Conditions: Severe Uncontrolled Asthma
Keywords: Pediatric PK severe asthma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This study will evaluate the PK, PD and long-term safety of Benralizumab administered subcutaneously in 30 children aged 6 to 11 years with severe eosinophilic asthma. Up to an additional 3 Japanese patients aged 12 to 14 years will be enrolled to meet local regulatory requirements.

Detailed description:

Arms:
arm 1: Below 35 kilos arm 2: Greater than/equal to 35 kilos

Interventions: intervention 1: Benralizumab
Intervention descriptions: intervention 1: Dose will be stratified by body weight at screening: Patients will receive Dose 1 or Dose 2 of Benralizumab administered by SC injection at Day 0 and Weeks 4, 8, and 16, 24, 32, and 40.

Protocol document:
Prot_000.pdf: 
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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CONFIDENTIAL AND PROPRIETARY 
 30 
 
 
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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CONFIDENTIAL AND PROPRIETARY 
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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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Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
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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 
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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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CONFIDENTIAL AND PROPRIETARY 
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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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Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 36 
 
 
• 
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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Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
 37 
 
 
• 
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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CONFIDENTIAL AND PROPRIETARY 
 39 
 
 
− 
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
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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 
REFERENCES 
AstraZeneca 2016 
AstraZeneca. Clinical Pharmacokinetic Modeling Report. Benralizumab Population 
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AstraZeneca 2017 
AstraZeneca. Clinical Population Pharmacokinetic Modeling Report Errata List. 
Benralizumab Population Pharmacokinetic Analysis – Errata List. 21 March 2017. 
Alonso and Saglani 2017 
Alonso AM and Saglani S. Mechanisms mediating pediatric severe asthma and potential novel 
therapies. Front Pediatr. 2017;5:154. 
Assa’ad et al 2011 
Assa’ad AH, Gupta SK, Collins MH, Thomson M, Heath AT, Smith DA, et al. An antibody 
against IL-5 reduces numbers of esophageal intraepithelial eosinophils in children with 
eosinophilic esophagitis. Gastroenterology. 2011;14:1593-604. 
Bateman et al 2010 
Bateman ED, Reddel HK, Eriksson G, Peterson S, Ostlund O, Sears MR, et al. Overall asthma 
control: The relationship between current control and future risk. American Academy of 
Allergy, Asthma & Immunology. 2010;125(3):600-08. 
Bleecker et al 2016 
Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and 
safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled 
corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo 
controlled phase 3 trial. Lancet 2016;29: 2115-27. 
Bossley et al 2012 
Bossley CJ, Fleming L, Gupta A, Regamey N, Frith J, Oates T, et al. Pedriatric severe asthma 
is characterized by eosinophilia and remodeling without TH2 cytokines. J Allergy Clin 
Immunol. 2012;129:974-82. 
Bousquet et al 1990 
Bousquet J, Chanez P, Lacoste JY, Barnéon G, Ghavanian N, Enander I, et al. Eosinophilic 
inflammation in asthma. N Engl J Med. 1990 Oct 11;323(15):1033-9. 
Busner and Targum 2007 
Busner J, Targum SD. The clinical global impressions scale: applying a research tool in 
clinical practice. Psychiatry (Edgmont). 2007;4(7):28-37 


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Busse et al 2010 
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Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
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5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
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Benralizumab (MEDI-563) – D3250C00025 
5.0, 22 February 2022 
CONFIDENTIAL AND PROPRIETARY 
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SAP_001.pdf: 
Statistical Analysis Plan 
AstraZeneca
D3250C00025 v2.0
18 October 2022
CONFIDENTIAL AND PROPRIETARY
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Statistical Analysis Plan
Study Code
D3250C00025
Edition Number v2.0 
Date
18 October 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


Statistical Analysis Plan 
AstraZeneca
D3250C00025 v2.0
18 October 2022
CONFIDENTIAL AND PROPRIETARY
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 5
AMENDMENT HISTORY................................................................................................... 8
1
STUDY DETAILS ............................................................................................. 9
1.1
Study objectives.................................................................................................. 9
1.1.1
Primary objectives .............................................................................................. 9
1.1.2
Secondary objectives .......................................................................................... 9
1.1.3
Safety objectives............................................................................................... 10
1.1.4
Exploratory objective........................................................................................ 10
1.2
Study design ..................................................................................................... 10
1.3
Number of subjects........................................................................................... 12
2
ANALYSIS SETS ............................................................................................ 12
2.1
Definition of analysis sets................................................................................. 12
2.1.1
Pharmacokinetic (PK) analysis set .................................................................... 12
2.1.2
Non-compartmental analysis (NCA) set............................................................ 13
2.1.3
Safety analysis set............................................................................................. 13
2.2
Violations and deviations.................................................................................. 13
3
PRIMARY AND SECONDARY VARIABLES ............................................... 13
3.1
General Principles............................................................................................. 13
3.1.1
Baseline definitions........................................................................................... 13
3.1.2
Study day.......................................................................................................... 14
3.1.3
Study Periods.................................................................................................... 14
3.1.4
Visit windows................................................................................................... 15
3.1.5
Handling of missing data .................................................................................. 17
3.2
Primary outcome variables................................................................................ 18
3.2.1
Primary PK variables........................................................................................ 18
3.2.2
Primary PD variable.......................................................................................... 18
3.2.2.1
Blood eosinophil levels..................................................................................... 18
3.3
Secondary outcome variables............................................................................ 18
3.3.1
Body weight-adjusted clearance........................................................................ 18
3.3.2
Immunogenicity Variable.................................................................................. 18
3.3.3
Pre-bronchodilator forced expiratory volume in first second (pre-BD FEV1).... 19
3.3.4
Interviewer-administered asthma control questionnaire (ACQ-IA).................... 19
3.3.5
Global Impression of Change............................................................................ 20
3.3.6
Safety outcome variables .................................................................................. 21
3.3.6.1
Adverse events (AEs) ....................................................................................... 21
3.3.6.2
Laboratory variables ......................................................................................... 22
3.3.6.3
Vital signs......................................................................................................... 23
3.3.6.4
ECG ................................................................................................................. 24


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18 October 2022
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3.3.6.5
Physical examination ........................................................................................ 24
3.3.7
Exploratory outcome variable ........................................................................... 25
3.3.7.1
Annualised asthma exacerbation rate ................................................................ 25
4
ANALYSIS METHODS................................................................................... 26
4.1
General principles............................................................................................. 26
4.2
Analysis methods.............................................................................................. 27
4.2.1
Patient disposition............................................................................................. 27
4.2.2
Demography data and patient characteristics..................................................... 27
4.2.3
Prior and concomitant medications ................................................................... 28
4.2.3.1
Prior medications.............................................................................................. 28
4.2.3.2
Concomitant medications.................................................................................. 28
4.2.4
Study treatment................................................................................................. 29
4.2.4.1
Exposure........................................................................................................... 29
4.2.4.2
Compliance....................................................................................................... 29
4.2.5
PK data............................................................................................................. 29
4.2.5.1
Non-compartmental /PopPK parameter analysis................................................ 30
4.2.5.2
Summary Statistics of PK serum concentrations................................................ 32
4.2.6
Pharmacodynamic variables.............................................................................. 33
4.2.6.1
Change in Eosinophils count............................................................................. 33
4.2.7
Body weight-adjusted clearance........................................................................ 34
4.2.8
Immunogenicity Analysis ................................................................................. 34
4.2.9
Forced expiratory volume in first second (FEV1).............................................. 35
4.2.10
Asthma control questionnaire (ACQ-IA)........................................................... 35
4.2.11
Global impression of change............................................................................. 35
4.2.12
Safety Analysis................................................................................................. 36
4.2.12.1
Adverse Events................................................................................................. 36
4.2.13
Laboratory variables ......................................................................................... 37
4.2.14
Vital signs......................................................................................................... 38
4.2.15
ECG variable .................................................................................................... 38
4.2.16
Physical examinations....................................................................................... 38
4.2.17
Exploratory analyses......................................................................................... 39
4.2.17.1
Annualised asthma exacerbation rate ................................................................ 39
4.2.18
Subgroup Analysis............................................................................................ 39
5
INTERIM ANALYSES.................................................................................... 39
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 40
7
REFERENCES................................................................................................. 41
8
APPENDIX ...................................................................................................... 42


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18 October 2022
CONFIDENTIAL AND PROPRIETARY
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LIST OF TABLES
Table 1: Visit windows for assessment................................................................................ 17
Table 2: Vital signs reference ranges for age 6 -11 years ..................................................... 23
Table 3: Vital signs reference ranges for age 12 -14 years ................................................... 24
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 12


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D3250C00025 v2.0
18 October 2022
CONFIDENTIAL AND PROPRIETARY
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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ACQ-IA
Interviewer-administered asthma control questionnaire
ADA
Anti-drug antibodies
AE
Adverse event
ALT
Alanine aminotransferase
Amean
Arithmetic mean
AAER
Annualized asthma exacerbation rate 
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
ATS
American thoracic society
AUC
Area under concentration time curve from time zero extrapolated to infinity
AUC(0-28)
Area under the concentration time curve from time zero to 28 days after dosing
BMI
Body mass index
CIs
Confidence intervals
CL/F
Apparent clearance for parent drug estimated as dose divided by AUC
Cmax
Observed maximum benralizumab concentration
CGIC
Clinician global impression of change
CRF
Case report form (electronic)
CSP
Clinical study protocol
CSR
Clinical study report
CSRHLD
Corporate clinical study report or higher level document
CTMS
Clinical trial management system
CV
Coefficient of variation
CV%
Coefficient of variation
DAE
Adverse event leading to discontinuation of investigational product
DBL
Database lock
DBP
Diastolic blood pressure
DSMB
Drug safety monitoring board
DXD
Early discontinuation visit
ECG
Electrocardiogram
eCRF
Electronic case report form
ED
Emergency department
EOT
End of treatment
ERS
European respiratory society
FEV1
Forced expiratory volume in 1 second


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Abbreviation or special 
term
Explanation
gCV%
Geometric coefficient of variation
GMean
Geometric mean
gSD
Geometric standard deviation
ICS
Inhaled corticosteroids
IP
Investigational product
Kg
Kilograms
LLOQ
Lower limit of quantification
M
Metres
Max
Maximum
MedDRA
Medical dictionary for regulatory activities
Min
Minimum
N
Number of patients
nAb
Neutralizing antibodies
NC
Not calculated
NCA
Non-compartmental analysis 
NQ
Not quantifiable
NR
Not reportable
NS
No sample
OCS
Oral corticosteroids
PD
Pharmacodynamic(s)
PE
Physical examination
PGIC-IA
Interviewer administered patient global impression of change
PopPK
Population pharmacokinetics
PK
Pharmacokinetic(s)
PT
Preferred term
Rsq
R-squared (coefficient of determination)
SABA
Short-acting β2 agonists
SAE
Serious adverse event
SAP
Statistical analysis plan
SBP
Systolic blood pressure
SC
Subcutaneous(ly)
SD
Standard deviation
SOC
System organ class
SRC
Safety review committee
t1/2
Terminal half-life
TBL
Total bilirubin


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Abbreviation or special 
term
Explanation
Tmax
Time to reach cmax
ULN
Upper limit of normal
λz 
Terminal rate constant


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AstraZeneca
D3250C00025 v2.0
18 October 2022
CONFIDENTIAL AND PROPRIETARY
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AMENDMENT HISTORY
Date
Brief description of change
14-Oct-2019
SAP v1.0 
18-Oct-2022
3.1.4.  Added further rules on how to handle the overlap in the week 1 and 2 visit 
windows schedule assessments  
18-Oct-2022
3.3.2 Added nAb will be tested for all ADA-positive samples 
4.2.8 Added that the nAb results will be reported as positive or negative.
4.2.8 Added the following summary categories for nAb:
-
nAb positive at baseline and/or post-baseline (nAb prevalence)
-
Treatment-induced nAb positive (nAb incidence)
4.2.8 Added that for ADA summaries at a single time point (e.g. baseline ADA or by 
visit) the corresponding titre summary will be based on the titre of the positive sample 
for that particular visit.
1 updated CSP version to v5.0 dated 22 February 2022
4.2.5.1 and 4.2.5.2 Updated to present PK concentration and parameter descriptive 
statistics to 2 decimals
18-Oct-2022
4.2.5.1 updated that <LLOQ concentrations will be set to zero both at pre-dose and 
after pre-dose timepoints
4.2.5.2 updated that All <LLOQ values will be substituted with a value of zero for 
descriptive statistics
Updated that <LLOQ samples will be plotted as LLOQ


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18 October 2022
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1
STUDY DETAILS
This is the statistical analysis plan (SAP) for study D3250C00025. The SAP is based on 
version 5.0 of the clinical study protocol (CSP) dated 22 February 2022. The SAP expands on 
the statistical analyses specified in the CSP; any changes with regards to what is already 
specified in the CSP will be described in Section 6 of this document. 
1.1
Study objectives
1.1.1
Primary objectives
Primary Objective:
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).
1.1.2
Secondary objectives
Secondary Objective:
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).


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 2 5 v 2. 0
1 8 Oct o ber 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 0 of 4 3
T o assess t he effect of be nraliz u ma b o n 
ast h ma s y m pt o ms a n d ot her ast h ma c o ntr ol 
m etri cs
C ha n ge fr o m baseli ne i n I nt er vie wer -
a d mi nistere d Ast h ma C o ntr ol Q uest i on naire 
( A C Q-I A) sc ore, meas ure d at scree ni n g a n d 
Wee ks 1, 2, 4, 8, 1 2, a n d 1 6 ( Part A), a n d Wee ks 
2 4, 3 2, 4 0 a n d 4 8, a n d at f o ll ow- u p ( Part B).
I nter vie wer-a d mi nistere d Patie nt Gl o bal 
I mpressi o n of C ha n ge ( P GI C -IA), meas ure d at 
Wee k 1 6 ( Part A), a n d Wee ks 2 4, 3 2 a n d 4 8 
( Part B).
Cli nicia n Gl o bal I m pressi o n o f C ha n ge ( C GI C), 
meas ure 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.
1. 1. 3
S afet y o bjecti ves
S afet y O bjecti ve:
E n d p oi nts/ v ari a bles:
T o assess t he safet y a n d t olera bilit y of 
be nraliz u ma b
A d verse e ve nts ( A Es)
Vi t al si g ns 
C ollect i on of cli nical c he mistr y / hae mat olo g y  
para m eters a n d uri nal ysis
1. 1. 4
E x pl or at or y o bjecti ve
E x pl or at or y O bjecti ve:
E n d p oi nts/ v ari a bles:
T o e val uate e xacer bati o ns e x perie nce d 
d uri n g treat me nt peri o d
A n n ualize d ast h ma e xacer bati o n rate ( A A E R)
1. 2
St u d y desi g n
T his is a n o pe n -la bel, p hase 3, 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 on g -t er m safety 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 y ears of a ge i n 
U S a n d Ja pa n wit h se vere e osi n o p hilic ast h ma. U p t o a n a d diti o nal 3 Ja pa nese pat ient s a ge d 
1 2 t o 1 4 years will be e nr o lle d.
P ati e 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).  
P ati e 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 owi n g re gi me n of 
be nraliz u ma b: 
m g a d mi nistere d b y S C i nject i on at Da y  0 a n d Wee ks 4, 8, a n d 1 6 ( Part A), 
f oll owe 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 owi 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 on 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 
C CI
C CI
C CI
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 2 5 v 2. 0
1 8 Oct o ber 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 1 of 4 3
4 0 ( Part B).   Ja pa nese patient s a ge d 1 2 t o 1 4 years will recei ve 
 m g re gar dless of t heir b o d y  
w ei g ht, a n d t hei r 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 (see Ta ble 1 bel o w f or P K assess me nts ti me p o i nts) a n d 
safety 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 
safety of  be nraliz u ma b.  All st u d y data will be s u m marize d t o get her, n ot se paratel y b y  st u d y 
part.
After i nit ial e nr ol me nt a n d c o nfir mati on of e ntr y  crit eria, patie nts will pr ocee d t o a scree ni n g 
p eri 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 crit eria 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 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 n ts a ge d 6 t o 1 1 years i n w hic h 4 patie nts wit h a b o d y 
w ei 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 p lete Part A t he n pr o gress 
di rectl y i nto Part B.  Eac h treat me nt/ wei g ht gr o u p will be assesse d se paratel y b y  t h e S afet y 
Re vie w C o m mittee ( S R C) i n acc or da nce with 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 nt l y i nto Part B.  After e val uat i o n of all a vaila ble P K a n d safet y data fr om 
t he i nit ial 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 pati e nts 
will e nter t he treat me nt p hase as i n sect i on 1. 2 of t he C S P. Patie nts a ge d 1 2 t o 1 4 y ears i n 
Ja pa n 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.
A n o ver vie w of t he ge neral st u d y  desi g n is s h ow n i n  Fi g ure 1 . T he sc he d ule of acti vit ies is 
prese nte d i n Ta ble 1 of t he C S P. 
C CI


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 2 5 v 2. 0
1 8 Oct o ber 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 2 of 4 3
Fi g ure 1
St u d y Desi g n
Ma y  be its m y scree n b ut ca n we ma ke i ma ge a little better
( a) Af t er h e fir st 4 p ati e nt s i n e a c 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 h e s 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 ), h e r e m ai ni n g p ati e nt s wit 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 a s e ..
P a e di atri c p ati e nt s 
wit h s e v er e 
e o si n o p hili c a st 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 mi c 
c orti c o st er oi d s , 
a n d/ or 
h o s pit ali s 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 e k 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 e k 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 e k 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 e k s 2 4 , 3 2, 4 0
S cr e e ni n g (- 2 8 t o -1 4 D a y s)
P art A
P K, P D, 
S a f et y
Tr e at m e nt P h a s e ( 48 W e e k 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
( We e k  5 2)
1. 3
N u m ber of s u bjects
T he sa m ple size is n ot base d o n a n y  for m al sa m ple size calc ulat i on.  A sa m ple size of 3 0 
e val ua ble pat ient s 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 
w ei g ht strata, wi t h a mi ni m u m of 8 e val ua ble 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 n -c o m part me ntal a nal ysis ( N C A). I n a d diti 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 will be e nr olle d. 
2
A N A L Y SI S S E T S
2. 1
Defi niti o n of a n al ysis sets
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 a n d P K a nal ysis set. 
2. 1. 1
P h ar m ac o ki netic ( P K) a n al ysis set
T his a nal ysis set c o m prises all pat ient s 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 s a m ples are n ot ass u m e d t o be affecte d b y fact ors s uc h as pr ot oc ol vi o lati ons 
C CI
C CI
C CI
C CI


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(Section 2.2 ) and who had at least one quantifiable serum PK observation post first 
investigational product (IP) dose.
2.1.2
Non-compartmental analysis (NCA) set
This analysis set comprises all patients who received the first dose of benralizumab and from 
whom PK blood samples are not assumed to be affected by factors such as protocol violations 
(Section 2.2) and who had at least 3 quantifiable serum PK observations post-dose on Days 1, 
7, 14, and 28.
2.1.3
Safety analysis set
This analysis set comprises all patients who receive at least one dose of benralizumab. All 
safety and PD analyses will be based on safety analysis set.
2.2
Violations and deviations
Important protocol deviations (IPDs) are considered any protocol deviation that may greatly 
impact the completeness, accuracy, and/or reliability of the study data or that may 
significantly affect a patient’s rights, safety, or well-being. They may include (but not be 
limited to):

Patients who were assigned to a study treatment even though they did not meet key 
entry criteria

Patients who developed withdrawal criteria during the study but were not withdrawn

Patients who received the wrong treatment or an incorrect dose

Patients who received a restricted or prohibited concomitant treatment.
Only IPDs will be listed and tabulated in the clinical study report (CSR). All the IPDs will be 
identified and documented by the study team prior to database lock.
IQVIA will prepare a separate protocol deviation Analysis Set Plan document to facilitate the 
identification of all IPDs to be documented prior to DBL. All the identified IPDs will be 
collected via the Clinical Trial Management System (CTMS) log.  Any protocol deviation 
which are not defined as important will not be reported or discussed in the CSR. Subjects 
excluded from the PK set will be listed.
3
PRIMARY AND SECONDARY VARIABLES
3.1
General Principles
3.1.1
Baseline definitions
In general, the last non-missing measurement prior to the first dose of study treatment will 
serve as the baseline measurement. If there is no value prior to first dose of study treatment, 


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then the baseline value will not be imputed, and will be set to missing. 
The screening clinical chemistry and haematology samples collected at Visit 1 (Day -28 to 
Day -14) will be used as baseline. However, if Visit 2 (Day 0) is done > 28 days after Visit 1,
then the corresponding clinical chemistry and haematology samples collected at Visit 2 and 
prior to the first dose of study treatment, will be used as baseline. 
The PK sample collected on the same day but at a time prior to the first dose of study 
treatment (Visit 2) will be included in the baseline definition. If there is no PK sample value 
prior to the first dose of study treatment, then the baseline value will not be imputed and will 
be set to missing. If the PK sample prior to the first IP is below the lower limit of 
quantification (LLOQ) then the baseline will be set to zero.
For physical examination and vital signs, baseline will be defined as the latest non-missing 
assessment prior to first dose at Visit 2. If no time is recorded for an assessment, and the 
assessment takes place at Visit 2, this will be assumed to be a pre-dose assessment.
3.1.2
Study day
Whenever data are summarised over time, study day will be calculated based on the actual 
assessment date, and is defined as: 
Study day = Date of assessment – date of first dose of study treatment. 
Study day 0 is defined as the date of the first dose of study treatment.
3.1.3
Study Periods
The following study periods are defined for analysis purposes:

Pre-Treatment (Screening period): starting on the date of the first study procedure and 
ending one day prior to date assigned study treatment (for subjects assigned study 
treatment) or on the date of the last study procedure (for screening failures). If any 
subject is re-screened, the latest available screening will be used for this purpose.

On-treatment period:  defined as starting between day of first dose of study treatment 
and scheduled end of treatment (EOT) visit or early discontinuation (DXD) visit for 
those patients who prematurely discontinue study treatment, inclusive. If both EOT and 
DXD visits are missing then the upper limit of the on-treatment period is defined as the 
day of last dose of study treatment + 56 days. If the upper limit is after the end of on-
study period, then the upper limit is end of on-study period

On-study period: starting on the date of first dose of IP and ending on the study     
completion or withdrawal date


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3.1.4
Visit windows
Table 1 of the CSP detailed the time points and visit window for the study assessments. All 
summaries which are presented by time point will use a visit window to classify the data 
record, which is derived from the assessment date relative to the reference start date (date if 
first dose of study treatment). This approach allows appropriate classification of visits which 
may have occurred significantly earlier or later than the protocol assessment schedule, as well 
as the use of data captured at visits which have no fixed timing.
Inclusion within the visit window should be based on the actual date and not the intended 
nominal date of the visit.
Any data collected at unscheduled or repeat visits will be listed, and will be included in 
baseline definitions (Section 3.1.1), and in any definitions of maximum value, minimum value 
or last value within the relevant study period.
Data collected at unscheduled or repeat visits will also be included in visit windows, and 
therefore may be included in summaries by visit. In the case of a missing value at a scheduled 
visit, which is then followed by a non-missing value at an unscheduled or repeat assessment 
within the same visit window, the non-missing value at the unscheduled/repeat assessment 
will replace the missing value at the scheduled visit.
If a subject has more than one non-missing value within the same visit window, the following 
rules will apply:

The non-missing value closest to the target day will be selected for analysis at that visit

If two non-missing values are the same distance from the target day, the earlier of the 
two values will be selected for analysis at that visit

If two non-missing values are recorded on the same day and have a different 
assessment time associated with both of them, the value with the earliest assessment 
time will be selected for analysis at that visit.

If two non-missing values are recorded on the same day and have no assessment time 
associated with at least one of them, or the same assessment time associated with both 
of them, the average of the two values will be selected for analysis at that visit.
If a subject has no value within a particular visit window, then the subject will have a 
missing value at that visit in summaries.
Due to the overlap in the week 1 and 2 visit window schedule of assessments the 
following rules will apply subject to the above rules described in this section above: 

If Week 1 timepoint has only one record within analysis days 3-10 then this will be 
assigned to the Week 1 analysis visit, as described above.

If Week 1 timepoint has multiple records (with evaluable results) within analysis days 
3-10 then: 


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a) if the latest record (using time) has analysis day = 10, then this record will be 
considered for selection within the Week 2 analysis visit, subject to the existing 
rules described in this section above, and
b) all earlier records within analysis days 3-10 will be considered for selection within 
the Week 1 analysis visit, subject to the existing rules described in this section 
above
For PK measures, if there are 2 samples from the same date, the value from the scheduled visit 
will be used. If the scheduled visit is missing, then the record from the unscheduled visit will 
be used. If the sampling times are different, both PK samples will be transferred to database 
and used in population PK (PopPK) analysis. 
Blood samples for determination of PK parameters in serum will be taken at timelines as 
specified in Table 1 of CSP.  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 on the eCRF
For PK serum concentration-time data, any post-dose samples taken outside the window from 
scheduled time point will be excluded from the summary tables and figures.
The adjusted analysis-defined windows will be based on the collection schedule listed in the 
protocol and variables will be windowed to the closest scheduled visit for that variable. 
Visit windows following baseline will be constructed in such a way that the upper limit of the 
interval falls halfway between the two visits (the lower limit of the first post-baseline visit will 
be study day 1). If an even number of days exists between two consecutive visits then the 
upper limit will be taken as the midpoint value minus 1 day. Visit windows are constructed so 
that every observation collected can be allocated to a visit (Table 1). No visit windows will be 
defined for screening visits. 


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Table 1: Visit windows for assessments
Timepoint            
Target 
                               Day
Visit Window
AE, CM,
Asthma 
Exac 
and VS
PK 
sampling
ACQ-IA
Clinical 
chemistry, 
Haematology
, Serology, 
Urinalysis, 
and FEV1
Brief
PE
ADA,
PGIC-
IA
and 
CGIC
Height 
and
Weight
ECG
Baseline
Week 0 day 0
0
See section 3.1.1 for baseline definitions
Week 0 day 1
1
1-2
1-2
Week 1
7
3-10
3-10
1-10
Week 2
14
11-20
11-20
11-20
Week 4
28
21-41
21-41
21-41
1-41
1-41
Week 8
56
42-69
42-69
42-69
42-69
42-69
1-83
Week 12
84
70-97
70-97
70-97
70-97
70-97
Week 16
112
98-139
98-139
98-139
98-139
98-139
84-139
1-139
1-139
1-251
Week 24
168
140-195
140-195
140-195
140-251
140-195
140-195
140-195 140-251
Week 32
224
196-251
196-251
196-251
196-279
Week 40
280
252-307
252-307
≥252
Week 48
336
308-348
308-348
308-348
≥252
308-348
≥280
≥252
≥252
Follow-up
(Week 52)
362
≥ 349
≥349
Abbreviations: ACQ-IA interviewer-administered asthma control questionnaire, ADA anti-drug antibody(ies), 
PGIC-IA interviewer administered patient global impression of change, PK pharmacokinetics, VS vital signs, AE 
adverse events, CM concomitant medication, ACQ-IA interviewer-administered asthma control questionnaire, 
Exac Asthma exacerbation, PE Physical examination, ECG electrocardiogram.
3.1.5
Handling of missing data
There will be no imputation for safety data.
Missing dates are not anticipated, except for concomitant medication dates. Medications with 
missing partial start date or end date such that it is not possible to classify as prior or 
concomitant will be considered as concomitant.
Details on the algorithm for handling medication and adverse event partial missing dates can 
be found in Appendix I .
Details on the handling of missing PK data can be found in section 4.2.5.1


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3.2
Primary outcome variables
3.2.1
Primary PK variables
The primary PK outcome measure is the evaluation of benralizumab administered SC in
children with severe eosinophilic asthma by assessing benralizumab concentrations versus 
time profile and the PK parameters derived.
The PK parameters to be determined are:

Clearance

AUC0-28

Cmax

t1/2

Tmax
3.2.2
Primary PD variable 
3.2.2.1
Blood eosinophil levels
Blood samples for determination of eosinophil count levels (haematology) will be taken at the 
time points detailed in Table 1 of the CSP and will be assessed in a central laboratory. Blood 
eosinophil counts levels will be evaluated at Screening (Visit 1, Day -28 to -14) and the 
change from baseline to Weeks 4, 8, 12 and 16 (Part A), and Weeks 24 and 48 (Part B) is the 
primary PD variable to evaluate the PD of benralizumab administered SC in children with 
severe eosinophilic asthma.
3.3
Secondary outcome variables
3.3.1
Body weight-adjusted clearance
Body weight-adjusted clearance parameter is one of the secondary variables that will be used 
to further assess the PK of benralizumab.  
3.3.2
Immunogenicity Variable
Serum samples for the determination of ADA in serum will be taken prior to IP administration 
at the study visits indicated in CSP Table 1.  Serum samples for ADA assessments will be 
conducted utilizing a tiered approach (screen, confirm, titre). ADA result from each sample 
will be reported as either positive or negative. If the sample is positive, the ADA titre will be 
reported as well. In addition, the presence of neutralizing antibody (nAb) will be tested in all 
ADA-positive samples using a ligand-binding assay. The nAb results will be reported as 
positive or negative. Details of the analytical methods used will be described in a separate 
validation report.


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3.3.3
Pre-bronchodilator forced expiratory volume in first second (pre-BD 
FEV1)
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) will be used as a secondary 
variable to evaluate the effect of benralizumab on pulmonary function.
The pre-BD FEV1 will be measured by spirometry at the study centre. 
Multiple forced expiratory efforts (at least 3 but no more than 8) will be performed for each 
centre spirometry session and the 2 best efforts that meet the American Thoracic Society 
(ATS)/ European Respiratory Society (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 value will be recorded using 
the local spirometer at the site with predicted values derived from a reference value.
3.3.4
Interviewer-administered asthma control questionnaire (ACQ-IA)
The change from baseline in ACQ-IA score, obtained at all post-baseline visits as indicated on 
Table 1 of the CSP will be used as a secondary variable to assess the effect of benralizumab 
on asthma symptoms and other asthma control metrics.
The ACQ-IA is a 6-item assessment comprised of 6 patient-reported items: 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 ACQ-IA score is calculated by 
taking the mean of the 6 equally weighted items.  
The ACQ score range is 0 (well controlled) to 6 (extremely poorly controlled).    
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, Juniper et al 2006, Juniper et al 2005). The estimated 
minimal clinically important difference is 0.5 (Juniper et al 2010)
The questionnaire will be completed at the study centre during every study visit except Visit 3 
on Day 1 as indicated in Table 1 of CSP. 
Other variables based on ACQ-IA to be reported at each time point include:
1. ACQ-IA responder (Yes=1/No=0):

Responder: Change from baseline ACQ-IA score ≤ -0.5

Non-responder: Change from baseline ACQ-IA score > -0.5. 


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2. ACQ-IA response (Improved/No Change/Deterioration):

Improvement: Change from baseline ACQ-IA score ≤ -0.5

No change: -0.5 < Change from baseline ACQ-IA score < 0.5

Deterioration: Change from baseline ACQ-IA score ≥ 0.5
3. Subject’s asthma control as measured by ACQ-IA score:

Well controlled: ACQ-IA score ≤ 0.75

Partly controlled: 0.75 < ACQ-IA score < 1.25

Not well controlled: ACQ-IA score ≥ 1.25. 
3.3.5
Global Impression of Change 
Clinician global impression of change (CGIC) and interviewer-administered patient global 
impression of change (PGIC-IA) instruments are used for an overall evaluation of response to 
treatment, conducted separately by the Investigator and by the patient administered by trained 
individuals, using a 7-point scale: 1=Very Much Improved; 2=Much Improved; 3=Minimally 
Improved; 4=No Change; 5=Minimally Worse; 6=Much Worse; and 7=Very Much Worse.
The Investigator (clinician) and the patient will be asked to rate the degree of change in the 
overall asthma status compared to the start of study treatment visit. The questionnaire will be 
completed by the patients and clinicians at Week 16 (Part A), and Weeks 24, 32, and 48 (Part 
B). 
Patients will also be categorized according to the following responses post-baseline, 
separately for CGIC and PGIC:

Very much improved, much improved, minimally improved → ‘Improved’

Very much improved, much improved → ‘Much improved’

Very much improved → ‘Very much improved’
Agreement between CGIC and PGIC-IA will be assessed at each visit, where agreement is 
achieved when both the patient and clinician provide the same response (e.g., if both the 
patient and clinician indicate a response of 1 (very much improved) at a particular visit, 
agreement is achieved for that visit). Agreement will also be assessed for categorized 
responses at each visit.


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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 (CSP table 1). 
3.3.6
Safety outcome variables
The following safety data will be collected: reported AEs (including SAEs), haematology,
clinical chemistry, urinalysis, 12-lead electrocardiogram (ECG), physical examination and
vital signs.
All safety measurements will use all available data for analyses, including data from 
unscheduled visits and repeated measurements.
Change from baseline to each post-treatment time point where scheduled assessments were
made will be calculated for relevant measurements.  AEs will be summarised by means of 
descriptive statistics and qualitative summaries.
No safety data will be imputed. The handling of partial/missing dates for AEs is detailed in 
Appendix I . 
3.3.6.1
Adverse events (AEs)
Adverse events (including SAEs) experienced by the patients will be collected throughout the 
entire study and will be coded by the AstraZeneca designee using the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse event data will be categorized according to their onset date into the following study 
periods: 

AEs in the on-study period, defined as:
date of first dose of IP ≤ AE onset date ≤ study completion or withdrawal date.

AEs in the pre-treatment period (screening period) are defined as those with onset 
before the day of first dose of study treatment. If any subject is re-screened, the latest 
available screening will be used for this purpose
If the AE has a completely missing (and unresolvable) onset date, then the AE will be 
assumed to be treatment-emergent, unless the end date indicates unambiguously that the AE 
resolved before treatment started. If the AE has a partially missing (and unresolvable) onset 
date, then the AE will also be assumed to be treatment-emergent, unless either the end date 


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indicates unambiguously that the AE resolved before treatment started, or the partial onset 
date is in the month/year prior to start of treatment.
3.3.6.2
Laboratory variables
Samples for determination of clinical chemistry, haematology, virology and urinalysis 
parameters will be taken at the times detailed in the Table 1 of the CSP and assessed in a 
central laboratory. The parameters outlined in Table 8 of the CSP will be collected. 
Changes in haematology and clinical chemistry variables between baseline and each post-
baseline assessment will be calculated. The change from baseline is defined as the post-
baseline value minus the baseline value. There will be no imputation for missing values. For 
values recorded with a leading greater than or less than (‘>’, ‘<’) symbol, the reported numeric 
value will be used for analysis and the value with the symbol will be included in the listings, 
unless otherwise specified. For example, a value of <0.01 will be analyzed as 0.01 and listed 
as <0.01.   
The investigator will assess the available lab results with regards to clinically relevant 
abnormalities. Absolute values will be compared to the relevant reference range and classified 
as low (below range), normal (within range or on limits) or high (above range). The central 
laboratory reference ranges that will be used will follow the most recent version of the AZ 
standard reference ranges and unit conversion external data. All absolute values falling outside 
the AZ provided reference ranges will be flagged in the listings. These classifications will also 
be used for shift tables.
Urinalysis data will be categorised as negative (0), positive (+), or strongly positive (++, +++, 
or >+++) at each timepoint.
For the purpose of shift tables, baseline will be defined as specified in section 3.1.1. 
Maximum or minimum value post-baseline will be calculated over the entire post-baseline 
period.
For the liver function tests: aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase and total bilirubin (TBL), the multiple of the central laboratory 
upper limit of the normal (ULN) range will be calculated for each data point:
Multiple = Value / ULN,
i.e. if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2.
Patients who meet any of the following criteria at any point during the study will be flagged:


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
AST ≥ 3x ULN 

ALT ≥ 3x ULN 

TBL ≥ 2x ULN
3.3.6.3
Vital signs
Vital signs such as systolic blood pressure, diastolic blood pressure, pulse rate, weight, height, 
Body mass index (BMI) and body temperature will be assessed. The assessment will be 
conducted while sitting with a completely automated device with a calibrated manometer 
using an appropriate pediatric cuff and in accordance with the visit schedule provided in Table 
1 of the CSP.
Changes in the vital signs variables between baseline and each subsequent scheduled 
assessment will be calculated. Absolute values will be compared to the given reference ranges 
(Table 2 and Table 3) and classified as low (below range), normal (within range or on limits) 
or high (above range). All values (absolute) falling outside the reference ranges will be 
flagged in the listings. 
Table 2: Vital signs reference ranges for age 6 -11 years
Parameter
Standard Units
Lower Limit
Upper Limit
Diastolic Blood Pressure
mmHg
57
80
Systolic Blood Pressure
mmHg
97
120
Pulse Rate
Beats/min
70
110
Body Temperature
Celsius
35.5
37.5
Weight 
kg
15
NA
Height 
cm
NA
NA


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Table 3: Vital signs reference ranges for age 12 -14 years
Parameter
Standard Units
Lower Limit
Upper Limit
Diastolic Blood Pressure
mmHg
64
83
Systolic Blood Pressure
mmHg
110
131
Pulse Rate
Beats/min
55
105
Body Temperature
Celsius
35.5
37.5
Weight 
kg
15
NA
Height 
cm
NA
NA
BMI will be calculated from the height and weight as follows:
BMI (kg/m2) = weight (kg) / (height (m)) 2
3.3.6.4
ECG
A 12-lead ECG will be obtained as outlined in Table 1 of the CSP using the site’s own ECG 
machines after the patient has rested in the supine position for at least 10 minutes.
The outcome of the investigator’s overall ECG evaluation will be recorded as 
normal/abnormal in the CRF and with any abnormalities recorded as not clinically significant 
or clinically significant. Changes from baseline in continuous 12-lead ECG variables will be 
calculated at relevant visits as specified in Table 1.
3.3.6.5
Physical examination
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 time points specified in CSP 
Table 1.  Baseline data will be collected prior to first dose and any new finding(s) or 
aggravated existing finding(s), judged as clinically significant by the investigator or designee, 
will be reported as an AE. 


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3.3.7
Exploratory outcome variable
3.3.7.1
Annualised asthma exacerbation rate
For 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.  
The start of an exacerbation is defined as the start date of systemic corticosteroids or of an 
increase in oral steroid dose, date of ED requiring systemic corticosteroids, or date of hospital 
admission due to asthma, whichever occurs earlier. The end date of an exacerbation is defined 
as the last date of systemic corticosteroids or of an increase in oral steroid dose, date of ED, or 
date of hospital discharge, whichever occurs later.
If less than 7 days have elapsed since the end date of an asthma exacerbation and the start date 
of a new asthma exacerbation, the second event will be considered a relapse of the prior 
asthma exacerbation and 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 collected for asthma exacerbation will include in-patient hospitalizations, number 
of days in the hospital, and ED visits collected by the investigator/authorized delegate at each 
visit (as shown in table 1 of the CSP) 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’.
Time to first asthma exacerbation is the time from first IP dose to the first asthma 
exacerbation and is derived as follows:
Start date of first asthma exacerbation − Date of first IP dose + 1.
The time to first asthma exacerbation for patients who do not experience an asthma 
exacerbation during the treatment period will be censored at EOT visit (Week 48) for patients 
who complete study treatment. Patients who discontinue study treatment or are lost to follow-
up before EOT visit will be censored at the last visit date after which an exacerbation could 
not be assessed.   
The annualised asthma exacerbation rate (AAER) is an exploratory variable and will be 
calculated using the time-based risk approach as:
AAER = 365.25*Total number of exacerbations /Total duration of at risk on-treatment period 
(days).


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 2 5 v 2. 0
1 8 Oct o ber 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 of 4 3
4
A N A L Y SI S M E T H O D S
4. 1
Ge ner al pri nci ples
T he stati stical a nal yses will be perf or me d b y I Q VI A u n der t he directi on of t he Bi ostatist ics 
Gr o u p, Astra Ze neca. T he data a nal yses will be c o n d ucte d usi n g S A S ® S yste m ( S A S I nst itute 
I nc., Car y, N C), Versio n 9. 4 or hi g her. All a nal yses will be pe rfor m e d acc or di n g t o 
Astra Ze neca sta n dar d o perati n g pr oce d ures u nless ot her wise state d.
N o f or m al st atistical h y p ot heses will be teste d i n t his st u d y .
F or P K relate d data s u m maries f or patie nts a ge d 6 t o 1 1 y ears will be prese nte d i n ta b ular 
f or mat b y tr e at me nt/ weig ht gr o u ps ( be nraliz u ma b 
 m g i n pat ient s < 3 5 k g at scree ni n g a n d 
be nraliz u ma b 
 m g i n pat ient s ≥ 3 5 k g at scree ni n g).   U p t o 3 Ja pa nese patie nts a ge d 1 2 t o 
1 4 years will be e nr olle d a n d liste d f or P K relate d data. A d dit i onal s u m maries f or n o n -P K 
r elate d data f or patie nts a ge d 6 t o 1 1 years, a n d a ge d 6 t o 1 4 years o verall will be pr o vi de d. 
Descri pt i ve statistics o n c o nti n u o us data will be s u m marise d b y treat me nt/ wei g ht gr o u p 
i ncl u di n g n u m ber of patient s wit h a vaila ble data ( n), arit h metic mea n ( A mea n), sta n dar d 
de viat i on ( S D), m e 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. Ge o metric mea n ( G mea n) a n d ge o metric c oefficie nt of variati o n ( g C V %) will 
als o be pr o d uce d f or l o g-tra nsf or me d data i ncl u di n g P K c o nce ntrati o n data. T he A mea n, 
me dia n, G mea n a n d g C V % will be prese nte d wit h o ne m ore deci mal place t ha n t he ra w data. 
T he S D will be prese nte d wit h t w o m ore deci mal places t ha n t he ra w data. I n ge neral, 
mi ni m u m a n d ma xi m u m val ues will ha ve t he sa me n u m ber of deci mal places as t he ra w data 
e xce pt s pecifie d ot her wise (see secti o n  4. 2. 5. 1 f or P K para meters).
G m ea n is calc ulate d as e x p[ μ], w here μ is t he mea n of t he data o n a l o garit h mic scale. 
g C V % is calc ulate d as 1 0 0 √ [e x p(s 2)-1], w here s is t he S D of t he data o n a l o g scal e.
Cate g orical data will be s u m marise d b y  tr e at me nt/ weig ht gr o u p usi n g t he n u m ber a n d 
perce nta ge of patie nts i n eac h cate g or y  a n d t he perce nta ges will be r o u n de d t o 1 deci mal 
pl ace.  Perce nta ges will be calc ulate d usi n g t he n u m ber of patie nts wit hi n eac h 
treat me nt/ wei g ht gr o u p a n d o verall as t he de n omi nat or.
W he n assessi n g mi ni m u m/ ma xi m u m d uri n g t he st u d y , all assess me nts, i ncl u di n g 
u nsc he d ule d/re peate d assess me nts will be use d.  F or a nal ysis assessi n g c ha n ge fr o m baseli ne, 
o nl y  patie nts wit h bot h  baseli ne a n d at least 1 p ost-baseli ne meas ure will be i ncl u de d.
U nless ot her wise s pecifie d, n o al g orit h m f or missi n g data i m p utati o n will be e m pl o ye d.
Alt h o u g h t he st u d y  is c o n d ucte d i n t w o parts, Part A a n d Part B f or 4 8 wee ks of treat me nt 
p eri o d, t he a nal ysis of t he st u d y o utc o me varia bles will be a nal yse d alt o get her n ot se paratel y 
C CI
C CI


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by part and will include all data captured during screening period of up to 28 days and a 
treatment period of 48 weeks, and a safety follow-up visit at Week 52. A patient who 
withdraws prior to the last planned observation in a study period will be included in the 
analyses up to the time of discontinuation, as appropriate.
Medical and surgical histories will be recorded using the latest version of medical dictionary 
for regulatory activities (MedDRA) Preferred Term (PT) within the System Organ Class 
(SOC) level of MedDRA.
Data listings will be sorted by patient number. Summaries by visit will include baseline.
4.2
Analysis methods
No formal analyses will be performed for this study. Demographic and other baseline 
characteristics, exposure, safety and tolerability data and PK will be summarised and listed.
4.2.1
Patient disposition
Patient disposition will be summarised using all enrolled subjects (all patients set) who signed 
the informed consent form, including screening failures.
The number and percentage of patients will be presented by the following categories: assigned 
study treatment, not assigned study treatment (including reason), received study treatment, did 
not receive study treatment (including reason), completed treatment, discontinued from study 
treatment (including reason), completed study, and prematurely withdrawn from study 
(including reason). Study discontinuation reasons are detailed in CSP Section 7.1. Also 
subjects who completed study will be summarized by subjects who completed IP and study, 
and subjects who discontinued IP but completed study assessments.
Reasons for not having received study treatment, discontinuation of IP and prematurely 
withdrawing from study will also be listed including the study day of treatment 
discontinuation.
Important protocol deviations will be summarised by treatment/weight group and listed for the 
safety analysis set. 
The number and percentage of patients included and excluded from each analysis set will be 
summarised by treatment/weight group, including the reason for exclusion from each analysis 
set. Patients in the safety analysis set excluded from the PK analysis set, including reason, will 
also be listed. 
4.2.2
Demography data and patient characteristics
Demography data such as age (years), gender, race, and ethnicity will be summarized by 
treatment/weight group and for all patients in the safety analysis set. Age will be derived from 


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the date of informed consent-date of birth, rounded down to the nearest integer. For patients in 
country where date of birth is not recorded the age as recorded in the eCRF will be used.
Various baseline characteristics will also be summarized by treatment/weight group and for all 
patients in the safety analysis set. These include patient characteristics (weight, height and 
BMI), maintenance asthma medications, maintenance inhaled corticosteroids (ICS) 
medications, maintenance oral corticosteroids (OCS) use, medical and surgical histories, 
spirometry lung function data at screening  such as  FEV1, FEV1/FVC, blood eosinophil count 
at baseline, and respiratory disease characteristics including asthma duration, age at onset of 
asthma, the number of exacerbations in the previous 12 months, and the number of 
exacerbations requiring hospitalizations in the previous 12 months. 
Medical and surgical histories will be summarized by MedDRA Preferred Term (PT) within 
System Organ Class (SOC) level on MedDRA.
4.2.3
Prior and concomitant medications
All medications will be classified by the AstraZeneca designee using the anatomical 
therapeutic chemical (ATC) classification system according to the latest version of the World 
Health Organisation (WHO) Drug Dictionary will be presented by treatment/weight group 
using the safety analysis set and will be categorised as:
prior medications and concomitant medications.
4.2.3.1
Prior medications 
A medication will be regarded as prior if it was stopped on or before the date of first dose of 
study treatment (medication stop date <= date of first dose of study treatment). 
4.2.3.2
Concomitant medications
A medication will be regarded as concomitant if the start date is on or after the first IP dose 
date, but prior to the end of study period (date of first dose of study treatment <= medication 
start date <= study completion or withdrawal date), or if it started on or prior to the first IP 
dose date and was ongoing after the first IP dose date.
The handling of partial/missing dates for prior/concomitant medications is detailed in 
Appendix I .
The number and percentage of patients taking maintenance asthma medications such as ICS/
long acting beta agonist (LABA) fixed dose combinations, at baseline will be summarised. 
Those patients taking ICS and/or OCS at baseline, the converted dose units will also be 
summarised. The number of patients treated with ICS at baseline will be summarised by ATC 
code and preferred term, with total daily dose (non-converted) at baseline summarised for 
each preferred term. A similar summary will be prepared to summarize total daily dose of 
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Disallowed medications will include medications defined as prohibited according to Section 
6.6 of the CSP. They will be defined following a physician review (prior to database lock) of 
the unique combinations of Anatomical Therapeutic Chemical (ATC) code classifications and 
generic terms captured.
Separate tables will be presented for all allowed and disallowed medications received during 
each of the following periods: pre-treatment and on study period respectively.
Prior and concomitant medications will be listed for the safety analysis set, including allowed 
and disallowed medications.
4.2.4
Study treatment
4.2.4.1
Exposure 
Investigational product total treatment duration (days) is defined as the date of last dose minus 
the date of first dose plus 1 day.  
Exposure to IP will be calculated in days as:
Exposure (days) =Last dose date of IP-first dose date of IP+1,
and will be summarized by treatment/weight group for the safety analysis set.
The date of all IP administrations, and all missed doses will be listed using the safety analysis 
set. Reason for missed dose will also be listed.
Exposure data will be summarised and listed for the safety analysis set.
4.2.4.2
Compliance
Study treatment compliance will be summarized descriptively by treatment/weight group for 
the safety analysis set and will be calculated as:
Treatment compliance (%) = (Total doses administered/total doses expected up to last 
treatment date) x 100%.
Patients who received no study treatment will have zero compliance.
4.2.5
PK data
The PK analysis of the serum concentration data for benralizumab will be performed by a 
third-party vendor, PPD.
The PK summaries, figures, and data listings will be produced by IQVIA.  Additional 
population PK analysis will be performed by AZ.


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Patients who have missing PK samples will be evaluated on a case-by-case basis. Any PK 
data available from patients excluded from the NCA population will be listed for each time 
point but not summarised. Any data to be excluded from the summary tables and figures for 
the PK analysis set will be clearly indicated. A deviation (gap between nominal and actual 
time points) column will be added into the listing of concentration data. The exclusion of any 
patients from the PK analysis set or from the analysis will be agreed by the study physician, 
statistician and PK Scientist during the data review meeting.
Serum concentrations and PK parameters will be summarized by treatment/weight group 
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 by safety analysis set and will be excluded from the summary statistics 
and mean profiles. If an entire concentration-time profile is below the lower limit of 
quantification (< LLOQ) the subject will be excluded from both NCA and PK analysis sets.
4.2.5.1
Non-compartmental /PopPK parameter analysis 
Blood samples for determination of benralizumab PK parameters in serum will be taken at 
timepoints specified in Table 1 of the CSP.  Benralizumab concentrations 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.
For all serum PK concentrations, values <LLOQ are replaced by a value of zero. 
The PK parameters listed in section 3.2.1 will be derived using NCA set or PK analysis set.  
PK analysis, where possible, will be carried out using actual time recorded in the raw data.  If 
actual times are missing, nominal times will be used.
The PK parameters will be derived using noncompartmental methods with Phoenix 
WinNonlin® (Certara USA, Inc.) Version 6.3 or higher and/or SAS® Version 9.2, or higher 
(SAS Institute, Inc., Cary, North Carolina), or via population PK (PopPK) method using 
NONMEM (version 7.3 or higher)
The following PK parameters will be derived:

Cmax
Maximum benralizumab concentration obtained directly from 
the observed concentration versus time over 0-28days.

tmax
Time to maximum concentration obtained directly from the 
observed concentration versus time data.


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
AUC(0-28)
Area under the concentration-time curve from time zero to the 
time of the last quantifiable concentration at time “Day 28”, 
calculated by linear up/log down trapezoidal summation.

t1/2
Terminal half-life, calculated as ln(2)/ terminal rate constant 
(λz). 

CL/F
Apparent clearance (L/h), estimated as dose divided by AUC.

Ctrough(W16)     Trough concentration week 16, the lowest concentration reached 
by Benralizumab before the next dose is administered
Additional PK parameters applicable to the actual PK sampling time may be determined if 
deemed appropriate.
All data received will be presented in data listings. Descriptive statistics for the PK parameters 
Cmax, tmax, AUC(0-28), t1/2, and CL/F as well as Ctrough week 16 for benralizumab will be 
presented using NCA or PK analysis set
Summary of PK parameters
Data from patients eligible for inclusion in the NCA and any samples taken outside of CSP 
scheduled time windows (as per CSP Table 1) will be included to determine the PK 
parameters. In the event where PK parameters cannot be estimated accurately using NCA, the 
PK parameters may be estimated via population PK approach using data from PK analysis set
All reportable PK parameter data for the patients in the NCA set or PK analysis set will be 
summarised and listed. 
All PK parameters, excluding tmax, will be summarised by treatment/weight group using the 
following descriptive statistics:

Number of observations (n)

Gmean, calculated as exp[μ], where μ is the mean of the data on a logarithmic scale

gCV%, calculated as 100 √ [exp(s2)-1], where s is the SD of the data on a log scale 

Amean

SD

Median (min, max)
For PK parameter tmax, only n, median, min and max will be produced.
Precision and rounding rules for PK parameters
PK parameter listings will be presented according to the following rules:


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
Cmax to be presented to the same number of significant figures as received from the 
bioanalytical laboratory

tmax, tlast (time to last quantifiable concentration)

AUC(0-28), t1/2, , CL/F, all ratios of PK parameters and coefficient of determination 
adjusted (Rsq) which is the goodness of fit statistic for calculation of λz

N to be presented as an integer (no decimals)
The descriptive statistics for PK parameter data will all be presented to at least 2 decimal 
places apart from the following:

tmax: present as received in the data, usually to 2 decimal places

n: present as integer
4.2.5.2
Summary Statistics of PK serum concentrations
Serum concentrations will be presented by assessment day in tables and listings. The serum 
concentrations summaries will include:

n

n<LLOQ ((n<LLOQ)/n at time point) *100%

Gmean (gCV%)

gSD Amean

arithmetic standard deviation (SD), median (min, max)
For DXD, only the PK samples collected within one dosing cycle after last dose will be 
included in the summary statistics of schedule visits during treatment period. 
The exclusion of concentration data from the PK analysis for an individual time point will be 
documented by the PK Scientist including the reason(s) for exclusion. These individual 
concentration data will also be excluded from the summary tables and corresponding figures.
For those patients eligible for inclusion in the PK Analysis set, the concentration-time data 
will be summarised by the scheduled time point. Any post-dose samples taken outside the 
window of the scheduled time will be flagged by the PK Scientist and excluded from the 
summary tables and figures but will be included in the PK analysis to determine the PK 
parameters.
Serum concentrations that are <LLOQ will be reported as follows:
Individual concentrations below the LLOQ of the bioanalytical assay are non-quantifiable  
and will be reported as <LLOQ in the listings with the LLOQ defined in the footnotes of the 
relevant tables, figures and listings. Non-reportable individual concentrations that is a PK 
parameter (e.g. Cmax) will be listed as not reportable (NR) and concentrations that are missing 


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will be listed as no sample (NS) in the listings. Serum concentrations that are <LLOQ, NR or 
NS will be handled as follows for the provision of descriptive statistics: 

Any values reported as NR or NS will be excluded from summary tables and figures. 

All <LLOQ values will be substituted with  a value of zero, and will be excluded from 
summary descriptive statistics.

If all concentrations are <LLOQ at a time point, no descriptive statistics will be 
calculated for that time point. The Gmean, Amean, SD, min, median and max will be 
reported as   <LLOQ and the gCV%, gSD, and SD as not calculated (NC).

The number of <LLOQ values, n will be reported for each time point along with the 
total number of collected values (n).
The serum PK concentration data for benralizumab will be displayed graphically.  For DXD, 
only the scheduled PK samples collected within one dosing cycle after last dose will be 
included in the mean serum-concentrations time profiles graphs.  Figures for the Gmean 
(gSD) concentration-time data will be presented on both a linear and semi-logarithmic scale. 
Individual concentration time will be graphically presented on linear and semi-logarithmic 
scales.  <LLOQ samples will be plotted as LLOQ with footnote in the graphs.  
Displays will include:

Individual patient serum concentration-time profiles on the linear and semi-log scale 
showing single dose on Day 1, 2 ,7,28 on same plot, stratified by treatment/weight 
groups and color-coded by ADA status.

Gmean serum concentration-time profiles (with gSD error bars) on the linear and 
semi-log scale showing single dose on Day 1, 2, 7 and 28, stratified by 
treatment/weight groups

Serum trough concentrations boxplots to include median and n values on the plot

n will be reported for each time point
Precision and rounding rules for PK concentration data
PK concentration data listings will be presented to the same number of significant figures as 
the data received from the bioanalytical laboratory. PK concentrations descriptive statistics 
will all be presented to 2 decimal places with the exception of n and number of <LLOQs 
which will be presented as integers.
4.2.6
Pharmacodynamic variables
4.2.6.1
Change in Eosinophils count
Peripheral blood eosinophils values and changes from baseline at each visit will be 
summarized using descriptive statistics for each treatment/weight group based on safety 


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analysis set.  For DXD, only the PD samples collected within one dosing cycle after last dose 
will be included in the summary statistics during treatment period.
4.2.7
Body weight-adjusted clearance
Body weight-adjusted clearance will be calculated using the PK population model by AZ and 
will be summarized descriptively by treatment/weight group based on PK analysis set.  
4.2.8
Immunogenicity Analysis
All listings and summary of ADA results will be based on safety analysis set. Immunogenicity 
of benralizumab (ADA) results by treatment/weight group will be listed by patient’s study 
status with positive study status first then followed by patients with negative status, and 
schedule visit including ADA. All ADA positive samples will be tested for neutralizing 
antibodies (nAb) using a ligand binding assay. The nAb results will be reported as positive or 
negative.
The number and percentage of subjects who developed detectable ADA to benralizumab will 
be determined for each of the following categories. However, if the number of ADA positive 
subjects in the safety analysis set is small then the ADA variables may be listed only in the 
CSR.

ADA positive at any time, including baseline and/or post-baseline. The denominator 
for percentage calculation is the number of subjects with any ADA result at baseline 
and/or post-baseline. This percentage is known as ADA prevalence. 

Treatment-emergent ADA positive, defined as either treatment-induced ADA positive 
(ADA negative at baseline and positive at post-baseline) or treatment-boosted ADA 
positive (baseline ADA titer that was boosted by greater than 4-fold following drug 
administration). The denominator for percentage calculation is the number of subjects 
with at least one post-baseline assessment. This percentage is known as ADA 
incidence.

ADA positive at both baseline and at least one post-baseline measurement. The 
denominator for percentage calculation is the number of subjects with an ADA result 
at baseline and at least one post-baseline assessment. 

ADA positive at baseline only. The denominator for percentage calculation is the 
number of subjects with an ADA result at baseline.

Persistently positive ADA, defined as having at least 2 post-baseline ADA positive 
measurements with at least 16 weeks (112 days) between the first and last positive 
measurements, or an ADA positive result at the last available assessment. The 


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denominator for percentage calculation is the number of subjects with at least one 
post-baseline assessment.

Transiently positive ADA, defined as having at least one post-baseline ADA positive 
measurement and not fulfilling the conditions for persistently positive. The 
denominator for percentage calculation is the number of subjects with at least one 
post-baseline assessment.

nAb positive at baseline and/or post-baseline (nAb prevalence). The denominator for 
percentage calculation is the number of subjects with any ADA result at baseline 
and/or post-baseline.

Treatment-induced nAb positive (nAb incidence); defined as nAb negative at baseline 
(or ADA negative at baseline) and nAb positive at any post-baseline visit. Subjects 
who are ADA-negative at baseline are included to ensure that all subjects who are nAb 
positive for the first time post-baseline satisfy this definition, given that all subjects 
who are ADA negative at baseline do not have a nAb result reported.
For ADA summaries at a single time point (e.g. baseline ADA or by visit) the corresponding 
titre summary will be based on the titre of the positive sample for that particular visit. For 
proportions summarising across visits (e.g. any ADA post-baseline) the corresponding titre 
summaries will be based on the maximum titre of all positive samples for each subject.
The hypersensitivity AEs reported on treatment period will be presented by preferred term for 
ADA status.
4.2.9
Forced expiratory volume in first second (FEV1)
FEV1 measurements and changes from baseline at each visit will be summarized using 
descriptive statistics for each treatment/weight group based on safety analysis set.  
4.2.10
Asthma control questionnaire (ACQ-IA)
The mean ACQ-IA score and change from baseline at each visit will be summarized for each 
time point using descriptive statistics for each treatment/weight group based on safety analysis 
set.
The number and percentage of ACQ-IA responders (yes, no), ACQ-IA responses (improved, 
no change, deterioration), subject’s asthma control (well controlled, partially controlled, and 
not well controlled) at each post-baseline visit will be also be presented.
4.2.11
Global impression of change
The CGIC and PGIC-IA responses will be summarised by treatment/weight group and visit 
using the safety analysis set.  The number and percentage of patients will be presented for 
CGIC, PGIC-IA, and for the response agreement between CGIC and PGIC-IA.


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The number and percentage of patients defined as responders based on categorized responses 
for CGIC and PGIC-IA (improved, much improved, very much improved) will also be 
presented by treatment/weight group and visit.
4.2.12
Safety Analysis
All safety and tolerability variables will be summarised by treatment/weight group and overall 
and evaluated descriptively using the safety analysis set. No formal hypothesis testing of 
safety data is planned. 
Out-of-range values for safety laboratory, vital signs, and ECGs will be flagged in individual 
listings. 
4.2.12.1
Adverse Events
All AEs experienced by the patients will be collected throughout the study, as per CSP Table 
1, and will be coded by the AstraZeneca designee using the latest version of MedDRA.
The timings of AEs will be assigned to the period in which they occurred. AEs occurring 
during the screening period will be listed, but not summarised separately.
AEs or Serious Adverse Events (SAEs) will be categorised as occurring on-study period based 
on their onset date:
An overall summary table will be produced showing the number and percentage of patients 
with at least one AE in each of the following categories: any AEs, SAEs, AEs with outcome 
of death, and AEs leading to discontinuation of IP (DAEs). The total number of AEs in the 
different AE categories in terms of AE counts will also be presented (i.e. accounting for 
multiple occurrences of the same event in a patient).
AEs, SAEs, AEs with outcome of death, and DAEs will be summarised by SOC and PT 
assigned to the event using the MedDRA dictionary by descending frequency order in the 
overall benralizumab treatment group. For each PT, the number and percentage of patients 
reporting at least one occurrence of the event will be presented (i.e. subjects with multiple 
occurrences of the same PT will only be counted once). A summary of the most common 
(frequency of >5%) AEs in any treatment group will be presented by PT.
AEs and SAEs will be summarized by PT and Investigator’s causality assessment (related 
versus not related) and maximum intensity.  If a patient reports multiple occurrences of the 
same AE within the same reported period, the maximum intensity will be taken as the highest 
recorded maximum intensity (the order being mild, moderate, and severe).
Separate listings of subjects with AEs, SAEs, AEs with outcome of death, or DAEs will be 
presented.


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4.2.13
Laboratory variables
All continuous laboratory parameters will be summarized descriptively by absolute value by 
each planned visit by treatment/weight group, together with the corresponding changes from 
baseline using the safety analysis set. These summaries will be produced for the on-study 
period, as defined in section 3.1.3. The summary statistics presented will be the minimum, 1st 
quartile, median, 3rd quartile, maximum, mean and SD. Mean changes from baseline over 
time will also be plotted by treatment group. All variables will be summarized in SI units, 
with the exception of blood eosinophil counts which will be summarized in both SI and 
conventional units.
Central laboratory normal reference ranges will be used for the identification of abnormalities. 
A shift table will be produced for each laboratory variable to display low, normal, high and 
missing values. The shift tables will present baseline and maximum/minimum/last post-
baseline values for each variable.
Shift plots showing each individual patients’ laboratory value at baseline and at 
maximum/minimum/last value post-baseline will be produced for each continuous laboratory 
variable. If any laboratory variables show any unusual features (high or low values or a 
general shift in the data points) at other time points then shift plots of these data may be 
produced. The diagonal line of no change, and horizontal and vertical reference lines 
indicating the limits of the normal reference ranges, will also be displayed on the shift plots.
Maximum post-baseline TBL elevations by maximum post-baseline ALT and AST will be 
presented, expressed as multiples of ULN. TBL will be presented in multiples of the following 
ULN ≤1.5, >1.5-2, >2, and AST and ALT will be presented in multiples of the following ULN 
≤1, >1-3, >3-5, >5-10, >10. 
Maximum post-baseline TBL will be presented (<2 and ≥2 x ULN) against maximum post-
baseline ALT (<3, ≥3 -<5, ≥5-<10, and ≥10 x ULN), expressed as multiples of ULN. This will 
be repeated to show maximum post-baseline TBL against maximum post-baseline AST. Data 
for patients with ALT or AST ≥3 x ULN, and bilirubin ≥2 x ULN will be presented, which 
will include all visits for this subset of patients.
For urinalysis data, a shift table will be generated to present changes from baseline to 
maximum post-baseline value for each variable and will include subjects with both baseline 
and post-baseline data.
shift table will also be provided for each urinalysis qualitative assessment using the number 
and percentage of patients with baseline results of negative, trace or positive versus the 
maximum on treatment result of negative, trace or positive. 
The number of patients with treatment-emergent changes will also be summarised.


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Any data outside the laboratory reference ranges will be flagged and explicitly noted on the 
listings that are produced.
4.2.14
Vital signs
All vital signs variables including height, weight and BMI will be summarized by absolute 
value at each visit by treatment/weight group using the safety analysis set, together with the 
corresponding changes from baseline. These summaries will be produced for the on-treatment 
period, as defined in section 3.1.3. The summary statistics presented will be the minimum, 1st 
quartile, median, 3rd quartile, maximum, mean and SD. The normal reference ranges listed in 
Table 2 and Table 3 will be used for the identification of individual abnormalities. A shift 
table will be produced for each vital sign variable to display low, normal, high and missing 
values. The shift tables will present baseline and maximum/minimum/last post-baseline values 
for each variable.
Shift plots showing each individual patient’s vital signs value at baseline and at 
maximum/minimum/last value post-baseline will be produced for each continuous vital sign 
variable.
All recorded vital signs data will be listed.
4.2.15
ECG variable
The outcome of the overall investigator ECG evaluation recorded as normal or abnormal with 
any abnormalities recorded as not clinically significant or clinically significant will be listed 
for all patients by safety analysis set.
Abnormal values will not be recorded as AEs unless deemed clinically significant.
A summary table will be produced for baseline ECG evaluation to display normal, abnormal –
not clinically significant, abnormal – clinically significant and not done.  ECG data will also 
be listed by safety analysis set.
A shift table will be produced for each ECG parameter to display normal (includes 
borderline), abnormal - not clinically significant, abnormal - clinically significant, and not 
done. The shift tables will present baseline and last observation post-baseline value.
4.2.16
Physical examinations
Physical examination data will not be summarized but will be listed only. 
Any new finding(s) or aggravated existing finding(s), judged as clinically significant by the 
investigator or designee, will be reported as an AE.


Statistical A nal ysis Pla n 
Astra Ze neca
D 3 2 5 0 C 0 0 0 2 5 v 2. 0
1 8 Oct o ber 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 9 of 4 3
4. 2. 1 7
E x pl or at or y a n al yses
4. 2. 1 7. 1
A n n u alise d ast h m a e x acer b ati o n r ate
E xacer bat i ons e x perie nce d d uri n g t he treat me nt peri o d will be s u m marize d descri pt i 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 bat i ons ass ociate d wit h a n E D 
visit or h os pitalizat i on.
F or t he pr o d ucti o n of s u m mar y statist ics, 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 o n -tre at me nt peri o d 
( d ays)
S u m maries will als o i ncl u d e t he n u m ber of patie nts e x perie nci n g at least o ne e xacer bati o n.  
Ka pla n -Meier pl ots will be use d t o descri be t he ti me t o first e xacer bati o n
4. 2. 1 8
S u b gr o u p A n al ysis 
F or t he f o ll owi n g data, descri pt i ve s u m maries i n Ja pa n s u b gr o u p b y treat me nt/ wei g ht gr o u p 
a n d o verall will be prese nte d:

Di s p ositio n

D e m o gra p h y  a nd pati e nt c haracteristics

St u d y  treat me nt

P K

P D

F E V 1

A C Q -I A

Gl o bal i m pressi o n of c ha n ge

A Es

Ast h ma e xacer bati o n
5
I N T E RI M A N A L Y S E S
 
 
 
 
  
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6
CHANGES OF ANALYSIS FROM PROTOCOL
No change to the analysis stated in the CSP


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7
REFERENCES
The following AZ internal documents are referenced:
D3250C00025-CSP-v3.0 (Study Protocol)
Nguyen et al 2014  
Nguyen JM, Holbrook JT, Wei CY, Gerald LB, Teague WG, Wise RA. Validation and 
psychometric properties of the Asthma Control Questionnaire among children. J Allergy Clin 
Immunol. 2014;133:91-7.
Juniper et al 2005
Juniper EF, Svensson K, Mork, A, Stahl E. Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. Respir Med. 2005;99:553-8.
Juniper et al 2006
Juniper EJ, Bousquet J, Abetz L, Batemain ED. Identifying ‘well-controlled’ and ‘not well-
controlled’ asthma using the Asthma Control Questionnaire. Respir Med. 2006;100:616-21.
Juniper et al 2010
Juniper EF, Gruffydd-Joes K, Ward S, Svensson K. Asthma Control Questionnaire in 
children: validation, measurement properties, interpretation. Eur Respir J. 2010;36:1410-16.


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8
APPENDIX
Appendix I Partial dates for AEs and prior/concomitant medication

Adverse Events

The missing day of onset of an AE will be set to:
-
First day of the month that the event occurred, if the onset YYYY-MM is after
the YYYY-MM of first study treatment
-
The day of the first study treatment, if the onset YYYY-MM is the same as
YYYY-MM of the first study treatment
-
The date of informed consent, if the onset YYYY-MM is before the
YYYY-MM of the first treatment.

The missing day of resolution of an AE will be set to:
-
The last day of the month of the occurrence. If the patient died in the same
month, then set the imputed date as the death date.

If the onset date of an AE is missing both the day and month, the onset date will be
set to:
-
January 1 of the year of onset, if the onset year is after the year of the first
study treatment.
-
The date of the first treatment, if the onset year is the same as the year of the
first study treatment.
-
The date of informed consent, if the onset year is before the year of the first
treatment.

If the resolution date of an AE or end date of a IP is missing both the day and
month, the date will be set to:
-
December 31 of the year of occurrence. If the patient died in the same year,
then set the imputed date as the death date.

Prior/concomitant medication
Dates missing the day or both the day and month of the year will adhere to the following 
conventions in order to classify prior/concomitant medications:

The missing day of start date of a therapy will be set to the first day of the month that the 
event occurred.

The missing day of end date of a therapy will be set to the last day of the month of the 
occurrence. 

If the start date of a therapy is missing both the day and month, the onset date will be set 
to January 1 of the year of onset.

If the end date of a therapy is missing both the day and month, the date will be set to 
December 31 of the year of occurrence.


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
If the start date of a therapy is null and the end date is not a complete date then the start 
date will be set to the date of the first study visit.

If the start date of a therapy is null and the end date is a complete date:
-
and the end date is after the date of the first study visit then the start date will be 
set to the date of the first study visit.
-
otherwise the start date will be set to the end date of the therapy.

If the end date of a therapy is null and the start date is not a complete date then the end 
date will be set to the date of the last study visit.

If the end date of a therapy is null and the start date is a complete date:
-
and the start date is prior to the date of the last study visit then the end date will 
be set to the date of the last study visit.
-
otherwise, the end date will be set to the start date of the therapy.


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: d 3 2 5 0c 0 0 0 2 5-sa p-e d- 2
D oc u me nt Title:
d 3 2 5 0c 0 0 0 2 5-sa p-e d- 2
D oc u me nt I D:
Versi o n L a bel:
1. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
1 9- Oct- 2 0 2 2 1 7: 0 8 U T C
C o nte nt A p pr o val
1 8- Oct- 2 0 2 2 1 4: 5 3 U T C
 Q UI N TI L E S
A ut h or A p pr o val
P P D
P P D
C CI
C CI