A Multinational, Randomized, Double-blind, Parallel-group, Placebo-controlled Study to Investigate the Use of Benralizumab as a Treatment Option for Patients With Bullous Pemphigoid (FJORD)
Phase: PHASE3
Conditions: Bullous Pemphigoid
Sponsor: AstraZeneca

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
1 
 
Clinical Study Protocol 
Study Intervention 
Benralizumab 
Study Code 
D325AC00002 
Version 
4.0 
Date 
26 April 2022 
A Multinational, Randomized, Double-blind, Parallel-group, 
Placebo-controlled Study to Investigate the Use of Benralizumab 
as a Treatment Option for Patients with Bullous Pemphigoid 
(FJORD) 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
 
S p o ns or N a me: Astr a Ze nec a A B  
Le gal Re gistere d A d dress: Astra Ze neca A B, 1 5 1 8 5 S ö dertälje, S we de n  
L ocal S p o ns or i n Ja pa n: Astra Ze neca K K, 3- 1 Of u ka-c h o, Kita- k u, Osa ka 5 3 0 - 0 0 1 1, Ja pa n 
Re g ul at or y A ge nc y I de ntifier N u m ber(s):  
E ur o pe a n Cli nic al Tri als D at a b ase ( E u dr a C T) n u m ber: 2 0 2 0- 0 0 0 2 8 7- 3 2; 
 
T his Cli nical St u d y Pr ot oc ol has bee n s u bject t o a peer re vie w acc or di n g t o Astra Ze neca 
Sta n da r d pr oce d ures. T he Cli nical St u d y Pr ot oc ol is p u blicl y re gistere d a n d t he res ults are 
discl ose d a n d/ or p u blis he d acc or di n g t o t he Astra Ze neca Gl o bal P olic y o n Bi oet hics a n d i n 
c o m plia nce wit h pre vaili n g la ws a n d re g ulati o ns. 
Pr ot oc ol N u m ber: D 3 2 5 A C 0 0 0 0 2 
A m e n d me nt N u m ber: 3 
St u d y I nter ve nti o n: Be nraliz u ma b.  
St u d y P hase: 3 
S h ort Title:  
A st u d y t o i n vesti gate t he use of be nraliz u ma b i n patie nts wit h b ull o us pe m p hi g oi d ( FJ O R D). 
S afet y P h ysici a n N a me a n d C o nt act I nf or m ati o n will be pr o vi de d se p ar atel y  
I nter n atio n al C o- or di n ati n g i n vesti g at or 
 
A d dress: 
  
  
I o wa Cit y,  
I A 5 2 2 4 2  
U S A  
 
 
 
P P D
P P D
P P D
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 
 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  
D O C U M E N T HI S T O R Y  
D oc u me nt  
D ate  
A me n d me nt 3  
2 6 A pr  2 0 2 2  
A me n d me nt 2  
1 7  Ma y 2 0 2 1  
A me n d me nt 1  
3 0 N o ve m ber 2 0 2 0  
Ori gi nal Pr ot oc ol  
2 4 J u ne 2 0 2 0  
 
A me n d me nt 3 ( 2 6 A P R  2 0 2 2) 
T his a me n d me nt is c o nsi dere d t o be n o n -s u bsta ntial base d o n t he criteria set f ort h i n Article 
1 0(a) of Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n 
U ni o n. 
O ver all R ati o n ale f or t he A me n d me nt  
T he pri mar y rati o nale f or t his a me n d me nt is t o decrease partici pa nt a n d site b ur de n a n d t o 
si m plify t he pr ot oc ol. Ot her c ha n ges were ma de f or ali g n me nt wit h t he u p date d c o m pa n y 
pr ot oc ol te m plate.  
Secti o n # a n d 
n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
S u bst a nti al/
N o n - 
s u bst a nti al 
Title Pa ge  
T he l ocal a me n d me nt n u m ber 
c ha n ge d t o 3 ( Pr ot oc ol Versi o n 
4) . 
U p date d t o reflect t he c orrect 
versi o n  n u m ber of t his pr ot oc ol.  
N o n -
s u bsta ntial 
1. 3  
Sc he d ule of 
Acti vities  
T hese assess me nts were re m o ve d 
t o re duc e partici pa nt a n d site 
b ur de n.  
N o n -
s u bsta ntial 
1. 3 Sc he d ule of 
Acti vities  
Ta ble u p date d t o reflect 
will o nl y be perf or me d at 
Scree ni n g  a n d Visit 1 3.  
T o re d uce partici pa nt a n d site 
b ur de n.  
N o n -
s u bsta ntial 
Ta ble u p date d t o reflect t hat 
sa m ples f or p har mac o ki netics, 
A D A a n d  
 at 
u nsc he d ule d visits will o nl y be 
c ollecte d if t he visit occ urs f or B P 
rela pse. 
Testi n g u p date d as t hese are o nl y 
nee de d if t he partici pa nt 
e x perie nces rela pse.  
N o n -
s u bsta ntial 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
4  
 
Secti o n # a n d 
n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
S u bst a nti al/
N o n - 
s u bst a nti al 
He patitis B a n d C testi n g a d de d  t o 
t he l ocal la b orat or y testi n g. 
O mitte d i n err or.  
N o n -
s u bsta ntial 
Ne utralizi n g  a nti b o dies a d de d t o 
i m m u n o ge nicit y testi n g. 
O mitte d i n err or.  
N o n -
s u bsta ntial 
F o ot n ote a d de d f or distri b uti o n of 
ha n d hel d de vice a n d i nstr ucti o n 
o n use t o clarif y t hat t he 
Astra Ze neca st u d y p h ysicia n will 
ha ve t he discreti o n t o e xe m pt 
partici pa nts wit h certai n me dical 
c o n diti o ns (e g, B P lesi o ns of t he 
fi n gers/ ha n d, ne ur ol o gic c o n diti o n 
affecti n g fi n gers/ ha n d, vis ual 
i m pair me nt) fr o m use of t he 
ha n d hel d de vice f or off -site P R O 
assess me nts. All partici pa nts will 
use t he ta blet f or o nsite P R O 
assess me nts. 
U p date d c o n diti o ns f or e xe m pti o n 
base d o n patie nt ce ntricit y. T his 
will n ot i m pact  t he st u d y 
e n d p oi nts. 
N o n -
s u bsta ntial 
Uri nal ysis ( di pstic k) re m o ve d  
T o re d uce partici pa nt b ur de n.  
N o n -
s u bsta ntial 
T o re d uce partici pa nt b ur de n, 
 will n o l o n ger be 
perf or me d e xce pt i n pre vi o usl y 
e nr olle d partici pa nts.  
N o n -
s u bsta ntial 
Re d uce d uri ne pre g na nc y testi n g 
re q uire me nts t o q uarterl y, rat her 
t ha n e ver y visit. All rele va nt 
secti o ns u p date d wit h ne w 
g ui da nce.  
F or clarificati o n a n d t o re d uce 
partici pa nt /site b ur de n. 
 
N o n -
s u bsta ntial 
3. O bjecti ves a n d 
E n d p oi nts  
N o n -
s ubsta ntial  
N o n -
s u bsta ntial 
5. 1 I ncl usi o n 
Criteria  
A d diti o n of i ncl usi o n Criteri o n 6 
t o be a ble t o c o m plete P R O 
U p date d c o n diti o ns f or e xe m pti o n 
base d o n patie nt ce ntricit y. T his 
N o n -
s u bsta ntial 
C CI
C CI
C CI

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
5 
 
Section # and 
name 
Description of change 
Brief rationale 
Substantial/
Non- 
substantial 
assessments on a tablet and on a 
handheld device, with some 
participants being exempted from 
completing home PROs on the 
handheld device upon agreement 
with the AstraZeneca physician 
(eg, if the patient has a medical 
condition such as BP lesions of 
the fingers/hand, a neurologic 
condition affecting fingers/hand, 
or severe visual impairment). 
will not impact the study 
endpoints. 
Criterion 8 was updated to specify 
that participants must have a 
negative pregnancy test at 
Screening only. 
Updated to align with 
benralizumab safety data and 
internal guidance for testing. 
Non-
substantial 
5.2 
Exclusion Criteria 
Criterion 1 was updated to 
remove the list of medications 
that could potentially induce 
Bullous pemphigoid (BP). 
Text amended to simplify the 
exclusion criterion language. 
Non-
substantial 
Criterion 2 was replaced with the 
following “Comorbid disease that 
in the Investigator's judgement 
might interfere with the 
evaluation of the IP or safety of 
the participant.” 
Text amended to simplify the 
language in the exclusion criteria. 
Non-
substantial 
Criterion 3a was updated to 
specify that only participants with 
in situ carcinoma of the cervix 
had to be treated and have been in 
remission for 12 months. 
Text amended as risks with 
superficial cancers have not been 
identified. 
 
Non-
substantial 
 
Criterion 3b added so participants 
with superficial basal cell or 
squamous skin cancers can be 
enrolled. 
Text amended as risks with 
superficial skin cancers have not 
been identified. 
Non-
substantial 
Assent removed from Criterion 3a 
and 3b (now renumbered as 3c). 
Text amendment as this is an 
adult only study. 
Non-
substantial 
Criterion 6 was updated to 
remove urinalysis and include 
electrocardiogram. 
To reduce participant burden and 
to include relevant assessments 
following on from the removal of 
Criterion 7. 
Non-
substantial. 
Criterion 7 was removed. 
Relevant assessments are included 
in updated Criteria 2 and 6. 
Non-
substantial 

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
6 
 
Section # and 
name 
Description of change 
Brief rationale 
Substantial/
Non- 
substantial 
Criterion 11 was updated to 
specify that participants that are 
on stable therapy for at least 
3 months before randomization 
that intend to stay on treatment 
throughout the study with 
marketed biologics that are not 
likely to interfere with the 
assessment of safety and/or 
efficacy of benralizumab may 
participate in the study. 
Updated to align with the updated 
project specific safety 
requirements for the benralizumab 
development program. 
Non-
substantial 
Criterion 18 was updated to 
clarify that only participants 
already enrolled in another 
interventional clinical trial 
including IP and devices will be 
excluded. 
To clarify the types of research 
projects that could confound the 
interpretation of the study. 
Non-
substantial 
Exclusion Criterion 20 updated to 
specify that a urine pregnancy test 
must be performed at Visit 1 only. 
For clarification and to reduce 
participant/site burden. 
Non-
substantial 
New Criterion 21 added to specify 
that participants with cognitive 
function conditions (eg, dementia) 
who cannot complete PROs will 
be excluded. 
To further clarify that participants 
must be able to understand and 
complete PRO assessments 
independently. 
Non-
substantial 
6.1 
Study Intervention 
Administered 
Requirement for urine pregnancy 
test prior to each administration of 
IP was removed. 
For clarification and to reduce 
participant/site burden. 
Non-
substantial 
6.1.2 
Investigational 
Product 
Administration Re-
scheduling 
Removal of febrile participants as 
a condition for not administering 
and rescheduling of IP. 
Updated based on the safety 
profile of benralizumab. 
Non-
substantial 
Text updated to remove 
pregnancy testing for 
recommendations when IP dosing 
needs to be postponed or 
rescheduled. 
For clarification and to reduce 
participant/site burden. 
Non-
substantial 
6.1.3 
Medical Devices 
New section added. 
Section added to include the use 
of a medical device. 
Non-
substantial 
6.5 
Concomitant 
Therapy 
Text on recording 
prednisolone/prednisone use 
using the handheld PRO device 
was updated.  
To clarify the use of the handheld 
device for the recording of 
concomitant 
prednisolone/prednisone use. 
Non-
substantial 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
7  
 
Secti o n # a n d 
n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
S u bst a nti al/
N o n - 
s u bst a nti al 
6. 5. 2  
Restricti o ns  
U p date d t o s pecif y t hat o n l y oral 
a nti micr o bial a ge nts wit h a nti -
i nfla m mat or y pr o perties are 
disall o we d a n d re m o val of 
a n gi ote nsi n -c o n verti n g e nz y me 
i n hi bit ors, pe nicilla mi ne, 
f ur ose mi de, a n d p he naceti n fr o m 
disall o we d me dicati o n.  
T he liste d c o nc o mita nt 
me dicati o ns t hat were restri cte d 
are n ot ass ociate d wit h dr u g -
i n d uce d B P a n d base d o n 
literat ure s u p p ort d oes n ot re q uire 
restricti o n d uri n g t he trial. 
 
N o n -
s u bsta ntial 
Te xt u p date d t o all o w C O VI D 
relate d pre ve nti o n a n d treat me nt.   
Treat me nts ma y be necessar y 
d uri n g t he trial a n d will n ot 
i m pact partici pa nt's efficac y or 
safet y e val uati o ns. 
N o n -
s u bsta ntial 
Pr ot oc ol u p date d t o re d uce 
partici pa nt a n d site b ur de n.  
N o n -
s u bsta ntial 
( 8. 1. 2) 
Ot her Fi n di n gs 
S u p p orti ve of 
Ster oi d -s pari n g 
Be nefit  
Sect i o n has bee n re m o ve d. 
Secti o n re m o ve d as partici pa nts 
will be recei vi n g ster oi ds d uri n g 
t he trial. 
N o n -
s u bsta ntial 
8. 1. 2  
Patie nt -re p orte d 
O utc o mes  
Te xt u p date d t o clarif y t hat 
ot her wise eli gi ble partici pa nts 
ma y be e nr olle d if t he 
Astra Ze neca st u d y p h ysicia n 
a grees t o e xe m pt t he partici pa nt 
fr o m ha n d hel d de vice usa ge d ue 
t o certai n me dical c o n diti o ns (e g, 
B P s ki n lesi o ns o n t he 
fi n gers/ ha n ds or, ne ur ol o gical 
i m pair me nt affecti n g 
fi n gers/ ha n ds). 
Te xt u p date d t o e ns ure t hat 
ot her wise eli gi ble partici pa nts 
s h o ul d be e nr olle d. 
N o n -
s u bsta ntial 
8. 2. 4  
Cli nical Safet y 
La b orat or y 
Assess me nts 
Uri nal ysis re m o ve d.  
T hese assess me nts are n ot 
re q uire d f or safet y m o nit ori n g. 
N o n -
s u bsta ntial 
Mea n c or p usc ular v ol u me a n d re d 
bl o o d cell c o u nt re m o ve d.  
T hese assess me nts are n ot 
re q uire d f or safet y m o nit ori n g. 
N o n -
s u bsta ntial 
8. 2. 4. 1  
Pre g na nc y Tests  
Uri ne H C G di pstic k pre g na nc y 
testi n g m o difie d t o reflect u p date d 
pre g na nc y testi n g sc he d ule.  
F or clarificati o n a n d t o re d uce 
partici pa nt/site b ur de n.  
N o n -
s u bsta ntial 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
8  
 
Secti o n # a n d 
n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
S u bst a nti al/
N o n - 
s u bst a nti al 
8. 3. 1 1  
Me dical De vice 
Deficie ncies a n d  
A p pe n di x  I 
Me dical De vice 
A Es, A D Es, S A Es, 
S A D Es, U S A D Es 
a n d Me dical De vice 
Deficie ncies: 
Defi niti o ns a n d 
Pr oce d ures f or 
Rec or di n g, 
E val uati n g, F oll o w -
u p, a n d Re p orti n g 
i n Me dical De vice 
St u dies  
Ne w s ecti o ns a d de d.  
T o e ns ure c o m plia nce wit h ne w 
re g ulat or y re q uire me nts. 
N o n -
s u bsta ntial 
8. 5. 2. 1 A nti -dr u g 
A nti b o dies  
Te xt re gar di n g ne utralizi n g 
a nti b o dies has bee n i ncl u de d at 
t he e n d of para gra p h. 
Te xt i ncl u de d t o i n dicate t hat 
ne utralizi n g a nti b o dies ma y be 
assesse d o n A D A p ositi ve 
sa m ples. 
N o n -
s u bsta ntial 
8. 6. 1. 2  
Tiss ue Hist ol o g y 
a n d 
I m m u n ostai ni n g 
Te xt u p date d t o re m o ve s ki n 
bi o ps y c ollecti o n at ti me of 
disease c o ntr ol.  
Te xt u p date d t o re d uce partici pa nt 
b ur de n.  
N o n -
s u bsta ntial 
9. 4. 3. 3  
Cli nical Safet y 
La b orat or y 
Assess me nts 
Uri nal ysis of s hifts fr o m n or mal 
t o a b n or mal bet wee n baseli ne a n d 
eac h p ost-baseli ne ti me p oi nt 
re m o ve d. 
T hese assess me nts are n ot nee de d 
si nce t here are n o uri nar y safet y 
para meters wit h t he I P. 
N o n -
s u bsta ntial 
9. 4. 6. 1 Patie nt 
Re p orte d O utc o mes  
Te xt re gar di n g a nal yses of t he 
Pea k Pr urit us N R S i nserte d after 
sec o n d para gra p h. 
Te xt i ncl u de d t o i n dicate t hat 
a nal yses of t he Pea k Pr urit us N R S 
e n d p oi nt will be c o m plete d i n t he 
s u bset of patie nts a ble t o use t he 
ha n d hel d de vice.  
 
9. 4. 6. 5 L o n ger 
Ter m P ote ntial 
Ster oi d -s pari n g 
Be nefits of 
Be nraliz u ma b  
Secti o n delete d.  
‘ T o e val uate t he l o n ger-ter m 
ster oi d-s pari n g be nefit of 
be nraliz u ma b’ was re m o ve d fr o m 
Ta ble 4 a n d t heref ore relate d 
secti o ns ha ve als o bee n re m o ve d. 
 
T his  secti o n was delete d fr o m t he 
pr ot oc ol.  
E x pl orat or y a nal ysis will be i n t he 
S A P f or assess me nts perf or me d 
pre vi o us t o t his a me n d me nt.  
N o n -
s u bsta ntial 
C CI

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
9 
 
Section # and 
name 
Description of change 
Brief rationale 
Substantial/
Non- 
substantial 
Appendix K 
Protocol 
Amendment 
History 
Updated with details for Protocol 
Amendment 2. 
To align with protocol template 
and procedures. 
Non-
substantial 
AE, adverse event; ADE, adverse device effect; BP, Bullous pemphigoid; IP, investigational product; IPD, 
investigational product discontinuation; NRS, Numeric Rating Scale; SADE, serious adverse device effect; SAE, 
serious adverse event; SAP, statistical analysis plan; USADE, unanticipated serious adverse device effect. 
 

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
10 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE...................................... 3 
TABLE OF CONTENTS ........................................................................................................ 10 
LIST OF TABLES .................................................................................................................. 13 
LIST OF FIGURES ................................................................................................................. 14 
LIST OF APPENDICES ......................................................................................................... 14 
1 
PROTOCOL SUMMARY ................................................................................... 15 
1.1 
Synopsis ................................................................................................................ 15 
1.2 
Schema .................................................................................................................. 21 
1.3 
Schedule of Activities ........................................................................................... 22 
2 
INTRODUCTION ................................................................................................ 32 
2.1 
Study Rationale ..................................................................................................... 32 
2.2 
Background ........................................................................................................... 33 
2.2.1 
BP Disease and Current Approaches to Disease Management ............................ 33 
2.3 
Benefit/Risk Assessment ...................................................................................... 35 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 36 
4 
STUDY DESIGN ................................................................................................. 39 
4.1 
Overall Design ...................................................................................................... 39 
4.1.1 
Screening Period ................................................................................................... 39 
4.1.2 
Double-blind Treatment Period ............................................................................ 39 
4.1.3 
Open-label Extension ........................................................................................... 40 
4.1.4 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 41 
4.2 
Scientific Rationale for Study Design .................................................................. 42 
4.3 
Justification for Dose ............................................................................................ 43 
4.4 
End of Study Definition ........................................................................................ 44 
5 
STUDY POPULATION ....................................................................................... 44 
5.1 
Inclusion Criteria .................................................................................................. 45 
5.2 
Exclusion Criteria ................................................................................................. 46 
5.3 
Lifestyle Considerations ....................................................................................... 49 
5.4 
Screen Failures ..................................................................................................... 49 
5.4.1 
Re-screening ......................................................................................................... 49 
6 
STUDY INTERVENTION .................................................................................. 50 
6.1 
Study Intervention(s) Administered ..................................................................... 50 
6.1.1 
Investigational Products ....................................................................................... 50 
6.1.2 
Investigational Product Administration Re-scheduling ........................................ 52 
6.1.3 
Medical Devices ................................................................................................... 53 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 53 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
 
6. 2. 1  
Pre parati o n a n d Ha n dli n g of I n vesti gati o nal Pr o d uct ...........................................  5 4 
6. 2. 2  
S hi p pi n g a n d St ora ge ............................................................................................  5 4 
6. 2. 3  
Acc o u nta bilit y ......................................................................................................  5 4 
6. 3  
Meas ures t o Mi ni mize Bias: Ra n d o mizati o n a n d Bli n di n g  .................................. 5 5 
6. 3. 1  
Ra n d o mizati o n ......................................................................................................  5 5 
6. 3. 2  
Bli n di n g ................................................................................................................  5 5 
6. 3. 3  
Met h o ds f or U n bli n di n g .......................................................................................  5 7 
6. 4  
St u d y I nter ve nti o n C o m plia nce ............................................................................  5 7 
6. 5  
C o nc o mita nt T hera p y ...........................................................................................  5 8 
6. 5. 1  
Oral C ortic oster oi ds a n d Ta peri n g  ....................................................................... 5 8 
6. 5. 2  
Restricti o ns  ........................................................................................................... 5 9 
6. 6  
D ose M o dificati o n  ................................................................................................ 6 0 
6. 7  
I nter ve nti o n After t he E n d of t he St u d y ............................................................... 6 0 
7  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ............................................................ 6 1 
7. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n .................................................................  6 1 
7. 1. 1  
Pr oce d ures f or Disc o nti n uati o n of St u d y I nter ve nti o n a n d at E n d of St u d y ........  6 1 
7. 1. 1. 1  
Disc o nti n uati o n of St u d y I nter ve nti o n .................................................................  6 2 
7. 1. 1. 2  
Disc o nti n uati o n of St u d y I nter ve nti o n U p o n N otificati o n of Cl os ure of St u d y  ... 6 2 
7. 1. 2  
Pr oce d ures f or Ha n dli n g I nc orrectl y E nr olle d or Ra n d o mize d Partici pa nts  ........ 6 2 
7. 2  
Partici pa nt Wit h dra wal fr o m t he St u d y  ................................................................ 6 3 
7. 2. 1  
Disc o nti n uati o n or S us pe nsi o n of t he W h ole St u d y Pr o gra m ..............................  6 3 
7. 3  
L ost t o F oll o w- u p .................................................................................................  6 4 
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ............................................... 6 4 
8. 1  
Efficac y Assess me nts  ........................................................................................... 6 5 
8. 1. 1  
Cli nicia n -re p orte d O utc o me Assess me nts ............................................................ 6 5 
8. 1. 1. 1  
B ull o us Pe m p hi g oi d Disease State .......................................................................  6 6 
8. 1. 1. 2  
B ull o us Pe m p hi g oi d Disease Area I n de x .............................................................  6 7 
8. 1. 1. 3  
I n vesti gat or Gl o bal Assess me nt ........................................................................... 6 8 
8. 1. 1. 7  
Healt hcare Res o urce Utilizati o n  ........................................................................... 6 9 
8. 1. 2  
Patie nt -re p orte d O utc o mes ................................................................................... 7 0 
8. 1. 2. 1  
Pea k Pr urit us N u meric Rati n g Scale  .................................................................... 7 0 
8. 1. 2. 2  
C ortic oster oi d Me dicati o n Usa ge  ......................................................................... 7 1 
8. 1. 2. 3  
B ull o us Pe m p hi g oi d Disease Area I n de x Pr urit us ...............................................  7 1 
8. 1. 2. 4  
A ut oi m m u ne B ull o us Disease Q ualit y of Life Q uesti o n n aire ( A B-Q o L)  ............ 7 1 
8. 1. 2. 5  
E ur o pea n Q ualit y of Life- 5 Di me nsi o ns ( E Q- 5 D- 5 L) .......................................... 7 1 
8. 1. 2. 6  
Q ualitati ve Patie nt I nter vie w S u b -st u d y ............................................................... 7 1 
8. 2  
Safet y Assess me nts  ............................................................................................... 7 3 
8. 2. 1  
P h ysical E xa mi nati o ns  .......................................................................................... 7 3 
8. 2. 2  
Vital Si g ns  ............................................................................................................ 7 3 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
 
8. 2. 3  
Electr ocar di o gra ms  ............................................................................................... 7 4 
8. 2. 4  
Cli nical Safet y La b orat or y Assess me nts  .............................................................. 7 4 
8. 2. 4. 1  
Pre g na nc y Tests  .................................................................................................... 7 5 
8. 2. 4. 2  
Ser ol o g y ................................................................................................................  7 5 
8. 3  
A d verse E ve nts a n d Seri o us A d verse E ve nts .......................................................  7 6 
8. 3. 1  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A E a n d S A E I nf or mati o n .................  7 6 
8. 3. 2  
F oll o w- u p of A Es a n d S A Es ................................................................................  7 7 
8. 3. 3  
Ca usalit y C ollecti o n  ............................................................................................. 7 8 
8. 3. 4  
A d verse E ve nts Base d o n Si g ns a n d S y m pt o ms ..................................................  7 8 
8. 3. 5  
A d verse E ve nts Base d o n E xa mi nati o ns a n d Tests  .............................................. 7 8 
8. 3. 6  
Disease U n der St u d y  ............................................................................................ 7 9 
8. 3. 7  
Re p orti n g of Seri o us A d verse E ve nts ...................................................................  7 9 
8. 3. 8  
Pre g na nc y .............................................................................................................  8 0 
8. 3. 8. 1  
Mate r nal E x p os ure ................................................................................................ 8 0 
8. 3. 9  
Me dicati o n Err or  ................................................................................................... 8 0 
8. 3. 1 0  
De vice C o nstit ue nt Deficie ncies  .......................................................................... 8 1 
8. 3. 1 1  
Me dical De vice Deficie ncies  ................................................................................ 8 1 
8. 3. 1 1. 1  
Ti me Peri o d f or Detecti n g Me dical De vice Deficie ncies  ..................................... 8 1 
8. 3. 1 1. 2  
F oll o w- u p of Me dical De vice Deficie ncies  .......................................................... 8 2 
8. 3. 1 1. 3  
Pr o m pt Re p orti n g of Me dical De vice Deficie ncies t o S p o ns or  ........................... 8 2 
8. 3. 1 1. 4  
Re g ulat or y Re p orti n g Re q uire me nts f or De vice Deficie ncies  ............................. 8 2 
8. 3. 1 2  
Seri o us A d verse De vice Effect Re p orti n g  ............................................................ 8 2 
8. 3. 1 3  
Ma na ge me nt of I n vesti gati o nal Pr o d u ct-relate d Dr u g Reacti o ns ......................... 8 3 
8. 4  
O ver d ose ...............................................................................................................  8 3 
8. 5  
H u ma n Bi ol o gical Sa m ples  .................................................................................. 8 4 
8. 5. 1  
P har mac o ki netics  .................................................................................................. 8 4 
8. 5. 1. 1  
Deter mi nati o n of Dr u g C o nce ntrati o n ..................................................................  8 5 
8. 5. 2  
I m m u n o ge nicit y Assess me nts .............................................................................. 8 6 
8. 5. 2. 1  
A nti - dr u g A nti b o dies ............................................................................................ 8 6 
8. 5. 3  
P har mac o d y na mics ...............................................................................................  8 6 
8. 6  
H u ma n Bi ol o gical Sa m ple Bi o mar kers  ................................................................ 8 6 
8. 6. 1  
C ollecti o n of Ma n dat or y Sa m ples f or Bi o mar ker A nal ysis  ................................. 8 6 
8. 6. 1. 1  
Ser u m a n d Plas ma  ................................................................................................ 8 6 
8. 6. 1. 2  
Tiss ue Hist ol o g y a n d I m m u n ostai ni n g .................................................................  8 7 
8. 6. 2  
St ora ge, Re- use a n d Destr ucti o n of Bi o mar ker Sa m ples .....................................  8 7 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................. 8 8 
9. 1  
Statistical H y p ot heses  ........................................................................................... 8 8 
9. 2  
Sa m ple Size Deter mi nati o n  .................................................................................. 8 9 
9. 3  
P o p ulati o ns f or A nal yses  ...................................................................................... 9 0 
9. 4  
Statistical A nal yses  ............................................................................................... 9 1 
9. 4. 1  
Ge neral C o nsi derati o ns  ......................................................................................... 9 1 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 3
 
9. 4. 2  
Efficac y A nal yses  ................................................................................................. 9 4 
9. 4. 2. 1  
Pri mar y A nal ysis Met h o d  ..................................................................................... 9 4 
9. 4. 2. 2  
A nal ysis Met h o ds f or Ke y Sec o n dar y Efficac y Varia bles  ................................... 9 5 
9. 4. 2. 3  
A nal ysis Met h o ds f or Sec o n dar y Efficac y Varia bles  ........................................... 9 8 
9. 4. 3  
Safet y A nal yses  .................................................................................................. 1 0 0 
9. 4. 3. 1  
A d verse E ve nts ...................................................................................................  1 0 1 
9. 4. 3. 2  
Treat me nt E mer ge nce  ......................................................................................... 1 0 1 
9. 4. 3. 3  
Cli nical Safet y La b orat or y Assess me nts  ............................................................ 1 0 1 
9. 4. 3. 4  
Vital Si g ns  .......................................................................................................... 1 0 2 
9. 4. 3. 5  
B o d y Wei g ht .......................................................................................................  1 0 2 
9. 4. 4  
P har mac o ki netic A nal yses  .................................................................................. 1 0 2 
9. 4. 5  
I m m u n o ge nicit y A nal yses .................................................................................. 1 0 2 
9. 4. 6  
Ot her A nal yses  ................................................................................................... 1 0 2 
9. 4. 6. 1  
Patie nt -re p orte d O utc o mes ................................................................................. 1 0 3 
9. 4. 6. 2  
Healt hcare Res o urce Utilizati o n  ......................................................................... 1 0 3 
9. 4. 6. 3  
E x pl orat or y Bi o mar kers  ..................................................................................... 1 0 4 
9. 4. 7  
Met h o ds f or M ulti plicit y C o ntr ol  ....................................................................... 1 0 4 
9. 4. 8  
Se nsiti vit y A nal yses  ........................................................................................... 1 0 5 
9. 4. 9  
S u b gr o u p A nal yses .............................................................................................  1 0 5 
9. 5  
I nteri m A nal yses ................................................................................................. 1 0 6 
9. 6  
Data M o nit ori n g C o m mittee  ............................................................................... 1 0 6 
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  .......................................................................................... 1 0 6 
1 1  
R E F E R E N C E S  ................................................................................................... 1 5 1 
 
LI S T O F T A B L E S  
D O C U M E N T HI S T O R Y  .......................................................................................................... 3 
Ta ble 1  
Pri mar y a n d Sec o n dar y O bjecti ves  ............................................................. 1 6 
Ta ble  2 
Sc he d ule of Acti vities  ................................................................................. 2 3 
Ta ble  3 
Sc he d ule of P R O Assess me nts  .................................................................... 3 1 
Ta ble 4   
O bjecti ves a n d E n d p oi nts ............................................................................ 3 6 
Ta ble  5  
I n vesti gati o nal Pr o d ucts .............................................................................. 5 0 
Ta ble  6  
Defi niti o ns f or B ull o us Pe m p hi g oi d O utc o me Meas ures ........................... 6 6 
Ta ble 7  
I G A Sc ores a n d Descri pti o ns ...................................................................... 6 8 
Ta ble  8 
La b orat or y Safet y Varia bles  ....................................................................... 7 5 
Ta ble 9  
P o p ulati o ns f or A nal ysis  ............................................................................. 9 0 
Ta ble 1 0  
Pri mar y a n d Ke y Sec o n dar y Esti ma n ds ......................................................  9 2 
C CI

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LIST OF FIGURES 
Figure 1 
Study Design ............................................................................................... 21 
Figure 2 
Injection Sites and Examples of Rotation Scheme ..................................... 51 
 

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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: 
A Multinational, Randomized, Double-blind, Parallel-group, Placebo-controlled Study to 
Investigate the Use of Benralizumab as a Treatment Option for Patients with Bullous 
Pemphigoid (FJORD). 
Short Title:  
A study to investigate the use of benralizumab in patients with bullous pemphigoid (FJORD) 
Rationale: 
Benralizumab is a humanized, afucosylated cytolytic monoclonal antibody that binds to the 
human interleukin-5 receptor alpha subunit (IL-5Rα) on eosinophils and basophils. The 
absence of fucose in the Fc domain of benralizumab results in high affinity for FcɣRIIIa 
receptors on immune effector cells such as natural killer cells, leading to apoptosis of 
eosinophils and basophils through enhanced antibody-dependent cell-mediated cytotoxicity. 
The pharmacodynamic response to benralizumab dosing is eosinophil depletion. Bullous 
pemphigoid (BP) is an autoimmune blistering disorder. The disease primarily occurs in the 
elderly, may last for several years, and tends to recur despite currently available treatment. 
Eosinophils are central to the pathology of BP. It is proposed that by depleting eosinophils in 
the blood and skin of patients with BP, benralizumab treatment could help achieve disease 
remission and maintain disease control, prevent relapses, allow tapering of oral corticosteroid 
(OCS) usage, and reduce corticosteroid load. The aim of this study is to investigate the use of 
benralizumab as treatment for patients with symptomatic BP. 
Objectives and Endpoints: 
The primary and secondary objectives and associated endpoints are detailed in Table 1. The 
primary and secondary efficacy objectives are based on the double-blind, placebo-controlled 
phase of the study. For tertiary/exploratory objectives and endpoints, see Section 3 of the 
protocol. 

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Table 1 
Primary and Secondary Objectives 
Objective 
Estimand descriptions/endpoints 
Primary 
 
To compare the clinical efficacy of benralizumab 
with placebo in participants with symptomatic BP 
• 
Population: Full analysis set 
• 
Endpoint: A binary response, whereby a 
responder is defined as a participant who is in 
complete remission while off OCS 
for ≥ 2 months at Week 36. Otherwise, a 
participant is a non-responder  
• 
Intercurrent events: Participants who receive 
restricted medications or withdraw from the 
study will be considered as non-responders from 
the time such events occur up to Week 36. 
• 
Summary measure: Difference in proportion of 
participants who are responders between 
benralizumab and placebo at Week 36. 
Secondary 
 
To compare the effect of benralizumab with placebo 
on supportive measures of clinical efficacy in 
participants with symptomatic BP up to Week 36 
• 
Key secondary a: Proportion of participants who 
remain relapse-free up to Week 36. 
• 
Key secondary a: Cumulative OCS exposure 
(mg/kg) from baseline to Week 36. 
• 
Key secondary a: Change from baseline in 
BPDAI activity score at Week 36. 
• 
Key secondary a: Change from baseline in 
BPDAI-Pruritus score at Week 36. 
• 
Proportion of participants in sustained 
complete/partial remission on minimal OCS/off 
OCS for at least 2 months at Week 36. 
• 
Cumulative time (weeks) in complete remission 
off OCS from baseline to Week 36. 
• 
Proportion of participants off OCS by Week 36. 
• 
IGA score at Week 36 
• 
Change from baseline in IGA score at Week 36 
To compare the effect of benralizumab with placebo 
on clinical efficacy in participants with symptomatic 
BP up to Week 16 
• 
Key secondary a Cumulative OCS exposure 
(mg/kg) from baseline to Week 16. 
• 
Proportion of participants who remain relapse-
free up to Week 16. 
• 
Proportion of participants with any clinical 
benefit (eg, partial and complete remission 
during taper, with no steroid use, or with 
minimal steroid use [ie, < 0.1 mg/kg/day]) at 
Week 16. 
• 
Time to disease control, OCS dose (mg/kg) at 
disease control and time to the end of the 
consolidation phase. 
• 
Change from baseline in BPDAI activity score at 
Week 16. 
• 
Change from baseline in BPDAI-Pruritus score 
at Week 16. 

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Table 1 
Primary and Secondary Objectives 
Objective 
Estimand descriptions/endpoints 
To estimate the PK and immunogenicity of 
benralizumab in participants with BP 
• 
Serum benralizumab concentration 
• 
ADA 
Safety 
 
To compare the safety and tolerability of 
benralizumab with placebo in participants with 
symptomatic BP 
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, and clinical laboratory values. 
Assessments related to AEs cover: 
• 
Occurrence/frequency 
• 
Relationship to IP as assessed by Investigator 
• 
Intensity 
• 
Seriousness 
• 
Death 
• 
AEs leading to discontinuation of IP 
 
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height. 
Assessments related to vital signs cover: 
• 
Observed value 
• 
Absolute and percent change from baseline 
values 
Estimands for the key secondary endpoints are detailed in Section 9. All other estimands will be detailed fully in 
the Statistical Analysis Plan. 
ADA, anti-drug antibodies; AE, adverse event; BP, bullous pemphigoid; BPDAI, Bullous Pemphigoid Disease 
Area Index; IGA, Investigator Global Assessment; IP, investigational product; OCS, oral corticosteroids; 
PK, pharmacokinetics. 
 
Overall Design: 
This is a multinational, randomized, double-blind, placebo-controlled, parallel-group, Phase 3 
study to assess the efficacy and safety of a benralizumab 60 mg loading dose followed by 
repeat dosing of subcutaneously (SC) administered benralizumab 30 mg versus placebo in 
adult participants with symptomatic BP. 
Disclosure Statement: 
This is a Phase 3 parallel-group, placebo-controlled study with 2 double-blind treatment 
groups. 
Number of Participants: 
Approximately 190 participants will be enrolled/screened in order to achieve approximately 
120 eligible study participants randomly assigned to study intervention. 

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Note: "Enrolled" is defined as a participant's agreement to participate in a clinical study 
following completion of the informed consent process. Potential participants who are screened 
for the purpose of determining eligibility for the study but are not randomized to the study will 
be considered “screen failures”, unless otherwise specified by the protocol. 
Intervention Groups and Duration: 
The study consists of a screening period, a randomized double-blind treatment period, and an 
open-label extension (OLE). 
Following screening, eligible participants will be randomized 1:1 to receive either 
benralizumab or placebo every 4 weeks (Q4W) by SC injection during the initial 36-week, 
double-blind phase of the study. After randomization, participants will receive a loading dose 
of 60 mg benralizumab or placebo, administered as 2 SC injections. After 4 weeks, 
participants will receive 30 mg benralizumab or placebo Q4W until the end of the 
double-blind treatment period at 36 weeks. Participants will also receive OCS at 
0.5 mg/kg/day (or higher if required) in addition to investigational product (IP) until BP 
disease control is achieved. The OCS dose can be increased, if necessary, to achieve disease 
control. The consolidation phase begins when disease control is achieved and continues until 
the time at which no new lesions or pruritic symptoms have developed for a minimum of 
2 weeks and the majority of established lesions have healed (end of consolidation phase). At 
this point, participants will begin protocolled OCS tapering, with the aim to taper off OCS 
completely within 3 to 4 months (ie, 4 to 5 months from randomization). 
After completion of the double-blind treatment period, all participants will have the option of 
entering an OLE period for at least 1 year, during which they will receive benralizumab 30 mg 
Q4W until study closure. During the OLE participants can receive OCS to address the BP 
relapse at the Investigator’s discretion, with the goal of tapering off the steroids to 
benralizumab monotherapy as soon as clinically indicated. 
Data Monitoring Committee: 
An Independent Data Monitoring Committee (IDMC) will be utilized for this study. 
Section A 5 provides more details on the rationale for the committee and its remit. 
Since the benefit/risk profile for benralizumab is favorable in other diseases, AstraZeneca has 
not pre-specified study safety stopping criteria and leaves this to the IDMC as they monitor 
the study data and fulfill their role to make necessary recommendations on this matter, as 
outlined in the IDMC charter. 

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Statistical methods: 
Sample size calculation 
For the initial 36-week, double-blind, placebo-controlled phase of the study, the aim is to 
recruit 60 participants in the placebo group and 60 participants in the benralizumab group. 
The sample size calculation was derived for the primary endpoint, the proportion of 
participants who are in complete remission while off OCS for ≥ 2 months at Week 36. 
Approximately 60 participants are needed per treatment group to detect a 30% difference 
between benralizumab and placebo with 90% power. The calculation is based on a 2-sided test 
and a 5% significance level and assumes a response rate of 50% for benralizumab and 20% 
for placebo. 
A non-binding interim futility analysis will be performed by an IDMC when approximately 
36 randomized participants (ie, when approximately 30% of the total amount of statistical 
information is available) have had the opportunity to complete at least 36 weeks of follow-up. 
By conducting the futility analysis the overall power will not be affected substantially. 
Assessment of the first 36 weeks of treatment intervention 
The primary efficacy analysis will be based on the initial 36-week, double-blind, 
placebo-controlled phase of the study and will compare benralizumab versus placebo. The 
primary endpoint is a binary response, whereby responders will be defined as participants who 
are in complete remission while off OCS for ≥ 2 months at Week 36. Otherwise, participants 
will be classified as non-responders. The primary estimand will be based on the full analysis 
set. Intercurrent events will consist of participants who receive restricted medications or 
withdraw from the study. The primary estimand will regard these participants as 
non-responders from the time such events occur up to Week 36. A participant with missing 
data at a specific time point will also be considered as a non-responder at that time point. Note 
that regardless of prior OCS use, participants who achieve complete remission while off OCS 
for ≥ 2 months at Week 36 will be classed as responders. For example, if participants who 
require an increase in OCS dose, or need to restart their OCS having had their disease 
controlled previously, satisfy the criteria for the primary endpoint at Week 36, they will be 
considered as responders. 
For the primary analysis, a logistic regression model will be fitted to the primary endpoint 
using a logit link function. The model will include treatment, baseline disease severity 
(moderate; severe) and time of BP diagnosis (ie, participants with newly diagnosed BP versus 
participants with a previous diagnosis of BP who have relapsed) as categorical covariates. 
(The effect of adding further covariates into the model, such as age and region, may also be 
assessed as a sensitivity analysis.) The model will be used to estimate the proportion of 
responders for benralizumab and placebo, the difference between these proportions 
(benralizumab – placebo), a rate ratio and an odds ratio, with corresponding 95% confidence 

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CONFIDENTIAL AND PROPRIETARY 
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limits. A p-value, corresponding to a 2-sided test, will be presented to compare the 
benralizumab and placebo treatment groups.  
There are 5 key secondary endpoints, which are supportive measures of clinical efficacy. They 
include: proportion of participants who remain relapse-free up to Week 36; cumulative OCS 
exposure (mg/kg) from baseline to Week 36; change from baseline in bullous pemphigoid 
disease area index (BPDAI) activity score at Week 36; change from baseline in 
BPDAI-Pruritus score at Week 36, and cumulative OCS exposure (mg/kg) from baseline to 
Week 16. 

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1.3 
Schedule of Activities 
The Schedule of Activities (SoA) at each visit for this study is provided in Table 2. Details of 
the schedule of at-home and site visit patient-reported outcome (PRO) assessments are 
provided in Table 3. 
 

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Table 2 
Schedule of Activities 
Study period 
Screen-
ing  
Double-blind treatment period 
OLE 
IPD/ 
EOTc 
FU  
(12  
wks 
after 
last 
dose 
of IP) 
UNSd 
Details in 
CSP 
section 
Visit 
V1 
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V10 
V11 
V
12 
V13/ 
EOTa 
Every 
4 wks 
(V14 
to 
V22)b 
V
19 
Every 
12 
weeks 
(From 
V23) 
Week (Wk)  
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40-72 
60 
From 
Week 
76  
 
 
 
 
Visit window 
(days) 
(Target 
0-4 
days) 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
 
 
General Procedures 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 
A 3 
Demography/ 
medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 5.2 
Inclusion/ 
exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sections 
5.1 and 5.2 
Record 
concomitant 
medications, 
including OCS 
dose and 
compliance 
checke 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
X 
X 
Section 6.5 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
6.3.1 

Cli nical St u d y Pr ot oc ol  - 4. 0  
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C O N FI D E N TI A L A N D P R O P RI E T A R Y  
2 4   
 
T a ble  2  
Sc he d ule of Acti vities  
St u d y peri o d  
Scree n -
i n g  
D o u ble -bli n d tre at me nt peri o d  
O L E  
I P D/ 
E O T c 
F U  
( 1 2  
w ks 
after 
l ast 
d ose 
of I P)  
U N S d  
Det ails i n 
C S P 
secti o n 
Visit  
V 1  
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V 1 0  
V 1 1  
V
1 2 
V 1 3/ 
E O T a 
E ver y 
4 w ks  
( V 1 4 
t o 
V 2 2) b  
V
1 9 
E ver y 
1 2 
wee ks 
( Fr o m 
V 2 3) 
Wee k ( W k)  
 
0 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6 
4 0- 7 2 
6 0 
Fr o m 
Wee k 
7 6  
 
 
 
 
Visit wi n d o w 
( d a ys) 
( T ar get 
0- 4 
d a ys) 
±
3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
± 7  
± 7  
 
 
Dise ase Me as ure me nts  
Disease state, 
B P D AI, I G A, 
a n d
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Secti o ns 
8. 1. 1. 1 , 
8. 1. 1. 2 , 
8. 1. 1. 3 , a n d 
8. 1. 1. 4  
 
 
 
 
 
 
 
X 
 
 
 
 
X 
X f 
 
 
 
 
 
Secti o n 
8. 1. 1. 5  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Secti o n 
8. 1. 1. 6  
Healt hcare 
res o urce 
utilizati o n  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Secti o n 
8. 1. 1. 7  
P R O Pr oce d ures  
Distri b uti o n of 
ha n d hel d de vice 
a n d i nstr ucti o n 
o n use h 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secti o n 
8. 1. 2  
C CI
C CI
C CI

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
25 
 
Table 2 
Schedule of Activities 
Study period 
Screen-
ing  
Double-blind treatment period 
OLE 
IPD/ 
EOTc 
FU  
(12  
wks 
after 
last 
dose 
of IP) 
UNSd 
Details in 
CSP 
section 
Visit 
V1 
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V10 
V11 
V
12 
V13/ 
EOTa 
Every 
4 wks 
(V14 
to 
V22)b 
V
19 
Every 
12 
weeks 
(From 
V23) 
Week (Wk)  
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40-72 
60 
From 
Week 
76  
 
 
 
 
Visit window 
(days) 
(Target 
0-4 
days) 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
 
 
Review OCS 
usage and 
compliance with 
at-home PRO 
assessmentsh 
(Table 3) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Section 
8.1.2 
Compliance 
with at home 
PRO 
assessmentsh. 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Section 
8.1.2 
BPDAI-
Pruritus, 
AB-QoL, and 
EQ-5D-5L 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 
8.1.2 
Select countries 
only: informed 
consent for 
qualitative 
patient 
interview 
sub-study 
X i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.1.2.6 

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
26 
 
Table 2 
Schedule of Activities 
Study period 
Screen-
ing  
Double-blind treatment period 
OLE 
IPD/ 
EOTc 
FU  
(12  
wks 
after 
last 
dose 
of IP) 
UNSd 
Details in 
CSP 
section 
Visit 
V1 
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V10 
V11 
V
12 
V13/ 
EOTa 
Every 
4 wks 
(V14 
to 
V22)b 
V
19 
Every 
12 
weeks 
(From 
V23) 
Week (Wk)  
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40-72 
60 
From 
Week 
76  
 
 
 
 
Visit window 
(days) 
(Target 
0-4 
days) 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
 
 
Select countries 
only: qualitative 
patient 
interview 
sub-study j 
X 
 
 
 
 
 
 
X 
 
From 
Weeks 60 to 
76 
 
 
 
Section 
8.1.2.6 
Safety Assessments 
AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.3 
Complete 
physical exam k  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Section 
8.2.1 
Brief physical 
exam including 
weight l 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
Section 
8.2.1 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xb 
X 
X 
X 
Section 
8.2.2 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.3 
Local Laboratory Assessments 
Hematology and 
Clinical 
chemistry  
X m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.4 

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
27 
 
Table 2 
Schedule of Activities 
Study period 
Screen-
ing  
Double-blind treatment period 
OLE 
IPD/ 
EOTc 
FU  
(12  
wks 
after 
last 
dose 
of IP) 
UNSd 
Details in 
CSP 
section 
Visit 
V1 
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V10 
V11 
V
12 
V13/ 
EOTa 
Every 
4 wks 
(V14 
to 
V22)b 
V
19 
Every 
12 
weeks 
(From 
V23) 
Week (Wk)  
 
0 
2 
4 
6 
8 
12 
16 
20 
24 
28 
32 
36 
40-72 
60 
From 
Week 
76  
 
 
 
 
Visit window 
(days) 
(Target 
0-4 
days) 
±
3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±7 
 
 
HIV express test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.4.2 
Hepatitis B and 
C serology m  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.4.2 
Urine 
pregnancy test 
in  
FOCBP n 
X 
 
  
 
 
 
X 
 
 
X 
 
 
Xb 
 
 
 
 
 
 
Section 
8.2.4.1 
Confirmatory 
BP diagnostic 
testing 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Central Laboratory Assessments 
Hematology and 
Clinical 
chemistry  
X m 
  
 
  
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
Xp 
Section 
8.2.4 
Hepatitis/HIV 
screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
8.2.4.2 
HbA1c 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
X q 
X q 
 
Section 
8.2.4 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
 
T a ble  2  
Sc he d ule of Acti vities  
St u d y peri o d  
Scree n -
i n g  
D o u ble -bli n d tre at me nt peri o d  
O L E  
I P D/ 
E O T c 
F U  
( 1 2  
w ks 
after 
l ast 
d ose 
of I P)  
U N S d  
Det ails i n 
C S P 
secti o n 
Visit  
V 1  
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V 1 0  
V 1 1  
V
1 2 
V 1 3/ 
E O T a 
E ver y 
4 w ks  
( V 1 4 
t o 
V 2 2) b  
V
1 9 
E ver y 
1 2 
wee ks 
( Fr o m 
V 2 3) 
Wee k ( W k)  
 
0 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6 
4 0- 7 2 
6 0 
Fr o m 
Wee k 
7 6  
 
 
 
 
Visit wi n d o w 
( d a ys) 
( T ar get 
0- 4 
d a ys) 
±
3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
± 7  
± 7  
 
 
F S H  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Secti o n 
8. 2. 4. 1  
P K sa m ple  
 
X 
X 
X 
X r 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X s 
Secti o n 
8. 5. 1  
A D A/ n A b  
 
X 
 
X r 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X s 
Secti o n 
8. 5. 2  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sec ti o n 
8. 7. 1  
E x pl or at or y Bi o m ar kers  
W h ole bl o o d 
(i ncl u di n g 
 
 
 a n d 
eosi n o p hil 
c o u nt), ser u m 
a n d plas ma f or 
bi o mar kers  
 
X 
X t 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X s 
Secti o n 
8. 6. 1. 1  
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
 
T a ble  2  
Sc he d ule of Acti vities  
St u d y peri o d  
Scree n -
i n g  
D o u ble -bli n d tre at me nt peri o d  
O L E  
I P D/ 
E O T c 
F U  
( 1 2  
w ks 
after 
l ast 
d ose 
of I P)  
U N S d  
Det ails i n 
C S P 
secti o n 
Visit  
V 1  
V
2 
V
3 
V
4 
V
5 
V
6 
V
7 
V
8 
V
9 
V 1 0  
V 1 1  
V
1 2 
V 1 3/ 
E O T a 
E ver y 
4 w ks  
( V 1 4 
t o 
V 2 2) b  
V
1 9 
E ver y 
1 2 
wee ks 
( Fr o m 
V 2 3) 
Wee k ( W k)  
 
0 
2 
4 
6 
8 
1 2 
1 6 
2 0 
2 4 
2 8 
3 2 
3 6 
4 0- 7 2 
6 0 
Fr o m 
Wee k 
7 6  
 
 
 
 
Visit wi n d o w 
( d a ys) 
( T ar get 
0- 4 
d a ys) 
±
3 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 7  
± 7  
± 7  
± 7  
± 7  
 
 
S ki n bi o ps y f or 
hist ol o g y/ 
i m m u n o hist o-
c he mistr y a n d 
u 
X  v 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
Secti o n 
8. 6. 1. 2  
Me dic ati o n Pr oce d ures  
Be nraliz u ma b 
or Place b o 
a d mi nistrati o n 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X w  
X b 
X 
X b 
 
 
 
Secti o n  6  
a 
F or partici pa nts c o nti n ui n g i n t he O L E peri o d, Visit 1 3 is t he first treat me nt of t he O L E peri o d. If a partici pa nt c h o oses n o t t o c o nti n ue t o t he O L E peri o d, 
t he patie nt will be c o nsi dere d t o ha ve c o m plete d t he st u d y, t he site will perf or m a n E O T visit at Wee k 3 6, a n d t he patie nt will ret ur n f or a f oll o w-u p visit 
1 2  wee ks ( +/ - 7 da ys) after t he last d ose of I P, after w hic h t he partici pa nt e xits t he st u d y. 
b 
Be nraliz u ma b a d mi nistrati o n a n d vital si g ns tests will c o nti n ue e ver y 4 wee ks , a n d uri ne pre g na nc y tests will c o nti n ue e ver y 1 2 wee ks fr o m Wee k  3 6 
( Visit 1 3),  d uri n g t he o pe n -la bel e xte nsi o n peri o d u ntil partici pa nt wit h dra wal or st u d y cl os ure.  
c 
T he I P D/ E O T visit re places t he nearest re g ular visit: I P D/ E O T visit pr oce d ures s h o ul d be perf or me d as s o o n as p ossi ble after t he decisi o n t o disc o nti n ue I P 
has bee n ma de, a n d at t he latest 4  wee ks ±  7 da ys after t he last d ose of I P. F or partici pa nts w h o disc o nti n ue I P a n d c o nti n ue wit h st u d y assess me nts d uri n g 
t he d o u ble-bli n d treat me nt peri o d, t he e n d of treat me nt will be at Visit 1 3 ( Wee k 3 6).  
d 
T he re q uire d assess me nts f or t his visit s h o ul d c o nti n ue t o Wee k 7 2. T hereafter, t he y will c o nti n ue at i n vesti gat or’s discreti o n.  
e 
I n vesti gat or/ dele gate t o rec or d t he O C S d ose i n t he e C R F at eac h st u d y visit a n d c hec k c o m plia nce a gai nst partici pa nt-re p orte d use bet wee n st u d y visits f or 
partici pa nts usi n g a ha n d hel d de vice . 
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 0   
 
h 
T he Astra Ze neca st u d y p h ysicia n will ha ve t he discreti o n t o e xe m pt partici pa nts wit h certai n me dical c o n diti o ns (e g, B P lesi o ns of t he 
fi n gers/ ha n d/ ne ur ol o gic c o n diti o n affecti n g fi n gers/ ha n d, vis ual i m pair me nt) fr o m use of t he ha n d hel d de vice f or off-site P R O assess me nts. All o nsite P R O 
assess me nts will h o we ver, be perf or me d b y all partici pa nts usi n g t he ta blet.  
i 
A se parate c o nse nt f or t he q ualitati ve i n ter vie w s u b-st u d y is re q uire d. I nter vie ws will o nl y be perf or me d wit h c o nse nti n g patie nts fr o m selecte d c o u ntries. 
j 
I nter vie w s u b-st u d y acti vities ca n o nl y be gi n after t he q ualitati ve i nter vie w s u b-st u d y c o nse nt is gi ve n. 
k 
C o m plete p h ysical e xa mi nati o n i ncl u des a n assess me nt of t he f oll o wi n g: hei g ht a n d wei g ht, ge neral a p peara nce, s ki n, hea d a n d nec k (i ncl u di n g e y es, ears, 
n ose, m o ut h, a n d t hr oat), l y m p h n o des, a b d o me n, m usc ul os keletal (i ncl u di n g s pi ne a n d e xtre mities), car di o vasc ular, res pir at or y, a n d ne ur ol o gical s yste ms.  
l 
Brief p h ysical e xa mi nati o n i ncl u des assess me nt of t he f oll o wi n g: wei g ht, ge neral a p peara nce, s ki n, a b d o me n, car di o vasc ular, a n d res pirat or y s yste m. F or 
t he brief p h ysical e xa mi nati o n, o nl y i nf or mati o n o n w het her t he assess me nt was perf or me d or n ot is t o be rec or de d. Wei g ht meas ure me nts will be 
perf or me d i n li g ht cl ot hi n g a n d wit h o ut s h oes a n d will be rec or de d i n kil o gra ms.  
m  
Testi n g  t o be c o n d ucte d at l ocal la b orat or y, c o nfir mati o n testi n g t o be c o n d ucte d b y a ce ntral la b orat or y. 
n 
A p ositi ve uri ne pre g na nc y test res ult m ust be c o nfir me d wit h a ser u m pre g na nc y test.  
o 
C o nfir mat or y l ocal testi n g is re q uire d f or t h ose w h o d o n ot ha ve a c o nfir me d B P dia g n osis.  
p 
A n u nsc he d ule d he mat ol o g y a n d cli nical c he mistr y s h o ul d be perf or me d if t he visit is f or rela pse . 
q 
If n ot c o n d ucte d i n t he pre vi o us 3 m o nt hs. 
r 
S a m ples will be ta ke n o nl y at o ne ti me p oi nt, ie, at t he visit w he n disease c o ntr ol has bee n ac hie ve d.  
s 
S a m ples will be ta ke n at a n u nsc he d ule d visit if t he visit is f or rela pse . 
t 
Bl o o d bi o mar kers will be c ollecte d o nl y at o ne of t he ti me p oi nts bet wee n Visits 4 a n d 6;  ie, o nl y  at t he visit t hat disease c o ntr ol has bee n ac hie ve d a n d 
bef ore ster oi d ta per is c o m me nce d.  
u 
S ki n bi o psies will be ta ke n fr o m peri -lesi o nal s ki n f or hist o pat h ol o g y a n d 
 researc h. 
v 
F or partici pa nts wit h o ut a c o nfir me d dia g n osis, n o bi o ps y f or 
 is c ollecte d. I n t hese partici pa nts, t he bi o ps y will be f or i ncl usi o n criteria 
c o nfir mati o n at t he l ocal la b a n d i m m u n o hist oc he mistr y f or e x pl orat or y researc h.  
w  
Be nraliz u ma b a d mi nistrati o n o nl y; f or partici pa nts w h o c o nti n ue t he st u d y i n t he o pe n -la bel e xte nsi o n.  
A B -Q o L, A ut oi m m u ne B ull o us Disease Q ualit y of Life; A D A, a nti -dr u g a nti b o dies; A E, a d verse e ve nt; B P, B ull o us pe m p hi g oi d; B P D AI, B ull o us Pe m p hi g oi d 
Disease Area I n de x; 
; C S P, cli nical st u d y pr ot oc ol; E C G, electr ocar di o gra m; E O T, e n d of treat me nt; E Q -5 D -5 L, 
E ur o pea n Q ualit y of Life -5 Di me nsi o ns; F O C B P, fe males of c hil d beari n g p ote ntial; F S H, f ollicle -sti m ulati n g h or m o ne; F U, f oll o w-u p; HI V, h u ma n 
i m m u n o deficie nc y virus; I G A,  I n vesti gat or Gl o bal Assess me nt; I P, i n vesti gati o nal pr o d uct; I P D, i n vesti gati o nal pr o d uct disc o nti n uati o n; n A b,  ne utralizi n g  
a nti b o dies; O C S, oral c ortic oster oi ds; O L E, o pe n -la bel e xte nsi o n; 
; P K, p har mac o ki netics; P R O, patie nt -re p orte d o utc o mes; 
S A E, seri o us a d verse e ve nt; U N S, u nsc he d ule d; V, visit; W ks,  wee ks.  
 
C CI
C CI
C CI
C CI

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
31 
 
Table 3 
Schedule of PRO Assessments 
Instruments 
Schedule 
Peak Pruritus Numeric Rating Scale and OCS Usage 
First assessment at site at V2, then at home every 
evening (17:00-23:59) starting the day after V2 at 
home thereafter until V22 (Week 72).a 
BPDAI-Pruritus, AB-QoL, EQ-5D-5L 
At site at every visit up to V22 (Week 72), and then 
every 12 weeks thereafter. At site at unscheduled, 
IPD, and follow-up visits. 
a 
Participants will complete BPDAI-pruritus, AB-QoL, and EQ-5D-5L onsite using the tablet. Some 
participants may be exempted from completing the at home PRO assessments on the handheld device (ie, Peak 
Pruritus Numeric Rating Scale and OCS Usage) upon agreement with the AstraZeneca physician. 
AB-QoL, Autoimmune Bullous Disease Quality of Life; BPDAI, bullous pemphigoid disease area index; 
EQ-5D-5L, European Quality of Life-5 Dimensions; IPD, investigational product discontinuation; OCS, oral 
corticosteroids; PRO, patient-reported outcomes; V, visit. 
 

Clinical Study Protocol - 4.0 
AstraZeneca 
Benralizumab - D325AC00002 
26 April 2022 
CONFIDENTIAL AND PROPRIETARY 
32 
 
2 
INTRODUCTION 
2.1 
Study Rationale 
Benralizumab is a humanized, afucosylated cytolytic monoclonal antibody that binds to the 
human interleukin-5 receptor α subunit (IL-5Rα) on eosinophils and basophils. The absence of 
fucose in the Fc domain of benralizumab results in high affinity for FcɣRIIIa receptors on 
immune effector cells such as natural killer cells, leading to apoptosis of eosinophils and 
basophils through enhanced antibody-dependent cell-mediated cytotoxicity  
(Kolbeck et al 2010, Laviolette et al 2013). The pharmacodynamic response to benralizumab 
dosing is eosinophil depletion. Benralizumab has been or is being investigated in eosinophil-
driven diseases including asthma, chronic obstructive pulmonary disease (COPD), 
hypereosinophilic syndrome (HES), nasal polyposis, eosinophilic chronic rhinosinusitis, 
eosinophilic granulomatosis with polyangiitis, and eosinophilic esophagitis. The direct 
eosinophil-depleting ability of benralizumab is effective in eosinophilic asthma  
(Bleecker et al 2016, FitzGerald et al 2016) and steroid-dependent asthma (Nair et al 2017), 
and it may show benefit in HES (Kuang et al 2019). In patients with eosinophilic asthma, 
benralizumab treatment leads to near-complete depletion of blood eosinophils and a reduction 
of annual asthma exacerbation rates (Bleecker et al 2016, FitzGerald et al 2016). 
Bullous pemphigoid (BP) is a rare disease mainly affecting the elderly. The etiology of BP is 
frequently unknown (Amber et al 2018a, Venning and Wojnarowska 1995). The incidence of 
BP worldwide is 6 to 7 new cases per million persons per year in the general population. In 
those aged over 80 years old, the incidence rises to 150 to 330 per million persons per year 
(Schmidt and Zillikens 2013). Bullous pemphigoid is associated with significant morbidity 
and increased mortality secondary to increased risk of secondary infections, comorbid 
conditions, and serious side effects from high-dose steroids and immunosuppressants. 
Comorbid conditions with an increased frequency in patients with BP include multiple 
sclerosis, Parkinson’s disease, Alzheimer's disease, stroke, and diabetes  
(Kibsgaard et al 2017). Common causes of mortality in patients with BP include sepsis, 
cardiovascular disease, and cerebrovascular accident (Joly et al 2002). 
Eosinophils play a central role in the pathophysiology of BP and present a potentially 
promising therapeutic target (de Graauw et al 2017). This is supported by a pilot study of 
bertilimumab, an antibody against the eosinophil chemoattractant eotaxin-1, that suggested the 
drug may be efficacious for treating patients with BP; 9 treated patients in the study showed 
rapid and durable improvement in disease activity with a mean 81% reduction in disease 
activity and lower doses of prednisone used than in a standard BP regimen (Lee et al 2018). 
Initial evidence of benralizumab’s eosinophil-depleting effect in skin was observed in 
2 clinical studies. In a Phase 2 study performed in 4 patients with HES with dermatological 
involvement, blood and tissue eosinophils were absent in 2 of the patients who received 

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benralizumab and had skin biopsies performed (Kuang et al 2019). Eosinophil reduction was 
associated with clinical improvement and the ability to taper background therapy. The second 
study, a small single-blinded, placebo run-in study in patients with chronic idiopathic 
urticaria, benralizumab treatment resulted in significant reductions in weekly Urticaria 
Activity Scores (assessing hives and itch) and improvements in Chronic Urticaria Quality of 
Life Questionnaire Scores (Bernstein and Singh 2019). Improvements in skin conditions 
following benralizumab treatment have also been reported in a patient with chronic 
symptomatic dermographism (Bergmann et al 2019). These studies provide further evidence 
of benralizumab’s significant eosinophil-depleting capabilities in the skin and suggest that 
benralizumab will also be effective for the treatment of BP. A short-term study with 
mepolizumab, a drug that indirectly depletes eosinophils, has also been investigated for the 
treatment of BP (Simon et al 2020). Efficacy of mepolizumab with 4 doses over 16 weeks was 
not demonstrated; the authors concluded that mepolizumab did not significantly affect tissue 
eosinophil infiltration and noted that insufficient control of tissue eosinophils by mepolizumab 
has also been observed in other studies (Simon et al 2020). Learnings from the mepolizumab 
study and evidence of benralizumab mechanism of action in skin helped inform the design of 
this Phase 3 study in adult patients with BP. 
Results from these studies suggest benralizumab could treat other conditions characterized by 
eosinophilia, such as BP. By depleting eosinophils in the blood and affected skin of patients 
with BP, benralizumab treatment could help achieve remission off oral corticosteroid (OCS) 
therapy, achieve disease control, prevent relapses, allow tapering of OCS usage, and reduce 
corticosteroid load. 
The aim of this randomized, double-blind, placebo-controlled, parallel-group, multinational 
Phase 3 study is to investigate the use of benralizumab as a treatment for patients symptomatic 
with BP. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of benralizumab is 
provided in the Investigator’s Brochure. 
2.2 
Background 
2.2.1 
BP Disease and Current Approaches to Disease Management 
Bullous pemphigoid is an autoimmune blistering disorder characterized by immunoglobulin E 
(IgE) and/or immunoglobulin G (IgG) autoantibodies against BP180 and/or BP230, 2 
structural proteins of the hemidesmosomes (a junctional adhesion complex in the skin). The 
autoimmune response against BP180 and BP230 results in damage to the dermal-epidermal 
junction, which manifests clinically as tense blisters, erythema, and erosions on the skin 
(Amber et al 2018a, Schmidt and Zillikens 2013). Before blisters develop, there is frequently a 
prodromal phase lasting for weeks or months during which patients experience itching and 
sometimes skin lesions (Bernard and Antonicelli 2017, Schmidt and Zillikens 2013). 

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Eosinophils are central to the pathology of BP. They are involved in the blister formation 
mediated by anti-BP180 IgE antibodies (Amber et al 2018b), and blood eosinophil count has 
been associated with disease severity (Kridin 2018). Patients with BP have high levels of 
blood and tissue eosinophils and markers of eosinophilic activation, particularly in and around 
blisters (Amber et al 2018b, Kridin and Ludwig 2018, Morshed et al 2012). Degranulated 
eosinophils, extracellular eosinophil granules, and free granule proteins are present within the 
bullous lesions in BP, and the eosinophil chemoattractant eotaxin-1 has been found in lesions 
and blister fluid. Findings on skin biopsies of developing lesions have shown that eosinophil 
degranulation precedes blister formation, and eosinophil granule proteins can cause significant 
keratinocyte detachment from matrix in vitro (Amber et al 2018c). These findings indicate 
that eosinophil infiltration and degranulation contribute to lesion formation and are not merely 
a consequence of tissue damage (Kridin 2018). 
The disease primarily occurs in the elderly, may last for several years, and tends to recur even 
with currently available treatment (Amber et al 2018a, Williams et al 2017).The main 
treatment goals in BP are to treat the skin eruptions and itching, reduce the risk of recurrence, 
and improve patients’ quality of life. Additionally, limiting the side effects associated with 
corticosteroid treatment is of particular importance in the patient population with BP as these 
patients are predominantly elderly and have significant comorbid conditions. 
The first-line treatment for BP is high-potency topical corticosteroids, but few patients achieve 
disease control on topical corticosteroids alone. Oral corticosteroids are used when disease 
control cannot be achieved with topical corticosteroids, when the affected areas are extensive, 
or when preferred by the patient (Feliciani et al 2015, Venning et al 2012). Oral 
corticosteroids are highly effective for controlling BP; in one study, disease control was 
achieved in 91% of patients at 3 weeks after initiating therapy (Joly et al 2002). However, the 
BP relapse rate after remission is high (27% to 53% [Wang et al 2018]), and steroid toxicity is 
one of the most common causes of iatrogenic illness associated with chronic diseases. The 
risks for adverse effects are both dose- and duration-dependent and can affect many organ 
systems. Adverse effects can include osteoporosis-related fractures, serious infections, 
diabetes, gastrointestinal bleeding, and cataracts (Schäcke et al 2002). 
Adjunct therapies are used to reduce corticosteroid dependency, in patients with severe or 
refractory disease, and in patients who do not tolerate corticosteroids. These therapies include 
immunosuppressants (eg, mycophenolate mofetil, azathioprine, and methotrexate), anti-
inflammatory agents (eg, tetracyclines with nicotinamide/dapsone), and biologic 
immunotherapies (eg, intravenous [IV] immunoglobulin and rituximab), although there is 
limited evidence of efficacy and limited guidance on the optimal use of these therapies 
(Feliciani et al 2015, Venning et al 2012). 

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Both BP and its only well-established treatment—corticosteroids—are associated with 
significant morbidity and mortality. An unmet need therefore remains for new treatments in 
particular, treatments that could enable a reduction of corticosteroid use, achieve remission, 
and prevent relapses. 
2.3 
Benefit/Risk Assessment 
The efficacy and safety of benralizumab have been established in patients with asthma. 
Previous studies have shown that the overall safety profile of benralizumab in severe asthma 
patients is similar to placebo for exposures up to approximately one year (Bleecker et al 2016 
and FitzGerald et al 2016). The most commonly reported adverse events (AEs) included 
nasopharyngitis, asthma, and upper respiratory tract infections. Most AEs were mild to 
moderate in nature. Fewer patients in the benralizumab group reported serious adverse events 
(SAEs) compared with placebo. Longer-term safety studies have been conducted in asthma 
patients who completed one of the predecessor studies for up to an additional one year (adults) 
and 2 years (adolescents). In general, the safety results were commensurate with the 
predecessor studies (Busse et al 2013). Safety and tolerability data from the Phase 2a study of 
benralizumab in patients with chronic spontaneous urticaria (CSU) showed that benralizumab 
was well-tolerated, with no AEs attributable to treatment with benralizumab  
(Bernstein and Singh 2019). Similarly, safety and tolerability data from the Phase 2a study of 
benralizumab in patients with HES; (Kuang et al 2019) showed that benralizumab had 
comparable rates of AEs observed between active and placebo groups. No new safety signals 
for benralizumab were identified in these studies and the safety profile of benralizumab was 
similar to that in the asthma pivotal studies. 
Serious hypersensitivity reactions (including anaphylaxis) are an identified risk of biologic 
therapy, including benralizumab. Anaphylaxis may be life-threatening. Risk minimization 
includes observation following investigational product (IP) administration for the appearance 
of any acute drug reactions, in line with clinical practice. 
Serious infections have been reported in patients using benralizumab. However, a relationship 
between eosinophil depletion and serious infection has not been established. 
Development of anti-drug antibodies (ADA) to benralizumab has been documented. Potential 
risks of developing ADA include decreased drug efficacy and hypersensitivity reactions (eg, 
anaphylaxis or immune complex disease). To date, no confirmed cases of immune complex 
disease have been observed following benralizumab administration and no appearance of a 
relationship between ADA and treatment-emergent AEs has been established. There was no 
impact of ADA on overall benralizumab safety or efficacy in the previous Phase 3 studies in 
asthma. 

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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 tumors. Helminthic parasitic infections and 
malignancy will continue to be monitored as part of routine pharmacovigilance practices. 
Based on benralizumab´s mechanism of action and evidence of benefit in other 
eosinophil-driven diseases (asthma and HES) and the Phase 2a study in CSU, there is a 
potential for benralizumab to provide benefits in patients with BP. Expected benefits of 
benralizumab over placebo include clinically significant reduction in disease relapse in 
patients with BP and with a potentially reduced corticosteroid load. In addition, there is 
extensive safety data already available, and therefore, the benefit/risk profile in patients with 
BP is expected to be commensurate with that observed in the benralizumab asthma pivotal 
trials. 
Risk minimization measures include exclusion of patients with allergy or reaction to any 
component of the IP formulation, untreated parasitic infection, a history of anaphylaxis to any 
biologic therapy, active or recent malignancy, and exclusion of pregnant females. Risk 
minimization measures will be maintained during the conduct of this study, in conjunction 
with the performance of AstraZeneca’s 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. 
3 
OBJECTIVES AND ENDPOINTS 
Table 4 lists the objectives of this study and the endpoints for each objective. The primary and 
secondary efficacy objectives are based on the double-blind, placebo-controlled phase of the 
study. 
Table 4 
Objectives and Endpoints 
Objective 
Estimand descriptions/Endpoints 
Primary 
 
To compare the clinical efficacy of 
benralizumab with placebo in participants 
with symptomatic BP 
• 
Population: Full analysis set. 
• 
Endpoint: A binary response, whereby a responder is 
defined as a participant who is in complete remission 
while off OCS for ≥ 2 months at Week 36. Otherwise, a 
participant is a non-responder. 
• 
Intercurrent events: Participants who receive restricted 
medications or withdraw from the study will be 
considered as non-responders from the time such events 
occur up to Week 36. 
• 
Summary measure: Difference in proportion of 
participants who are responders between benralizumab 
and placebo at Week 36. 

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Table 4 
Objectives and Endpoints 
Objective 
Estimand descriptions/Endpoints 
Secondary 
 
To compare the effect of benralizumab with 
placebo on supportive measures of clinical 
efficacy in participants with symptomatic 
BP up to Week 36 
• 
Key secondary a: Proportion of participants who remain 
relapse-free up to Week 36. 
• 
Key secondary a: Cumulative OCS exposure (mg/kg) 
from baseline to Week 36. 
• 
Key secondary a: Change from baseline in BPDAI activity 
score at Week 36. 
• 
Key secondary a: Change from baseline in 
BPDAI-Pruritus score at Week 36. 
• 
Proportion of participants in sustained complete/partial 
remission on minimal OCS/off OCS for at least 2 months 
at Week 36. 
• 
Cumulative time (weeks) in complete remission off OCS 
from baseline to Week 36. 
• 
Proportion of participants off OCS by Week 36. 
• 
IGA score at Week 36 
• 
Change from baseline in IGA score at Week 36 
To compare the effect of benralizumab with 
placebo on clinical efficacy in participants 
with symptomatic BP up to Week 16 
• 
Key secondary a Cumulative OCS exposure (mg/kg) from 
baseline to Week 16. 
• 
Proportion of participants who remain relapse-free up to 
Week 16. 
• 
Proportion of participants with any clinical benefit (eg, 
partial and complete remission during taper, with no 
steroid use, or with minimal steroid use [ie, 
< 0.1 mg/kg/day]) at Week 16. 
• 
Time to disease control, OCS dose (mg/kg) at disease 
control and time to the end of the consolidation phase. 
• 
Change from baseline in BPDAI activity score at 
Week 16. 
• 
Change from baseline in BPDAI-Pruritus score at 
Week 16. 
To estimate the PK and immunogenicity of 
benralizumab in participants with BP 
• 
Serum benralizumab concentration 
• 
ADA 
Safety 
 
To compare the safety and tolerability of 
benralizumab with placebo in participants 
with symptomatic BP 
Safety and tolerability will be evaluated in terms of AEs, vital 
signs, and clinical laboratory values. 
Assessments related to AEs cover: 
• 
Occurrence/frequency 
• 
Relationship to IP as assessed by Investigator 
• 
Intensity 
• 
Seriousness 
• 
Death 
• 
AEs leading to discontinuation of IP 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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   
 
T a b le 4  
O bjecti ves a n d E n d p oi nts  
O bjecti ve  
Esti m a n d descri pti o ns/ E n d p oi nts  
Vital si g ns para meters i ncl u de s yst olic a n d diast olic bl o o d 
press ure, a n d p ulse, as well as res pirati o n rate, b o d y 
te m perat ure, b o d y wei g ht, a n d hei g ht. 
Assess me nts relate d t o vital si g ns c o ver:  
• 
O bser ve d val ue  
• 
A bs ol ute a n d perce nt c ha n ge fr o m baseli ne val ues  
Terti ar y/e x pl or at or y  
 
T o e x pl ore t he effect of be nraliz u ma b 
vers us place b o o n patie nt -re p orte d, 
healt h -relate d, q ualit y of life, meas ures i n 
partici pa nts wit h s y m pt o matic B P  
• 
C ha n ges i n Pea k Pr urit us N u meric Rati n g Scale  
• 
C ha n ge fr o m baseli ne at Wee k 3 6 f or:  
° 
A B -Q o L  
° 
E Q- 5 D -5 L  
T o e x pl ore t he effect of be nraliz u ma b 
vers us place b o o n healt hcare res o urce 
utilizati o n i n partici pa nts wit h s y m pt o matic 
B P  
• 
Assess me nt of all -ca use a n d B P -relate d healt hcare 
res o urce utilizati o n o ver 3 6 wee ks i ncl u di n g a n n ualize d 
rate of h os pitalizati o ns, le n gt h of h os pital sta y, office 
visits, e mer ge nc y r o o m visits, tests a n d pr oce d ures.  
• 
C ha n ge s i n A B-Q o L  
• 
C ha n ges i n E Q -5 D -5 L  
• 
S ki n hist ol o g y a n d i m m u n o hist oc he mistr y  
• 
 a n d ser u m a n d plas ma 
bi o mar kers  
• 
S ki n hist ol o g y a n d i m m u n o hist oc he mistr y  
• 
 a n d ser u m a n d plas ma 
bi o mar kers  
T o c haracterize t he patie nt’s e x perie nce 
wit h t he disease a n d st u d y treat me nt 
t hr o u g h q ualitati ve i nter vie ws (s u b-st u d y) 
• 
Q ualitati ve i nter vie ws t o c haracterize t he patie nt’s 
e x perie nce wit h t he disease a n d treat me nt recei ve d  
a 
Esti ma n ds f or t he ke y sec o n dar y e n d p oi nts are detaile d i n Secti o n 9 . All ot her esti ma n ds will be detaile d 
f ull y i n t he Statistical A nal ysis Pla n. 
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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A B -Q o L, A ut oi m m u ne B ull o us Disease Q ualit y of Life; A D A, a nti -dr u g a nti b o dies; A E, a d verse e ve nt; 
B MI,  b o d y mass i n de x; B P, b ull o us pe m p hi g oi d; B P D AI, B ull o us Pe m p hi g oi d Disease Area I n de x; 
; E Q-5 D -5 L, E ur o pea n Q ualit y of Life -5 Di me nsi o ns; 
I G A, In vesti gat or Gl o bal Assess me nt; I P, i n vesti gati o nal pr o d uct; O C S, oral c ortic oster oi ds; 
 
; P K, p har mac o ki netics; 
 
 
4  
S T U D Y D E SI G N  
4. 1  
O ver all Desi g n  
T his is a m ulti nati o nal, ra n d o mize d, d o u ble- bli n d, place b o- c ontr olle d, parallel- gr o u p, P hase 3 
st u d y t o assess t he efficac y a n d safet y of re peat d osi n g of be nraliz u ma b i n a d ult partici pa nts 
wit h s y m pt o matic B P. T he st u d y c o nsists of a scree ni n g peri o d ( Secti o n 4. 1. 1 ), a ra n d o mize d 
d o u ble- bli n d treat me nt peri o d ( Secti o n  4. 1. 2 ), a n d a n o pe n-la bel e xte nsi o n ( O L E) 
( Secti o n 4. 1. 3 ). T he d o u ble-bli n d treat me nt peri o d f or eac h partici pa nt will last f or 3 6 wee ks.  
T he pri mar y data base l oc k ( D B L) will occ ur w he n all ra n d o mize d partici pa nts ha ve ha d t he 
o p p ort u nit y t o c o m plete at least 3 6 wee ks of f oll o w - u p. T he fi nal D B L will occ ur w he n all 
partici pa nts ha ve c o m plete d t he O L E peri o d. A d diti o nal l oc ks, bet wee n t he pri mar y a n d fi nal 
D B Ls, ma y be perf or me d  t o re p ort data acc u m ulate d d uri n g t he O L E peri o d t o s u p p ort 
decisi o n ma ki n g. 
F or a n o ver vie w of t he st u d y desi g n see  Fi g ure 1 . F or details of o bjecti ves a n d e n d p oi nts, see 
Secti o n 3 . F or a detaile d list of pr oce d ures at eac h peri o d see Ta ble  2. 
4. 1. 1  
Scree ni n g Peri o d  
After o btai ni n g i nf or me d c o nse nt, all partici pa nts will e nter a scree ni n g peri o d. T he scree ni n g 
peri o d is tar gete d t o last 0 t o 4 da ys de pe n di n g u p o n t he st u d y assess me nt re q uire me nts (e g, 
t here ma y be dela ys be y o n d 4 da ys a waiti n g c o nfir mat or y bi o ps y a n d ser ol o g y res ults). 
D uri n g t he scree ni n g peri o d, partici pa nts ma y c o nti n ue t heir t o pical or oral c ortic oster oi ds; 
h o we ver, a n y t o pical c ortic oster oi ds will nee d t o be disc o nti n ue d at ra n d o mizati o n. 
T he f oll o wi n g will occ ur d uri n g t his peri o d: 
•  
Assess me nt of partici pa nt eli gi bilit y base d o n i ncl usi o n/e xcl usi o n criteria  
•  
Assess me nt of B P  
•  
Rec or di n g of me dical hist or y a n d c o nc o mita nt me dicati o ns  
•  
Cli nical a n d la b orat or y e val uati o ns, i ncl u di n g bi o psies 
 
4. 1. 2  
D o u ble -bli n d Tre at me nt Peri o d  
A p pr o xi matel y 1 2 0 eli gi ble partici pa nts will be ra n d o mize d 1: 1 at baseli ne ( Visit 2), t o 
recei ve eit her be nraliz u ma b or place b o e ver y 4 wee ks ( Q 4W) b y s u bc uta ne o us ( S C) i njecti o n. 
C CI
C CI
C CI
C CI

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The randomization will be stratified by disease severity and time of BP diagnosis (participants 
with newly diagnosed BP; participants with a previous diagnosis of BP who have relapsed). 
Bullous pemphigoid disease area index (BPDAI) activity score will be used to assess disease 
severity, whereby participants with a score greater than or equal to 56 points will be classified 
as severe. The double-blind treatment period for each participant will last for 36 weeks. 
Participants will receive a loading dose of either 60 mg benralizumab or placebo, administered 
as 2 SC injections at Visit 2. After 4 weeks, participants will receive 30 mg benralizumab or 
placebo Q4W per their initial randomization until the end of the double-blind treatment 
period. Starting at Visit 2, participants will also receive OCS 0.5 mg/kg/day until BP disease 
control is achieved. In participants who do not achieve disease control, the OCS dose can be 
increased (eg, 0.75 mg/kg; (Feliciani et al 2015) to achieve disease control. The steroid doses 
and time necessary to achieve disease control of BP may vary between participants.  
After participants have achieved disease control and the end of the consolidation phase has 
been reached (see Table 6 for definitions of disease control and consolidation phase), 
participants will begin OCS tapering according to a protocolled taper regimen. This period is 
expected to allow sufficient effect of benralizumab on systemic eosinophil depletion to 
facilitate steroid tapering. For details on prednisolone/prednisone tapering see Section 6.5.1. 
The steroid taper will continue according to the protocolled schedule until relapse or until 
corticosteroid treatment is completely tapered off. The steroid taper schedule will direct 
participants to reduce their steroid dose by 20% per week until it reaches 10 mg per day. After 
that, the dose should be reduced by 2.5 mg every other week until completely tapered off or 
until BP relapse. The aim will be to taper participants off steroids completely within 3 to 4 
months (ie, 4 to 5 months from randomization). An example of how the protocolled tapering 
schedule would be applied for participants of different body weights, and OCS doses 
achieving disease control is provided in Appendix F. 
Participants who relapse during the double-blind period (which includes during the 
protocolled taper regimen) will be treated with OCS along with their continued randomized 
treatment to control BP symptoms as necessary. If the relapse occurs during the steroid 
tapering period, the OCS dose may be increased to the previous dosage that symptoms were 
controlled (Feliciani et al 2015). Further attempts to taper steroids will be based on the 
Investigator’s judgment; however, it is recommended to follow the protocolled OCS taper 
schedule (Section 6.5.1). Participants who prematurely discontinue IP will be asked to 
complete all visits and study assessments up to Week 36. 
4.1.3 
Open-label Extension 
After completion of the double-blind treatment period, all participants will have the option of 
entering an OLE period, during which they will receive benralizumab 30 mg Q4W for at least 
1 year. Assessments will be conducted according to the SoA (Table 2). During the OLE 

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participants can receive corticosteroids (topical and/or oral) for BP relapse at the 
Investigator’s discretion, with the goal of tapering off the steroids to benralizumab 
monotherapy as soon as clinically indicated. If in the opinion of the Investigator, a participant 
requires the addition of immunosuppressants, the participant will discontinue benralizumab 
and will withdraw from the OLE. Participants will be asked to complete the follow-up visit 
assessment 12 weeks after their last dose according to the SoA (Table 2). Participants may 
additionally be asked to allow future contact to provide follow-up clinical details regarding 
their health and information on disease state. 
4.1.4 
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 participants 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 participant’s 
ability to conduct the study. The Investigator or designee should contact the study Sponsor 
representative to discuss whether the mitigation plans below should be implemented. The 
study participants will be required to complete the screening and randomization visits on site 
prior to having the option to participate in the mitigation plans.  
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 participants, maintain 
compliance with Good Clinical Practice (GCP), and minimize 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 for the mitigation procedures (note, in the case of verbal consent, the 
Informed Consent Form (ICF) should be signed at the participant’s next contact with the 
study site). 
• 
Re-screening: Additional re-screening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. 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 participants 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, or by the participant or the participant’s caregiver, if possible. Additional 
information related to the visit can be obtained via telemedicine. 

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• 
If participant testing is performed due to the public health crisis the results may be 
documented for this study. 
 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H. 
4.2 
Scientific Rationale for Study Design 
As detailed in Section 2, the central role of eosinophilia in the pathophysiology of BP suggests 
that a direct eosinophil-depleting approach, as provided by benralizumab, may prove 
beneficial in the treatment of BP. There are several lines of evidence that indicate eosinophils 
are central to the disease pathology of BP (Amber et al 2018b, Messingham et al 2019). 
This is a Phase 3 study designed to evaluate the efficacy and safety of benralizumab in the 
treatment of participants with BP. 
This study’s inclusion/exclusion criteria are designed to capture a population appropriate for 
treatment with benralizumab. For inclusion in the study, participants should be candidates for 
systemic corticosteroid therapy based on the extent or seriousness of their disease. The study 
will include participants with classic, predominantly cutaneous BP. Participants with drug-
induced BP, a small subset of BP participants; will be excluded as the initial treatment 
approach in these participants is discontinuation of the offending drug. 
The study’s randomized, double-blind, placebo-controlled, parallel-group treatment period is 
designed to demonstrate the efficacy and safety of benralizumab. 
The primary endpoint chosen is to assess the effect of benralizumab on sustained disease 
remission. This endpoint was chosen based on outcome measures recommended by the 
consensus statement (Murrell et al 2012) and feedback from a panel of clinical experts on BP 
who were consulted on the feasibility of using benralizumab as a treatment for BP and on the 
optimal study design. While OCS are the only well-established treatment for BP and highly 
effective for achieving disease control, the relapse rate is high on tapering and discontinuation, 
and OCS are associated with significant morbidity and mortality. The overall treatment goal in 
participants with BP is to reduce the dose of OCS and associated side effects while 
maintaining disease control. The ability of participants to taper steroids and achieve complete 
remission off steroids (the proposed primary variable) and the proportion of participants who 
have relapsed after tapering steroid therapy (the first key secondary variable) are therefore 
clinically important outcomes in this participant population. Both are accepted endpoints for 
BP studies (Murrell et al 2012). The key secondary variables, proportion of participants who 
remain relapse-free up to Week 36, cumulative OCS exposure (mg/kg) up to Week 16 and up 
to Week 36, and change in BPDAI activity and pruritus scores at Week 36, will also provide 
an opportunity to assess benralizumab’s efficacy in participants with symptomatic BP. 

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The OLE will provide an opportunity to assess long-term safety and tolerability, in addition to 
assessing efficacy of benralizumab monotherapy, and to ensure that all participants who 
complete the double-blind treatment period can have access to treatment with benralizumab. 
4.3 
Justification for Dose 
The approved dosing regimen of benralizumab in severe asthma is 30 mg Q4W for the first 
3 doses, followed by 30 mg Q8W thereafter. In patients with severe asthma (SIROCCO 
[Bleecker et al 2016] and CALIMA [FitzGerald et al 2016]), treatment with benralizumab 
30 mg Q8W and Q4W resulted in near complete blood eosinophil depletions for both the 
Q8W and Q4W dosing regimens. Treatment with benralizumab 30 mg Q4W has also been 
shown to reduce blood and tissue eosinophilia in tissues of patients with varied clinical 
subtypes of HES where patients have higher blood eosinophils and significant organ 
manifestations of eosinophilic inflammation (Kuang et al 2019).  
Patients with BP have peripheral blood and tissue eosinophilia and elevated eosinophils in 
tissue (Kridin 2018). Data is available for benralizumab pharmacokinetics (PK) in blood, lung 
tissue and bone marrow (Laviolette et al 2013), but not in skin. As the skin compartment is 
thicker than lung tissue and not as vascular skin tissue may follow different PK and may 
benefit from a higher initial dose. This strategy aligns with other biologics in skin diseases 
where a higher initial dose is indicated to ensure skin partitioning in an efficient manner. 
Efficient delivery of drug to diseased tissue is paramount in this disease given the acute and 
marked symptomatology.  
The PK of benralizumab are well-characterized (Wang et al 2017), and benralizumab is 
expected to demonstrate consistent PK across different disease populations. According to 
Population PK modeling in asthma patients, a loading dose of 60 mg benralizumab followed 
by 30 mg benralizumab Q4W SC will result in greater exposure and rapid partitioning into the 
skin to ensure eosinophil depletion, maximizing the potential of disease control in patients 
with BP. Post loading dose, the more frequent regimen, 30 mg Q4W, was selected to maintain 
eosinophil depletion in BP patients, as there is high eosinophil burden in blood and skin. 
The safety and tolerability of a range of doses of benralizumab have been demonstrated. In 
Phase 3 asthma studies, over 3500 patients have received 30 mg doses of benralizumab. In 
Phase 2 and 3 studies in patients with COPD, over 1100 patients have received benralizumab 
30 mg, and over 1100 patients have received benralizumab 100 mg. No dose-limiting safety 
issues have been identified with dosing in clinical studies up to 100 mg for 52 weeks (refer to 
the Investigator Brochure for details). In clinical trials in COPD using the 100 mg dose, 
tolerability was demonstrated in 450 patients aged 65 years to 74 years old and 166 patients 
aged over 75 years old received benralizumab. 

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Therefore, the proposed dosing regimen for benralizumab in this study is 60 mg loading 
followed by 30 mg SC Q4W. 
4.4 
End of Study Definition 
The end of study is defined as the last expected visit/contact of the last participant undergoing 
the study. A participant is considered to have completed the study when he/she has completed 
his/her last scheduled visit/telephone contact. 
As participants may be offered the opportunity to participate in an OLE (Section 4.1.3) of at 
least 1 year after completing the double-blind period of the study on IP, the end of study is 
planned to be when the last randomized participant completes 1 year in the OLE. 
However, as AstraZeneca may choose to extend the OLE period, this decision will determine 
when the end of the study is declared. Notification of closure of the study will be 
communicated to sites at least 3 months in advance of the end of study, unless faster 
termination is warranted (eg, emergence of a safety concern). 
After the end of the study, participants should be given standard-of-care therapy, at the 
discretion of their treating physician, per local practice. 
See Appendix A 6 for guidelines for the dissemination of study results. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to inclusion or exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be randomized to IP. Under no circumstances can there be exceptions to 
this rule. Participants who do not meet the entry requirements are screen failures (Section 5.4). 
In this protocol, “enrolled” is defined as a participant's agreement to participate in a clinical 
study following completion of the informed consent process. “Randomized” participants are 
defined as those who undergo randomization and receive a randomization number. 
For procedures for withdrawal of incorrectly enrolled participants, refer to Section 7.1.2. 

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5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Informed Consent/Age 
1 
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
2 
Adult participants ≥ 18 years of age at the time of signing the ICF. 
 
Type of Participant and Disease Characteristics 
3 
Participants must have clinical features of BP (eg, urticarial or eczematous or 
erythematous plaques, bullae, pruritus) at the screening visit and confirmed diagnosis 
with histology, direct immunofluorescence, and serology at randomization. Required for 
inclusion: 
(a)  Histology. 
(b)  Positive direct immunofluorescence (from skin biopsy) (IgG and/or C3 at the 
basement membrane zone).  
(c)  AND at least one of the following serologic assessments positive (all assessed from 
participant’s blood sample):  
(i) indirect immunofluorescence (IgG on the roof of salt- split skin). 
(ii) positive serology on ELISA for BPAG1 (230-kd). 
(iii) positive serology on ELISA for BPAG2 (180-kd). 
4 
BPDAI activity score ≥ 24 at the screening and randomization visits.  
5 
Candidate for systemic corticosteroid therapy. 
6 
Able to complete PRO assessments on a tablet and on a handheld device. Some 
participants may be exempted from completing home PROs on the handheld device upon 
agreement with the AstraZeneca physician (eg, if the patient has a medical condition such 
as BP lesions of the fingers/hand, a neurologic condition affecting fingers/hand, or severe 
visual impairment). 
 
 
Sex 
7 
Male or female. 
 
Reproduction 
8 
Female participants capable of having children must meet both of the following 
conditions ([a] and [b]): 

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(a) Have a negative urine pregnancy test at Screening and 
(b) Must agree to use a highly effective method of birth control (confirmed by the 
investigator) from randomization throughout the study duration and within 12 weeks 
after last dose of IP. Highly effective forms (those that can achieve a failure rate of 
less than 1% per year when used consistently and correctly) of birth control include: 
(i) Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation – oral, intravaginal, or transdermal. 
(ii) Progestogen-only hormonal contraception associated with inhibition of ovulation 
- oral, injectable, or implantable. 
(iii) Intrauterine device. 
(iv) Intrauterine hormone-releasing system. 
(v) Bilateral tubal occlusion. 
(vi) Sexual abstinence, ie, refraining from heterosexual intercourse (the reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the participant). 
(vii) Vasectomized sexual partner provided that partner is the sole sexual partner of 
the female of childbearing potential (FOCBP) study participant and that the 
vasectomized partner has received medical assessment of the surgical success. 
(c) Females not of childbearing potential are defined as females who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Females will be considered 
postmenopausal if they have been amenorrhoeic for ≥ 12 months prior to the planned 
date of randomization without an alternative medical cause. The following age-
specific requirements apply: 
(i) Females < 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle-stimulating hormone (FSH) levels in the postmenopausal 
range. Until FSH is documented to be within menopausal range, treat the 
participant as a female of childbearing potential. 
(ii) Females ≥ 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment. 
 
5.2 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 

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Medical Conditions 
1 
Forms of BP other than classic, predominantly cutaneous BP: eg, mucous membrane BP, 
epidermolysis bullosa acquisita, Brunsting-Perry BP, p200 BP, p105 BP, BP with 
concomitant pemphigus vulgaris, and drug-induced BP. 
2 
Comorbid disease that in the Investigator's judgement might interfere with the evaluation 
of the IP or safety of the participant. This includes any disorder that in the opinion of the 
Investigator is not stable (eg, cardiovascular, gastrointestinal, hepatic, renal, neurological, 
musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major 
physical impairment). 
3 
Current or history of malignancy within 5 years before the screening visit with the 
following exceptions: 
(a) Participants treated for in situ carcinoma of the cervix who have completed curative 
therapy and are in remission for at least 12 months prior to signing the informed 
consent and 
(b) Participants with superficial basal cell or squamous skin cancer. 
(c) Participants who have had other malignancies are eligible provided that the 
participant is in remission and curative therapy was completed at least 5 years prior to 
the date informed consent was obtained. 
4 
History of anaphylaxis to any biologic therapy or vaccine. 
5 
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent is obtained that has not been treated with, or has failed to respond to standard of 
care therapy. 
6 
Any clinically significant abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG), hematology, or clinical chemistry during screening, which in 
the opinion of the Investigator, may put the participant at risk because of his/her 
participation in the study or may influence the results of the study. 
7 
Current active liver disease. 
(a) Chronic stable hepatitis B and C (including positive testing for hepatitis B surface 
antigen or hepatitis C antibody), or other stable chronic liver disease are acceptable if 
participant otherwise meets eligibility criteria. Stable chronic liver disease should 
generally be defined by the absence of ascites, encephalopathy, coagulopathy, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis. 
(b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥ 3 times 
the upper limit of normal, confirmed by repeated testing during screening period. 
Transient increase of AST/ALT level that resolves by the time of randomization is 
acceptable if in the Investigator’s opinion the participant does not have an active liver 
disease and meets other eligibility criteria. 

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8 
A history of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test. 
 
Prior/Concomitant Therapy 
9 
Use of immunosuppressive medication, including, but not limited to: methotrexate, 
cyclosporine, azathioprine within 4 weeks or 5 half-lives prior to the date informed 
consent is obtained, whichever is longer. 
 
Other Exclusions 
10 Receipt of immunoglobulin or blood products within 30 days prior to the date informed 
consent is obtained. 
11 Receipt of any marketed or investigational biologic within 4 months or 5 half-lives prior 
to the date informed consent is obtained, whichever is longer. Participants on stable 
therapy for at least 3 months before randomization who intend to stay on treatment 
throughout the study with marketed biologics that are not likely to interfere with the 
assessment of safety and/or efficacy of benralizumab (eg, for the treatment of 
osteoporosis, migraine, pain, diabetes, obesity, ocular, cardiovascular, or metabolic 
diseases) can participate in the study. 
12 Known history of allergy or reaction to any component of the IP formulation. 
13  Receipt of live attenuated vaccines 30 days prior to the date of randomization.  
14 Previously received benralizumab (MEDI-563, FASENRA). 
15 Change to allergen immunotherapy or new allergen immunotherapy within 30 days prior 
to the date of informed consent and anticipated changes in immunotherapy throughout the 
study. 
16 Planned elective major surgical procedures during the conduct of the study. 
17 Previous randomization in the present study. 
18 Concurrent enrollment in another interventional (eg, investigational drug or device) 
clinical trial. 
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).  
20 For females only: Currently pregnant, breastfeeding, or lactating females. 
(a) A urine pregnancy test must be performed for FOCBP at Visit 1. A positive urine test 
result must be confirmed with a serum pregnancy test. If serum test is positive, the 
participant should be excluded. 
21 Participant is unable to complete PRO assessments because of cognitive function (eg, 
dementia). 

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5.3 
Lifestyle Considerations 
Female participants of childbearing potential must use highly effective contraceptive methods 
throughout the study and at least for 12 weeks after last administration of the IP, as stated in 
inclusion criterion 8b, Section 5.1. 
Participants must abstain from donating blood, plasma, or platelets from the time of informed 
consent and for 12 weeks after last dose of IP. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention/entered in the study. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials publishing requirements 
and to respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria not fulfilled, and any SAE. A pregnancy 
test is not required for FOCBP who are screen failures. 
These participants should have the reason for study withdrawal recorded as ‘Screen Failure’ 
(ie, participant does not meet the required inclusion/exclusion criteria) in the electronic case 
report form (eCRF). This reason for study withdrawal is only valid for screen failures and not 
randomized participants. 
5.4.1 
Re-screening 
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, transient 
events during the screening period that contraindicate IP dosing, etc), participants may 
potentially be re-screened. Re-screening of a participant for any reason will also be allowed 
only upon approval of the AstraZeneca representative study physician and allowed only once 
per participant. A documented approval for re-screening should be filed in the Investigator 
Study File. 
Re-screened participants should be assigned the same participant number as for the initial 
screening, meaning that the participant should keep the same E-code as was originally 
assigned. 
Re-screened participants should sign a new ICF. All procedures from the screening period 
(with the exception of biopsy) should be repeated (eg, a serum pregnancy test must be 
completed for FOCBP). 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 0   
 
6  
S T U D Y I N T E R V E N TI O N  
St u d y i nter ve nti o n is defi ne d as a n y i n vesti gati o nal i nter ve nti o n(s), mar kete d pr o d uct(s) or 
place b o i nte n de d t o be a d mi nistere d t o or me dical de vice(s) utilize d b y a st u d y part ici pa nt 
acc or di n g t o t he st u d y pr ot oc ol. St u d y i nter ve nti o n i n t his st u d y refers t o be nraliz u ma b a n d 
place b o, b ot h pr o vi de d i n a prefille d s yri n ge. 
6. 1  
St u d y I nter ve nti o n(s) A d mi nistere d  
6. 1. 1  
I n vesti g ati o n al Pr o d ucts 
Descri pti o ns of t he I Ps are pr o vi de d i n Ta ble  5. 
T a ble  5  
I n vesti g ati o n al Pr o d ucts 
 
St u d y i nter ve nti o n  
 
Be nr aliz u m a b  
Pl ace b o  
D osa ge f or m ulati o n  
Be nraliz u ma b   m g/ m L s ol uti o n 
(
 m M L -histi di ne/ L -histi di ne 
h y dr oc hl ori de m o n o h y drate,  
M 
tre hal ose di h y drate, a n d  
% w/ v 
p ol ys or bate   p H  
 f or i njecti o n i n 
A P F S,   m L fill v ol u me  
Matc hi n g place b o s ol uti o n (  
m M 
L histi di ne/ L -histi di ne h y dr oc hl ori de 
m o n o h y drate,  
M tre hal ose 
di h y drate a n d  
% ( w/ v) p ol ys or bate 
, p H  
) f or i njecti o n i n a n A P F S, 
 m L fill v ol u me  
R o ute of a d mi nistrati o n  
S u bc uta ne o us i njecti o n  
S u bc uta ne o us i njecti o n  
D osi n g i nstr ucti o ns  
Be nraliz u ma b acti ve s ol uti o n will be 
a d mi nistere d s u bc uta ne o usl y t o 
partici pa nts b y healt hcare 
pr ofessi o nals usi n g a n A P F S  
Place b o s ol uti o n will be a d mi nistere d 
s u bc uta ne o usl y t o partici pa nts b y healt h 
care pr ofessi o nals usi n g a n A P F S  
Use 
E x peri me ntal  
Place b o -c o m parat or 
I M P a n d NI M P 
I M P 
I M P 
S o urci n g  
Astra Ze neca  
Astra Ze neca  
Pac ka gi n g a n d la beli n g  
St u d y i nter ve nti o n will be pr o vi de d i n 
a n A P F S. 
Eac h s yri n ge will be la bele 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. 
St u d y i nter ve nti o n will be pr o vi de d i n 
a n A P F S. 
Eac h s yri n ge will be la bele 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.  
A P F S, access orize d prefille d s yri n ge; G M P, G o o d Ma n ufact uri n g Practice; I M P, i n vesti gati o nal me dici nal 
pr o d uct; NI M P, n o n -i n vesti gati o nal me dici nal pr o d uct; w/ v, wei g ht b y v ol u me. 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C
CI
C CI
C CI
C CI
C
CI

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Before IP Administration 
All applicable visit procedures, including collection of biomarker, PK, and ADA samples and 
on-site PRO assessments, should be completed prior to IP administration. 
Prior to each IP administration: 
• 
Investigator, or designee, will evaluate the participant's condition for potential 
contraindications for dosing (Section 6.1.2). 
• 
Investigator, or designee, will assess the injection site as per standards of medical care. 
 
IP Administration 
Benralizumab or matching placebo will be administered SC initially as a 60 mg loading dose, 
and 30 mg Q4W after 4 weeks. Participants will receive the loading dose as 2 single injections 
via the accessorized prefilled syringe (APFS) by the Investigator, or designee; a single SC 
injection will be administered for subsequent doses thereafter. The 2 injections for the loading 
dose will be administered at the same anatomical site with a distance of at least 3 cm between 
the 2 injections. It is advised that the site of IP injection be rotated such that the participant 
receives IP at a different anatomical site at each treatment visit. If a particular injection site is 
not favorable for the participant and/or Investigator, a separate site may be used. The site, as 
well as the reason for not using the suggested site, is to be documented. Suggested injection 
site rotation sequence is presented below (Figure 2). The injection site must be documented in 
the source at each treatment visit and recorded in the eCRF. The date and time of all IP 
administrations, as well as any missed doses, should be recorded in the appropriate section of 
the eCRF. 
Figure 2 
Injection Sites and Examples of Rotation Scheme  
 
 

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If rotation of the injection site is not possible, the reason for this must be documented in the 
source. 
The specific details for IP administration are provided in the IP Handling Instruction. The IP 
administration must be carried out in line with these instructions. 
After IP Administration 
The participant should be observed on-site after IP administration for the appearance of any 
acute drug reactions, in line with clinical practice. 
6.1.2 
Investigational Product Administration Re-scheduling 
Every effort should be taken to keep IP administration within the scheduled window. 
If a participant presents with a condition that contraindicates dosing, IP will be withheld and 
administered as soon as possible after the contraindicating condition resolves. 
The IP should not be administered, and the dosing is to be rescheduled in the presence of the 
following conditions: 
• 
The participant has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the participant in the study. 
• 
The participant has signs of a clinically significant infection. Benralizumab should not be 
administered to a participant with a clinically significant active infection treated with oral 
or IV antimicrobials, antivirals, or antifungals until it is confirmed by the Investigator that 
the infection has resolved. 
• 
Any event or laboratory abnormality that, in the opinion of the Investigator or 
AstraZeneca, contraindicates dosing or could result in complications. 
 
It is recommended that the AstraZeneca representative study physician, or designee, be 
contacted in case of any questions. 
When IP dosing needs to be postponed, it is recommended that all scheduled treatment visit 
procedures (except for IP administration) are still performed within the visit window. 
Rescheduled IP dose can then be administered at an unscheduled visit. The vital signs 
assessments are the minimum procedures to be performed at this visit. It may also include 
remaining visit procedures (not performed at the scheduled visit) and additional assessments 
as deemed necessary by the Investigator. 
If the visit procedures cannot be conducted within the window (eg, the participant is unable to 
attend the study site), then the entire visit will be rescheduled along with IP dose. 

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If a dose is significantly delayed, it is recommended to keep at least a 2-week interval before 
the next dose. If a postponed dose overlaps with the next treatment visit window, the 
postponed dose will be skipped, and the next dose of IP given at the regularly scheduled visit. 
The visit schedule will always be calculated from the randomization visit date. 
If 2 or more doses (consecutive or non-consecutive) of IP are missed, a conversation between 
the Investigator and the AstraZeneca representative study physician should take place to 
review treatment compliance and decide on the participant's further disposition. All 
participants, regardless of whether they remain on IP or not, will be encouraged to remain in 
the study through the end of the treatment period. Discontinuation procedures are described in 
Section 7.1.1. 
6.1.3 
Medical Devices 
1 
The AstraZeneca manufactured medical device (or medical device manufactured for 
AstraZeneca by a third party) provided for use in this study is a prefilled syringe (Status, 
FDA Approved/CE Marked). 
2 
Instructions for medical device use are provided in the Investigational Product 
Instructions for Use manual. 
3 
All medical device deficiencies (including malfunction, use error and inadequate labeling) 
shall be documented and reported by the investigator throughout the clinical investigation 
(see Section 8.3.11) and appropriately managed by the sponsor. 
 
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 participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the Investigator and authorized site 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual. 

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6.2.1 
Preparation and Handling of Investigational Product 
The IP will be administered at the study site, on treatment visits, and within visit windows as 
specified in the SoA (Table 2). The IP will be supplied to the site in kits with an APFS of 
either benralizumab or placebo. Each kit will have a unique identifier (ID) that is printed on 
all labels within the kit (ie, the outer carton label and the label of each container within the 
carton). 
Only participants randomized to the study may receive IP and only authorized site staff may 
dispense and administer IP. 
6.2.2 
Shipping and Storage 
All shipments of IP include a data logger which will allow the Investigator, or designee, to 
confirm that appropriate temperature conditions have been maintained during transit for all IP 
received. Any discrepancies must be reported and resolved before use of the IP. 
In the following cases, the site staff should not use affected IP and should immediately contact 
the AstraZeneca representative for further guidance: 
• 
Temperature excursion upon receipt or during storage at the study site 
• 
Damaged kit upon receipt 
• 
Damaged syringe/cartridge 
 
Damaged or temperature excursed IP should be documented using an Interactive Voice 
Response System/Interactive Web Response System (IxRS) (refer to IxRS manual and the 
Pharmacy Manual for further details). 
All IP (ie, benralizumab and matching-placebo) must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, in the original outer container. The IP 
(ie, benralizumab and matching-placebo) must be kept under conditions specified on the label 
(refrigerated between 2°C to 8°C [36°F to 46°F], protected from light and must not be frozen), 
with access limited to the Investigator and authorized site staff. The temperature should be 
monitored on a daily basis and documented in the temperature-monitoring log. 
6.2.3 
Accountability 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
An AstraZeneca representative site monitor will account for all IP received at the site, for 
unused IP, and for appropriate destruction of unused study treatments. Any unused kits will be 
destroyed locally (for further details, refer to the Pharmacy Manual). Documentation of IP 

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delivery and destruction should be maintained according to applicable AstraZeneca and 
institution procedures. 
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual (provided to the sites). In the case of a malfunctioning IP 
APFS device, the site should contact the AstraZeneca representative study monitor to initiate a 
product complaint process according to applicable guidelines. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization 
All participants will be centrally assigned to randomized IP using an IxRS. Randomization 
codes will be assigned strictly sequentially in each stratum as participants become eligible for 
randomization. The randomization will be stratified by disease severity (moderate; severe) and 
time of BP diagnosis (participants with newly diagnosed BP; participants with a previous 
diagnosis of BP who have relapsed). BPDAI activity score will be used to assess disease 
severity, whereby participants with a score greater than or equal to 56 points will be classified 
as severe. Participants who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be randomized or receive IP. There can be no exceptions to this rule. 
Participants may be re-screened under certain conditions (Section 5.4.1). 
If a participant withdraws from the study, then his/her enrollment/randomization code cannot 
be reused unless the participant is re-screened. Withdrawn participants will not be replaced. 
6.3.2 
Blinding 
Benralizumab and placebo will not be visually distinct from each other. All packaging and 
labeling of the IP will be done in such a way as to ensure blinding for all AstraZeneca, 
AstraZeneca representative, and investigational site staff. Neither the participant nor any of 
the Investigators or AstraZeneca/AstraZeneca representative staff who are involved in the 
treatment, clinical evaluation, and monitoring of the participants will be aware of the 
treatment received. Since benralizumab and placebo are not visually distinct, IP will be 
handled by an appropriately qualified member of the study team (eg, pharmacist, Investigator, 
or designee) at the site. 
Benralizumab is available only as a 30 mg dose in a prefilled syringe. At Visit 2, the 60 mg 
loading dose requires 2 SC injections and all participants will receive 2 injections to maintain 
the blind at this visit. At Visit 3 through to the end of study, participants will receive one SC 
injection. 
A site monitor will perform IP accountability. If the treatment allocation for a participant 
becomes known to the Investigator or other study staff involved in the management of study 

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participants or needs to be known to treat an individual participant for an AE, AstraZeneca 
must be notified promptly by the Investigator and before unblinding (if possible). 
The following personnel will have access to the randomization list during the study, prior to 
the primary DBL: 
• 
Those generating the randomization list 
• 
Personnel at the IxRS company 
• 
The AstraZeneca supply chain department 
• 
Patient safety department at AstraZeneca 
• 
Bioanalytical laboratory performing the PK and ADA sample analysis 
 
The information in the randomization list will be kept from other personnel involved in the 
conduct of the study in a secure location until after the primary DBL; restricted members of 
the study team will become unblinded after the primary DBL. No other member of the 
extended study team, including AstraZeneca, or any Contract Research Organization (CRO) 
handling data, will have access to the randomization scheme during the conduct of the study. 
Maintaining the Blind to the Participant’s Blood Eosinophil and Basophil Counts 
Participants on active benralizumab treatment are expected to have lower eosinophil and 
basophil blood counts than participants on placebo based on its established mechanism of 
action. Procedures to prevent unblinding based on eosinophil and basophil counts will be in 
place during the double-blind treatment period: 
• 
Screening hematology assessments will initially be conducted by a local laboratory and 
confirmation will be conducted by a central laboratory. Post-randomization, AstraZeneca, 
AstraZeneca representative, study site personnel, and participants will be blinded to the 
eosinophil, basophil, and monocyte counts. The absolute eosinophil, basophil, and 
monocyte counts and percentages will be redacted from the hematology reports provided 
to the investigational sites; absolute neutrophils and absolute lymphocytes will be 
provided. 
• 
If the Investigator orders any local safety laboratory assessments, the requested tests 
should be restricted to the question at hand. For example, if hemoglobin is desired, the 
Investigator should avoid ordering a complete blood cell count with a differential count. 
• 
In cases where the Investigator requires an eosinophil, basophil, or monocyte count for 
managing safety issues, he/she may order these tests as per regular site practice. 
AstraZeneca should be notified of all such cases without being revealed absolute 
eosinophil counts, absolute basophil counts, or absolute monocyte counts. 
• 
Site staff who are directly involved in the participant’s management should remain 
blinded to any eosinophil, basophil, and monocyte results included as part of an outside 
laboratory report or electronic medical record. To help ensure this, each investigational 
site will designate an individual (eg, administrator or another ancillary person) not 

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directly involved in participant management, to receive and redact any eosinophil, 
basophil, and monocyte results prior to the report being handed over to the site staff 
involved in the participant’s management and prior to filing the laboratory report as a 
source document. Similarly, eosinophil, basophil, and monocyte results must be redacted 
from all communications with AstraZeneca and the AstraZeneca representative. 
 
After the primary DBL, restricted members of the study team will become unblinded to all 
participants' blood and biopsy cell counts obtained during the double-blind treatment period. 
6.3.3 
Methods for Unblinding 
The IxRS will provide the Investigator(s) or pharmacists the kit ID number(s) to be allocated 
to the participant at the study site visit (refer to the IxRS manual and the unblinding plan). 
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. The Investigator will document and report the action to the AstraZeneca 
representative, without revealing the participant’s treatment randomization to the AstraZeneca 
representative or AstraZeneca staff. 
Emergency unblinding should also be available to a third-party physician/medical professional 
who is not participating in the study (eg, staff in hospital emergency room). As soon as 
possible, the Investigator should first contact the Safety Physician to discuss the medical 
emergency and the reason for revealing the actual treatment received by that participant; 
however, this may not be mandatory and should not cause any delay in unblinding in case of 
emergencies. The treatment assignment will be unblinded by the Investigator through IxRS. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented. 
6.4 
Study Intervention Compliance 
Participants are dosed at the site, receiving study intervention directly from the Investigator or 
designee, under medical supervision. The administration of all study treatments should be 
recorded in the appropriate section of the eCRF. The study treatment provided for this study 
will be used only as directed in this CSP. 
The IP will be administered at the study site on treatment visits and within visit windows as 
specified in the SoA (Table 2). Any change from the dosing schedule, dose interruptions, or 
dose discontinuations must be recorded in the eCRF; dose modifications are prohibited. Sites 
should call participants 1 to 2 days before each visit to remind the participant of the visit. 

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6.5 
Concomitant Therapy 
The Investigator must be informed as soon as possible about any medication(s) taken from the 
time of screening until the end of the study. Any prior biologic medication(s) and concomitant 
medication(s), including herbal preparations, taken during the study will be recorded in the 
eCRF, along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
 
Investigator, or designee, will collect and record information about concomitant medications 
as follows: 
• 
Background OCS 
• 
All other medications used for any reason in the 3 months prior to Visit 1 (except for 
prior biologic medication[s], which will be collected regardless of the time of 
administration) 
• 
Concomitant treatments given during the study (at each study visit) 
 
For corticosteroids (prednisolone/prednisone), the dose must be recorded as well as all dose 
changes. Specific guidance on the dose /adjustment of dose of OCS is provided in 
Section 6.5.1. In order to monitor compliance, participants will use the at home handheld PRO 
device to record the daily dose of prednisolone/prednisone (Table 3). The OCS dosage 
recorded in the eCRF will be the source for analysis. 
6.5.1 
Oral Corticosteroids and Tapering 
The background medication OCS (prednisolone/prednisone) is not regarded as an IP. 
During the double-blind treatment period, participants will be treated with IP and OCS until 
BP disease control is achieved (Figure 1). If participants were applying topical corticosteroids 
prior to randomization, the topical corticosteroids will be discontinued at randomization. The 
OCS dose will target 0.5 mg/kg/day to achieve disease control. In participants who do not 
achieve disease control, the OCS dose can be increased (eg, 0.75 mg/kg; Feliciani et al 2015) 
to achieve disease control. Participants will begin protocolled OCS tapering at the end of the 
consolidation phase (see Table 6 for definitions of disease control and consolidation phase). 
The recommended steroid taper schedule will direct participants to reduce their steroid dose 
by 20% per week until it reaches 10 mg per day. After that, the dose should be reduced by 
2.5 mg every other week until completely tapered off or until BP relapse. The aim will be to 
taper participants off steroids completely within 3 to 4 months (ie, 4 to 5 months from 
randomization), if the participant does not relapse during the taper. If participants experience 
clinically significant AEs or are at a high risk of experiencing these AEs related to OCS 

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therapy, the Investigator will have the option to start taper sooner or taper the participant off 
the OCS more rapidly. An example tapering schedule is provided in Appendix F. 
Participants who have a relapse (as defined in Table 6) during steroid taper may increase their 
OCS dose to the previous dosage where symptoms were controlled prior to relapse 
occurrence. The intention of determining the lowest effective OCS dose is to provide 
information to the Investigator for use during any subsequent tapering. Participants who have 
a relapse after tapering completely off steroids, will be restarted on steroids with dosing at the 
Investigator’s discretion. 
During the OLE, participants can receive corticosteroids (topical and/or oral) for BP relapse at 
the Investigator’s discretion, with the goal of tapering off the steroids to benralizumab 
monotherapy as soon as clinically indicated.  
Participants who are treated with OCS and then tapered can be at risk for acute adrenal 
insufficiency. The possibility of acute adrenal insufficiency should be considered, according 
to the guidance in Appendix G, in any acutely unwell participant undergoing withdrawal of 
chronic systemic corticosteroid treatment. Assessment of hypothalamic-pituitary-adrenal axis 
integrity may be performed, according to standard of care, at the discretion of the Investigator.  
If the Investigator is considering addition of an immunosuppressant for the treatment of BP 
relapse, a discussion with the designated study physician should occur to review study options 
which may include discontinuation of IP. If in the opinion of the Investigator, a participant 
requires the addition of immunosuppressants for control of relapse, the participant will 
discontinue IP administration. Participants who are in the double-blind period will be asked to 
complete all visits and study assessments up to Week 36. Participants who are in the OLE will 
withdraw from the study and will be asked to complete the study assessments for the final 
follow-up visit as outlined in the SoA (Table 2). 
While OCS compliance will be captured daily on the handheld device (unless exempted), the 
main source of data for analysis of OCS-related endpoints will be saved in the eCRF. 
6.5.2 
Restrictions 
Use of any of the following concomitant treatments will not be permitted throughout the study 
duration, unless otherwise specified. If a participant should require or receives restricted 
medication, there should be a discussion between the Investigator and the AstraZeneca 
representative study physician to establish whether discontinuation of IP is required. 
Restricted concomitant treatments are as follows: 
• 
Immunosuppressive medication (other than for recurrent relapse at the Investigator’s 
discretion or for treatment of AEs where no alternative treatment is available) 

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• 
Dipeptidyl peptidase-4 inhibitors or Immuno-Oncology therapies 
• 
Oral antimicrobial agents with anti-inflammatory properties (eg, Tetracycline antibiotics, 
dapsone, erythromycin) 
• 
Topical immunosuppressive medications 
• 
Topical corticosteroids after randomization during the double-blind treatment period 
− 
Topical corticosteroids will be permitted during the OLE at the Investigator's 
discretion 
− 
Topical corticosteroids for non-BP related dermatological conditions (eg, poison ivy) 
may be permitted for short term use (approximately 7 calendar days) 
• 
Receipt of live attenuated vaccines is disallowed 30 days prior to first dose of IP, during 
IP administration, and for 12 weeks after the last dose of IP 
• 
Receipt of inactive/killed vaccinations (eg, inactive influenza) is allowed provided they 
are not administered within 1 week before/after any IP administration; additionally, it is 
recommended to rotate the next IP site injection to a site distant from the vaccine site 
injection 
• 
Any marketed or investigational biologic (monoclonal or polyclonal antibody) is not 
allowed during the treatment period and is ideally not recommended within 12 weeks 
after the last dose of the IP. Participants on stable therapy for at least 3 months before 
randomization who intend to stay on treatment throughout the study with marketed 
biologics that are not likely to interfere with the assessment of safety and/or efficacy of 
benralizumab (eg, for the treatment of osteoporosis, migraine, pain, diabetes, obesity, 
ocular, cardiovascular, or metabolic diseases) can participate in the study (AstraZeneca 
should be informed when COVID prevention or treatment is utilized). 
• 
Other IPs during the study duration or within 12 weeks after the last dose of 
benralizumab/placebo. 
 
It is recommended that participants should not receive allergen immunotherapy on the same 
day as the IP administration. 
6.6 
Dose Modification 
Modification of the dose (benralizumab or placebo) is not permitted. 
6.7 
Intervention After the End of the Study 
After the end of the study, the participant should be given standard of care therapy according 
to local practice, at the discretion of the Investigator. 

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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Intervention 
Participants discontinuing from IP are strongly encouraged to continue in the study up to the 
end of the double-blind treatment period (Visit 13/Week 36) as described in Section 7.1.1. The 
IP discontinuation (IPD) visit should be done 4 weeks (± 7 days) after the last dose of IP. 
Participants who discontinue IP can continue in the study until Visit 13/Week 36.  
Discontinuation from IP does NOT automatically lead to a complete withdrawal from the 
study.  
Participants will be discontinued from IP in the following situations: 
• 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. The participant should always be asked about the reason(s) 
and presence of any AEs. 
• 
AE that, in the opinion of the Investigator, contraindicates further dosing. 
• 
Severe non-compliance with the CSP. 
• 
Risk to participant as judged by the Investigator or AstraZeneca. 
• 
Pregnancy.  
• 
IP unblinding. 
• 
Development of any of the following study-specific criteria for discontinuation: 
− 
Anaphylactic reaction to IP administration, in the opinion of the Investigator, 
requiring administration of epinephrine. 
− 
Development of helminth parasitic infestation requiring hospitalization. 
− 
New or active malignancy.  
− 
If after randomization, the result of the central laboratory HIV test is positive. 
 
Refer to the SoA (Table 2) and Section 7.1.1 (IPD visit) for data to be collected at the time of 
IPD and follow-up and for any further evaluations that need to be completed.  
The reason for premature discontinuation of IP should be documented in the source 
documentation and recorded in the eCRF. 
7.1.1 
Procedures for Discontinuation of Study Intervention and at End of 
Study 
A participant who decides to discontinue IP should always be asked about the reason(s) and 
the presence of any AEs. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Participants permanently discontinuing IP 

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administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. Participants who discontinue IP at any time will be allowed to modify their 
background therapy and still be followed at study visits. Discontinuation of IP will be 
registered in IxRS. 
See the SoA (Table 2) for data to be collected at the IPD visit and for any further evaluations 
to be completed. 
7.1.1.1 
Discontinuation of Study Intervention 
All participants who prematurely discontinue IP should return to the study site for an IPD visit 
4 weeks ( ± 7 days) after the last dose of IP for procedures, or as soon as feasible if this 
interval is missed (eg, if decision on discontinuation was made later), as described in Table 2. 
The IPD visit replaces the nearest scheduled visit after IP discontinuation. 
The participant will be offered the following options for further follow-up: 
• 
In the double-blind treatment period if a participant discontinues prior to 36 weeks, he/she 
is encouraged to return to all scheduled site visits and perform all procedures/blood 
draws, but without IP administration, until the end of the double-blind treatment period 
(Visit 13, Week 36). The participant should attend the IPD visit and follow-up visit 
(12 weeks after the last dose of IP). Ideally, during this time, all ePRO assessments 
should continue at home; otherwise, participants will return the ePRO device at the IPD 
visit. 
• 
In the OLE period, if a participant discontinues at any time, he/she should attend the IPD 
visit 4 weeks after discontinuation, as well as the follow-up visit (12 weeks after the last 
dose of IP). 
• 
If the participant is unwilling or unable to attend the scheduled site visits until the end of 
the study, he/she will be offered a follow-up option that includes monthly telephone 
contact instead. During follow-up telephone contact, the Investigator will collect 
information about concomitant medications, information on disease state (Section 8.1), 
BP symptoms, and AE/SAE(s) (Section 8.3). The participant will be encouraged to attend 
the follow-up visit at the study site, if feasible. 
 
7.1.1.2 
Discontinuation of Study Intervention Upon Notification of Closure of Study 
The end of treatment visit (4 weeks [± 7 days] after the last dose of IP) and follow-up visit 
(12 weeks after last dose) should be conducted for all ongoing participants within 3 months of 
notification from AstraZeneca of closure of the study (Section 7.2.1). 
7.1.2 
Procedures for Handling Incorrectly Enrolled or Randomized 
Participants 
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive IP. Participants who are enrolled but subsequently found not to meet all 

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the eligibility criteria must not be randomized and must be withdrawn (screen failed) from the 
study. 
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on IP, the Investigator should inform the AstraZeneca representative study 
physician immediately, and a discussion should occur between the AstraZeneca representative 
study physician and the Investigator regarding whether to continue or discontinue the 
participant from IP. 
The decision to discontinue/continue IP must be appropriately documented, including 
rationale, particularly if the agreed decision is to continue IP treatment. 
7.2 
Participant Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. This is expected to be uncommon. 
A participant who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records). 
At the time of withdrawal from the study, if possible, both the IPD visit and the follow-up 
visit should be conducted. See the SoA (Table 2) for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed. 
If the participant withdraws consent for disclosure of future information, AstraZeneca may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be carried 
out in line with what was stated in the informed consent and local regulations. The 
Investigator must document the decision on use of existing samples in the site study records 
and inform the AstraZeneca representative.  
Participants who withdraw from the study will return the handheld PRO device. 
7.2.1 
Discontinuation or Suspension of the Whole Study Program 
If AstraZeneca decides to prematurely terminate or suspend the study, the Investigator and 
regulatory authorities should receive written notification of the reasons for the premature 
termination or suspension. The Investigator will immediately notify the decision to the 

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participants and, if relevant, give appropriate medical treatment, take necessary measures, and 
document these in the source notes. 
There are no pre-specified safety stopping rules or criteria for this study. 
7.3 
Lost to Follow-up 
A participant 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.  
To prevent a participant being lost to follow-up, it is recommended that the study sites 
maintain up-to-date contact details for participants, including next of kin or other emergency 
contacts (if allowed by national regulation). 
The Investigator should educate the participant on the importance of maintaining contact with 
the Investigator/study site throughout the study. 
The following actions must be taken if a participant fails to return to the site for required study 
visits: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule. 
• 
Repeated attempts must be made to regain contact with the participant or next of 
kin/emergency contact by repeat telephone calls, emails, and/or certified letter. These 
contact attempts should be documented in the participant’s medical record. 
 
Efforts to reach the participant should continue until the end of the study. 
The participant will be classified as lost to follow-up only if he/she has failed to return for the 
required study visits and his/her vital status remains unknown at the end of the study, despite 
all above listed efforts. For the primary analysis purposes, a participant will be classified as 
lost to follow-up if he/she has failed to return for the required study visits and his/her vital 
status remains unknown at the time of primary DBL. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Table 2). PRO assessment 
schedules are summarized in Table 3. 
The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture system will be used for data collection and query handling. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 5   
 
T he I n vesti gat or e ns ures t he acc urac y, c o m plete ness, le gi bilit y, a n d ti meli ness of t he data 
rec or de d a n d of t he pr o visi o n of a ns wers t o data q ueries acc or di n g t o t he Cli nical St u d y 
A gr ee me nt. T he I n vesti gat or will si g n t he c o m plete d e C R Fs. A c o p y of t he c o m plete d e C R Fs 
will be arc hi ve d at t he st u d y site.  
I m me diate safet y c o ncer ns s h o ul d be disc usse d wit h t he Astra Ze neca re prese ntati ve 
i m me diatel y u p o n occ urre nce or a ware ness t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue or 
disc o nti n ue I P.  
A d here nce t o t he st u d y desi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he S o A ( Ta ble  2), is 
esse ntial a n d re q uire d f or st u d y c o n d uct. 
All scree ni n g e val uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial 
partici pa nts meet all eli gi bilit y criteria. T he I n vesti gat or will mai ntai n a scree ni n g l o g t o 
rec or d details of all partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or 
scree ni n g fail ure, as a p plica ble. 
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge me nt a n d o btai ne d 
bef ore si g ni n g of t he I C F ma y be utilize d f or scree ni n g or baseli ne p ur p oses pr o vi de d t he 
pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me fra me 
defi ne d i n t he S o A ( Ta ble  2). 
N ote: f or la b orat or y  assess me nts, if n ot all la b orat or y kits are a vaila ble at a gi ve n visit, t he 
I n vesti gat or s h o ul d c o ntact t he St u d y P h ysicia n t o c o nfir m w het her assess me nt is critical or 
ma y be p ost p o ne d u ntil s u p plies are a vaila ble.  
8. 1  
Effic ac y Assess me nts  
8. 1. 1  
Cli nici a n -re p orte d  O utc o me Assess me nts  
I n vesti gat ors will c o m plete cli nicia n-re p orte d o utc o me assess me nts d uri n g site visits i n 
acc or da nce wit h t he S o A ( Ta ble  2). It is str o n gl y e nc o ura ge d t o ha ve t he cli nicia n-re p orte d 
o utc o me assess me nts be perf or me d b y t he sa me I n vesti gat or at eac h site t o mi ni mize 
varia bilit y i n t he assess me nts. T he f oll o wi n g assess me nts will be c o m plete d b y t he 
I n vesti gat or or desi g nee: B P disease state ( Secti o n 8. 1. 1. 1 ), B P D AI ( Secti o n 8. 1. 1. 2 ), I G A 
( Secti o n 8. 1. 1. 3 ),
a n d healt hcare res o urce utilizati o n 
(Secti o n  8. 1. 1. 7 ). 
Patie nt -re p orte d o utc o mes assess me nts will be c o m plete d b y t he partici pa nts usi n g an 
electr o nic  P R O de vice ( Secti o n  8. 1. 2 ). 
C CI
C CI

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8.1.1.1 
Bullous Pemphigoid Disease State 
Investigators will be asked to make a clinical assessment of the participants to determine their 
BP disease state (ie, active disease, disease control, end of consolidation phase, remission, and 
relapse) from baseline (Visit 2) until the end of the double-blind period, during the OLE, and 
then in addition at the IPD, and follow-up visit. The BP disease state will be considered 
"active disease" until one of the disease states in Table 6 is achieved. 
At each visit, investigators will be required to assess a participant’s outcome measures, 
including the states defined in Table 6. The outcome measure will be documented in the 
eCRF. 
Table 6 
Definitions for Bullous Pemphigoid Outcome Measures 
Outcome measure 
Definition b 
Disease control/beginning of consolidation phase 
The time at which new lesions cease to form and 
established lesions begin to heal, or pruritic 
symptoms start to abate 
End of consolidation phase 
Time at which no new lesions have developed for a 
minimum of 2 weeks and approximately 80% of 
lesions have healed and pruritic symptoms are 
minimal   
Sustained partial remission on minimal steroid a/off 
steroid therapy 
The presence of transient new lesions that heal within 
1 week while the participant is on minimal steroid 
therapy or off steroid therapy for at least 2 months 
Sustained complete remission on minimal steroid a 
/off steroid therapy 
The absence of new or established lesions or pruritus 
while the participant is on minimal steroid therapy/ 
off steroid therapy for at least 2 months 
Relapse 
The appearance of 3 or more new lesions per month 
(blisters, eczematous lesions, or urticarial plaques) or 
at least one large (> 10 cm diameter) eczematous 
lesion or urticarial plaques that do not heal within 1 
week, or the extension of established lesions or daily 
pruritus in participants who have achieved disease 
control 
a Minimal steroid therapy is defined as less than or equal to 0.1 mg/kg/d of prednisone or equivalent 
Definitions as per Murrell et al 2012 
 
Disease Control/Consolidation Phase 
During the first 8 weeks of the study, participants will be assessed every 2 weeks for disease 
control (see Table 6 for definition). When disease control is achieved, this marks the 
beginning of the consolidation phase. The end of the consolidation phase is the point that 
corticosteroid tapering will be initiated and documented in the eCRF. 

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BP Remission 
BP remission (see Table 6 for definition) will be assessed at each study visit per the SoA 
(Table 2). Remission can be partial or complete and can occur off steroid therapy or on 
minimal steroid therapy. 
BP Relapse 
In the event of a suspected BP relapse (see Table 6 for definition), the participant should 
attend an unscheduled visit. A BPDAI evaluation will be conducted at the time of the relapse, 
or as soon as possible afterwards. 
Investigators will be required to record details pertaining to each relapse event in the eCRF 
from baseline (Visit 2) until IPD visit/end of treatment and follow-up visit. Details should 
include the BPDAI activity and pruritus score and the required intervention(s), eg, OCS dose 
increase, the OCS dose at the time of relapse, addition of immunosuppressive therapy or 
requirement for hospitalization. Participants who require the addition of OCS after taper or an 
increase in the dose of OCS will be defined as having a relapse. 
The management of participants who relapse will be according to standard of care. See 
Section 6.5.1 for further details. The participant's relapse is managed with the addition of OCS 
and tapering should be recommended as soon as the relapse has been appropriately controlled 
as per current guidelines (Feliciani et al 2015). In case of a relapse during steroid tapering, the 
OCS dose may be increased to the previous dosage that symptoms were controlled. For 
recurrent relapses the OCS dosing regimen and tapering schedule will be at the Investigator’s 
discretion. If the participant requires therapy other than OCS (eg, immunosuppressants), the 
study treatment may need to be discontinued but this should be discussed with the study 
physician prior to decision making. In the event that discontinuation of IP is required, the 
participant will still be asked to continue with the study assessments until the end of the 
double-blind period at Week 36. For relapse during OLE, the use of topical and/or oral 
corticosteroids and the schedule of taper will be at the discretion of the Investigator; however, 
it is recommended to follow the protocol taper schedule. The goal of therapy will be to taper 
off steroids to benralizumab monotherapy as soon as clinically indicated. In the event that the 
Investigator will need to control relapse with an immunosuppressant in the OLE, the 
participant will be withdrawn from the study and will not receive further benralizumab 
therapy. Participants may additionally be asked to allow future contact to provide follow-up 
clinical details regarding their health and information on disease state. 
8.1.1.2 
Bullous Pemphigoid Disease Area Index 
Bullous Pemphigoid Disease Area Index is a clinician completed tool that is used for 
independent disease severity assessment to measure disease extent in BP  
(Wijayanti et al 2017). 

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The Investigator will be required to complete the BPDAI on a tablet at screening (Visit 1), 
randomization (Visit 2), and then at each visit until the end of the double-blind treatment 
period, at the time of presentation with relapse or suspected relapse, at unscheduled visit, and 
at IPD/end of treatment and follow-up visit. 
During the subsequent OLE (if applicable), the Investigator is required to complete BPDAI 
Q4W, at unscheduled visits (eg, in the event of a relapse), and at the IPD/end of treatment and 
follow-up visit.  
The BPDAI tool computes 2 scores: total BPDAI activity and total BPDAI damage. The total 
BPDAI activity score (0 to 360) is the arithmetic sum of the 3 subcomponents – cutaneous 
blisters/ erosions, cutaneous urticaria/erythema, and mucosal blisters/ erosions. The total 
BPDAI damage score (0 to 12) is the arithmetic sum of the items rated regionally for damage 
caused by more permanent features such as post-inflammatory hyperpigmentation, scarring 
and other. BPDAI quantifies lesion number and size thresholds. Lesions are rated based on the 
regions affected. BPDAI gives additional weighting to areas of the skin primarily affected in 
BP, such as the limbs, and less emphasis to scalp and face. The BPDAI total activity and 
BPDAI damage give an indication of disease activity, with higher scores indicating greater 
disease activity or damage. 
8.1.1.3 
Investigator Global Assessment 
An IGA scale uses clinical characteristics to assess overall disease severity at any given time 
point. This scoring system allows clinicians to rate skin disease activity by general overall 
impressions. This IGA scale uses key signs of BP with ordinal levels of severity. The IGA is a 
5-point categorical scale ranging from 0 (clear) to 4 (severe) with higher scores indicating 
greater disease activity or damage (Table 7). The IGA uses clinical characteristics based on 
the number of lesions, blisters, erosions, erythema and number of anatomical locations. The 
IGA scale will be completed at the site by the investigator according to the SoA (Table 2). 
Table 7 
IGA Scores and Descriptions 
Score 
Description 
0 – Clear 
No skin lesions 
1 – Almost Clear 
Very few small skin lesions 
2 – Mild 
Few skin lesions 
3 – Moderate 
Multiple lesions in > 1 anatomical area OR any large erosive 
area 
4 - Severe 
Extensive skin lesions/erosive areas 
Note: Examples of skin lesions include blisters, small round erosions, and erythema. 
 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 9   
 
8. 1. 1. 7  
He al t hc are Res o urce Utiliz ati o n 
Br oa d -base d all -ca use a n d B P -relate d healt hcare res o urce utilizati o n i nf or mati o n will be 
c ollecte d b y t h e I n vesti gat or, or desi g nee, i n acc or da nce wit h t he S o A ( Ta ble  2) a n d rec or de d 
i n t he a p pr o priate e C R F m o d ule. Pr ot oc ol- ma n date d pr oce d ures, tests, a n d enc o u nters are n ot 
i ncl u de d. 
At ra n d o mizati o n, retr os pecti ve all -ca use a n d B P -relate d healt hcare res o urce utilizati o n 
i nf or mati o n will be c ollecte d wit h a o ne-year recall peri o d. At all s u bse q ue nt visits, all -ca use 
a n d B P- relate d healt hcare res o urce utilizati o n i nf or mati o n will be c ollecte d wit h a recall 
peri o d of ‘si nce last sc he d ule d visit’. 
T he data c ollecte d ma y be use d t o c o n d uct e x pl orat or y ec o n o mic a nal yses a n d i ncl u de:  
•  
N u m ber a n d d urati o n of me dical care e nc o u nters, i ncl u di n g s ur geries, a n d ot her sel ecte d 
pr oce d ures (i n patie nt a n d o ut patie nt) 
•  
D urati o n of h os pitalizati o n (t otal da ys or le n gt h of sta y, i ncl u di n g d urati o n b y war ds 
[e g, i nte nsi ve care u nit]) 
•  
O ut patie nt me dical e nc o u nters a n d i nter ve nti o ns (i ncl u di n g s pecialist visits, Ge neral 
Practiti o ner  visits, h o me healt h care visits, a n d e mer ge nc y r o o m visits, etc.)  
•  
N u m ber a n d t y pe of dia g n ostic a n d t hera pe utic tests a n d pr oce d ures 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
7 0   
 
 
 
8. 1. 2  
P atie nt -re p orte d O utc o mes  
Partici pa nts will c o m plete all P R O assess me nts usi n g pr o visi o ne d de vices . All partici pa nts 
will c o m plete P R Os o n t he ta blet at o nsite visits. Dail y P R Os are c o m plet e d o n t he ha n d hel d 
de vice at h o me. If t he I n vesti gat or belie ves t hat t he partici pa nt has a me dical c o n diti o n (e g, 
B P s ki n lesi o ns o n t he fi n gers/ ha n d, ne ur ol o gic c o n diti o n affecti n g t he fi n gers/ ha n d, or se vere 
vis ual i m pair me nt), t he n a n e xe m pti o n fr o m at -h o me P R Os ma y be re q ueste d fr o m t he 
Astra Ze neca st u d y p h ysicia n pri or t o t he scree ni n g visit. 
T he I n vesti gat or will e ns ure t hat partici pa nts are pr o perl y trai ne d o n t he use of t he ha n d hel d 
P R O de vice a n d t he i m p orta nce of c o m pleti n g at- h o me assess me nts as sc he d ule d. Co m plia nce 
s h o ul d be c hec ke d wee kl y (at a mi ni m u m) t o e ns ure t hat t he partici pa nt is c o m pleti n g t he 
assess me nts as sc he d ule d, i ncl u di n g a c hec k of t he dail y oral ster oi d d oses ta ke n. T he 
I n vesti gat or or desi g nee will be res p o nsi ble f or m o nit ori ng partici pa nt a d here nce wit h t he 
dail y assess me nts a n d f oll o w u p as necessar y.  
T he at -h o me ha n d hel d de vice will be pr o gra m me d at Visit 2 wit h re mi n der alar ms f or t he 
dail y q uesti o n naires. St u d y site staff will be a ble t o a dj ust alar ms f or s pecific partici p a nt nee ds 
as nee de d. T he partici pa nt will be re q uire d t o c o m plete a trai ni n g m o d ule bef ore ta ki n g t he 
de vice h o me. 
Partici pa nts m ust bri n g t he at - h o me ha n d hel d de vice t o e ver y visit.  
C o nfir mati o n of t he visit i n t he P R O s yste m, c o m pleti o n of at -site P R O assess me nts, a n d 
re vie w of partici pa nt c o m plia nce wit h at- h o me P R O assess me nts s h o ul d be c o m plete d pri or t o 
ot her st u d y pr oce d ures. T he ti mi n g a n d fre q ue nc y f or eac h P R O is pr o vi de d i n Ta ble  3. T he 
ha n d hel d de vice will be ret ur ne d t o t he st u d y site at Visit 2 2 ( Wee k 7 2) or at t he I P D visit f or 
partici pa nts w h o pre mat urel y disc o nti n ue fr o m I P a n d are u n willi n g/ u na ble t o c o nti n ue wit h 
visit pr oce d ures.  
8. 1. 2. 1  
Pe a k Pr urit us N u meric R ati n g Sc ale  
T he Pea k Pr urit us N u meric Rati n g Scale ( N R S) is a o ne -ite m assess me nt t hat as ks partici pa nts 
t o rate t he i nte nsit y of t heir w orst itc h d uri n g t he past 2 4 h o urs. T he scale ra n ges fr o m 0 ( n o 
itc h) t o 1 0 ( w orst itc h i ma gi na ble). 
T he partici pa nt will c o m plete t he Pea k Pr urit us N R S o n a pr o visi o ne d ha n d hel d de vice at 
h o me acc or di n g t o t he sc he d ule i n Ta ble  3. 
C CI

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8.1.2.2 
Corticosteroid Medication Usage 
The participant will be asked to report the dosage of OCS taken over the past 24 hours. 
The participant will complete the Corticosteroid Medication Usage question on a provisioned 
handheld device at home according to the schedule in Table 3. 
Patient-reported corticosteroid use and dosage will be checked at each clinic visit/telephone 
contact visit. This check should include a review of compliance with the prescribed OCS dose 
between each visit and/or tapering of dose, as described in Section 6.5.1. 
8.1.2.3 
Bullous Pemphigoid Disease Area Index Pruritus 
The BPDAI-Pruritus is a separate component of the BPDAI that asks the participant to grade 
the severity of pruritus over the past 24 hours, the past week, and the past month. For each 
recall period, severity of pruritus is rated on an NRS ranging from 0 for no itch to 10 for 
maximal itching. The three scores are then summed for a total score ranging from 0 to 30. 
The participant will complete the BPDAI-Pruritus on a tablet at the site as per schedule of 
assessments (Table 2). 
8.1.2.4 
Autoimmune Bullous Disease Quality of Life Questionnaire (AB-QoL) 
The AB-QoL is a 17-item assessment of the health-related quality of life impact of 
autoimmune bullous diseases, including BP. The recall period is one week. The participant 
will complete the AB-QoL on a tablet at the site as per schedule of assessments (Table 2). 
8.1.2.5 
European Quality of Life-5 Dimensions (EQ-5D-5L) 
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, 
slight problems, moderate problems, severe problems, and extreme problems) that reflect 
increasing levels of difficulty. 
The participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a visual analog 
scale, where the participant will be asked to rate current health status on a scale of 0 to 100, 
with 0 being the worst imaginable health state. 
The participant will complete the EQ-5D-5L on a tablet at the site as per schedule of 
assessments (Table 2). 
8.1.2.6 
Qualitative Patient Interview Sub-study  
Participants who complete the ICF in select languages, and one primary caregiver (if 
applicable), will be invited to participate in a qualitative patient interview sub-study. Up to 
34 participants (or participant-caregiver dyads) will be enrolled in the sub-study. The 

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sub-study consists of interviews at 3 timepoints (prior to treatment/early treatment, end of 
double-blind treatment, and after at least 6 months of OLE). The interviews will be non-
interventional and will collect data on participants’ experiences with BP and the study 
treatment, and the participants’ conceptions of meaningful change on some of the PROs used 
in this study. If a caregiver can participate, the caregiver’s perspective will be included to 
better understand the familial and social burdens of the disease. Interviews will be conducted 
remotely (eg, by telephone) at a time convenient for the participant and/or caregiver; they will 
not be conducted during the course of a site visit. The duration of each interview will be 
approximately 90 minutes.  
A detailed description of sub-study procedures is available in the Qualitative Patient Interview 
Sub-Study Manual. 
Participants will be introduced to the sub-study during the informed consent process using the 
participant communication materials attached to the Qualitative Patient Interview Sub-study 
Manual. Interested participants and/or caregivers will consent specifically for this sub-study 
(participation in this sub-study is optional and independent from the main study). Participants 
and/or caregivers will be contacted according to procedures described in the Qualitative 
Patient Interview Sub-study Manual.  
Each sub-study participant will be interviewed at the following timepoints: 
• 
Prior to treatment/early treatment: between Week 0 and Week 4, to capture experiences 
before starting study treatment and/or in the first month of study treatment 
• 
End of double blind: between Week 28 and Week 36, to examine participants’ 
experiences during study treatment 
• 
Open-label extension: between Week 60 and Week 76, to examine participants’ 
experiences with BP in the open label period 
During each interview, participants (and caregivers, if applicable) will be asked a set of 
open-ended questions. The interview discussion guide is provided as an appendix to the 
Qualitative Patient Interview Sub-study Manual. 
The interview will be audio recorded with the participant's permission (and caregiver’s 
permission, if applicable), confirmed verbally prior to the start of the interview. The 
recordings will be transcribed, and transcripts will be coded using qualitative data analysis 
software.  
Participants’ and caregivers’ confidentiality and personal information will be protected 
throughout the sub-study to the same standard as all other coded data in the study.  

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Due to the qualitative nature of the data and the analysis, the results will be presented in a 
separate report (ie, not in the Clinical Study Report [CSR]) and the data (transcriptions) will 
not be entered into the study database. No identifiable data will be reported. 
AstraZeneca will follow standard procedures for handling AE reporting involving these 
participants (as described in Appendix B). At the beginning and end of each interview, 
participants will be advised to report any AE to the Investigator or designee. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 2). 
8.2.1 
Physical Examinations 
Physical examinations (complete or brief), including height and weight, will be conducted in 
accordance with the schedule provided in Table 2. Baseline measurements will be assessed at 
screening (Visit 1) or the randomization visit (Visit 2) before first dose of IP. Any new 
findings or aggravated existing abnormalities, judged as clinically significant by the 
Investigator, will be reported as an AE as described in Section 8.3.5. 
The complete physical examination will include an assessment of the following: height and 
weight, general appearance, skin, head and neck (including eyes, ears, nose, mouth, and 
throat), lymph nodes, abdomen, musculoskeletal (including spine and extremities), 
cardiovascular, respiratory, and neurological systems. 
The brief physical examination will include an assessment of the following: weight, general 
appearance, skin, abdomen, cardiovascular, and respiratory system. For the brief physical 
examination, only information on whether the assessment was performed or not is to be 
recorded. Weight measurements will be performed in light clothing and without shoes and 
will be recorded in kilograms. 
8.2.2 
Vital Signs 
Pre-dose vital signs (pulse rate, blood pressure, respiratory rate, and body temperature) will be 
assessed in accordance with the SoA (Table 2). 
It is recommended that vital signs are assessed before any interventional study procedures 
(blood test collection, IP administration). 
Body temperature will be measured in Celsius in accordance with local standards. 
Blood pressure and pulse measurements will be assessed while sitting with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. The pulse rate and blood pressure will be measured after the participant has been 

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resting for at least 5 minutes in a quiet setting without distractions (eg, television, cell 
phones). The pulse rate should be obtained before blood pressure. 
The respiration rate will be obtained after the participant has been resting for at least 5 
minutes, by counting the number of breaths (how many times the chest rises) for one minute. 
8.2.3 
Electrocardiograms 
Single 12-lead ECG will be obtained locally during screening (Table 2) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals. 
The ECG results will be interpreted locally.  
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. The ECG printouts will 
be signed and dated by the Investigator and stored at the study site. Any findings will be 
recorded in the eCRF. 
ECG will be taken in the supine position, after the participant has been resting for at least 
5 minutes. The assessment should be performed before interventions with the participant 
(eg, IP administration). 
8.2.4 
Clinical Safety Laboratory Assessments 
Table 8 lists the clinical safety laboratory tests to be performed. Refer to the SoA (Table 2) for 
the timing and frequency. All protocol-required laboratory assessments, as defined in the 
table, must be conducted in accordance with the Laboratory Manual and the SoA (Table 2).  
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
site as source data for laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.5. 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will 
be recorded in the participant’s medical records. 
The clinical chemistry, and hematology assessments will be performed at a central laboratory, 
and at both local and central laboratories at Visit 1.  
Instructions for sample collection, processing, storage, and shipment are provided in the 
central laboratory manual. 

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Table 8 
Laboratory Safety Variables 
Clinical chemistry 
Hematology 
Alkaline phosphatase 
Gamma-GT (gamma-glutamyl 
transpeptidase) 
Hematocrit 
ALT (alanine aminotransferase) 
Glucose 
Hemoglobin 
AST (aspartate 
aminotransferase) 
Phosphorus 
 
BUN (blood urea nitrogen) 
Potassium 
Platelet count 
Calcium 
Sodium 
 
Chloride 
Total bilirubin 
WBC count (absolute and 
differential) a 
CO2 (carbon dioxide) b 
Uric acid 
HbA1c c 
Creatinine 
Creatinine kinase 
 
Cholesterol, total 
 
 
a 
Eosinophil, basophil, and monocyte counts will be redacted from the central laboratory reports starting from 
Visit 2 (see Section 6.3.2). 
b 
Measured as bicarbonate. 
c 
Refer to the schedule of assessments (Table 2) for details of HbA1c. 
 
8.2.4.1 
Pregnancy Tests 
The following tests are applicable to female participants only and will be conducted in 
accordance with the SoA (Table 2). 
• 
FSH: To be performed at Visit 1 only for female participants < 50 years who have been 
amenorrhoeic for ≥ 12 months prior to the planned date of randomization to confirm 
postmenopausal status. This test is to be sent to and analyzed at the central laboratory; all 
females should be treated as pre-menopausal until results are received from the central 
laboratory. 
• 
Urine human chorionic gonadotropin (HCG; dipstick): To be performed locally at the 
study site according to the SoA for all female participants except for those who are NOT 
of childbearing potential as defined in inclusion criterion 7(c). A positive urine pregnancy 
test result must be confirmed with a serum pregnancy test (beta-HCG). 
 
8.2.4.2 
Serology 
Hepatitis B surface antigen and hepatitis C antibody tests will be assessed in accordance with 
the SoA (Table 2). The testing may be performed at the study site for participants who require 
immediate results for randomization, however this will also require confirmatory tests sent to 
the central laboratory. The test to be performed at the central laboratory for all other 
participants. 

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In case of positive result of hepatitis B surface antigen or hepatitis C virus antibody, additional 
testing (eg, hepatitis C ribonucleic acid [RNA] polymerase chain reaction test) may be 
performed. 
HIV-1 and HIV-2 antibodies (along with p24 antigen): Local HIV express test will be 
performed at Visit 1 to inform eligibility; the sample from Visit 1 will also be sent to the 
central laboratory. If, after randomization, the result of the central laboratory HIV test is 
positive, the participant will be discontinued from treatment. 
Instructions for sample collection, processing, storage, and shipment are provided in the 
laboratory manual. 
8.3 
Adverse Events and Serious Adverse Events 
The Principal 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 B. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up AEs see 
Section 8.3.2. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs will be collected starting from Visit 1, throughout the treatment period, and including 
the follow-up period last contact with participant. 
Serious AEs will be recorded from the time the participant signs the ICF, throughout the 
duration of the study. All SAEs will be recorded and reported to the AstraZeneca 
representative or designee within 24 hours, as indicated in Appendix B. The Investigator will 
submit any updated SAE data to the AstraZeneca representative within 24 hours of it being 
available. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 

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treated by him or her, the Investigator shall, without undue delay, report the SAE to the 
AstraZeneca representative. 
8.3.2 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up. 
Any AEs that are unresolved at the end of the study (final DBL) will be followed-up by the 
Investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse Event Variables 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
Maximum intensity 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the IP (yes or no) 
• 
Action taken with regard to the IP 
• 
AE caused participant’s withdrawal from study (yes or no) 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
• 
Description of AE 
• 
Date AE met criteria for SAE 
• 
Date Investigator became aware of SAE 
• 
AE is serious due to (see definition of SAE in Appendix B 2)  
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment to other medication 

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8.3.3 
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 investigational product?’ 
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix B. 
8.3.4 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: ‘Have you had any health problems since the 
previous visit/you were last asked?’ or revealed by observation will be collected and recorded 
in the 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. 
8.3.5 
Adverse Events Based on Examinations and Tests 
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and 
vital signs should therefore only be reported as AEs if they fulfill any of the SAE criteria, are 
the reason for discontinuation of treatment with the IP, or are considered to be clinically 
relevant as judged by the Investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
study intervention, eg, dose adjustment or drug interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 

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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 
Disease Under Study 
Symptoms of disease under study are those which might be expected to occur as a direct result 
of BP (eg, pruritus, eczematous lesions, urticarial plaques, blisters/bulla, mucosal lesions). 
Events which are unequivocally due to BP should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of the IP. 
8.3.7 
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. 
If any SAE occurs in the course of the study, Investigators or other site personnel will 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 will work with the Investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one 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 will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it. 
If the electronic data capture system is not available, then the Investigator or other study site 
staff reports an SAE to the appropriate AstraZeneca representative by telephone. 
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
The reference document for definition of expectedness/listedness is the Investigator's 
Brochure for benralizumab.  
For further guidance on the definition of an SAE, see Appendix B. 

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8.3.8 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the AstraZeneca 
representative unless the pregnancy is discovered before the study participant has received any 
IP. 
If a pregnancy is reported, the Investigator should inform the AstraZeneca representative 
within 24 hours of learning of the pregnancy. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.8.1 
Maternal Exposure 
If a participant becomes pregnant during the course of 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 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed-up and documented even if the 
participant was discontinued from the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (Section 8.3.7) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
8.3.9 
Medication Error 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within one day (ie, 
immediately but no later than 24 hours of when he or she becomes aware of it). 
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
(initial fatal/life-threatening or follow-up fatal/life-threatening) or 5 (other serious initial and 

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follow-up) calendar days if there is an SAE associated with the medication error 
(Section 8.3.1) and within 30 days for all other medication errors. 
The definition of a Medication Error can be found in Appendix B. 
8.3.10 
Device Constituent Deficiencies 
• 
In a combination drug-device IMP (eg, APFS), the device constituent deficiency is an 
inadequacy of a device constituent with respect to its identity, quality, durability, 
reliability, safety, or performance. These deficiencies include malfunctions, use errors, 
and information supplied by the manufacturer.  
• 
Serious adverse device effect (SADE) is defined as any device constituent deficiency that 
might have led to an SAE if appropriate action had not been taken, intervention had not 
occurred, or circumstances had been less fortunate.  
• 
For device constituent deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency. 
• 
A remedial action is any action other than routine maintenance or servicing of a device 
constituent where such action is necessary to prevent recurrence of a device constituent 
deficiency. This includes any amendment to the device constituent design to prevent 
recurrence. 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the device constituent deficiency as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals. 
 
8.3.11 
Medical Device Deficiencies 
Medical devices are being provided for use in this study as prefilled syringes are being utilized 
to deliver the IMP under study. In order to fulfill 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 I. 
NOTE: Incidents and deficiencies fulfilling the definition of an AE/SAE will also follow the 
processes outlined in Appendix I of the protocol.  
8.3.11.1 
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. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
8 2   
 
•  
If t he i n vesti gat or lear ns of a n y me dical de vice deficie nc y at a n y ti me after a partici pa nt 
has bee n disc har ge d fr o m t he st u d y, a n d s uc h i nci de nt is c o nsi dere d reas o na bl y relate d t o 
a me dical de vice pr o vi de d f or t he st u d y, t he i n vesti gat or will pr o m ptl y n otif y t he s p o ns or. 
T he met h o d of d oc u me nti n g Me dical De vice Deficie nc y is pr o vi de d i n A p pe n di x I . 
8. 3. 1 1. 2  
F oll o w- u p of Me dic al De vice Deficie ncies  
•  
F oll o w- u p a p plies t o all partici pa nts, i ncl u di n g t h ose w h o disc o nti n ue st u d y i nter ve nti o n. 
•  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat f oll o w - u p i ncl u des a n y s u p ple me ntal 
i n vesti gati o ns as i n dicate d t o el uci date t he nat ure a n d/ or ca usalit y of t he deficie nc y.  
•  
Ne w or u p date d i nf or mati o n will be rec or de d o n t he ori gi nall y c o m plete d f or m wit h all 
c ha n ges si g ne d a n d date d b y t he i n vesti gat or. 
8. 3. 1 1. 3  
Pr o m pt Re p orti n g of Me dic al De vice Deficie ncies t o S p o ns or  
•  
Me dical de vice deficie ncies will be re p orte d t o t he s p o ns or wit hi n 2 4 h o urs after t he 
i n vesti gat or deter mi nes t hat t he e ve nt meets t he pr ot oc ol defi niti o n of a me dical de vice 
deficie nc y. 
•  
T he Me dical De vice Deficie nc y Pa per Re p ort F or m will be se nt t o t he s p o ns or b y e mail 
or fa x (
 or 
 
res pecti vel y). 
•  
T he s p o ns or will be t he c o ntact f or t he recei pt of me dical de vice deficie nc y re p orts.  
8. 3. 1 1. 4  
Re g ul at or y Re p orti n g Re q uire me nts f or De vice Deficie ncies  
•  
T he i n vesti gat or will pr o m ptl y re p ort all me dical de vice deficie ncies occ urri n g wit h a n y 
me dical de vice pr o vi de d f or use i n t he st u d y i n or der f or t he s p o ns or t o f ulfil l t he le gal 
res p o nsi bilit y t o n otif y a p pr o priate re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n 
safet y i nf or mati o n relati n g t o me dical de vices bei n g use d i n cli nical st u dies. 
•  
T he i n vesti gat or, or res p o nsi ble pers o n acc or di n g t o l ocal re q uire me nts (e g, t he hea d of 
t he me dical i nstit uti o n), will c o m pl y wit h t he a p plica ble l ocal re g ulat or y re q uire me nts 
relati n g t o t he re p orti n g of me dical de vice deficie ncies t o t he I R B/I E C. 
•  
F or f urt her g ui da nce o n t he defi niti o n of a n S A E, see A p pe n di x I . 
8. 3. 1 2  
Seri o us A d verse De vice Effect Re p orti n g  
N ote: T here are a d diti o nal re p orti n g o bli gati o ns f or de vice c o nstit ue nt deficie ncies t hat are 
p ote ntiall y relate d t o S A Es t hat m ust f ulfill t he le gal res p o nsi bilit y t o n otif y a p pr o priate 
re g ulat or y a ut h orities a n d ot her e ntities a b o ut certai n safet y i nf or mati o n relati n g t o de vice 
c o nstit ue nts bei n g use d i n cli nical st u dies.  
•  
A n y de vice c o nstit ue nt deficie nc y t hat is ass ociate d wit h a n S A E m ust be re p orte d t o t he 
s p o ns or wit hin 2 4 h o urs after t he i n vesti gat or deter mi nes t hat t he e ve nt meets t he 
defi niti o n of a de vice c o nstit ue nt deficie nc y.  
•  
T he s p o ns or will re vie w all de vice c o nstit ue nt deficie ncies a n d deter mi ne a n d d oc u me nt 
i n writi n g w het her t he y c o ul d ha ve le d t o a n S A E. T hese de vice c o nstit ue nt deficie ncies 
P P D
P P D

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will be reported to the regulatory authorities and IRBs/IECs as required by national 
regulations. 
 
8.3.13 
Management of Investigational Product-related Drug Reactions 
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as well 
as medical equipment to treat acute anaphylactic reactions should be immediately available 
when IP is administered, and study site personnel must be trained to recognize and treat 
anaphylaxis (Lieberman et al 2010). Details on anaphylaxis management are provided in 
Appendix E. 
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios: 
1 
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both and at least one of the following: 
(a) respiratory compromise; or 
(b) reduced blood pressure or symptoms of end-organ dysfunction; or 
2 
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms; or 
3 
Reduced blood pressure after exposure 
 
Further details on the clinical criteria for defining anaphylaxis and immune complex disease 
are provided in Appendix E 2. 
Participants will have had a pre-assessment (ie, vital signs) prior to IP administration. 
Participants should be observed after each IP administration for the appearance of any acute 
drug reactions, in line with clinical practice. 
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local laboratory at the discretion of the Investigator. 
8.4 
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 
participant 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. 

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• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel inform the AstraZeneca representative immediately, or no later than 
24 hours of when he or she becomes aware of it. 
The 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 an SAE, the standard reporting timelines apply, see 
Section 8.3.2. For other overdoses, reporting must occur within 30 days. 
8.5 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples, see Appendix C.  
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
• 
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless consented 
for future analyses. 
− 
PK samples may be disposed of or anonymized by pooling. Additional analyses may 
be conducted on the anonymized, pooled PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately 
from the CSR. 
• 
Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 
the assay as well as additional assay development work. The results from future analysis 
will not be reported in the CSR. 
 
8.5.1 
Pharmacokinetics 
All PK samples will be collected according to the SoA (Table 2). Pharmacokinetic samples 
will be collected before administration of IP, except Week 2, as there is no IP administered at 
Week 2. Pharmacokinetic samples will also be collected at disease control if no IP 
administration has occurred. 

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Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
AstraZeneca and site study files but will not constitute a protocol amendment. The 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) will be informed of 
any safety issues that require alteration of the safety monitoring scheme or amendment of the 
ICF. 
For the PK analysis, it is important that the date, time, and location of each SC injection is 
recorded for each participant. 
Instructions for sample collection, processing, storage, and shipment are provided in the 
Laboratory Manual. 
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report. 
8.5.1.1 
Determination of Drug Concentration 
Samples for determination of benralizumab concentration in serum will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the analytical method used will be described in 
a separate Bioanalytical Report. 
The bioanalytical laboratory will have access to the randomization list (Section 6.3.2). The 
following samples will be analyzed: 
Double-blind treatment period: 
• 
PK samples from participants assigned to the benralizumab treatment group 
 
Open-label extension period: 
• 
PK samples at Visit 19 (Week 60) in the OLE period in all groups. 
 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
8 6   
 
8. 5. 2  
I m m u n o ge nicit y Assess me nts 
8. 5. 2. 1  
A nti -dr u g A nti b o dies  
Bl o o d sa m ples f or deter mi nati o n of A D A i n ser u m will be c ollecte d as detaile d i n t he S o A 
(Ta ble  2) a n d will be assa ye d at t he discreti o n of Astra Ze neca b y bi oa nal ytical test sites 
o perate d b y or o n be half of Astra Ze neca, usi n g a n a p pr o priatel y vali date d bi oa nal ytical 
met h o d. F ull details of t he met h o ds use d will be descri be d i n a se parate re p ort.  Ne utraliz i n g 
a nti b o dies ma y be assesse d o n A D A p ositi ve sa m ples. Sa m ples will be c ollecte d acc or di n g t o 
t he S o A (Ta ble  2). 
Ot her a nal yses ma y be perf or me d t o verif y t he sta bilit y of a nti b o dies t o be nraliz u ma b a n d/ or 
f urt her c haracterize t he i m m u n o ge nicit y of be nraliz u ma b. 
Sa m ples will be c ollecte d, la bele d, st ore d, a n d s hi p pe d as detaile d i n t he La b orat or y Ma n ual. 
8. 5. 3  
P h ar m ac o d y n a mics  
Bl o o d a n d tiss ue e osi n o p hil a n d bas o p hil le vels a re a n i m p orta nt mar ker of t he 
p har mac o d y na mic effect of be nraliz u ma b, a n d bl o o d le vels of t hese 2 t y pes of cells will be 
assesse d as part of t he he mat ol o g y safet y testi n g ( Secti o n  8. 2. 4 ). Tiss ue e osi n o p hil a n d 
bas o p hil le vels will be assesse d as part of t he bi o mar ker e val uati o n ( Secti o n  8. 6 ). Bi o mar kers 
t h o u g ht t o pla y a r ole i n e osi n o p hilic i nfla m mati o n a n d/ or B P pat h o ge nesis ma y als o be 
assesse d as part of e x pl orat or y researc h ( Secti o n  8. 6 ). 
8. 6  
H u m a n Bi ol o gic al S a m ple Bi o m ar kers  
8. 6. 1  
C ollecti o n of M a n d at or y S a m ples f or Bi o m ar ker A n al ysis  
Ma n dat or y c ollecti o n of sa m ples f or e x pl orat or y bi o mar ker researc h is a part of t his st u d y. 
Sa m p les f or e x pl orat or y bi o mar ker researc h are re q uire d a n d will be c ollecte d fr o m all 
partici pa nts i n t his st u d y as s pecifie d i n t he S o A ( Ta ble  2). 
Bl o o d ( w h ole bl o o d, ser u m, a n d plas ma) a n d s ki n tiss ue will be c ollecte d acc or di n g t o t he 
S o A ( Ta ble  2) i n or der t o e val uate t he effect of be nraliz u ma b o n 
 
, i nfla m mati o n, a n d i m m u n ol o gical mec ha nis ms relate d t o t he pat h o ge nesis 
of B P.  
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt are pr o vi de d i n t he 
La b orat or y Ma n ual. Res ults fr o m t he e x pl orat or y bi o mar ker a nal yses, if perf or me d, will be 
re p orte d se paratel y fr o m t he C S R. (I n vesti gat ors will n ot recei ve t he res ults.) 
8. 6. 1. 1  
Ser u m a n d Pl as m a  
Ser u m a n d plas ma sa m ples will be c ollecte d acc or di n g t o t he S o A ( Ta b le 2) t o e val uate t he 
p har mac ol o g y of be nraliz u ma b as well as bi o mar kers of e osi n o p hil recr uit me nt, acti vati o n, 
a n d s ur vi val (e g, a bs ol ute e osi n o p hil c o u nt, I L- 5, E D N, e ota xi n). A d diti o nal mar kers of 
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nrali z u ma b - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
8 7   
 
cell ular i nfla m mati o n a n d/ or acti vati o n ma y be assesse d i ncl u di n g, b ut n ot li mite d t o, t h ose 
ass ociate d wit h h u m oral a ut oi m m u nit y (t otal ser u m I g E, I g G directe d a gai nst a ut o -a nti ge ns 
B P - 1 8 0 a n d/ or B P- 2 3 0), T cell s u bsets (e g, I L- 1 3, I F N- ga m ma, I L-1 7), e osi n o p hil gra n ule 
pr otei ns (e g, M B P, e osi n o p hil per o xi dase), e pit helial cell da ma ge (e g, T S L P, I L- 2 5, I L- 3 3), 
itc h (I L- 3 1), a n d pai n (s u bsta nce P). T he res ults fr o m s uc h st u dies will n ot be re p orte d i n t he 
C S R b ut i n se parate re p orts or p u blicati o n s as a p pr o priate. 
I nstr ucti o ns f or sa m ple c ollecti o n, pr ocessi n g, st ora ge, a n d s hi p me nt will be f o u n d i n t he 
La b orat or y Ma n ual.  
8. 6. 1. 2  
Tiss ue Hist ol o g y a n d I m m u n ost ai ni n g  
S ki n bi o psies will be c ollecte d at scree ni n g a n d Wee k 3 6 (as per S o A [ Ta ble  2]). S ki n bi o psies 
will be ta ke n fr o m peri -lesi o nal s ki n f or hist o pat h ol o g y a n d 
 researc h. If lesi o ns 
ha ve res ol ve d, s ki n bi o psies will be ta ke n at a site pr o xi mal t o t he pre vi o usl y peri- lesi o nal site. 
If lesi o ns persist, bi o psies will be ta ke n at peri-lesi o nal sites pr o xi mal t o t he ori gi nal 
peri- lesi o nal site. S ki n bi o psies will be c ollecte d a n d pr ocesse d l ocall y at t he cli nical sites as 
descri be d i n detail  i n t he La b orat or y Ma n ual. F or partici pa nts wit h o ut a c o nfir me d dia g n osis, 
n o bi o ps y f or 
 is c ollecte d. I n t hese partici pa nts, t he bi o ps y will be f or 
i ncl usi o n criteria c o nfir mati o n at t he l ocal la b a n d i m m u n o hist oc he mistr y f or e x pl orat or y 
researc h. 
Stai ni n g of t he bi o psies will be c o n d ucte d at a n a p pr o priate c o ntract la b a n d/ or at 
Astra Ze neca. T he s ki n bi o psies will be stai ne d f or mar kers f or t he detecti o n a n d e n u merati o n 
of 
8. 6. 2  
St or a ge, Re -use a n d Destr ucti o n of Bi o m ar ker S a m ples  
Sa m ples will be st ore d f or a ma xi m u m of 1 5 years fr o m t he date of t he last partici pa nt’s last 
visit (e n d of st u d y is defi ne d i n Secti o n 4. 4 ), after w hic h t he y will be destr o ye d. T he res ults of 
t his bi o mar ker researc h ma y be p o ole d wit h bi o mar ker data fr o m ot her st u dies t o pr o vi de data 
f or greater u n dersta n di n g of pat h o p h ysi ol o g y of B P a n d p ossi ble partici pa nt s u bsets. 
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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  
8 8   
 
G ui da nce re gar di n g ha n dli n g, tra ns p ort, a n d destr uc ti o n of h u ma n bi ol o gical sa m ples is 
pr o vi de d i n A p pe n di x C . 
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  
9. 1  
St atistic al H y p ot heses  
T he pri mar y e n d p oi nt is t he pr o p orti o n of partici pa nts w h o are i n c o m plete re missi o n w hile 
off O C S f or  ≥ 2 m o nt hs at Wee k 3 6. T he n ull h y p ot hesis is: t he pr o p orti o n of partici pa nts o n 
be nraliz u ma b is e q ual t o t he pr o p orti o n of partici pa nts o n place b o. W hereas  t he alter nati ve 
h y p ot hesis is: t he pr o p orti o n of partici pa nts o n be nraliz u ma b is n ot e q ual t o t he pr o p orti o n of 
partici pa nts o n place b o. T hat is:  
H 0: Differe nce i n pr o p orti o ns ( be nraliz u ma b – place b o) = 0 
H 1: Differe nce i n pr o p orti o ns ( be nraliz u ma b – place b o) ≠ 0  
T here are 5 ke y sec o n dar y e n d p oi nts. T he first ke y sec o n dar y e n d p oi nt is t he pr o p orti o n of 
partici pa nts w h o re mai n rela pse -free u p t o Wee k 3 6. Rela pse is defi ne d as partici pa nts 
e x perie nci n g: 3 or m ore ne w lesi o ns a per m o nt h ( blisters, ecze mat o us lesi o ns, or urticarial 
pla q ues); or at least o ne lar ge ( >  1 0 c m dia meter) ecze mat o us lesi o n or urticarial pl a q ues t hat 
d o n ot heal wit hi n 1 wee k; or t he e xte nsi o n of esta blis he d lesi o ns or dail y pr urit us i n 
partici pa nts w h o ha ve ac hie ve d disease c o ntr ol. T he n ull h y p ot hesis states: t here is n o 
differe nce i n pr o p orti o n rela pse- free bet wee n be nraliz u ma b a n d place bo. T he alter nati ve 
h y p ot hesis states: t here is a differe nce i n pr o p orti o n rela pse- free bet wee n be nraliz u ma b a n d 
place b o. T hat is: 
H 0: Differe nce i n pr o p orti o ns ( be nraliz u ma b - place b o) = 0  
C CI

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H1: Difference in proportions (benralizumab - placebo)  ≠ 0 
The remaining 4 key secondary endpoints are continuous outcomes, and they are: cumulative 
OCS exposure (mg/kg) from baseline to Week 36; change from baseline in BPDAI activity 
score at Week 36; change from baseline in BPDAI-Pruritus score at Week 36; cumulative 
OCS exposure (mg/kg) from baseline to Week 16. For each of these endpoints, the null 
hypothesis is: the mean for benralizumab is equal to the mean for placebo. Whereas the 
alternative hypothesis is: the mean for benralizumab is not equal to the mean for placebo. That 
is: 
H0: Difference in means (benralizumab – placebo) = 0 
H1: Difference in means (benralizumab – placebo) ≠ 0 
Hypothesis testing for the primary and key secondary endpoints will be based on a 2-sided test 
and carried out using a 5% significance level. If a p-value is less than 0.05, the treatment 
effect favors benralizumab and the decision will be to reject the null hypothesis (H0) and the 
alternative hypothesis (H1) will be accepted. 
A hierarchical testing procedure will be used to control the overall Type I error rate at 5% 
across the primary and key secondary endpoints (Section 9.4.2). The variables will be tested 
sequentially in the following order using a 2-sided test and a 5% significance level: 
1 
Proportion of participants who are in complete remission and have taken no OCS for 
≥ 2 months at Week 36 
2 
Proportion of participants who remain relapse-free up to Week 36 
3 
Cumulative OCS exposure (mg/kg) from baseline to Week 36 
4 
Change from baseline in BPDAI activity score at Week 36 
5 
Change from baseline in BPDAI-Pruritus score at Week 36 
6 
Cumulative OCS exposure (mg/kg) from baseline to Week 16 
 
9.2 
Sample Size Determination 
The sample size calculation was derived for the primary endpoint, the proportion of 
participants who are in complete remission while off OCS for ≥ 2 months at Week 36. 
Approximately 60 participants are needed per treatment group to detect a 30% difference 
between benralizumab and placebo with 90% power. The calculation is based on a 2-sided test 
and a 5% significance level and assumes a response rate of 50% for benralizumab and 20% 
for placebo. 
There is limited evidence currently available from completed comparative BP trials to date to 
base the study size assumptions on. However, a mepolizumab Phase 2 trial with a similar 

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participant population, design, and steroid taper rate reported a low proportion who were 
relapse free up to 36 weeks (20% versus 33% for mepolizumab versus placebo;  
Simon et al 2020). From this study, the assumption that an expected remission rate off steroids 
at Week 36 would be low, at most 20%, was extrapolated. A 30% improvement in this 
remission rate was recommended by a panel of BP experts to be at the lower end of what may 
be clinically meaningful, and so was considered to be a conservative assumption. 
A non-binding interim futility analysis will be performed by an Independent Data Monitoring 
Committee (IDMC) when approximately 36 randomized participants (ie, when approximately 
30% of the total amount of statistical information is available) have had the opportunity to 
complete at least 36 weeks of follow-up. By conducting the interim analysis, the overall 
power will not be affected substantially. Full details are provided in Section 9.5. 
9.3 
Populations for Analyses 
Analyses presented in the CSR will be based on the populations as defined in Table 9. 
Table 9 
Populations for Analysis 
Population 
Description 
All participants analysis set  
All participants screened for the study, to be used for reporting disposition 
and screening failures. 
Full analysis set 
All randomized participants who received at least 1 dose of IP, irrespective 
of their protocol adherence and continued participation in the study. 
Participants will be analyzed according to their randomized treatment 
irrespective of whether or not they have prematurely discontinued, 
according to the ITT principle. Participants who withdraw consent to 
participate in the study will be included up to the date of their study 
termination. 
Safety analysis set 
The safety analysis set consists of all participants who have received at least 
one dose of IP. 
Erroneously treated participants (eg, those randomized to treatment A but 
actually given treatment B) are accounted for in this analysis set by 
assigning them to the treatment they actually received. 
A participant who has on one or several occasions received active IP is 
classified as active. 
Safety, and ADA data will be based on this analysis set and for whom any 
post-dose data are available. 
Pharmacokinetic analysis set 
All participants who received at least one dose of benralizumab and from 
whom PK blood samples are assumed not to be affected by factors such as 
protocol violations (eg, received wrong dose) and who had at least 1 
quantifiable serum PK observation post first dose. All PK summaries will be 
based on this analysis set. 
OLE benralizumab analysis set 
All participants who start or carry on receiving at least 1 dose of 
benralizumab after the end of the DB treatment period 

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ADA, anti-drug antibodies; DB, double-blind; IP, investigational product; ITT, intent-to-treat; OLE, open-label 
extension; PK, pharmacokinetic. 
 
9.4 
Statistical Analyses 
A comprehensive statistical analysis plan (SAP) will be developed and finalized prior to the 
primary DBL and will include a more technical and detailed description of the statistical 
analyses described below. Any deviations from this plan will be reported in the CSR. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
All personnel involved in the analyses of the study will remain blinded until the primary DBL 
and protocol deviations are identified. 
Analyses will be performed by AstraZeneca or its representatives. 
Categorical variables will be summarized using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population unless otherwise stated. 
Continuous variables will be summarized with descriptive statistics of number of available 
observations, mean, standard deviation, median, minimum and maximum, and quartiles where 
more appropriate. 
All point estimates will be presented together with 95% confidence intervals (CIs). P-values, 
corresponding to a 2-sided test, will be presented for comparisons between treatments. 
Methods for controlling multiplicity across the primary and key secondary endpoints are 
discussed in Section 9.4.7. 
9.4.1 
General Considerations 
The primary analysis will be based on the initial 36-week, double-blind, placebo-controlled 
phase of the study, and will compare all participants randomized to benralizumab until 
Week 36 against all participants randomized to placebo until Week 36. 
Table 10 outlines the estimands which will be used for the primary analyses of the primary 
and key secondary endpoints, with additional detail on each endpoint in the sections below. 
 

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Table 10 
Primary and Key Secondary Estimands 
Statistical 
category 
Treatment condition 
Endpoint 
(Population) 
Intercurrent event strategy 
Population level summary 
(Analysis) 
Primary objective: To compare the clinical efficacy of benralizumab with placebo in participants with symptomatic BP 
Primary 
Treatment with 
benralizumab versus 
placebo, regardless of IP 
compliance; restricted 
medication use indicates 
treatment failure 
Proportion of 
participants who are 
in complete 
remission while off 
OCS for ≥ 2 months 
at Week 36 (FAS) 
• 
Treatment discontinuation – treatment 
policy 
• 
Rescue with OCSa – treatment policy 
• 
Restricted medication use – composite 
(non-responder) 
• 
Study withdrawal – composite (non-
responder) 
Odds ratio and difference in 
proportion of participants who 
are responders at Week 36 
(logistic regression model) 
Secondary objective: To compare the effect of benralizumab with placebo on supportive measures of clinical efficacy in participants with 
symptomatic BP up to Week 36/up to Week 16 
Key 
Secondary 
Treatment with 
benralizumab versus 
placebo, regardless of IP 
compliance; rescue with 
OCS and restricted 
medication use indicate 
treatment failure 
Proportion of 
participants who 
remain relapse-free 
up to Week 36 
(FAS) 
• 
Treatment discontinuation – treatment 
policy 
• 
Rescue with OCSa – composite (not 
relapse free) 
• 
Restricted medication use – composite 
(not relapse free) 
• 
Study withdrawal – composite (not 
relapse free) 
Odds ratio and difference in 
proportion of participants 
remaining relapse free up to 
Week 36 (logistic regression 
model) 
Key 
Secondary 
Treatment with 
benralizumab versus 
placebo, regardless of IP 
compliance 
Cumulative OCS 
exposure (mg/kg) 
from baseline to 
Week 36 and from 
baseline to 
Week 16 (FAS) 
• 
Treatment discontinuation – treatment 
policy 
• 
Restricted medication use – effectiveness 
(includes OCS dosing up to occurrence of 
event) 
• 
Study withdrawal – effectiveness 
(includes OCS dosing up to occurrence of 
event) 
Difference in mean cumulative 
OCS exposure (mg/kg) from 
baseline to Week 36 and from 
baseline to Week 16 (MMRM) 

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Table 10 
Primary and Key Secondary Estimands 
Statistical 
category 
Treatment condition 
Endpoint 
(Population) 
Intercurrent event strategy 
Population level summary 
(Analysis) 
Key 
Secondary 
Treatment with 
benralizumab versus 
placebo, regardless of IP 
compliance; rescue with 
OCS and restricted 
medication use indicate 
treatment failure 
Change from 
baseline in BPDAI 
activity score at 
Week 36, change 
from baseline in 
BPDAI-Pruritus 
score at Week 36 
(FAS) 
• 
Treatment discontinuation – treatment 
policy 
• 
Rescue with OCSa – composite (LOCF) 
• 
Restricted medication use – composite 
(LOCF) 
• 
Study withdrawal – hypothetical (multiple 
imputation) 
Difference in mean change from 
baseline in BPDAI activity 
score/BPDAI-Pruritus score at 
Week 36 (ANCOVA) 
a Rescue with OCS is defined as needing to increase OCS dose after previously having achieved disease control. 
ANCOVA, analysis of covariance; BP, bullous pemphigoid; BPDAI, bullous pemphigoid disease area index; FAS, full analysis set; IP, investigational product; 
LOCF, last observation carried forwards; MMRM, mixed-effect model for repeated measures; OCS, oral corticosteroids. 
 

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The amount of missing data for this study is expected to be low, as participants who 
prematurely discontinue IP will be asked to come in for all visits and complete all study 
assessments up to the end of the study. Any participant with missing data at a specific time 
point will be considered as a non-responder at that time point. 
Further estimands will be specified for the primary and key secondary endpoints to carry out 
sensitivity analyses for assessing the robustness of results. These sensitivity analyses will 
explore different methods for handling intercurrent events and different assumptions for 
missing data. Further description is given in Section 9.4.8 and will be fully specified in the 
SAP. 
All analyses for the OLE endpoints will be descriptive, as no placebo-control data will be 
available for this period. Consequently, no hypothesis testing will be performed. 
Demography and baseline characteristics will be summarized by treatment for the FAS. If 
there are major differences between the FAS and the safety analysis set, the summaries will be 
repeated and presented for the safety analysis set. 
9.4.2 
Efficacy Analyses 
9.4.2.1 
Primary Analysis Method 
Proportion of participants who are in complete remission and have taken no oral 
corticosteroids for ≥ 2 months at Week 36 
The primary endpoint is a binary response whereby participants will be classified as 
responders if they are in complete remission while off OCS for ≥ 2 months at Week 36. 
Otherwise, participants will be classified as non-responders. 
The estimand strategy is outlined in Table 10 above. Intercurrent events (use of restricted 
medications, study withdrawal) are unfavorable outcomes and will be handled with a 
composite strategy whereby participants experiencing these events prior to Week 36 will be 
considered as non-responders in the analysis. Likewise, participants with missing data at 
Week 36 for any other reason will be considered as non-responders. However, for this 
endpoint, if a participant needs to increase OCS after previously achieving disease control but 
still tapers and achieves the remission criteria by Week 36, this will count as response in the 
analysis. It is considered unlikely that this situation would emerge often, but given the clinical 
relevance of still being able to achieve remission and that OCS use is built into the remission 
definition, it is considered appropriate to count this situation as response in the analysis. 
For the primary analysis, a logistic regression model will be fitted to the primary endpoint 
using a logit link function. The model will include treatment, baseline disease severity 
(moderate; severe) and time of BP diagnosis (ie, participants with newly diagnosed BP versus 
participants with a previous diagnosis of BP who have relapsed) as categorical covariates. 

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(Note that participants will be classified as severe based on a cut-off of 56 points for baseline 
BPDAI activity score.) The effect of adding further covariates into the model, such as age and 
region, may also be assessed as a sensitivity analysis if any potentially significant imbalances 
occur in the set of baseline characteristics. 
The model will be used to estimate the proportion of responders for benralizumab and 
placebo, the difference between these proportions (benralizumab – placebo), a rate ratio 
(benralizumab/placebo) and an odds ratio, with corresponding 95% confidence limits. A 
p-value, corresponding to a 2-sided test, will be presented to compare the benralizumab and 
placebo treatment groups. Note that if the logistic regression model does not converge to a 
solution due to low response rates in certain categories, the endpoint will be analyzed using a 
Cochran–Mantel–Haenszel test. 
To support this analysis, the observed proportion of responders will be summarized using 
descriptive statistics by treatment group and each scheduled visit up to Week 36. 
9.4.2.2 
Analysis Methods for Key Secondary Efficacy Variables 
Proportion of participants who remain relapse-free up to Week 36 
The proportion of participants who remain relapse-free up to Week 36 will be analyzed as a 
binary response variable, where participants who remain relapse-free throughout the study up 
to Week 36 will be considered responders, but otherwise participants will be considered 
non-responders. Relapse is defined as the appearance of: 3 or more new lesions per month 
(blisters, eczematous lesions, or urticarial plaques); or at least one large (> 10 cm diameter) 
eczematous lesion or urticarial plaques that do not heal within 1 week; or the extension of 
established lesions or daily pruritus in participants who have achieved disease control. 
The estimand strategy is outlined in Table 10 above. Intercurrent events of rescue use with 
OCS after having previously achieved disease control, restricted medication use, and study 
withdrawal are unfavorable outcomes and will be handled with a composite strategy whereby 
participants experiencing these events prior to Week 36 will be considered as non-responders 
(ie, not relapse-free) in the analysis. Likewise, participants with missing data at Week 36 for 
any other reason will be considered as not-relapse free. 
For the primary analysis of the proportion of participants relapse-free at Week 36, a logistic 
regression model will be fitted using a logit link function. The model will include treatment, 
baseline disease severity (moderate or severe, with a BPDAI activity score of 56 points used 
as the threshold between moderate and severe) and time of BP diagnosis (ie, participants with 
newly diagnosed BP versus participants with a previous diagnosis of BP who have relapsed) 
as categorical covariates. 
The model will be used to estimate the proportion who are relapse-free for benralizumab and 
placebo, the difference between these proportions (benralizumab – placebo), a rate ratio 

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(benralizumab/placebo), and an odds ratio, with corresponding 95% confidence limits. A 
p-value, corresponding to a 2-sided test, will be presented to compare the benralizumab and 
placebo treatment groups. Note that if the logistic regression model does not converge to a 
solution due to low response rates in certain categories, the endpoint will be analyzed using a 
Cochran–Mantel–Haenszel test. 
As supportive analyses to explore the timing of relapse events, the time to first BP relapse will 
also be analyzed, where time to first relapse is defined as the earliest time after randomization 
that any of the relapse criteria are met. This analysis will use a log-rank test stratified by 
baseline disease severity (moderate; severe) and time of BP diagnosis (ie, participants with 
newly diagnosed BP versus participants with a previous diagnosis of BP who have relapsed). 
A p-value, corresponding to a 2-sided test, will be presented to compare the benralizumab and 
placebo treatment groups. A Cox-proportional hazards model will be used to estimate the 
hazard ratio and its 95% CI. The median time to first relapse will be estimated from the 
Kaplan-Meier curves for the benralizumab and placebo treatment groups. 
Cumulative OCS exposure (mg/kg) from baseline to Week 36 and from baseline to 
Week 16 
Two cumulative OCS exposure endpoints are defined: the cumulative OCS exposure over the 
36-week double-blind period, and the cumulative OCS exposure over the first 16 weeks of the 
study. Each of these endpoints will be assessed from a mixed-effect model for repeated 
measures (MMRM), examining each participant’s cumulative OCS exposure in 4-week 
periods. The cumulative exposure over the 36 (and 16) weeks will be estimated as the sum 
over the relevant 4-week periods from the MMRM model. This analysis method was selected 
to utilize all available data in the situation of any participants dropping out prior to 36 weeks. 
This ensures that any such participants can still contribute to the analysis for the period they 
remain in the study, without needing to make potentially implausible imputation assumptions 
around future OCS exposures in these situations (eg, carrying forward a high last observation 
of 0.75 mg/kg/d, which would not be a feasible dose to maintain for a 36-week period). 
As highlighted in Table 10, the intercurrent events of restricted medication use and study 
withdrawal will be handled with an effectiveness strategy, including all available data in the 
MMRM model until the occurrence of such events. As described above, this avoids needing to 
make potentially implausible imputation assumptions that a composite strategy would involve. 
Likewise, use of a treatment policy strategy is also not considered appropriate, as use of 
restricted medications would confound future OCS use. For example, if OCS were 
discontinued to receive another treatment due to lack of response or intolerability to OCS, the 
treatment policy approach would show a low cumulative OCS dose, which is a positive 
outcome and does not fairly represent the overall picture. Note that the list of intercurrent 
events does not include rescue with OCS (ie, increases in OCS dose after achieving disease 

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control), as by definition of the endpoint, increases in OCS dosing will be reflected in the 
cumulative OCS dose. 
The model will include cumulative OCS exposure (mg/kg) as the dependent variable 
(calculated for each participant over 4 weekly intervals up to Week 36); treatment, 4 weekly 
interval, baseline disease severity and time of BP diagnosis as categorical covariates; 
treatment-by-4 weekly interval as an interaction term. The inclusion of baseline OCS dose as a 
covariate will also be considered. An unstructured variance-covariance matrix will be used to 
model within-participant errors, and the Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom and to adjust standard errors. (If the model fails to 
converge, alternative variance-covariance models will be tried in the following order: 
Toeplitz, first-order regressive, compound symmetry.) For each 4 weekly interval and for the 
sum of the 4-weekly intervals over the whole of the 36-week treatment period, and for the sum 
of the 4-weekly intervals over the initial 16-week treatment period, the model will be used to 
estimate the mean cumulative OCS exposure (mg/kg) for each treatment group and the 
difference versus placebo, with corresponding 95% confidence limits. P-values, corresponding 
to 2-sided tests, will be presented to compare the benralizumab and placebo treatment groups 
for each interval, including the whole of the 36-week treatment period and the initial 16-week 
treatment period. 
To support this analysis, observed means will be summarized using descriptive statistics by 
treatment group and each 4 weekly interval, are for the whole of the 36-week treatment period 
and the initial 16-week treatment period. 
Change from baseline in BPDAI activity score at Week 36 
BPDAI activity score is a continuous endpoint that will be completed at the visits specified in 
the SoA (Table 2) during the initial 36-week treatment period.  
The estimand strategy is outlined in Table 10 above. For this endpoint, intercurrent events of 
rescue use with OCS after having previously achieved disease control and restricted 
medication use are considered unfavorable outcomes and will be handled with a composite 
strategy whereby participants experiencing these events prior to Week 36 will have their last 
observation prior to rescue/restricted medication use carried forward to Week 36. For 
participants who discontinue the study without having rescue or restricted medications, 
missing data at Week 36 will be imputed using multiple imputation based on participants who 
don’t have rescue/restricted medication use. Once these imputations are made, the available 
change from baseline in BPDAI score at Week 36 will then be analyzed using an analysis of 
covariance (ANCOVA) model. 
The model will include change from baseline at Week 36 as the dependent variable, baseline 
BPDAI score as a continuous covariate, and treatment, baseline disease severity, and time of 

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BP diagnosis as categorical covariates. The model will be used to estimate the mean change 
from baseline at Week 36 for each treatment group and the difference versus placebo, with 
corresponding 95% confidence limits. A p-value, corresponding to a 2-sided test, will be 
presented to compare the benralizumab and placebo treatment groups. 
To support this analysis, observed means and mean changes from baseline will be summarized 
using descriptive statistics by treatment group and each scheduled visit up to Week 36.  In 
addition, the cumulative distribution function of absolute changes from baseline in BPDAI 
activity score at Week 36 will also be plotted, to allow the treatment difference at various 
response thresholds to be explored. Responder analyses using minimal clinically important 
differences presented in the literature (Wijayanti et al 2017) may be presented, if appropriate. 
Change from baseline in BPDAI-Pruritus score at Week 36 
BPDAI-Pruritus score is a continuous endpoint that will be completed at the visits specified in 
the SoA (Table 2) during the initial 36-week treatment period. The statistical analysis 
described above for BPDAI activity score will be carried out for this endpoint, with the same 
estimand approach and the same ANCOVA model will be fitted to these data. 
To support this analysis, observed means and mean changes from baseline will be summarized 
using descriptive statistics by treatment group and each scheduled visit up to Week 36. In 
addition, the cumulative distribution function of absolute changes from baseline in 
BPDAI-Pruritus score at Week 36 will also be plotted to allow the treatment difference at 
various response thresholds to be explored. 
9.4.2.3 
Analysis Methods for Secondary Efficacy Variables 
Proportion of participants in sustained complete/partial remission on minimal OCS/off 
OCS for at least 2 months at Week 36 
A supportive responder analysis will be performed where any participant who achieved 
complete or partial remission, while on minimal OCS or off OCS for at least 2 months at 
Week 36 will be defined as responders. The statistical methodology described for the primary 
analysis will be carried out for this endpoint. 
Summaries of the different combinations of complete and partial remission, each on minimal 
OCS or off OCS, will also be produced to understand the distribution of these clinical benefit 
categories at visits throughout the study up to Week 36. 
Cumulative time (weeks) in complete remission off OCS from baseline to Week 36 
Cumulative time in complete remission while off OCS will be derived for each participant 
over the initial 36-week treatment period. These times will then be assigned to a set of ordered 
categories (which will include a category for no weeks in complete remission off OCS), to be 

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fully defined in the SAP. An ordered logistics regression model will be fitted to these 
categories, assuming proportional odds.  
The model will include cumulative time as the dependent variable and treatment, baseline 
disease severity and time of BP diagnosis as categorical covariates. The model will be used to 
estimate an odds ratio, with 95% CIs.  
Proportion of participants off OCS by Week 36 
Participants will be defined as responders if they are off OCS by Week 36. Otherwise, 
participants will be classified as non-responders. The statistical methodology described for the 
primary analysis will be carried out for this endpoint. (The p-value will be nominal, as 
secondary objectives are not controlled for multiplicity and do not appear in the testing 
hierarchy.) To support this analysis, the observed proportion of responders will be 
summarized using descriptive statistics by treatment group and each scheduled visit up to 
Week 36. 
IGA score at Week 36 and change from baseline in IGA score at Week 36 
IGA score achieved (clear, almost clear, mild, moderate, severe) will be summarized using 
descriptive statistics by treatment group at each scheduled visit up to Week 36. 
A responder analysis will be performed where participants will be classified as responders if 
they achieve IGA 0/1 (ie, clear or almost clear) at Week 36. Otherwise, participants will be 
classified as non-responders. The statistical methodology described for the primary analysis 
will be carried out for this endpoint (the p-value will be nominal, as secondary objectives are 
not controlled for multiplicity and do not appear in the testing hierarchy). 
Number of points change from baseline in IGA score will be summarized, and a shift table 
comparing IGA score at baseline against IGA score achieved at Week 36 (and other visits 
throughout the study, as relevant) will be produced. 
Proportion of participants who remain relapse-free up to Week 16 
Referring to the statistical analysis for the proportion of participants who remain relapse-free 
up to Week 36, proportion of participants who remain relapse-free up to Week 16 will also be 
analyzed as a binary endpoint with a similar logistic regression model. 
Proportion of participants with any clinical benefit at Week 16 
To assess signs of clinical efficacy during the first 16 weeks of the study, the observed 
proportion of participants showing partial remission or complete remission at Week 16 will be 
summarized using descriptive statistics by treatment group. The summary will categorize each 
of these disease states into: during taper, with no steroids, and with minimal steroids 
(ie, < 0.1 mg/kg/day). 

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If a consistent message can be drawn across these categories and treatment groups, a 
supportive analysis will be carried out, whereby a participant will be classified as a responder 
if they show any clinical benefit (ie, partial remission or complete remission) during taper, 
with no steroids or with minimal steroid use at Week 16. Otherwise, a participant will be 
classified as a non-responder. This binary variable will then be analyzed using a logistic 
regression model with a logit link function. The model will include treatment, baseline disease 
severity and time of BP diagnosis as covariates. The model will be used to estimate the 
proportion of responders for benralizumab and placebo, the difference between these 
proportions (benralizumab – placebo) and an odds ratio, with corresponding 95% confidence 
limits. A p-value, corresponding to a 2-sided test, will be presented to compare the 
benralizumab and placebo treatment groups. (The p-value will be nominal, as secondary 
objectives are not controlled for multiplicity and do not appear in the testing hierarchy.)   
Time to disease control, OCS dose at disease control and time to the end of the 
consolidation phase 
Time to disease control, OCS dose at disease control and time to the end of the consolidation 
phase will be summarized using descriptive statistics by treatment group. The time to disease 
control and time to the end of the consolidation phase may also be grouped into ordered 
categories and summarized by treatment group. Statistical analysis and Kaplan Meier plots 
may be performed if appropriate. Full details will be provided in the SAP. 
Change from baseline in BPDAI activity score at Week 16 
Referring to the statistical analysis for change from baseline in BPDAI activity score at Week 
36, the same analysis methods will be used for the change from baseline at Week 16 endpoint 
(the p-value at Week 16 will be nominal, as secondary objectives are not controlled for 
multiplicity and do not appear in the testing hierarchy). 
Change from baseline in BPDAI-Pruritus score at Week 16 
Referring to the statistical analysis for change from baseline in BPDAI-Pruritus score at 
Week 36, the same analysis methods will be used for the change from baseline at Week 16 
endpoint (the p-value at Week 16 will be nominal, as secondary objectives are not controlled 
for multiplicity and do not appear in the testing hierarchy). 
9.4.3 
Safety Analyses 
Summaries will be based primarily on the safety analysis set and focus on the initial 36-week 
treatment period. A key subset of these summaries will also be repeated for the entire study 
period and the OLE. Full details will be provided in the SAP.  

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9.4.3.1 
Adverse Events 
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at 
AstraZeneca/designee. 
Safety data will be presented using descriptive statistics, unless otherwise specified. 
Adverse events will be presented for each treatment group by system organ class and 
preferred term, including the number and percentage of participants reporting at least 1 event, 
number of events and exposure-adjusted rates, where appropriate. 
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE, AEs with outcome of death, serious AEs, and AEs 
leading to discontinuation of IP. 
Separate AE tables will be provided taking into consideration the relationship as to IP 
assessed by the Investigator, maximum intensity, seriousness, death and events leading to 
discontinuation of IP, as well as other action taken related to IP. 
An additional table will present number and percentage of participants with most common 
AEs (frequency of ≥ 3%). 
In accordance with the requirements of the Food and Drug Administration, a separate table 
will present non-serious AEs occurring in more than 5% of participants in any treatment 
group. 
Key participant information will be presented for participants with AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of IP. 
An AE listing for the safety analysis set will cover details for each individual AE. 
9.4.3.2 
Treatment Emergence 
The following events are considered treatment emergent: 
• 
AEs with an onset date on or after the first dose of IP 
• 
Worsening of pre-existing events on or after first dose of IP 
 
9.4.3.3 
Clinical Safety Laboratory Assessments 
Laboratory data for hematology and clinical chemistry will be summarized. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given.  

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 2   
 
9. 4. 3. 4  
Vit al Si g ns  
Details of all vital si g ns a nal yses will be pr o vi de d i n t he S A P. As a n o ver vie w, descri pti ve 
statistics will be prese nte d f or o bser ve d a n d c ha n ge fr o m baseli ne val ues f or all vital si g n 
para meters, w hic h i ncl u de t he c o nti n u o us meas ures: s yst olic bl o o d press ure, diast olic bl o o d 
press ure, p ulse rate, res pirati o n rate a n d b o d y te m perat ure. 
F or eac h treat me nt gr o u p:  
•  
T he para meters will be s u m marize d at eac h sc he d ule d p ost -baseli ne visit a n d will i ncl u de: 
n u m ber of a vaila bl e o bser vati o ns, mea n, sta n dar d de viati o n, me dia n, mi ni m u m a n d 
ma xi m u m, a n d q uartiles w here m ore a p pr o priate. 
•  
T he n u m ber a n d perce nta ge of partici pa nts falli n g i nt o s pecific vital si g ns cate g ories 
( defi ne d i n t he S A P) will be prese nte d at eac h sc he d ule d p ost- baseli ne visit i n a fre q ue nc y 
ta ble. 
•  
C ha n ges i n vital si g ns meas ure me nts will be e xa mi ne d at eac h sc he d ule d p ost- baseli ne 
visit a n d cli nicall y n ote w ort h y val ues o bser ve d d uri n g t he st u d y ( defi ne d i n t he S A P) will 
be prese nte d i n a fre q ue nc y ta ble.  
 
9. 4. 3. 5  
B o d y Wei g ht 
F or eac h treat me nt gr o u p, descri pti ve statistics will be prese nte d f or o bser ve d a n d c ha n ge 
fr o m baseli ne val ues at eac h sc he d ule d p ost-baseli ne visit a n d will i ncl u de: n, mea n, sta n dar d 
de viati o n, mi ni m u m, Q 1, me dia n, Q 3 a n d ma xi m u m. C ha n ges i n b o d y wei g ht will be 
e xa mi ne d at eac h sc he d ule d p ost - baseli ne visit a n d cli nicall y n ote w ort h y val ues o bser ve d 
d uri n g t he st u d y ( defi ne d i n t he S A P) will be prese nte d i n a fre q ue nc y ta ble. 
9. 4. 4  
P h ar m ac o ki netic A n al yses  
T he P K a nal yses will be perf or me d at or u n der t he g ui da nce of Astra Ze neca Researc h a n d 
De vel o p me nt. Be nraliz u ma b ser u m c o nce ntrati o ns will be s u m marize d usi n g descri pti ve 
statistics at eac h sc he d ule d visit f or partici pa nts i n t he P K a nal ysis set. 
9. 4. 5  
I m m u n o ge nicit y A n al yses 
A nti - dr u g a nti b o dies t o be nraliz u ma b will be s u m marize d usi n g descri pti ve statistics b y 
treat me nt gr o u p a n d eac h visit s pecifie d i n t he S o A (Ta ble  2). T he A D A titers-ti me pr ofiles of 
be nraliz u ma b ma y be ge nerate d. T he i m pact of A D A o n P K a n d e osi n o p hil le vel will be 
assesse d. T he p ote ntial ass ociati o n of A D A wit h safet y a n d efficac y will be e val uate d. F ull 
details will be pr o vi de d i n t he S A P. 
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9.4.6.1 
Patient-reported Outcomes 
Quality of life will be assessed using the AB-QoL total score and the EQ-5D-5L score at the 
visits specified in the SoA (Table 2). For each of these continuous endpoints, observed means 
and mean changes from baseline will be summarized using descriptive statistics by treatment 
group and each scheduled visit. To support these summaries, an MMRM model may be fitted 
to each of these outcome variables if deemed appropriate, following the details outlined in 
Section 9.4.2.2 for BPDAI activity score. 
Itch will be assessed using the Peak Pruritus NRS and recorded every day from Visit 2 
onwards by participants using a handheld device. Note that this endpoint is not collected 
during the screening period and so a baseline score will not be available. All changes will be 
assessed in an exploratory manner, relative to disease control. Analyses of the Peak Pruritus 
NRS endpoint will be completed in the subset of patients able to use the handheld device. 
For each participant, if at least 4 non-missing daily assessments are available in a weekly 
period, a weekly mean score will be derived starting from the seventh day after disease 
control, by summing the daily score over the available assessment and dividing by the number 
of available assessments in that week. If there are less than 4 non-missing daily assessments 
included in the calculation of the weekly score, the weekly score is missing for that week. The 
weekly scores will be summarized by descriptive statistics for observed means and mean 
changes from disease control.  
Binary endpoints will be derived using these weekly mean scores, whereby participants will 
be classified as a responder or a non-responder for each week using pre-specified clinically 
meaningful thresholds. As no threshold for a clinically relevant within-person response 
definition has been established for BP, the ≥ 2- to 4-point change threshold proposed for 
atopic dermatitis by Yosipovitch et al 2019 will be used for this study. Atopic dermatitis is an 
appropriate comparison point as it is another intensely pruritic inflammatory skin condition 
associated with eosinophilia (Jenerowicz et al 2007). Therefore, in the current study, a 
participant will be considered to have an improvement for a given week if a ≥ 2-point 
reduction versus disease control is observed and will be considered to have a worsening for a 
given week if a ≥ 2-point increase versus disease control is observed for the weekly mean 
score. However, depending on distribution of the data, other thresholds for response may be 
explored. The responder definition will be finalized and documented before unblinding. 
Observed proportion of responders will be summarized using descriptive statistics by 
treatment group and week. 
9.4.6.2 
Healthcare Resource Utilization 
BP-related healthcare resource utilization assessments will be completed at the visits specified 
in the SoA (Table 2). The set of assessments will include the frequency and duration of 
hospitalization, and frequency of office visits and emergency room visits. These endpoints 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 4   
 
will be s u m marize d usi n g descri pti ve statistics f or eac h treat me nt gr o u p, a n d will i ncl u de a n 
a n n ualize d rate of h os pitalizati o ns d ue t o B P a n d a n a vera ge le n gt h of h os pital sta y d ue t o B P. 
T o s u p p ort t hese s u m maries, a ne gati ve bi n o mial re gressi o n m o del ma y als o be fitte d t o eac h 
of t hese e n d p oi nts if dee me d a p pr o priate. 
9. 4. 6. 3  
E x pl or at or y Bi o m ar kers 
T o e x pl ore t he mec ha nis m of acti o n of be nraliz u ma b a n d t he pre dicti ve val ue of bi o mar ker 
data wit h cli nical o utc o mes, t he f oll o wi n g assess me nts will be carrie d o ut at t he visits 
s pecifie d i n t he S o A (Ta ble  2): s ki n hist ol o g y a n d i m m u n o hist oc he mistr y;  
 
 ser u m a n d plas ma bi o mar kers. Statistical a nal yses will be f ull y descri be d i n 
t he S A P. 
9. 4. 6. 4  
Effect of Be nr aliz u m a b i n t he O L E  
T he effect of be nraliz u ma b will be e x pl ore d i n partici pa nts i n t he O L E peri o d b y assessi n g 
e n d p oi nts s uc h as: 
 
 
Pea k Pr urit us  N R S , A B - Q o L a n d E Q- 5 D- 5 L. 
T hese e n d p oi nts will be s u m marize d usi n g descri pti ve statistics f or eac h treat me nt gr o u p at 
pre- defi ne d ti me p oi nts i n t he O L E peri o d u p t o Wee k 7 2 of t he st u d y. F ull details will be 
pr o vi de d i n t he S A P. 
9. 4. 7  
Met h o ds f or M ulti plicit y C o ntr ol  
A hierarc hical testi n g pr oce d ure will be use d t o c o ntr ol t he o verall T y pe I err or rate at 5 % 
acr oss t he pri mar y a n d ke y sec o n dar y e n d p oi nts. T he var ia bles will be teste d se q ue ntiall y i n 
t he f oll o wi n g or der usi n g a 2-si de d test a n d a 5 % si g nifica nce le vel: 
1  
Pr o p orti o n of partici pa nts w h o are i n c o m plete re missi o n w hile off O C S f or ≥ 2 m o nt hs at 
Wee k 3 6 ( pri mar y e n d p oi nt) 
2  
Pr o p orti o n of partici pa nts w h o r e mai n rela pse -free u p t o Wee k 3 6 ( ke y sec o n dar y 
e n d p oi nt) 
3  
C u m ulati ve O C S e x p os ure ( m g/ k g) fr o m baseli ne t o Wee k 3 6 ( ke y sec o n dar y e n d p oi nt) 
4  
C ha n ge fr o m baseli ne i n B P D AI acti vit y sc ore at Wee k 3 6 ( ke y sec o n dar y e n d p oi nt) 
5  
C ha n ge fr o m baseli ne i n B P D AI- Pr uri t us sc ore at Wee k 3 6 ( ke y sec o n dar y e n d p oi nt) 
6  
C u m ulati ve O C S e x p os ure ( m g/ k g) fr o m baseli ne t o Wee k 1 6 ( ke y sec o n dar y e n d p oi nt) 
 
If t he treat me nt c o m paris o n f or ( 1) is statisticall y si g nifica nt, testi n g will pr ocee d t o ( 2). If t he 
treat me nt c o m paris o n f or ( 2) is statisticall y si g nifica nt, testi n g will pr ocee d t o ( 3). If t he 
treat me nt c o m paris o n f or ( 3) is statisticall y si g nifica nt, testi n g will pr ocee d t o ( 4). If t he 
treat me nt c o m paris o n f or ( 4) is statisticall y si g nifica nt, testi n g will pr ocee d t o ( 5). If t he 
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treatment comparison for (5) is statistically significant, testing will proceed to (6). If, at any 
point in this hierarchy, a null hypothesis cannot be rejected at the 5% significance level in 
favor of benralizumab, further testing will stop, and no subsequent null hypotheses will be 
rejected. 
9.4.8 
Sensitivity Analyses 
Sensitivity analyses will be explored to assess the robustness of treatment effects for the 
primary and key secondary endpoints. 
Alternative estimand approaches for handling intercurrent events will be explored including 
treatment policy approaches, or alternative imputation techniques for handling of treatment 
failure intercurrent events for continuous endpoints, if relevant. 
For missing data due to study withdrawal of incomplete data for other reasons, different 
missing data mechanisms (eg, values missing at random and values missing not at random) 
will be considered to assess the robustness of the treatment effect for these endpoints. The use 
of multiple imputation approaches, including dropout reason-based multiple imputation will 
be considered. 
To examine the impact of missing data, including the impact of non-responder/not relapse free 
imputations due to study withdrawal, for the primary and first key secondary endpoint 
respectively, tipping point analyses may be performed. These analyses will systematically 
vary the assumptions about outcomes among the subsets of participants on the treatment arms 
who withdraw from the study early or have missing data at Week 36 for any other reason. 
Tipping point analyses are intended to identify the point at which the results would tip from 
statistically significant to not statistically significant. Thus, the tipping point analyses will 
only be performed if an endpoint achieves a nominally statistically significant result (ie, 
nominal p-value < 0.05). 
Full details of all sensitivity analyses will be provided in the SAP. 
9.4.9 
Subgroup Analyses 
Exploratory analyses will be carried out to assess the consistency of the treatment effect 
across key, pre-defined, subgroups. These analyses will focus on the primary endpoint, and 
they may be performed on key secondary endpoints if deemed appropriate. The list of 
subgroups will include, but may not be limited to: disease severity using baseline BPDAI to 
categorize participants; time of BP diagnosis (ie, participants with newly diagnosed BP versus 
participants with a previous diagnosis of BP who have relapsed); age; region; OCS dose at 
randomization; baseline blood eosinophils. Full details of all subgroup analyses will be 
described in the SAP, including hypotheses that will be tested and the covariates and 
interaction terms to be included in the statistical models. 

Cli nical St u d y Pr ot oc ol  - 4. 0  
Astra Ze neca  
Be nraliz u ma b  - D 3 2 5 A C 0 0 0 0 2  
2 6 A pril 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 6   
 
9. 5  
I nteri m A n al yses 
A n o n- bi n di n g f utilit y a nal ysis will be carrie d o ut b y t he I D M C w he n a p pr o xi matel y 
3 6 ra n d o mize d partici pa nts (ie, w he n a p pr o xi matel y 3 0 % of t he t otal a m o u nt of statistical 
i nf or mati o n is a vaila ble) ha ve ha d t he o p p ort u nit y t o c o m plete at least 3 6 wee ks of f oll o w- u p. 
Recr uit me nt will re mai n o n g oi n g w hile t he f utilit y a nal ysis is perf or me d.  
I n t he f utilit y a nal ysis, a pre dicti ve p o wer- base d h ur dle will be use d f or t he pri mar y e n d p oi nt 
(re missi o n w hilst off O C S f or at least 2 m o nt hs b y Wee k 3 6) s uc h t hat, gi ve n t he data 
acc u m ulate d t o date, if t here is l o w c ha nce ( 
 of ac hie vi n g statistical si g nifica nce at t he 
fi nal a nal ysis if t he st u d y were t o c o nti n ue, t he n a st o p decisi o n f or f utilit y s h o ul d be 
rec o m me n de d. 
 
 
If a decisi o n is 
ma de t hat t he st u d y s h o ul d c o nti n ue, t he pri mar y a nal ysis will be perf or me d w he n all 
ra n d o mize d partici pa nts ha ve ha d t he o p p ort u nit y t o c o m plete at least 3 6 wee ks of f oll o w- u p. 
T he sa m ple size calc ulati o n descri be d i n Secti o n  9. 2  i nc or p orates t he s mall l oss of p o wer 
( < 2 %) t hat res ults fr o m perf or mi n g t he f utilit y a nal ysis t o mai ntai n t he o verall p o wer at 
> 9 0 %. 
9. 6  
D at a M o nit ori n g C o m mittee  
A n I D M C will be utilize d f or t his st u d y. A p pe n di x A 5  pr o vi des m ore details o n t he rati o nale 
f or a n I D M C a n d t he re mit of t he c o m mittee. 
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
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11 
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