir b o d y wei g ht w he n e nr olle d, c o nsiste nt wit h t he 
a p pr o ve d d ose of be nraliz u ma b i n patie nts of t his a ge.     
T he perce nta ge a n d titre of A D As a n d t he i m pact of A D As o n t he P K pr ofile were ass u me d t o 
be t he sa me f or c hil dre n a n d f or a d ults.  
4. 4  
E n d of st u d y defi niti o n  
T he e n d of st u d y is de fi ne d as t he last e x pecte d visit/c o ntact of t he last patie nt u n der g oi n g t he 
st u d y. 
A patie nt is c o nsi dere d t o ha ve c o m plete d t he st u d y w he n he/s he has c o m plete d his/ her last 
sc he d ule d pr oce d ure s h o w n i n Ta ble 1 . 
See A p pe n di x  A  6  f or g ui deli nes f or t he disse mi nati o n of st u d y res ults. 
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr ol me nt criteria, als o k n o w n 
as pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.  
Eac h patie nt s h o ul d meet all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria f or t his 
st ud y t o be assi g ne d t o a st u d y i nter ve nti o n.  U n der n o circ u msta nces ca n t here be e xce pti o ns 
t o t his r ule.  Patie nt s w h o d o n ot meet t he e ntr y re q uire me nts are t o be classe d as scree n 
fail ures, defi ned  i n Secti o n 5. 4 . 
F or pr oce d ures f or wit h dra wal of i nc orrectl y e nr olle d patie nts see Secti o n 7. 3 . 
5. 1  
I ncl usi o n criteri a 
Patie nt s are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g i ncl usi o n criteria 
a n d n o ne of t he e xcl usi o n criteria a p pl y:  
I nf or me d c o nse nt 
1  
Pare nt(s)/ g uar dia n are a ble t o gi ve writte n i nf or me d c o nse nt pri or t o partici pati o n i n t he 
st u d y, w hic h will i ncl u de t he a bilit y t o c o m pl y wit h t he re q uire me nts a n d restricti o ns 
liste d i n t he c o nse nt f or m.  If a p plica ble, t he patie nt  m ust be a ble a n d willi n g t o gi ve 
asse nt t o ta ke part i n t he st u d y acc or di n g t o t he l ocal re q uire me nt . 
T he I C F pr ocess is descri be d i n A p pe n di x A  3 . 
A ge  
2  
Patie nt  m ust be 6 t o 1 1 years of a ge i ncl usi ve  ( 6 t o 1 4 years of a ge i ncl usi ve i n Ja pa n), at 
t he ti me of si g ni n g t he I C F. 
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Type of subject and disease characteristics 
3 
Diagnosis of severe asthma, defined by the regional guidelines (ie, National Institutes of 
Health [NIH], Global Initiative for Asthma [GINA], American Thoracic Society [ATS], 
European Respiratory Society [ERS], Japanese Society of Pediatric Allergy and Clinical 
Immunology [JSPACI], etc.), for at least 12 months prior to Visit 1.  If the patient is naïve 
to the study site, the patient/guardian must self-report a physician diagnosis of asthma and 
the investigator must confirm by review of medical history with the patient/guardian. 
4 
A previously confirmed history of two or more exacerbations requiring treatment with 
systemic corticosteroids* and/or hospitalization in the 12 months prior to Visit 1, despite 
the use of ICS, or a persistent need for oral corticosteroid maintenance treatment to 
maintain asthma control, for at least 3 of the last 12 months prior to Visit 1, despite the 
use of ICS.  *For patients receiving maintenance oral corticosteroids, the OCS treatment 
for the exacerbations must have been a two-fold increase or greater in the dose. 
5 
Eosinophilic airway inflammation that is related to asthma characterized as eosinophilic 
in nature as indicated by peripheral blood eosinophil count of ≥150 cells / µL at Visit 1. 
6 
A well-documented requirement for regular treatment with ICS: total daily dose 
equivalent to ≥250 µg fluticasone propionate, or ≥400 µg budesonide (≥320 µg 
budesonide ex-actuator), or ≥200 µg fluticasone furoate, or ≥220 µg mometasone furoate, 
or ≥160 µg ciclesonide, or ≥1000 µg triamcinolone acetonide, or ≥500 µg 
beclomethasone dipropionate, or ≥200 µg beclomethasone dipropionate (HFA) in the 12 
months prior to Visit 1, with or without maintenance oral corticosteroids.  Medium dose 
ICS as per local guidelines will also satisfy the inclusion criterion after agreement with 
the Study Physician.  
7 
Current treatment with at least 1 additional controller medication, such as inhaled LABA, 
leukotriene receptor antagonist, long acting anti-muscarinic agent, or theophylline, since 
at least 3 months prior to Visit 1. 
8 
Forced expiratory volume in 1 second (FEV1): Flow/ volume curve indicating airflow 
obstruction at either Visit 1 or 2 (performed prior to first dose of study medication), 
associated with: a pre-bronchodilator FEV1 ≤ 110% predicted normal, or, FEV1/Forced 
Vital Capacity ratio ≤ 0.8. 
Weight 
9 
Body weight ≥15 kg. 
Sex 
10 Male or female 
Reproduction 
11 Females of childbearing potential (FOCBP) who are sexually active, as judged by the 
investigator, must commit to consistent and correct use of an acceptable method of 
contraception for the duration of the study and for 12 weeks after the last dose of IP.  

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5.2 
Exclusion criteria  
Patients are eligible to be included in the study only if all of the inclusion criteria and none of 
the exclusion criteria apply: 
Medical conditions 
1 
Any history of life-threatening asthma (eg, requiring intubation). 
2 
Clinically important pulmonary disease other than asthma such as active lung infection, 
bronchiectasis, pulmonary fibrosis, cystic fibrosis, alpha 1 anti-trypsin deficiency, and 
primary ciliary dyskinesia. 
3 
Previous diagnosis of pulmonary or systematic disease, other than asthma, that is 
associated with elevated peripheral eosinophil counts such as allergic bronchopulmonary 
aspergillosis/mycosis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss 
syndrome), and hypereosinophilic syndrome. 
4 
Ever been diagnosed with malignant disease. 
5 
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, immunological, psychiatric, or major physical impairment 
that is not stable in the opinion of the investigator and could: 
(a) Affect the safety of the patient throughout the study. 
(b) Influence the findings of the study or their interpretations. 
(c) Impede the patient’s ability to complete the entire duration of the study. 
6 
History of anaphylaxis to any biologic therapy. 
7 
Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the investigator may put the patient at risk because of his/her participation in 
the study, or may influence the results of the study, or the patient’s ability to complete the 
entire duration of the study. 
8 
Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality 
obtained during the screening period, which in the opinion of the investigator may put the 
patient at risk or interfere with study assessments. 
9 
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive 
medical history for hepatitis B or C.  Patients with a history of hepatitis B vaccination 
without history of hepatitis B are allowed to enrol. 
10 A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed 
consent and assent is obtained that has not been treated with, or has failed to respond to, 
standard of care therapy. 

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11 Alanine aminotransferase or aspartate aminotransferase level ≥1.5 times the upper limit of 
normal confirmed during the screening period. 
12 A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test. 
Prior/concomitant therapy 
13 Use of immunosuppressive medication, including, but not limited to, methotrexate, 
troleandomycin, cyclosporine, azathioprine, intramuscular long-acting depot 
corticosteroid, or any experimental anti-inflammatory therapy, within 3 months prior to 
Visit 1.  Chronic maintenance corticosteroid for the treatment of asthma is allowed. 
14 Receipt of immunoglobulin or blood products within 30 days prior to Visit 1. 
15 Receipt of any marketed (eg, omalizumab, mepolizumab, or off-label benralizumab) or 
investigational biologic within 4 months or 5 half-lives, whichever is longer, prior to 
Visit 1. 
16 Receipt of live attenuated vaccines 30 days prior to the date of first dose of IP. 
17 Initiation of new allergen immunotherapy is not allowed within 30 days prior to Visit 1.  
However, allergen immunotherapy initiated prior to this period can be continued provided 
there is a gap of 7 days between the immunotherapy and IP administration. 
18 Current use of any oral or ophthalmic non-selective β-adrenergic antagonist (eg, 
propranolol). 
19 Planned surgical procedures during the conduct of the study. 
Prior/concurrent clinical study experience 
20 Participation in another clinical study with an investigational nonbiologic product 
administered in the last 30 days or 5 half-lives prior to enrolment, whichever is longer. 
21 Known history of allergy or reaction to any component of the IP formulation. 
22 Concurrent enrolment in another clinical study. 
Other exclusions 
23 Parent/guardian has a history of psychiatric disease, intellectual deficiency, substance 
abuse, or other condition (eg, inability to read, comprehend and write) which will limit 
the validity of consent to participate in this study. 
24 Unwillingness or inability of the patient or parent/guardian to follow the procedures 
outlined in the protocol. 
25 Children who are wards of the state or government. 
26 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
27 Judgement by the investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 3  
 
 
2 8  Pre vi o us treat me nt i n t he prese nt st u d y.  
 
5. 3  
Lifest yle restricti o ns  
5. 3. 1  
Me als a n d diet ar y res tricti o ns 
Patie nts s h o ul d a v oi d eati n g a lar ge meal f or at least 2 h o urs pri or t o s pir o metr y 
meas ure me nts.   
5. 3. 2  
C affei ne, alc o h ol, a n d t o b acc o  
T he patie nt  m ust be a n o n -s m o ker. 
5. 3. 3  
Acti vit y  
Patie nts s h o ul d a v oi d e n ga gi n g i n stre n u o us e xerti o n f or at least 3 0 mi n u tes pri or t o 
s pir o metr y meas ure me nts.   
5. 4  
Scree n f ail ures  
Scree n fail ures are defi ne d as patie nts w h o si g ne d t he I C F t o partici pate i n t he cli nical st u d y 
b ut are n ot s u bse q ue ntl y e ntere d i n t he st u d y.  A mi ni mal set of scree n fail ure i nf or mati o n is 
re q uire d t o e ns ure tra ns pare nt re p orti n g of scree n fail ure patie nts t o meet t he C o ns oli date d 
Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries 
fr o m re g ulat or y a ut h orities.  Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n failure details, 
eli gi bilit y criteria, a n d a n y seri o us a d verse e ve nt ( S A E).  
I n di vi d uals w h o d o n ot meet t he criteria f or partici pati o n i n t his st u d y (scree n fail ure) ma y be 
rescree ne d o nce.  Rescree ne d patie nts s h o ul d be assi g ne d t he sa me patie nt n u m ber as f or t he 
i nitial scree ni n g.  H o we ver, rescree ni n g s h o ul d be d oc u me nte d s o t hat its effect o n st u d y 
res ults, if a n y, ca n be assesse d. 
T hese patie nts s h o ul d ha ve t he reas o n f or st u d y wit h dra wal rec or de d i n t he electr o nic  case 
re p ort f or m (eC R F ). 
6  
S T U D Y T R E A T M E N T S  
St u d y treat me nt is defi ne d as a n y I P(s) (i ncl u di n g mar kete d pr o d uct c o m parat or a n d place b o) 
i nte n de d t o be a d mi nistere d t o a st u d y patie nt  acc or di n g t o t he st u d y pr ot oc ol .  St u d y 
treat me nt i n t his st u d y refers t o be nraliz u ma b. 
6. 1  
Tre at me nts a d mi nis tere d 
Patie nts a ge d 6 t o 1 1 years wit h a b o d y wei g ht < 3 5  k g at scree ni n g will recei ve t he f oll o wi n g 
re gi me n of be nraliz u ma b: 
 m g a d mi nistere d b y S C i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 
1 6 ( Part A), f oll o we d b y 
 m g at Wee ks 2 4, 3 2, a n d 4 0 ( Part B).  P atie nts a ge d 6 t o 1 1 years 
C CI
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Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 4  
 
 
wit h a b o d y wei g ht ≥3 5  k g at scree ni n g will recei ve t he f oll o wi n g re gi me n of be nraliz u ma b: 
 m g a d mi nistere d b y S C i njecti o n at Da y 0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), f oll o we d b y 
 m g at Wee ks 2 4, 3 2, a n d 4 0 ( Part B).   Ja pa nese patie nts a ge d 1 2 t o 1 4 years will recei ve 
 
m g, a n d t heir visit sc he d ules will be t he sa me as patie nts a ge d 6 t o 1 1 years t hr o u g h o ut t he 
st u d y. 
6. 1. 1  
I n vesti g ati o n al pr o d ucts 
St u d y treat me nts are o utli ne d i n Ta ble 3 . 
T a ble 3  
St u d y Tre at me nts  
 
A ge d 6 t o 1 1 ye ars a n d b o d y wei g ht 
< 3 5  k g  
A ge d 6 t o 1 1 ye ars a n d b o d y wei g ht 
≥3 5  k g , or a ge d 1 2 t o 1 4 ye ars 
St u d y tre at me nt n a me:  
Be nraliz u ma b  
Be nraliz u ma b  
T y pe  
C o m bi nati o n pr o d uct  
C o m bi nati o n pr o d uct  
D os e f or m ul ati o n: 
 
 
 
 
 
 
 
 
 
U nit d ose stre n gt h  
m g/ m L  
 m g/ m L  
D os a ge le vel  
Part  A: 
 m g o n Da y  0, Wee ks  4, 8 
a n d 1 6. 
Part  B: 
 m g o n Wee ks  2 4, 3 2 a n d 
4 0.  
Part  A: 
 m g o n Da y  0, Wee ks  4, 8 
a n d 1 6. 
Part  B: 
 m g o n Wee ks  2 4, 3 2 a n d 
4 0.  
R o ute of a d mi nistr ati o n  
S u bc uta ne o us i njecti o n  
S u bc uta ne o us i njecti o n  
Use  
E x peri me ntal  
E x peri me ntal  
I M P a n d NI M P 
I M P 
I M P 
S o urci n g  
Pr o vi de d b y t he sp o ns or  
Pr o vi de d b y t he sp o ns or  
P ac k a gi n g a n d l a belli n g:   
St u d y treat me nt will be pr o vi de d i n 
a n A P F S .  Eac h  s yri n ge will be 
la belle d i n acc or da nce wit h G o o d 
Ma n ufact uri n g Practice ( G M P) 
A n ne x 1 3 a n d per c o u ntr y re g ulat or y 
re q uire me nt. 
St u d y treat me nt will be pr o vi de d i n 
a n A P F S .  Eac h  s yri n ge will be 
la belle d i n acc or da nce wit h G M P 
A n ne x 1 3 a n d per c o u ntr y re g ulat or y 
re q uire me nt. 
C urre nt/f or mer n a me(s) or 
ali as(es)  
M E DI -5 6 3  
M E DI -5 6 3  
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6.2 
Preparation/handling/storage/accountability 
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 study treatment. 
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment.   
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual. 
Benralizumab is to be stored at the study centre in a secured facility with limited access and 
controlled temperature. The temperature should be monitored on a daily basis and documented 
in the temperature monitoring log. 
Benralizumab must be kept in the original outer container and under conditions specified on 
the label (between 2°C to 8°C [36°F to 46°F], protected from the light). 
In the following cases the centre staff should not use affected study treatment and should 
immediately contact an AstraZeneca representative for further guidance: 
• 
Temperature excursion upon receipt or during storage at the study 
• 
Damaged kit upon receipt 
• 
Damaged syringe/cartridge 
Damaged study treatment should be documented via interactive web response system 
(IWRS)/interactive voice response system (IVRS) (refer to IWRS/IVRS manual for further 
details). 
6.3 
Investigational drug administration 
6.3.1 
Before investigational product administration 
Study treatment is stored refrigerated and should be allowed to warm to room temperature 
before administration.  Prior to each IP administration: 
• 
Investigator/authorised delegate will assess injection site as per standards of medical care; 

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• 
For FOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative.  A FOCBP is defined as a premenopausal female capable of 
becoming pregnant. 
6.3.2 
Investigational product administration 
The IP will be administered by the investigator/authorised delegate. 
Investigational product should be administered into the upper arm, thighs, or the abdomen.  It 
is suggested that the site of injection is rotated such that the patient receives IP at a different 
anatomical site at each treatment visit.  Investigational product should not be administered 
into areas where the skin is tender, bruised, erythematous, or hardened. 
6.3.3 
After investigational product administration 
After IP administration, the sponsor recommends that the patient should be observed for a 
minimum of 1 hour in case of any acute drug reactions. 
6.3.4 
Conditions requiring investigational product administration 
rescheduling 
If any of the following occur, the investigator should reschedule the visit and the IP should not 
be administered until the rescheduled visit: 
• 
The patient has an intercurrent illness, that in the opinion of the investigator may 
compromise the safety of the patient in the study (eg, viral illnesses); 
• 
The patient is febrile (≥38°C; ≥100.4°F) within 72 hours prior to the IP administration. 
6.4 
Measures to minimise bias: randomisation and blinding 
Not applicable as this is an open-label study. 
6.5 
Treatment compliance 
Any change from the dosing schedule and dose discontinuations should be recorded in the 
eCRF. 
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. 
6.6 
Concomitant therapy 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrolment or receives 
during the study must be recorded in the eCRF along with: 

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• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency. 
 
Restricted medications are listed in Table 4. 
Table 4 
Restricted medications 
Medication/class of drug: 
Usage (including limits for duration permitted and 
special situations in which it’s allowed ): 
Bronchodilator medication: 
SABA or SAMA 
Twice daily LABA or LAMA 
Once daily therapies containing LABA or LAMA 
Should be withheld prior to scheduled spirometry for: 
6 hours 
12-24 hours 
≥24 hours 
Topical immunosuppressive medication 
May be administered at the discretion of the investigator 
after discussion with the AstraZeneca Study Physician  
Allergen immunotherapy injection 
Should not be administered within 7 days of IP 
administration 
Inactive/killed vaccines (eg, inactive influenza) 
Should not be administered 7 days before or 7 days after IP 
administration 
Abbreviations: IP  investigational product, LABA  long-acting β2 agonists, LAMA  long-acting anti-muscarinic, 
SABA  short-acting β2 agonists, SAMA  short-acting anti-muscarinic 
 
Prohibited medications are listed in Table 5. 
Table 5 
Prohibited medications 
Prohibited medication/class of drug: 
Duration 
Immunosuppressive medication other than prior 
stable systemic corticosteroid for the maintenance 
treatment of asthma and for asthma exacerbations 
Study period 
Live attenuated vaccines 
Within 30 days prior to first dose of IP, during the 
treatment period, and for 12 weeks (5 half-lives) after the 
last dose of IP 
Oral or ophthalmic non-selective β-adrenergic 
antagonist (eg, propranolol) 
Study period 
Any marketed or investigational biologic 
(monoclonal or polyclonal antibody) 
4 months or 5 half-lives (whichever is longer) prior to 
Visit 1, during the treatment period, and 4 months or 
5 half-lives (whichever is longer) after the last dose of the 
IP 
Other IP 
30 days or 5 half-lives (whichever is longer) prior to first 
dose of IP and during the study period 
Abbreviations: IP investigational product 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 3 8  
 
 
6. 6. 1  
B ac k gr o u n d me dic ati o n  
T he patie nt’s us ual pre -st u d y I C S a n d/ or O C S f or m ulati o ns, d oses a n d re gi me ns, a n d a n y 
ot her a d diti o nal all o we d ast h ma c o ntr ollers t hat t he y ma y ha ve bee n ta ki n g pri or t o e nr ol me nt, 
s h o ul d be c o nti n ue d t hr o u g h o ut t he scree ni n g a n d treat me nt peri o d s.  All c ha n ges i n t he 
patie nt’s bac k gr o u n d me dicati o n s h o ul d be d oc u me nte d i n s o urce al o n g wit h t he rati o nale f or 
t he c ha n ge a n d rec or de d i n t he e C R F. 
6. 6. 2  
Ot her c o nc o mit a nt tre at me nt  
Ot her me dicati o n ot her t ha n t hat descri be d a b o ve, w hic h is c o nsi dere d necessar y f or t he 
patie nt’s safet y a n d well bei n g, ma y be gi ve n at t he discreti o n of t he i n vesti gat or a n d rec or de d 
i n t he a p pr o priate secti o ns of t he eC R F . 
6. 6. 3  
Resc ue me dic ati o n  
W orse ni n g of ast h ma s y m pt o ms s h o ul d be treate d acc or di n g t o sta n dar d practice.  
6. 7  
D ose m o dific ati o n  
N o d ose m o dificati o n is all o we d i n t his st u d y .  Patie nts a ge d 6 t o 1 1 years will  recei ve t he 
sa me d ose of be nraliz u ma b t hr o u g h o ut t he st u d y base d o n t heir wei g ht at scree ni n g.   Patie nts 
a ge d 1 2 t o 1 4 years will  recei ve t he 
 m g d ose of be nraliz u ma b t hr o u g h o ut t he st u d y. 
6. 8  
Tre at me nt after t he e n d of t he st u d y  
T he patie nt s h o ul d c o nti n ue t heir us ual ast h ma me dicati o n at t he discreti o n of t he i n vesti gat or.  
7  
DI S C O N TI N U A TI O N O F T R E A T M E N T A N D S U B J E C T 
WI T H D R A W A L  
7. 1  
Disc o nti n u ati o n of st u d y tre at me nt  
Patie nts ma y be disc o nti n ue d fr o m I P i n t he f oll o wi n g sit uati o ns .  N ote t hat disc o nti n uati o n 
fr o m st u d y treat me nt is N O T t he sa me t hi n g as a c o m plete wit h dra wal fr o m t he st u d y. 
•  
Patie nt or g uar dia n decisi o n .  T he patie nt is at a n y ti me free t o disc o nti n ue treat me nt, 
wit h o ut prej u dice t o f urt her treat me nt  
•  
A d verse eve nt  
•  
Se vere n o n -c o m plia nce wit h t he C S P   
•  
Eli gi bilit y re q uire me nt f o u n d n ot t o be f ulfille d  
•  
P ositi ve pre g na nc y test at a n y ti me d uri n g t he st u d y  
•  
L ost t o f oll o w -u p  
•  
De vel o p me nt of a n y st u d y s pecific criteria f or disc o nti n uati o n:  
− 
A na p h ylactic reacti o n t o t he I P re q uiri n g a d mi nistrati o n of e pi ne p hri ne  
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− 
Development of helminth parasitic infestations requiring hospitalization 
− 
If 2 consecutive doses of IP are missed or more than 2 scheduled doses of IP are 
missed during Part A dosing 
− 
An asthma-related event requiring mechanical ventilation. 
See Table 1 for data to be collected at the time of treatment discontinuation and follow-up and 
for any further evaluations that need to be completed. 
7.1.1 
Procedures for discontinuation of study treatment 
A patient that decides to discontinue study treatment will always be asked about the reason(s) 
and the presence of any AEs.  The date of last administration of study treatment should be 
documented in the eCRF.  Patients permanently discontinuing study treatment should be given 
locally available standard of care therapy, at the discretion of the investigator. 
All patients who prematurely discontinue IP should return to the study site and complete the 
procedures described for the Early Discontinuation (DXD) Visit within 4 weeks after the last 
dose of IP.  At that visit, although no longer on IP, patients should be encouraged to remain in 
the study.  Although only AEs, SAEs, and concomitant medication are required to be collected 
after the DXD Visit, safety data collection should continue according to the study protocol.  
Note that in this case, the DXD Visit replaces the nearest regular visit while the following 
visits continue as possible.  If the patient or guardian does not agree to continue in-person 
study visit(s), a modified follow-up, such as telephone contact with the patient or guardian, 
should be arranged to ensure the collection of safety information through the 48-week time 
point. 
7.2 
Lost to follow-up 
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.   
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit: 
• 
The site must attempt to contact the patient or guardian and reschedule the missed visit as 
soon as possible and counsel the patient on the importance of maintaining the assigned 
visit schedule. 
• 
Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient or next of kin by eg, repeat telephone calls, 
certified letter to the patient´s or guardian’s last known mailing address or local 
equivalent methods.  These contact attempts should be documented in the patient’s 
medical record.  
• 
Efforts to reach the patient or guardian should continue until the end of the study.  Should 
the patient be unreachable at the end of the study the patient should be considered to be 

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lost to follow-up with unknown vital status at end of study and censored at the latest 
follow-up contact. 
 
7.3 
Withdrawal from the study 
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. 
If the patient 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 patient withdraws from the study, he/she or his/her guardian may request destruction of 
any samples taken, and the investigator must document this in the site study records.   
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The investigator will follow-up patients as medically indicated.  
See Table 1 for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed.   
If a patient withdraws from the study, then his/her enrolment code cannot be reused.  
Withdrawn patients may be replaced if they discontinue within Part A of the study. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarised in Table 1.   
The investigator will ensure that data are recorded in the eCRF.  The Web Based Data Capture 
system will be used for data collection and query handling. 
The investigator ensures the accuracy, completeness, legibility, and timeliness of the data 
recorded in the eCRF and of the provision of answers to data queries according to the Clinical 
Study Agreement.  The investigator will sign the completed eCRF.  A copy of the completed 
eCRF will be archived at the study site.  Additional data to assess the impact of civil crisis, 
natural disaster, or public health crisis will be collected. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in Table 1, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 

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all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.   
Procedures conducted as part of the patient’s routine clinical management and obtained before 
signing of the ICF may be utilised for screening or baseline purposes provided the procedures 
met the protocol-specified criteria and were performed within the time frame defined in 
Table 1. 
The recommended sequence for completion of assessments at each visit is: 
• 
Complete ACQ-IA, PGIC-IA, CGIC 
• 
Measure vital signs, ECG, conduct physical examination 
• 
Conduct spirometry assessment 
• 
Take blood samples 
• 
Administer benralizumab. 
Based on the European Medicines Agency’s (EMA) Ethical Considerations for Clinical Trials 
on Medicinal Products Conducted with the Paediatric Population (EMA 2008), the maximum 
amount of blood collected, including any losses in the manoeuvre, from each patient should 
not exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 
1% at any single time during the study (Table 6).  
Table 6 
Maximum volume of blood to be withdrawn from a patient 
Patient weight (kg) 
Total blood volume 
(mL)a 
Maximum blood 
volume (mL) to be 
withdrawn at any visit 
Maximum blood 
volume (mL) to be 
withdrawn within a 
4-week period 
15-20 
1200-1600 
12.0-16.0 
36.0-48.0 
21-25 
1680-2000 
16.8-20.0 
50.4-60.0 
26-30 
2080-2400 
20.8-24.0 
62.4-72.0 
31-35 
2480-2800 
24.8-28.0 
74.4-84.0 
36-40 
2880-3200 
28.8-32.0 
86.4-96.0 
41-45 
3280-3600 
32.8-36.0 
98.4-108.0 
46-50 
3680-4000 
36.8-40.0 
110.8-120.0 
51-55 
4080-4400 
40.8-44.0 
122.4-132.0 
56-60 
4480-4800 
44.8-48.0 
134.4-144.0 
61-65 
4880-5200 
48.8-52.0 
146.4-156.0 
66-70 
5280-5600 
52.8-56.0 
158.4-168.0 
71-75 
5680-6000 
56.8-60.0 
170.4-180.0 
76-80 
6080-6400 
60.8-64.0 
182.4-192.0 

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Table 6 
Maximum volume of blood to be withdrawn from a patient 
Patient weight (kg) 
Total blood volume 
(mL)a 
Maximum blood 
volume (mL) to be 
withdrawn at any visit 
Maximum blood 
volume (mL) to be 
withdrawn within a 
4-week period 
81-85 
6480-6800 
64.8-68.0 
194.4-204.0 
86-90 
6880-7200 
68.8-72.0 
206.4-216.0 
91-95 
7280-7600 
72.8-76.0 
218.4-228.0 
96-100 
7680-8000 
76.8-80.0 
230.4-240.0 
a 
The total blood volume is estimated at 80 mL/kg body weight. 
Source: EMA 2008 
 
The total maximum volume of blood that will be withdrawn from each patient at each study 
visit is listed in Table 7. 
Table 7 
Maximum volume of blood to be withdrawn from each patient 
Visit 
Samples required 
Total maximum volume (mL)a 
Visit 1 (Screening) 
clinical chemistry; haematology; serology 
13.0  
Visit 2  
PK; ADA 
5.0  
Visit 3 
PK 
2.5  
Visit 4 
PK 
2.5 
Visit 5 
PK 
2.5 
Visit 6 
clinical chemistry; haematology; PK 
7.0 
Visit 7 
clinical chemistry; haematology; PK; ADA 
9.5 
Visit 8 
clinical chemistry; haematology; PK 
7.0 
Visit 9 
clinical chemistry; haematology; PK; ADA 
9.5 
Visit 10 
clinical chemistry; haematology; PK; ADA 
9.5 
Visit 11 
 
0 
Visit 12 
 
0 
Visit 13 (End of 
Treatment) 
clinical chemistry; haematology; PK; ADA 
9.5 
Visit 14 (Follow-up) 
 
0 
Early discontinuation 
(DXD) 
clinical chemistry; haematology; PK; ADA 
9.5 
Total (mL) 
 
87.0 
a  
Volumes exclude serum pregnancy testing and excludes any re-testing requirements.  If serum pregnancy 
testing is needed, it will be analysed from samples collected at Visit 1, Visit 6, Visit 7, Visit 8, Visit 9, Visit 
10, Visit 13, and the DXD Visit.  If serum pregnancy testing is to be analysed at other visits then an 
additional 2.5mL blood collection will be required. 
 

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8.1 
Efficacy assessments  
This is a PK/PD study; therefore, the primary outcome measures are described in Section 8.5 
and Section 8.6. 
8.1.1 
Spirometry 
8.1.1.1 
General requirements 
Lung function (FEV1) at the study centre will be measured by spirometry using the site’s own 
equipment.  Spirometry should be performed by the investigator or authorised delegate 
according to American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines 
(Miller et al 2005).   
Important!  Patients should withhold their bronchodilator medications prior to scheduled 
spirometry per Section 6.6.  The patient’s usual asthma medications may be administered 
following completion of the lung function procedures. 
8.1.1.2 
Spirometry technique 
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to 
spirometry measurements.  Patients should avoid eating a large meal for at least 2 hours prior 
to spirometry measurements at the centre.  Forced expiratory manoeuvres should be 
performed with the patient seated in an upright position.  If this is not comfortable for the 
patient, standing is permitted.  The same position should be used by the patient for each forced 
expiratory manoeuvre from enrolment throughout the study.  The head must not be tilted 
during manoeuvres and the thorax should be able to move freely; hence, tight clothing should 
be loosened.  A nose-clip should be used for the manoeuvre.  Mouthpieces of the same 
dimension and shape should be used by the patient from enrolment throughout the study. 
The forced expiratory manoeuvre (FEV1) should start with a maximal inspiration and then 
followed by a fast and forceful expiration that should last for at least 6 seconds (3 seconds for 
children aged <10 years).  It is important to encourage the patient to continue the expiration to 
be fast and forceful throughout the manoeuvre.  Ensure that none of the following has 
occurred:  
• 
coughing during the first second 
• 
glottis closure 
• 
leak or  
• 
obstruction of the mouthpiece (by the tongue). 
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
center spirometry session and the 2 best efforts that meet the ATS/ERS acceptability and 
reproducibility criteria will be recorded in the eCRF.  The best efforts will be based on the 
highest FEV1.  The absolute measurement (for FEV1), and the percentage of predicted normal 

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value will be recorded using the local spirometer at the site with predicted values derived from 
the reference value of choice, eg, Nair et al 2017, NHANES III 2010, Quanjer et al 2012, etc.  
8.1.2 
Clinical outcome assessments 
Asthma Control Questionnaire-Interviewer Administered 
The Asthma Control Questionnaire (ACQ) is a 7-item assessment comprised of 
6 patient-reported items and a single clinical item pertaining to pre-bronchodilator FEV1 % 
predicted (Juniper et al 1999).  The ACQ was developed for self-administration by adults and 
adolescents.  Patients are asked to record their experience with 5 symptoms (night-time 
waking, symptoms on waking, activity limitation, shortness of breath, and wheezing) and use 
of short-acting β2 agonist (SABA) over the previous week using a 7-point scale (0 = no 
impairment; 6 = maximum impairment).  The final item pertaining to FEV1 uses a similar 
7-point response scale.  Shortened versions of the ACQ can be produced by omitting the FEV1 
item (ACQ-6) or the FEV1 and SABA items (ACQ-5) from the assessment or scoring 
(Wyrwich et al 2011).  The ACQ score is calculated by taking the mean of the 7 equally 
weighted items.  The ACQ score range is 0 (well controlled) to 6 (extremely poorly 
controlled).  Individual score change of at least 0.5 is meaningful and is used to support the 
responder definition (Juniper et al 2005).  Mean ACQ scores ≤ 0.75 indicate well-controlled 
asthma, scores between 0.75 and ≤ 1.5 indicate partly controlled asthma, and a score >1.5 
indicates poorly controlled asthma (Juniper et al 2006).   
An interviewer-administered version of the ACQ, which was developed for use with children 
aged ≥6 years (ACQ-IA), will be used in this study with the omission of item 7.  The only 
difference between the ACQ-IA and the ACQ is the mode of administration.  The ACQ-IA is 
administered by trained individuals according to standardized instructions to help the child 
understand concepts like “during the last week” and the 7-point scale.  Per the assessment 
instructions, help from parents/caregivers is sought only as a last resort.  Thresholds for 
defining poor asthma control and responder status have been evaluated but not to the extent of 
the self-administered version for adults and adolescents.  The estimated threshold indicating 
poor asthma control is an ACQ-IA score ≥1.25 in patients ages 6 to 17 years 
(Nguyen et al 2014).  The estimated minimal clinically important difference is 0.5 
(Juniper et al 2010, Nguyen et al 2014). 
The questionnaire will be completed at the study centre during every study visit except Visit 3 
on Day 1 (Table 1).  This will capture the early onset of effect and the effect of maintenance 
treatment.  Completion of the ACQ-IA may also provide early insight into potential safety 
concerns.  

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Patient Global Impression of Change Interviewer Administered 
The Patient Global Impression of Change (PGIC) question captures the patient’s overall 
evaluation of response to treatment (Guy 1976). The PGIC is included to assess how a patient 
perceives their overall change in health status since the start of study treatment(s).  This item 
is useful in characterizing the overall impact of the treatment. The patient is asked to report 
the degree to which they have changed since entering the treatment period using a 7-point 
scale (‘Much Better’, to ‘About the same’, to ‘Much worse’). The patient is instructed to 
select the one response that gives the most accurate description of his/her state of health 
(overall status). 
An interviewer administered PGIC (PGIC-IA) will be used in this study to help the child 
understand what is being asked. The PGIC-IA will be administered by trained individuals 
according to standardized instructions to help the child understand the question and response 
options.  Help from caregivers/parents is sought only as a last resort. The PGIC-IA will be 
completed at the study centre at Visits 9, 10, 11 and 13 (Table 1).  
Clinician Global Impression of Change  
The Clinician Global Impression of Change (CGIC) question captures the patient’s overall 
evaluation of response to treatment from the perspective of the clinician 
(Busner and Targum 2007; Guy 1976). The CGIC is included to assess how the clinician 
interprets and perceives the patients overall change in health status since the start of study 
treatment(s).  This item is useful in characterizing the overall impact of the treatment from the 
clinician’s perspective. It provides a brief, stand-alone assessment of the clinician’s view of 
the patient’s global functioning prior to and after initiating a study medication.  
The clinician is asked to report the degree to which they perceive the patient has changed 
since entering the treatment period using a 7-point scale (‘Much Better’, to ‘About the same’, 
to ‘Much worse’). The CGIC will be completed by the clinician at the study centre at Visits 9, 
10, 11 and 13 (Table 1). 
8.2 
Safety assessments  
Planned time points for all safety assessments are provided in Table 1. 
8.2.1 
Clinical safety laboratory assessments 
See Table 8 for the list of clinical safety laboratory tests to be performed and Table 1 for the 
timing and frequency.  All protocol-required laboratory assessments, as defined in Table 8, 
must be conducted in accordance with the laboratory manual and Table 1.   

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The investigator should assess the available results with regard to clinically relevant 
abnormalities.  The laboratory results should be signed and dated and retained at the centre as 
source data for laboratory variables.   
For information on how AEs based on laboratory tests should be recorded in the eCRF and 
reported, see Section 8.3.7. 
Local clinical routine procedures to reduce pain and discomfort from blood sampling in 
children will be followed, eg, offering topical anaesthesia, coordinated sampling to avoid 
repeated punctures and use of in-dwelling catheters as appropriate in accordance with ethical 
and instruction guidelines for paediatric blood sampling.  Additional safety samples may be 
collected if clinically indicated at the discretion of the investigator.   
The clinical chemistry, haematology, virology, and urinalysis will be performed at a central 
laboratory. 
Table 8 
Laboratory safety variables 
Haematology (complete blood counts with 
differential) 
Clinical chemistry (serum or plasma) 
B-Haemoglobin (Hb) 
S/P-Creatinine 
B-basophil count differential count (absolute count) 
S/P-Bilirubin, total 
B-lymphocyte differential count (absolute count) 
S/P-Alkaline phosphatise (ALP) 
B-Platelet count 
S/P-Aspartate transaminase (AST) 
B-eosinophil count differential count (absolute count) 
S/P-Alanine transaminase (ALT) 
B-monocytes differential count (absolute count) 
S/P-Glucose 
B-neutrophils differential count (absolute count) 
S/P-C-reactive protein 
White blood cell (WBC) count 
S/P-Urea 
 
S/P-Albumin 
Urinalysis (dipstick) 
S/P-Potassium 
U-Hb/Erythrocytes/Blood  
S/P-Calcium, total 
U-Protein/Albumin  
S/P-Sodium 
U-Glucose  
S/P-Creatine kinase (CK) 
 
S-hCG test (Section 8.2.5.3) 
Virology screen 
 
Hepatitis B surface antigen (HBsAG)a 
 
Hepatitis C virus (HCV) 
 
Human immunodeficiency virus (HIV) 
 
a 
If a positive antibody test from Hepatitis B surface antigen (HBsAG) is received, standard reflex 
confirmation testing is to be carried out. 
 

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8.2.2 
Physical examinations 
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose, and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities), and neurological systems. 
A brief physical examination will include the following: general appearance, respiratory, 
cardiovascular, and abdomen systems. 
Complete and brief physical examinations will be performed at timelines as specified in 
Table 1.  Investigators should pay special attention to clinical signs related to previous serious 
illnesses, new or worsening abnormalities may qualify as AEs, see Section 8.3.7 for details. 
8.2.3 
Vital signs 
• 
Body temperature, pulse rate, and blood pressure (BP) will be assessed. 
• 
Blood pressure and pulse measurements will be assessed sitting with a completely 
automated device with a calibrated manometer using an appropriate paediatric cuff.  
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 patient in a quiet setting without distractions (eg, television, cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 BP measurements (3 consecutive BP readings will be recorded at intervals of at 
least 1 minute).  The average of the 3 BP readings will be recorded in the eCRF. 
 
8.2.4 
Electrocardiograms 
A 12-lead ECG will be obtained as outlined in Table 1 using the site’s own ECG machines 
after the patient has rested in the supine position for at least 10 minutes. 
The investigator or authorised delegate will judge the overall ECG as normal or abnormal and 
report this evaluation.  If abnormal, it will be further documented as to whether the 
abnormality is clinically significant by the Principal Investigator.  For all abnormalities 
(regardless of clinical significance), the specific type and nature of the abnormality will be 
documented.  Clinically significant findings should also be documented on the AE page of the 
eCRF if applicable. 
The investigator or authorised delegate may add extra 12-lead resting ECG safety assessments 
if there are any abnormal findings or if the investigator considers it is required for any other 
safety reason.  These assessments should be entered as an unscheduled assessment.  
All ECG readings will be digitally stored as source documents.  Additionally, ECG readings 
can be printed and placed in the subject’s source file.  

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8.2.5 
Other safety assessments 
8.2.5.1 
Weight and height 
Weight and height will be measured at timelines as specified in Table 1. 
Weight and height measurements will be performed in light clothing and with shoes off, using 
calibrated weighing scales and stadiometer. 
The patient’s weight will be recorded in kilograms; height will be recorded in centimeters. 
8.2.5.2 
Medical/surgical history 
Details of each patient’s medical and/or surgical history will be recorded in the eCRF at 
timelines as specified in Table 1. 
8.2.5.3 
Pregnancy test 
A serum pregnancy test will be done for FOCBP at screening (Visit 1), and a urine pregnancy 
test must be performed for FOCBP at each treatment visit prior to IP administration.  A 
positive urine test result must be confirmed with a serum pregnancy test.  If the serum test at 
screening is positive, the patient should be excluded.  If a urine pregnancy test at a treatment 
visit and the confirmatory serum pregnancy test are positive, IP treatment must be 
discontinued. 
Females of childbearing potential will be determined at the discretion of the investigator. 
8.2.5.4 
Concomitant medications 
A list of a patient’s concomitant medications will be recorded in the eCRF at timelines as 
specified in Table 1. 
8.2.5.5 
Asthma exacerbation 
In this study, an asthma exacerbation is defined by a worsening of asthma requiring the use of 
systemic corticosteroids (or an increase in oral steroid dose for those already on systemic 
corticosteroids) and/or an emergency department (ED) visit requiring use of systemic 
corticosteroids and/or an in-patient hospitalization due to asthma.  An asthma exacerbation 
that occurs ≤ 7 days following the last dose of systemic steroid, prescribed for a prior 
exacerbation, will be recorded in the eCRF as the same exacerbation event.  Asthma 
exacerbation information will be collected with a recall period of ‘since the last scheduled 
visit’. 
Information on in-patient hospitalizations, number of days in the hospital, and ED visits will 
be collected by the investigator/authorised delegate at each visit (as shown in Table 1) and 
recorded in the eCRF.  Asthma-related hospitalization and ED visit information will be 
collected with a recall period of ‘since the last scheduled visit’. 

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A copy of the medical record should be obtained for exacerbations evaluated and treated at 
non-study centres (eg, by the primary care health care provider or at an ED/hospital) and 
details entered into the exacerbation eCRF in a timely fashion.  Changes in concomitant 
medication due to exacerbation must be recorded in the eCRF.  
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 C. 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, 
surrogate, or the patient's legally authorised representative).   
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE in the eCRF.  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 patient is the preferred method to inquire about 
AE occurrences.   
8.3.2 
Time period and frequency for collecting AE and SAE information  
Adverse events and SAEs will be collected from the time of signature of the ICF throughout 
the treatment period and including the follow-up period (Visit 14). 
All SAEs will be recorded in the eCRF and reported to the sponsor or designee within 
24 hours, as indicated in Appendix C.  The investigator will submit any updated SAE data to 
the sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients.  However, 
if the investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the investigator may notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix C. 

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8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts.  All SAE/non-serious AEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the patient is lost to follow-up 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.3.4 
Adverse event data collection 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP(s) (yes or no) 
• 
Action taken with regard to IP(s) 
• 
AE caused patient’s withdrawal from study (yes or no) 
• 
Outcome. 
 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for serious AE 
• 
Date investigator became aware of serious AE 
• 
AE is serious due to 
• 
Date of hospitalisation 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 
 
8.3.5 
Causality collection 
The investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the 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 C to the CSP. 
8.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’ or revealed by observation will be collected and recorded 
in the eCRF.  When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms.  However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
8.3.7 
Adverse events based on examinations and tests 
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR).  Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the IP. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study, see Section 8.3.8. 
8.3.8 
Disease-under study (DUS) 
Symptoms of the DUS are those which might be expected to occur as a direct result of asthma.  
Events which are unequivocally due to the disease under study should not be reported as an 
AE during the study unless they meet SAE criteria or lead to discontinuation of the IP. 
8.4 
Safety reporting and medical management 
8.4.1 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF. 

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If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1 
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. 
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.   
For further guidance on the definition of a SAE, see Appendix C of the CSP. 
8.4.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.4.2.1 
Maternal exposure 
If a patient becomes pregnant during the study, IP should be discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 

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birth or congenital abnormality) should be followed up and documented even if the patient 
was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.3.2) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.4.2.2 
Paternal exposure  
There is no restriction on fathering children or donating sperm during the study.  However, 
information on a pregnancy of a partner will be collected. 
8.4.3 
Overdose 
For this study, any dose of benralizumab greater than 200 mg will be considered an overdose. 
There is no specific treatment for an overdose with benralizumab.  If overdose occurs, the 
patient should be treated supportively with appropriate monitoring as necessary. 
• 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module 
 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.4.1.  For other overdoses, reporting must occur within 30 days. 
8.4.4 
Management of investigational product-related reaction 
Appropriate drugs (eg, epinephrine, H1 and H2 antihistamines, and corticosteroids), and 
medical equipment to treat acute anaphylactic reactions must be immediately available at the 
clinical research site where IP is administered.  Study personnel must be trained to recognize 

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and treat anaphylaxis (Laviolette et al 2013, Lieberman et al 2010).  Details on anaphylaxis 
management are provided in Appendix F. 
Anaphylaxis will be defined as a serious reaction that is rapid in onset (minutes to hours) and 
that may result in death (Sampson et al 2006).  Anaphylaxis to an IP that the patient has not 
been previously exposed to (such as benralizumab) is deemed highly likely when Sampson 
criterion 1 is fulfilled.  Sampson criteria 2 and 3 are also listed for completeness: 
1. The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, AND AT LEAST 1 of the following: a) respiratory compromise or b) 
reduced BP or symptoms of end-organ dysfunction. 
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient including: involvement of the skin/mucosal tissue, respiratory compromise, 
reduced BP or associated symptoms and/or persistent gastrointestinal symptoms. 
3. Reduced BP after exposure. 
 
Patients will have had a pre-assessment (ie, vital signs) prior to IP administration and the 
sponsor recommends that patients should be observed after IP administration for a minimum 
of 1 hour for the appearance of any acute drug reactions. 
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local lab at the discretion of the investigator. 
8.4.5 
Medication error 
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours) of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 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 C. 

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8.4.6 
Medical device deficiencies 
Medical devices (APFSs) are being utilised to deliver the IMP under study. In order to fulfil 
regulatory reporting obligations worldwide, the investigator is responsible for the detection 
and documentation of events meeting the definitions of medical device deficiency that occur 
during the study with such medical devices. 
The definition of a Medical Device deficiency can be found in Appendix G. 
NOTE: Incidents and deficiencies fulfilling the definition of an AE/SAE will also follow the 
processes outlined in Appendix G of the protocol. 
8.4.6.1 
Time period for detecting medical device deficiencies 
• 
Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used. 
• 
If the investigator learns of any medical device deficiency at any time after a participant 
has been discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify the sponsor. 
 
The method of documenting Medical Device Deficiency is provided in Appendix G. 
8.4.6.2 
Follow-up of medical device deficiencies 
• 
Follow-up applies to all participants, including those who discontinue study intervention. 
• 
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency. 
• 
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator. 
 
8.4.6.3 
Prompt reporting of medical device deficiencies to sponsor 
• 
Medical device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency. 
• 
The Medical Device Deficiency Paper Report Form will be sent to the sponsor. 
• 
The sponsor will be the contact for the receipt of medical device deficiency reports. 
 
8.4.6.4 
Regulatory reporting requirements for device deficiencies 
• 
The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies. 

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• 
The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the IRB/IEC. 
• 
For further guidance on the definition of an SAE, see Appendix G of the CSP. 
 
8.5 
Pharmacokinetics 
8.5.1 
Collection of samples 
Blood samples for determination of PK parameters in serum will be taken at timelines as 
specified in Table 1.  Blood samples taken at visits when a dose of benralizumab is 
administered must be taken pre-dose.  Blood samples taken at visits when no benralizumab 
dose is administered may be taken at any time during the day of the visit.  The time and date 
of blood samples taken for PK analysis must be recorded in the eCRF. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.5.2 
Determination of drug concentration 
Samples for determination of drug concentration in serum will be analysed by a central 
laboratory on behalf of AstraZeneca, using a validated bioanalytical method.  Full details of 
the analytical method used will be described in the bioanalytical report. 
8.5.3 
Storage and destruction of pharmacokinetic samples 
The PK samples will be destroyed within 5 years of the CSR finalisation. 
8.6 
Pharmacodynamics 
8.6.1 
Collection of samples 
Samples for analysis of peripheral blood eosinophils will be collected as part of standard 
haematology assessment (complete blood count [CBC], Section 8.2.1) at timelines as 
specified in Table 1.  Sampling will occur pre-dose on visits when IP is administered. 
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
8.6.2 
Storage, re-use and destruction of pharmacodynamic samples 
The PD samples will be destroyed after analysis. 
8.7 
Genetics 
Genetic testing is not evaluated in this study. 
8.8 
Biomarkers 
Additional biomarkers are not evaluated in this study. 

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8.9 
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
8.10 
Immunogenicity 
8.10.1 
Collection of samples 
Serum samples for the determination of ADA in serum will be taken at the study visits 
indicated in Table 1.  Sampling will occur pre-dose on visits when IP is administered.    
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Samples will be analysed using validated bioanalytical methods.  Details of the analytical 
methods used will be described in a separate validation report. 
8.10.2 
Storage and destruction of immunogenicity samples 
The ADA samples will be destroyed within 5 years of the CSR finalisation. 
9 
STATISTICAL CONSIDERATIONS  
9.1 
Statistical hypotheses 
Data will be summarised descriptively.  No formal statistical hypotheses will be tested in this 
study.  
9.2 
Sample size determination  
The sample size is not based on a formal sample size calculation.  A sample size of 30 
evaluable patients, with at least 8 patients in each weight stratum, was chosen to provide 
sufficient data across the dosing and weight categories for PK parameter estimations using 
NCA criteria assuming 30% for CV%.  In addition, a cohort of up to 3 Japanese patients aged 
12 to 14 years will be enrolled. 
9.3 
Patient evaluability 
For the purpose of the initial safety review by the SRC, evaluable patients are defined as those 
patients receiving at least one dose of study medication, with at least 3 post-first IP dose PK 
assessments above the lower limit of quantification.  Any patients discontinuing the study in 
Part A due to a treatment-related safety reason will also be considered evaluable for safety 
assessment. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 5 8  
 
 
9. 4  
P o p ul ati o ns f or a n al yses  
F or p ur p oses of a nal ysis, t he f oll o wi n g p o p ulati o ns are defi ne d i n Ta ble  9 .  All data (i ncl u di n g 
P D) e xce pt f or P K data will be a nal yse d usi n g t he safet y a nal ysis set.  P K data will be 
a nal yse d usi n g t he N C A or P K a nal ysis set.  
T a ble  9  
A n al ysis p o p ul ati o ns  
P o p ul ati o n  
Descri pti o n  
P har mac o ki netic a nal ysis set  
All patie nts w h o recei ve d at least 1 d ose of be nraliz u ma b a n d fr o m w h o m 
P K bl o o d sa m ples are n ot ass u me d t o be affecte d b y fact ors s uc h as pr ot oc ol 
vi olati o ns (e g, restricte d me dicati o ns) a n d w h o ha d at least o ne q ua ntifia ble 
ser u m P K o bser vati o n p ost first I P d ose  
N o n -c o m part me ntal a nal ysis 
set 
All patie nts w h o recei ve d t he first d ose of be nraliz u ma b a n d fr o m w h o m P K 
bl o o d sa m ples are n ot ass u me d t o be affecte d b y fact ors s uc h as pr ot oc ol 
vi olati o ns (e g, restricte d me dicati o ns ) a n d w h o ha d at least 3  q ua ntifia ble 
ser u m P K o bser vati o ns p ost -d ose o n Da ys 1, 7, 1 4, a n d 2 8  
Safet y a nal ysis set  
All patie nts w h o recei ve at least o ne d ose of be nraliz u ma b  
 
9. 5  
St atistic al a n al yses  
9. 5. 1  
O ver vie w  
T he statistical met h o d ol o g y bel o w descri be s t he hi g h-le vel statistical a nal ysis pri nci ples as 
f oresee n w he n t he st u d y is bei n g pla n ne d.  T he statistical a nal ysis pla n ( S A P) will be pre pare d 
pri or t o t he first patie nt e nteri n g t he treat me nt peri o d, a n d a n y s u bse q ue nt a me n d me nts will be 
d oc u me nte d wit h t he fi nal a me n d me nts c o m plete d pri or t o data base l oc k.  
9. 5. 2  
Ge ner al st atistic al met h o d ol o g y  
S u m mar y data f or patie nts a ge d 6 t o 1 1 years will be prese nte d i n ta b ular f or mat b y 
treat me nt/ wei g ht gr o u ps (b e nraliz u ma b 
 m g i n patie nts < 3 5  k g at scree nin g a n d 
b e nraliz u ma b 
 m g i n patie nts ≥3 5  k g  at scree ni n g).  Cate g orical data will be s u m marise d b y 
t he n u m ber a n d perce nta ge of patie nts i n eac h cate g or y.  C o nti n u o us varia bles f or para metric 
data will be s u m marise d b y descri pti ve statistics i ncl u di n g n, mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m val ue , a n d ma xi m u m val ue ( u nless state d ot her wise) f or n o n -P K data .  F or 
t he s u m mar y of P K c o nce ntrati o n le vels, i n a d diti o n, ge o metric mea n a n d C V % base d o n l o g-
tra nsf or me d data will be prese nte d.  
U p t o 3 Ja pa nese patie nts a ge d 1 2 t o 1 4 years will be e nr oll e d.  E x pl orat or y a nal yses i ncl u di n g 
b ot h patie nts a ge d 1 2 t o 1 4 years a n d patie nts a ge d 6 t o 1 1 years will be c o n d ucte d.   I n 
a d diti o n, s u b gr o u p a nal yses f or Ja pa nese a n d f o r n o n-Ja pa nese patie nts will be c o n d ucte d. 
C CI
C CI

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9.5.3 
Primary variables 
9.5.3.1 
Pharmacokinetics 
PK parameters will include clearance, body weight-adjusted clearance, area under 
concentration time curve to Day 28 (AUC0-28), maximum serum concentration (Cmax), terminal 
phase elimination half-life (t1/2), and time to reach Cmax (Tmax). 
PK parameters will be derived using either NCA or PK analysis set.  PK analysis will, where 
possible, be carried out using actual time recorded in the raw data.  If actual times are missing, 
nominal times will be used.  
A listing of PK blood sample collection times, as well as derived sampling time deviations 
will be provided.  Serum concentrations and PK parameters will be summarised using 
appropriate descriptive statistics.  Figures showing individual and mean of PK concentration-
time profiles will be produced on both semi-log and linear scales.  Serum concentration data 
associated with positive ADA status will be flagged in the PK concentration listings and may 
be excluded from the summary statistics and/or mean profiles.  The observed paediatric PK 
will be compared with the projection from the population PK model in adult and adolescent 
asthma patients (AstraZeneca 2016, AstraZeneca 2017). 
9.5.3.2 
Pharmacodynamics 
Peripheral blood eosinophils values and changes from baseline at each visit will be 
summarised using descriptive statistics for each treatment/weight group.  
9.5.4 
Secondary variables 
9.5.4.1 
Pharmacokinetics 
Body weight-adjusted clearance will be computed, based on a population PK model. 
9.5.4.2 
Immunogenicity  
Anti-drug antibodies (ADA) to benralizumab will be summarised using descriptive statistics at 
each visit by treatment/weight group.  Anti-drug antibody titres-time profiles of benralizumab 
by treatment/weight group will be generated.  The impact of ADA on PK and eosinophil level 
will be assessed.  The potential association of ADA with safety will be evaluated.  Any 
hypersensitivity AEs reported during the on-study period will be evaluated by ADA status. 
9.5.4.3 
Spirometry 
FEV1 measurements and changes from baseline at each visit will be summarised using 
descriptive statistics for each treatment/weight group.   
9.5.4.4 
Asthma Control Questionnaire 
ACQ-IA scores and changes from baseline at each visit will be summarised for each time 
point using descriptive statistics for each treatment/weight group. 

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 0  
 
 
9. 5. 4. 5  
Gl o b al I m pressi o n of C h a n ge Q uesti o n n aires  
P GI C -I A a n d C GI C sc ores at eac h visit will be s u m marise d f or eac h ti me p oi nt usi n g 
descri pti ve statistics f or eac h treat me nt/ wei g ht gr o u p.  
9. 5. 5  
S afet y v a ri a bles 
All safet y a nal yses will be perf or me d o n t he safet y anal ysis set. 
A d verse e ve nts will be liste d f or eac h patie nt a n d s u m marise d b y S yste m Or ga n Class a n d 
Preferre d Ter m assi g ne d t o t he e ve nt b y Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A).   
La b orat or y safet y varia bles ( hae mat ol o g y, cli nical c he mistr y, a n d uri nal ysis) a n d c ha n ges 
fr o m baseli ne will be s u m marise d usi n g sta n dar d s u m mar y statistics as a p pr o priate .  S hift 
ta bles usi n g n or mal ra n ges ( baseli ne t o m ost e xtre me p ost-baseli ne val ue) will als o be 
prese nte d.  C ha n ge fr o m baseli ne of e osi n o p hils c o u nt will als o be s u m marise d a n d be 
rec or de d i n t he e C R F as part of sta n dar d hae mat ol o gical assess me nts.  
T he res ul ts of t he vital si g ns meas ure me nts will be liste d a n d s u m marise d. 
Res ults of t he p h ysical e xa mi nati o n a n d 1 2 -lea d E C G will be d oc u me nte d as n or mal or 
a b n or mal f or eac h patie nt.  
Ot her safet y varia bles will be s u m marise d as a p pr o priate.  
9. 5. 6  
E x pl or at or y v ari a bles  
9. 5. 6. 1  
A n n u alize d ast h m a e x acer b ati o n r ate  
E xacer bati o ns e x perie nce d d uri n g t he treat me nt peri o d will be s u m marise d descri pti vel y  f or 
eac h treat me nt/ wei g ht gr o u p , i ncl u di n g t he n u m ber of e xacer bati o ns ass ociate d wit h a n  E D 
visit or h os pitalizati o n.  F or t he pr o d ucti o n of s u m mar y statistics, t he A A E R  will be calc ulate d 
usi n g t he ti me -base d ris k a p pr oac h: 
A A E R = 3 6 5. 2 5 * T ot al n u m ber of ex acer b ati o ns / T ot al d ur ati o n of at risk tre at me nt peri o d 
( d ays) 
I n a d diti o n, t he n u m ber of patie nts e x perie nci n g at least o ne e xacer bati o n will be s u m marise d.  
Ka pla n -Meier pl ots ma y als o be c o nsi dere d t o descri be t he ti me t o first e xacer bati o n.  
9. 6  
I nteri m a n al yses  
 
 
 
C CI

Cli nical St u d y Pr ot oc ol  
Astra Ze neca  
Be nraliz u ma b ( M E DI -5 6 3) –  D 3 2 5 0 C 0 0 0 2 5  
5 . 0, 2 2  Fe br uar y 2 0 2 2  
C O N FI D E N TI A L A N D P R O P RI E T A R Y  
 6 1  
 
 
9. 6. 1  
D at a S afet y M o nit ori n g B o ar d  
A D S M B will be utilize d f or t his st u d y.  A p pe n di x A, Secti o n  A  5  pr o vi des m ore details o n 
t he rati o nale f or a n d t he re mit of t he D S M B . 
9. 6. 2  
S afet y Re vie w C o m mittee  
I n a d diti o n t o t he D S M B , t he S R C will m o nit or safet y i n t he st u d y.  T he S R C will c o nsist of 
3  c ore me m bers: Pri nci pal I n vesti gat or ( or dele gate), St u d y P h ysicia n / Gl o bal Cli nical  Lea d 
( or dele gate) a n d Gl o bal Safet y P h ysicia n ( or dele gate).  T he St u d y Cli nical P har mac ol o gist, 
St u d y Statisticia n, Patie nt Safet y Scie ntist, St u d y Deli ver y Lea der a n d ot her e x perts ma y als o 
be i n vite d as a p pr o priate.  
 
 
 
  
9. 7  
Se nsiti vit y a n al yses  
A d diti o nal a nal yses assessi n g t he i m pact of ci vil crisis, nat ural disaster, or p u blic healt h crisis 
ma y be i ncl u de d i n t he S A P.  
C CI

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10 
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Alonso AM and Saglani S. Mechanisms mediating pediatric severe asthma and potential novel 
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Castro et al 2014 
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