An Open-Label, Proof of Concept Study Designed to Evaluate the Safety, Efficacy and Pharmacodynamic Effect of Bertilimumab in Patients With Newly Diagnosed, Moderate to Extensive Bullous Pemphigoid
Phase: PHASE2
Conditions: Pemphigoid, Bullous
Sponsor: Alexion Pharmaceuticals, Inc.

P RI VI L E G E D &  C O N FI D E N TI A L  
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 of 7 2  
Fi nal Versi o n 8. 0  
Fe br uar y 2 8, 2 0 1 8  
C LI NI C A L S T U D Y P R O T O C O L  
A n O pe n -L a bel, Pr o of of C o nce pt St u d y Desi g ne d t o E v al u ate t he S afet y, 
Effic ac y a n d P h ar m ac o d y n a mic Effect of Bertili m u m a b i n N e wl y Di a g n ose d 
P atie nts a n d P atie nts  Resist a nt T o C ortic oster oi d T a peri n g  wit h M o der ate 
t o E xte nsi ve  B ull o us Pe m p hi g oi d  
St u d y P r o d uct:  
Bertili m u ma b  
I n dic ati o n: 
M o derate t o E xte nsi ve  B ull o us Pe m p hi g oi d  ( B P) 
P r ot oc ol N u m ber  
I m m u ne/ B R T/B P -0 1  
P h ase:  
2a  
N a me a n d A d dress of S p o ns or:  
I m m u ne P har mace uticals I nc. 
5 5 0 S yl va n A ve n ue, S uite 1 0 1 
E n gle w o o d Cliffs, NJ 0 7 6 3 2 
T el: ( 2 0 1)  4 6 4 - 2 6 7 7 
Fa x: ( 2 0 1)  4 6 4- 2 6 7 7 
G C P St ate me nt:  
T his st u d y will be perf or me d i n c o m plia nce wit h G C P, i ncl u di n g 
t he arc hi vi n g of esse ntial d oc u me nts. 
Versi o n N u m ber a n d D ate : 
Versi o n 8. 0  
Fe br uar y 2 8, 2 0 1 8 
T he i nf or m ati o n i n t his d oc u me nt is c o nfi de nti al a n d is pr o priet ary t o I m m u ne P h ar m ace utic als , I nc. 
Inf or m ati o n i n t his d oc u me nt s h all n ot be discl ose d t o a ny t hir d p arty, i n a ny f or m,  
wit h o ut pri or writte n  c o nse nt fr o m I m m u ne P h ar m ace utic als, I nc. 
1
N C T #: N C T 0 2 2 2 6 1 4 6

P R J Vl L E G E D & C O N F I DE N TI A L 
P R O T O C O L SI G N A T U R E P A G E 
P r ot o c ol Title: 
P r ot o c ol 
I d e ntifi c ati o n: 
St u d y P h as e: 
S p o ns o r : 
S p o ns o r R e p r es e nt ati v e: 
A n O p e n -L a b el , Pr o of of C o n c e pt St u d y D esi g n e d t o E v al u at e t h e S af e t y, 
Effi c a c y a n d P h ar m a c o d y n a m ic Eff e ct of B ertili m u m a b i n N e wl y Di a g n o se d 
P ati e nts a n d P a ti e nts R esist a nt T o C o rti c ost er oi d T a p eri n g wit h M o d er a t e t o 
E x t ensi v e B ull o us P e m p hi g o i d 
I m m u n e/B R T/ B P - 0 1 
2a 
I m m u n e P h ar m a c e uti c als, I n c., U S A 
I, t h e u n d ersi g n e d, h a v e r e a d t his pr ot o c ol a n d a gr e e t h at it c o nt ai ns all n e c ess ar y i nf or m ati o n r e q uir e d 
t o c o n d u ct t he tri al a n d t h at t h e pr ot o c ol is i n c o m pli a n c e w it h I nt er n ati o n al C o nf er e n c e o n 
H ar m o ni z ati o n (! C H) a n d G o o d Cli ni c al Pr a cti c e ( G C P) g ui d eli n es . 
N a m e, Titl e 
Si g n at ur e 
D at e 
P ri n ci p al I n v esti g at o r 
B y si g ni n g b el o w , I, t h e I nv esti g at or, a p pr o v e t h e pr ot o c ol a n d a gr e e t o c o n d u ct t h e cl ini c al tri al a c c or di n g 
t o all sti p ul ati o ns of t h e pr ot o c ol a s s p e cifi e d i n b ot h t h e cli ni c al a n d a d mi n istr ati ve s e cti o ns, C R F a n d a n y 
pr ot o c ol-r el at e d d o c u m e nts. I a gr e e t o c o m pl y w it h t h e I C H-G C P , W orl d M e di c al Ass o ci ati o n D e cl a r ati o n 
of H elsi n ki ( a n d r el ev a nt u p d at es ) a n d a p pli c a bl e l ocal r e g ul ati o ns. I a gr e e t o e ns ur e th at t h e c o nfi d e nti al 
i nf or m ati o n c o nt ai n e d i n t his d o c u m e nt wil 1 n ot be us e d f or a n y p ur p os e ot h er t h a n t h e e val u ati o n or c o n d u ct 
of t h e cli ni c al i n v esti g ati o n wit h o ut t h e pri or w ritt e n c o ns e nt of I m m u n e P h ar m a c e uti c als , I n c. I u n d erst a n d 
t h at t h e st u d y m a y b e ter mi n at e d or e nr oll m e nt s us p e n d e d at a n y t i m e b y  t h e S p o ns or , or b y m e , at m y 
c e nt er, if it b e c o m es n e c ess ar y i n m y o pi ni o n , t o pr ot e ct t h e b es t i nter ests of t h e st u dy p ati e nts. 
N a m e 
I n v esti g at or Si g n a ture 
C e nt er N a m e 
Pr ot o c ol : I m m u ne/ B R T/B P - 0 I 
D at e 
Ci t y, C o u nt r y 
Fi n al V ersi o n 8 . 0 
Fe br uar y 2 8, 2 0 1 8 
Pa ge 2 of 7 2
2

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
P R O T O C O L V E R SI O N HI S T O R Y  
Versi o n  
M ai n C h a n ges  
1. 0  
Ori gi nal  
2. 0  
•  
S p o ns or a d dresses u p date d t o reflect ne w  offices i n U S A a n d Israel  
•  
S p o ns or re prese ntati ve c ha n ge d t o 
 
 
•  
S p o ns or na me (I m m u ne P har mace uticals I nc/ Lt d.) u p date d t o reflect offices i n 
U S A a n d Israel  
•  
I ncl usi o n of Pr ot oc ol Versi o n Hist or y  
•  
A d diti o n of w or di n g t o all o w i ncl usi o n of sites i n E ur o pe a n d/ or t he U S i n t he 
e ve nt of sl o w recr uit me nt  
•  
Si m plificati o n of pri mar y  o bj ecti ve  w or di n g  
•  
I ncrease i n c o nc o mita nt ster oi d starti n g d ose fr o m 0. 3 m g/ k g/ da y t o 3 0 m g/ da y a n d 
re place me nt of ta peri n g re gi me wit h cli nical sta n dar d all o wi n g in vesti gat or t o 
deci de o n d ose re d ucti o n acc or di n g t o cli nical res p o nse.  
•  
A d diti o n of pr urit us vis ual a nal o g ue scale a n d Q O L q uesti o n naire t o assess me nts 
d uri n g treat me nt a n d f oll o w -u p peri o d.  
•  
N u m ber of patie nts i ncrease d fr o m 1 0 t o “ u p t o 1 5”.  
•  
A d diti o n of B P se verit y defi niti o n s t o i ncl usi o n criteri o n 4 a n d e xcl usi o n criteria 5. 
•  
Deleti o n of i ncl usi o n criteri o n 7 a n d a d diti o n of e xcl usi o n criteri o n 9 t o e xcl u de 
y o u n g, c hil dless males or t h os e pla n ni n g t o ha ve m ore c hil dr e n i n t he f u t ure. 
•  
A d diti o n of e xcl usi o n criteria relati n g t o pri or treat me nt wit h macr oli des or 
tetrac ycli nes, a n d i ncl usi o n of t hese dr u gs i n t he list of pr o hi bite d me dicati o ns 
d uri n g t he st u d y  (secti o n 6. 8. 3 ).  
•  
I ncrease i n bertili m u ma b d ose fr o m 5 m g/ k g t o 1 0 m g/ k g. S ecti o n 1. 3. 1  ( Rati o nale 
f or D ose Selecti o n) a n d  6. 6  ( St ora ge a n d I nstr ucti o ns f or Pre parati o n a n d I nf usi o n 
of t he I n vesti gati o nal Pr o d uct) u p date d acc or di n gl y.  
•  
Clarificati o n of resc ue t hera p y i n s y n o psis a n d secti o n 6. 8. 2 . 
•  
B P D AI m o ve d t o pri mar y effi cac y e n d p oi nt.  A d diti o n of st er oi d d ose at visit 7 as 
c o -pri mar y e n d p oi nt a n d f urt her sec o n dar y e n d p oi nts relate d t o disease c o ntr ol, 
pr urit us vis ual a nal o g ue scale a n d Q O L q uesti o n naire. Deleti o n of cli nical 
re missi o n as pri mar y e n d p oi nt a n d d urati o n of i nitial h os pitalizati o n as sec o n dar y 
e n d p oi nt.  
•  
A d diti o n of w or di n g t o secti o n 1. 1  relate d t o p o or c o m plia nce ass ociate d wit h use 
of t o pical ster oi ds i n t he el derl y.  
•  
Delete d Fi g ure 1, St u d y desi g n sc he matic.  
3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
Secti o n 5. 6  a me n de d t o reflect a d diti o n of pr urit us vis ual a nal o g ue scale a n d Q O L 
q uesti o n naire a n d a me n de d efficac y e n d p oi nts.  
•  
Secti o n 1 0. 0  u p date d d ue t o i nc or p orati o n of electr o nic data ca pt ure s yste m . 
•  
A d diti o n of  refere nces 1 8  a n d  9 . 
•  
A p pe n di x A,  Sc he d ule of Acti vities, u p date d t o reflect c ha n ges i n pr ot oc ol. 
•  
Deleti o n of A p pe n di x C, Decl arati o n of Helsi n ki.  
•  
Defi niti o ns f or a d diti o nal acr o n y ms a d de d t o t he gl ossar y.  
3. 0  
•  
C ha n ge i n S p o ns or Re prese nt ati ve  
•  
Re m o val of dr u g pre parati o n i nstr ucti o ns fr o m secti o n 6 a n d i nserti o n of refere nce  
t o p har mac y ma n ual. 
4. 0  
•  
U p date d I m m u ne P har mace uti cals, Lt d ., Israel l ocati o n 
•  
Re vise d n u m ber of cli nical sit es a n d c o u ntries f or cli nical s t u d y c o n d uct 
•  
Re vise d pri mar y o bj ecti ve a n d e n d p oi nts t o e val uate t he safet y of bertili m u ma b i n 
patie nts wit h ne wl y dia g n ose d, m o derate t o e xte nsi ve B P o nl y  
•  
Re vise d sec o n dar y o bj ecti ves a n d e n d p oi nts t o i ncl u de t he e val uati o n of cli nical 
efficac y a n d p har ma c o ki netics. A d de d a n e x pl orat or y o bj ecti ve a n d e n d p oi nt f or 
P B M C bi o mar kers.  
•  
C ha n ge of treat me nt peri o d fr o m 2 wee ks t o 4 wee ks  (re visi o n of Da y 2 8 fr o m a 
f oll o w-u p t o a treat me nt visit).  
•  
A d diti o n of f oll o w -u p visits at Da y  7 0, Da y 84 a n d Da y 1 1 8  
•  
C ha n ge of d osi n g fr o m t w o I V i nf usi o ns at 2 -wee k i nter vals t o t hree I V i nf usi o ns 
at 2 -wee k i nter vals  
•  
A d diti o n of p har mac o ki netics ( P K)  assess me nts fr o m Da y 0 t o Da y 8 4  
•  
A d diti o n of P B M C bi o mar ker assess me nts  at Da y 0, Da y 4 2 a n d Da y 8 4  
•  
A d diti o n of p ost -treat me nt ski n p u nc h bi o psies, i ncl u di n g e osi n o p hil c o u nt a n d I F  
o n Da y 4 2  ( Visit 6) 
•  
Re visi o n of patie nt p o p ulati o n  t o i ncl u de males or fe males ≥ 6 0 years of a ge  
•  
Re visi o n of i ncl usi o n criteria  t o i ncl u de males w h o ha ve ha d a vasect o m y or ha ve 
declare d t hat t he y ha ve n o i nterest i n fertilit y i n t he f ut ure.  
•  
Re visi o n of oral c ortic oster oi d ta peri n g re gi me n  
•  
Re visi o n of st u d y visit 7 fr o m D a y 6 0 t o D a y 5 6   
•  
Re visi o n of pr oce d ure  t o i ncl u de se me n a nal yses f or a n y fertile male i n t he trial at 
Da y s 0, 1 4 a n d 2 8 pre -d ose ( baseli ne) as well as at ma xi mal d ose ( a p pr o xi matel y 
3 0 mi n utes p ost -d ose) . N ote: t he pre -d osi n g sa m ples ca n be  ta ke n u p t o 2 da ys 
pri or t o d osi n g.  
4

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
Re visi o n of safet y la b orat or y assess me nts  t o i ncl u de se me n a nal ysis f or t he 
e val uati o n of s per m c o u nt, m or p h ol o g y a n d az o os per mia.  
•  
F or fertile males w h o ha ve ha d a b n or mal se me n a nal ysis res ults o n Da y 0, Da y 1 4 
or Da y 2 8, a d diti o nal se me n assess me nt after o ne s per mat o ge nic c ycle ( 3 m o nt hs 
f oll o wi n g t he last a d mi nistere d d ose (Da y 1 1 8 ) or at earl y disc o nti n uati o n will be 
f oll o we d u p f or a n assess me nt of re versi bilit y. 
•  
Re visi o n of pr oce d ure  t o i ncl u de a ser u m pre g na nc y test at s cree ni n g, a n d uri ne 
pre g na nc y test s o n  Da y 0 , D a y 7, Da y 1 4, Da y 2 8, Da y 4 2  a n d Da y 8 4  f or w o me n 
of c hil d beari n g p ote ntial  
•  
A d mi nistrati ve c ha n ges s uc h as fa x n u m ber a d diti o n t o S A E re p orti n g pr oce d ures 
a n d defi niti o ns f or a d diti o nal acr o n y ms a d de d t o t he gl ossar y  
•  
A d diti o n of a +/ - 2 da y visit wi n d o w f or all visits  
•  
A d diti o n of scree ni n g f or HI V, He patitis B, He patitis C a n d C M V i nfecti o n at 
Scree ni n g  
•  
A d diti o n of e xcl usi o n criteri o n # 5  f or detaili n g cli nicall y si g nifica nt a b n or mal 
la b orat or y resul ts 
•  
A d diti o n of ser u m e ota xi n -1 l e vel meas ure me nt at Da y 0, D a y 7, Da y 1 4, Da y 2 8, 
Da y 4 2 , Da y 5 6, Da y 7 0  a n d Da y 8 4  
•  
C ha n ge i n e xcl usi o n criteri o n # 1 3 fr o m s u per p ote nt t o class 1 a n d 2 t o pical 
ster oi ds. Clarifie d t hat use of ot her  t o pical ster oi ds ( ot her t ha n class 1 a n d 2) is 
all o we d  t hr o u g h o ut t he st u d y at t he discreti o n of t he i n vesti gat or. 
•  
A d diti o n of la n g ua ge t o all o w re -scree ni n g of patie nts a n d re peat la bs f or s p uri o us 
test res ults 
•  
Clarifie d pr oce d ure wi n d o ws  
•  
A d de d Q O L  q uesti o n naire, pr uritis vis ual a nal o g scale a n d B P D AI  t o all st u d y 
visits (e xce pt Scree ni n g)  
•  
A d de d E C G a n d he mat ol o g y a n d bi oc he mistr y t o Da y 7, Da y 2 8, Da y 4 2 a n d Da y 
8 4  
•  
A d de d a nti -bertili m u ma b a nti b o dies a n d B P 1 8 0 a n d B P 2 3 0 a ut o a nti b o dies t o all 
st u d y visits (e xce pt Scree ni n g) 
•  
Clarifie d a nal ysis at l ocal vs. c e ntral la b orat or y, s o urce d oc u me nt a n d d oc u me nt 
rete nti o n re q uire me nts 
•  
A d diti o n of A p pe n di x D : T o pical Ster oi ds P ote nc y Class T a ble 
5. 0  
•  
Deleti o n of pri nci pal i n vesti gat or i nf or mati o n d ue t o pr ot oc ol te m plate f or mat 
c ha n ge . 
5

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
Deleti o n of I m m u ne P har mac e uticals, Lt d., Israel i nf or mati o n d ue t o 
a d mi nistrati ve reas o ns. It has bee n c o nfir me d t hat I m m u ne P har mace uticals, 
I nc. al o ne will be t he s p o ns or f or t he st u d y. 
•  
U p date d P B M C bi o mar ker o bj ecti ve t o be less s pecific si nc e it is a n 
e x pl orat or y o bj ecti ve . 
•  
I ncl u de d m ore s pecific defi niti o n of ‘ ne wl y dia g n ose d’ a n d a d de d s pecific 
dia g n ostic pr oce d ures t hat will be a nal yze d ce ntrall y, w here p ossi ble.  
•  
I ncl u de d m ore detail a n d clarit y t o t he defi niti o n of m o derate t o e xte nsi ve 
b ull o us pe m p hi g oi d. Als o, i ncl u de d t he assess me nt of B P se verit y i n or der t o 
d o c u me nt t he n u m ber of ne w b ullae a n d/ or uticarial pla q ues.  
•  
E xte nsi o n of scree ni n g fr o m 2 wee ks t o 4 wee ks.  
•  
Da y 7 Visit delete d as t he visit was dee me d u n necessar y. It is felt t hat n o 
safet y or efficac y iss ues s h o ul d be detecte d at st u d y da y 7. All visit n u m bers 
ha ve bee n a dj uste d acc or di n gl y.  
•  
Clarifie d e xcl usi o n criteria # 1 t o state t hat i n vesti gat or ca n deter mi ne w het her 
or n ot me dical c o n diti o ns, i ncl u di n g me ntal i m pair me nt a n d de me ntia, is 
se vere e n o u g h t o dis q ualif y t he patie nt. 
•  
U p date d e xcl usi o n criter ia t o be c o nsiste nt wit h p oi nt of refere nce t o be Visit 2 
– Da y 0 rat her t ha n baseli ne, e xce pt w here ot her wise state d . 
•  
F urt her clarifie d a n d a me n de d s yste mic oral c ortic oster oi d usa ge g ui deli nes  
i ncl u di n g t he all o wa nce of s yste mic oral c ortic oster oi d usa ge u p t o 4 wee ks 
pri or t o Visit 2 – Da y 0 u p t o d oses of 4 0 m g/ da y pre d ni d o ne e q ui vale nt.  
•  
E x pa n de d ‘i nf usi o n site reacti o ns’ t o all ‘i nf usi o n reacti o ns’.  
•  
U p date d B P D AI t o be t he c urre nt vali date d versi o n . Pr uritis V A S is part of t he 
B P D AI.  
•  
F urt her clarifie d t he efficac y e n d p oi nts . 
•  
M o ve d 4 -h o ur p ost -d ose assess me nts u p t o 2 -h o ur p ost -d ose assess me nts t o 
s h orte n t he le n gt h of visits. It is felt t hat a n y safet y iss ues w o ul d be i de ntifie d 
b y 2 h o urs after treat me nt i nf usi o n.  
•  
I ncl u de d t he ‘ Pr oce d ures f or E nr oll me nt of Eli gi ble P atie nts’ i n secti o n 5. 2 . 
•  
I ncl u de d t hat a n y pri or treat me nts ta ke n wit hi n 9 0 da ys of s cree ni n g s h o ul d be 
d oc u me nte d . 
6

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 7 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
Li mite d t he n u m ber of E C G assess me nts as it was felt t hat t hese w o ul d n ot 
i de ntif y a n y safet y iss ues. 
•  
Clarifie d w hic h la bs will be d o ne ce ntrall y vers us l ocall y.  
•  
U p date d se me n a nal ysis testi n g: p ost -d ose sa m ple c ollecti o n will n o w occ ur as 
cl ose t o t he c o m pleti o n of treat me nt i nf usi o n, rat her t ha n 3 0 mi n utes f oll o wi n g 
t he i nitiati o n of treat me nt i nf usi o n, d ue t o l o gistical diffic ulties of sa m ple 
c ollecti o n. Als o state d t hat i nfertile males or t h ose w h o ha ve reli gi o us 
c o nstrai nts will n ot ha ve t o pr o vi de sa m ples  
•  
Clarifie d T B scree ni n g re q uire me nts . 
•  
I ncl u de d ‘ Assess me nt of lesi o n heali n g’ i n secti o n 5. 3. 9  i n or der t o perf or m a 
t h or o u g h e val uti o n of c o ntr ol of disease acti vit y. 
•  
Left details of p h ot o gra p h y t o be i ncl u de d i n t he P h ot o gra p h y User Ma n ual 
rat her t ha n i n t he pr ot oc ol. 
•  
U p date d t hat s yste mic oral c ortic oster oi d usa ge ca n be m o difie d d uri n g a 
p h o ne call f oll o w -u p rat her t ha n at a cli nic visit.  
•  
U p date d S A E secti o n 7. 2  t o i ncl u de m ore details re gar di n g S A E c ollecti o n 
pr oce d ures.  
•  
C orrecte d fa x n u m ber f or me dical m o nit or.  
•  
Delete d s o me details re gar di n g data ma na ge me nt as t hese ar e better left i n data 
ma na ge me nt pla ns . 
•  
Delete d P B M C a nal ysis fr o m Visit 9.  
•  
Sc he d ule of E ve nts u p date d t o reflect u p date d assess me nt sc he d ule . 
6. 0  
•  
C ha n ge of title : re m o val of “N e wl y D ia g n ose d” a n d a d diti o n of “ Ne wl y 
Dia g n ose d P atie nts a n d P atie nts Resista nt t o C ortic oster oi d T a peri n g”  
•  
A d diti o n of patie nts resista nt t o  c ortic oster oi d ta peri n g  as i ncl usi o n criteri o n  # 3  
•  
A d diti o n of a p ost treat me nt f oll o w u p call 2 a n d 4 m o nt hs after Visit 8 ( Da y 
8 4)  
•  
C ha n ge i n t he sec o n dar y e n d p oi nt: Pr o p orti o n of patie nts w h o ha ve ta pere d t o 
pre d nis o ne d ose of ≤1 0 m g/ da y at Visit 8 ( Da y 8 4) a n d / or 2 a n d 4 m o nt hs after 
Visit 8 ( Da y 8 4)   
•  
E xcl usi o n Criteri o n # 1 1 “ Use of pre vi o ustreat me nt f or b ull o us pe m p hi g oi d ” 
re vise d t o re m o ve re d u n da nc y wit h i ncl usi o n criteri o n # 3 
7

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 8 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
E xcl usi o n criteri o n # 1 5  re vise d: Treat me nt wit h a f ull c o urs e of macr oli des  or 
tetrac ycli nes wit hi n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 
- Da y 0)  
•  
C ha n ge i n i ncl usi o n  criteri o n # 2  t o “ P atie nts wit h a Kar n ofs k y perf or ma nce 
stat us > 4 0 %” t o all o w f or patie nts w h o ma y re q uire a care gi ver 
•  
C o nfir mat o n of dia g n osi s of m o derate t o e xte nsi ve B P o n 3 se parate occasi o ns 
d uri n g t he 4 wee k peri o d (as o p p ose d t o o n 3 c o nsec uti ve da ys) a n d re m o val of 
re q uire me nt f or “ ne w” b ullae a n d urticarial pla q ues as l o n g as criteria of 
“ m o derate t o e xte nsi ve” are met.  
•  
D oi n g t he B P D AI,  V A S , a n d A B Q O L at t he scree ni n g visit  
•  
T he assess me nt B P D AI, Pr urit us V A S, a n d A B Q O L  will be ma de i n relati o n 
t o: 
o  
Scree ni n g, if patie nt is resista nt t o c ortic oster oi d ta peri n g  
o  
Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d  
•  
Sc he d ule of E ve nts u p date d t o reflect u p date d assess me nt sc he d ule. 
7. 0  
•  
C o v er p a g e  u p d at e d t o i ncl u d e n e w S p o ns or A d dr ess 
•  
P a g e 2  r e vis e d wit h n e w S p o ns or R e pr es e nt ati v e i nf or m ati o n f or   
 
•  
P a g e 5 0 u p d at e d wit h 
 i nf or m ati o n as S p o ns or C o nt act f or 
n otific ati o n of s eri o us or u n ex p ect e d a d v ers e ev e nts  
7. 1  
S u b mitte d t o 
/ Site N o.
 i n Israel, o nl y 
(all c ha n ges n ote d i n t his versi o n a p pear i n t he versi o n 8. 0, detaile d bel o w, 
pr o vi de d t o all sites).   
8. 0  
•  
C o ver pa ge  u p date d t o i ncl u de c orrecte d S p o ns or A d dress a n d c o ntact 
i nf or mati o n 
•  
P a ge 2 - pr ot oc ol si g nat ure pa ge, u p date d wit h ne w c orrecte d S p o ns or 
Re prese ntati ve I nf or mati o n f or 
 
 
•  
P a ge 5 0,  S A E N otificati o n P a ge, u p date d wit h ne w c orr ecte d S p o ns or 
I nf or mati o n wit h 
 c o ntact data pr o vi de d  as S p o ns or C o ntact 
f or n otificati o n of seri o us or u ne x pecte d a d verse e ve nts 
•  
A p pe n di x B - Assess me nt of B P Se verit y - u p date d wit h c orrecte d f or m t o 
assess B P se verit y d uri n g scre e ni n g; o mitte d i n err or fr o m pre vi o us pr ot oc ol 
versi o ns  
8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 9 of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Versi o n  
M ai n C h a n ges  
•  
A p pe n di x D - B ull o us P e m p hi g oi d Disease Area I n de x - u p date d wit h c orrecte d 
f or m; t y p o gra p hical err ors were prese nt i n t he pre vi o us pr ot oc ol versi o ns  
•  
Se veral e dit orial c ha n ges i nserte d as necessar y t o e ns ure c o nsiste nc y wit hi n all 
secti o ns of t he te xt a n d bet we e n t he te xt a n d A p pe n di x A - S c he d ule of  
E val uati o ns   
•  
Se veral mi n or la n g ua ge/ gra m matical/ p u nct uati o n c ha n ges i nserte d as 
necessar y t o e ns ure acc urac y a n d clearer c o m pre he nsi o n b y t he rea der  
 
 
 
9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
P R O T O C O L S Y N O P SI S  
St u d y Title  
A n O pe n -La bel, Pr o of of C o nce pt St u d y Desi g ne d t o E val uate t he Safet y, Efficac y 
a n d P har mac o d y na mic Effect of Bertili m u ma b i n N e wl y Dia g n ose d Patie nts a n d 
Patie nts  Resista nt T o C ortic oster oi d T a peri n g  wit h M o derate t o E xte nsi ve  B ull o us  
Pe m p hi g oi d 
P r ot oc ol N o.  
I m m u ne/ B R T/ B P- 0 1 
Cli nic al Sites  
U p t o 1 0 sites i n Israel a n d U S  
A d diti o nal sites ma y be a d de d as necessar y t o c o m plete e nr oll me nt  
St u d y P h ase  
2a 
I n dic ati o n 
M o derate t o e xte nsi ve  B ull o us Pe m p hi g oi d ( B P)  
St u d y O bjecti ves  
P ri m ar y O bjecti ve :  
•  T o e val uate t he safet y of bertili m u ma b i n ne wl y dia g n ose d patie nts a n d patie nts 
resista nt t o c ortic oster oi d ta peri n g wit h m o derate t o e xte nsi ve B P  
Sec o n d ar y O bjecti ve :  
•  T o e val uate t he preli mi nar y e vi de nce of cli nical efficac y, p har mac o ki netics 
( P K) a n d t he p har mac o d y na mic ( P D) effect of bertili m u ma b ne wl y dia g n ose d 
a n d patie nts resista nt t o c ortic oster oi d ta peri n g wit h m o derate t o e xte nsi ve B P 
E x pl or at or y O bjecti ve:  
•  
T o deter mi ne c ha n ge fr o m baseli ne of P B M C bi o mar kers  
St u d y Desi g n  
T his  is  a n  o pe n -la bel,  pr o of- of-c o nce pt,  si n gle  gr o u p  st u d y  i n a d ult ne wl y 
dia g n ose d patie nts a n d patie nts resista nt  t o  c ortic oster oi d  ta peri n g wit h 
m o derate t o e xte nsi ve B P.  
Eli gi ble patie nts are t h ose w h o: 
a.   I deall y, ha ve  n ot  bee n  pre vi o u sl y  treate d  f or  B P.  H o we ver,  t he  f oll o wi n g 
treat me nts are per mitte d f or ne wl y dia g n ose d patie nts  
•  
S yste mic oral c ortic oster oi ds ≤4 0. 0 m g/ da y ( pre d nis o ne e q ui vale nt) wit hi n 
4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
•  
T o pical c orti c oster oi ds ot her t ha n t h ose t hat are Class 1 or Class 2 ( See 
A p pe n di x  F ) wit hi n 2  wee ks  pri or  t o  t he  first  treat me nt  a d mi nistrati o n 
( Visit 2 - Da y 0)  
b.   Ha ve  bee n  pre vi o usl y  dia g n ose d  wit h  B P ,  a n d are  resista nt t o  c ortic oster oi d 
ta peri n g, i n w hic h case ot her c ortic oster oi d re gi me ns are per mitte d. No was h - o ut 
peri o d is re q uire d.   
c.  Ha ve bee n dia g n ose d b y t he f oll o wi n g assess me nts:  
•  
Cli nical e val uati o n c o nfir mi n g B P  
1 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
•  
He mat o x yli n a n d e osi n ( H & E) stai ni n g of a s ki n p u nc h bi o ps y fr o m t he 
e d ge  of  a  lesi o n  t o  c hec k  t he  e osi n o p hil  ma ke - u p (i ncl u di n g  e osi n o p hil 
c o u nt) of t he i nfla m mat or y i nfiltrate  
•  
Ser u m testi n g f or a nti B P 1 8 0 a n d a nti B P 2 3 0 a ut oa nti b o dies  
•  
Direct i m m u n ofl u oresce nce ( DI F) o n salt s plit s ki n of a s ki n p u nc h 
bi o ps y fr o m a perilesi o nal area t o c hec k t he li near de p ositi o n of I g G 
a n d/ or C 3 o n t he blister r o of (e pi der mal si de) 
•  
I n direct i m m u n ofl u oresce nce (II F) of t he patie nt’s ser u m t o c hec k f or t he 
prese nce of I g G circ ulati n g a ut oa nti b o dies   
Alt h o u g h all of t hese assess me nts m ust be perf or me d, ulti mate deter mi nati o n of a 
p ositi ve B P dia g n osis is u p t o t he i n vesti gat or.  
I n  ne wl y-dia g n ose d  patie nts,  i f  a n y  of  t hese  assess me nts  ha ve  bee n  perf or me d 
pre vi o usl y wit hi n  4  wee ks  pri or  t o  first  treat me nt  a d mi nistrati o n,  t he  s pecific 
assess me nt will n ot ha ve t o be re peate d.  
I n  patie nts  resista nt  t o  c ortic oster oi d  ta peri n g,  if  eit her  DI F  or  II F 
i m m u n ofl u oresce nce  assess me nts  ha ve  bee n  perf or me d  pre vi o usl y,  t he  s pecific 
assess me nt will n ot ha ve t o be re peate d . 
M o derate t o e xte nsi ve b ull o us pe m p hi g oi d is defi ne d b y t he mea n n u m ber of b ullae 
a n d/ or  urticarial  pla q ues  t hat  a p pear o n  t he  patie nt’s b o d y,  as  d oc u me nte d  o n 3 
se parate  occasi o ns  d uri n g  t he  4  wee k  scree ni n g  peri o d,  b y  t he  i n vesti gat or, 
referri n g p h ysicia n or re p orte d b y t he patie nt or care gi ver.  T o meet t his criteri o n,  
it m ust be d oc u me ntate d t hat  t he patie nt has  “ m o derate t o e xte nsi ve B P”, o n t hree 
se parate occasi o ns, w here m o derate disease is defi ne d b y 2 - 1 0 b ullae a n d/ or ≥ 5 
urticarial pla q ues  a n d exte nsi ve disease is defi ne d b y > 1 0 b ullae a n d/ or urticarial 
pla q ues [3 ].  
T he st u d y will c o nsist of t hree peri o ds:  
•  
A scree ni n g peri o d of u p t o 4 wee ks  
•  
A n o pe n- la bel treat me nt peri o d lasti n g 4 wee ks c o nsisti n g of I V i nf usi o n 
of bertili m u ma b at Visit 2 (D a y 0), Visit 3 ( Da y 1 4) a n d Visit 4 ( Da y 2 8)  
•  
A safet y a n d efficac y f oll o w- u p peri o d of a p pr o xi matel y 5 6 da ys ( or 9 0 
da ys f or males w h o ha ve ha d a b n or mal se me n a nal ysis res ults f or p ost -
d ose Visit 2 ( Da y 0) , Visit 3  ( Da y 1 4) or Visit 4 ( Da y 2 8) c o m pare d t o 
t he pre- d ose Visit 2 ( Da y 0) res ults), pl us a f oll o w- u p p h o ne call at 2 a n d 
4 m o nt hs f oll o wi n g Visit 8 ( Da y 8 4 )  
 
1 1

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Scree ni n g –  Visit 1 ( D a y -2 8  t o D a y  -1)  
F oll o wi n g  si g ni n g  of  i nf or me d  c o nse nt,  patie nts  will  be  scree ne d  f or  st u d y 
eli gi bilit y (assess me nt  of  i ncl usi o n  a n d  e xcl usi o n  criteria). T he  f oll o wi n g 
assess me nts  will  be  perf or me d:  c ollecti o n  of  de m o gra p hic  i nf or mati o n, me dical 
hist or y,  pri or a n d  c o nc o mita nt me dicati o ns, a n d  a d verse  e ve nt  data. Kar n ofs k y 
perf or ma nce  stat us,  p h ysical  e xa mi n ati o n,  hei g ht  a n d  wei g ht,  vital  si g ns,  E C G, 
scree ni n g  f or  acti ve/late nt t u berc ul osis  ( T B),  s ki n  p u nc h  bi o ps y  f or  DI F  o n  salt 
s plit ski n, s ki n p u nc h bi o ps y f or H & E i ncl u di n g e osi n o p hil c o u nt, ser u m c ollecti o n 
f or  II F  a n d  B P 1 8 0  &  B P 2 3 0  a ut oa nti b o dies, assess me nt  of  B P  se verit y, 
p h ot o gra p h y, B P Disease Area I n de x ( B P D AI ) i ncl u di n g Pr urit us V A S a n d M D 
assess me nt  of  lesi o ns , A B Q O L, 
a n d  la b orat or y  e val uati o ns  ( he mat ol o g y, 
bi oc he mistr y, ser ol o g y a n d  ser u m  pre g na nc y  test (f or  fe males  of  c hil d beari n g 
p ote ntial) ). B P  Disease  Area  I n de x  ( B P D AI ) i ncl u di n g  Pr urit us  V A S  a n d  M D 
assess me nt  of  lesi o ns  a n d  A B Q O L s h o ul d  be  perf or me d  if  p ossi ble  pri or  t o 
c o m me nce me nt of c ortic oster oi d re gi me n.  C ortic oster oi d usa ge will be ma na ge d 
a n d  d oc u me nte d  d uri n g  t he  scree ni n g  peri o d.  C or tic oster oi d  ma na ge me nt  ca n 
occ ur eit her d uri n g a sc he d ule d visit, u nsc he d ule d visit, or p h o ne -call f oll o w- u p 
base d o n t he i n vesti gat or’s discreti o n.  
T he scree ni n g visit ma y be c o n d ucte d o ver m ulti ple da ys. Patie nts w h o meet all 
t he i ncl usi o n criteria a n d no ne of t he e xcl usi o n criteria ma y  be e nr olle d i n t he st u d y.  
If s u bjects fail scree ni n g, t he s u bject ma y be rescree ne d o nce at t he discreti o n of 
t he i n vesti gat or. Rescree ne d s u bjects  will get a ne w st u d y i de ntificati o n n u m ber o n 
rescree ni n g.  A la b assess me nt  d uri n g t he scree ni n g peri o d ma y be re peate d at t he 
discreti o n of t he i n vesti gat or if dee me d s p uri o us wit h o ut re peati n g t he e ntire set of 
scree ni n g re q uire me nts.  I n t his partic ular case, t he s u bject will n ot get a ne w st u d y 
i de ntificati o n n u m ber. 
Tre at me nt P eri o d a – Visit 2 ( D a y 0, b aseli ne), Visit 3 ( D a y 1 4) a n d Visit 4 ( D a y 
2 8)  
At Visit 2, i ncl usi o n a n d e xcl usi o n criteria will be re vie we d.  
T he f oll o wi n g assess me nts will be perf or me d o n Visit  2 ( Da y 0), Visit 3 ( Da y 1 4), 
a n d Visit 4 ( Da y  2 8)  pri or  t o  a d mi nistrati o n  of  bertili m u ma b: c ollecti o n  of 
c o nc o mita nt  treat me nt  a n d  a d verse  e ve nt  data, p h ysical  e xa mi nati o n  (i ncl u di n g 
wei g ht), vital  si g ns, B P  Disease  Area  I n de x  ( B P D AI ) i ncl u di n g  Pr urit us  V A S, 
p h ysicia n’s assess me nt  of  lesi o n  heali n g , c o m pleti o n  of A ut oi m m u ne  B ull o us 
Disease  Q ualit y  of  Life  ( A B Q O L )  q uesti o n naire, p h ot o gra p h y ,  uri ne  pre g na nc y 
test (f or fe males of c hil d beari n g p ote ntial), ser u m c ollecti o n f or B P 1 8 0 a n d B P 2 3 0 
a ut oa nti b o dies ,  ser u m  e ota xi n-1  le vels,  a nti -bertili m u ma b  a nti b o dies,  safet y 
la b orat or y  e val uati o ns  ( he mat ol o g y,  bi oc he mistr y), P B M C  bi o mar kers  ( Visit  2 
o nl y) , P K sa m pli n g ( pre-d ose ti me p oi nt) , a n d se me n a nal ysis ( N ote: t he pre - d osi n g 
se me n a nal ysis sa m ples ca n be ta ke n u p t o 2 da ys pri or t o d osi n g).  
O n Visit 2  ( Da y 0), Visit 3 ( Da y 1 4), a n d Visit 4 ( Da y 2 8), f oll o wi n g c o m pleti o n 
of pre -d ose assess me nts, bertili m u ma b will be a d mi nistere d b y I V i nf usi o n o ver 3 0 
mi n utes of i nf usi o n ti me .  
Vital  si g ns  will  be assesse d  a n d  P K  p ost -d ose  sa m ples  will  be  c ollecte d  at t he 
c o mpleti o n  of  treat me nt  i nf usi o n  ( a p pr o xi matel y  3 0  mi n utes f oll o wi n g  t he 
i nitiati o n of st u d y dr u g i nf usi o n ) a n d a p pr o xi matel y 2  h o urs f oll o wi n g i nitiati o n of 
1 2

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
st u d y dr u g i nf usi o n. Se me n a nal ysis will first be perf or me d at t he c o m pleti o n of 
treat me nt i nf usi o n (a p pr o xi matel y 3 0 mi n utes f oll o wi n g t he i nitiati o n) or as cl ose 
t o  t his  ti me  as  p ossi ble.  Assess me nt f or e vi de nce  of  i nf usi o n  reacti o n  will  be 
c o n d ucte d at  t he  c o m pleti o n  of  treat me nt  i nf usi o n  (a p pr o xi matel y  3 0  mi n utes  
f oll o wi n g t he i nitiati o n) a n d a p pr o xi matel y 2  h o urs f oll o wi n g i nitiati o n of d osi n g , 
a n d a d verse e ve nts a n d c o nc o mita nt me dicati o ns will be rec or de d. C ortic oster oi d 
usa ge will be ma na ge d a n d d oc u me nte d as necessar y. C ortic oster oi d ma na ge me nt 
ca n occ ur eit her d uri n g a sc he d ule d visi t, u nsc he d ule d visit, or p h o ne-call f oll o w-
u p base d o n t he i n vesti gat or’s discreti o n.  
F oll o w- U p Peri o d 
b - Visit  5 ( D a y 4 2), Visit 6 ( D a y 5 6), Visit 7 ( D a y 7 0), Visit 
8 ( D a y 8 4), Visit 9 ( D a y 1 1 8), a n d P h o ne C all F oll o w -u p a p pr o xi m atel y 2 a n d 
4 m o nt hs afte r Visit 8 ( D a y 8 4)  
T he f oll o wi n g assess me nts will be perf or me d at t he f oll o w -u p cli nic visits e xce pt 
f or Visit 9 ( Da y 1 1 8): p h ysical e xa mi nati o n (i ncl u di n g wei g ht), B P D AI i ncl u di n g 
Pr urit us V A S,  p h ysicia n’s  assess me nt of lesi o n heali n g , c o m pleti o n of A B QO L 
q uesti o n naire, p h ot o gra p h y, vital si g ns, A E a n d c o nc o mita nt me dicati o n rec or di n g 
a n d ser u m c ollecti o n f or B P 1 8 0 a n d B P 2 3 0 a ut oa nti b o d y titres, P K, bl o o d sa m ple 
c ollecti o n f or meas ure me nt of ser u m e ota xi n -1 a n d a nti -bertili m u ma b a nti b o dies. 
S ki n  p u nc h  bi o ps y  f or  H & E  stai ni n g  a n d e osi n o p hil  c o u nt  i n  tiss ue  will  be 
c o n d ucte d ( Visit 5 o nl y). Uri ne pre g na nc y test ( Visit 5 a n d Visit 8) f or fe males of 
c hil d beari n g p ote ntial o nl y), P B M C bi o mar ker bl o o d sa m pli n g ( Visit 5 o nl y) a n d 
safet y la b orat or y e val uati o ns ( he mat ol o g y, bi oc he mistr y) will be perf or me d ( Visits 
5 a n d 8 o nl y).  E C G will be perf or me d at Visit 8 ( Da y 8 4). T he o nl y assess me nts 
t hat  will  be  perf or me d  o n  Visit  9  ( Da y  1 1 8)  are  c ollecti o n  of  c o nc o mita nt 
me dicati o n a n d a d verse e ve nt i nf or mati o n, a n d se me n a nal ysis f or males w h o ha ve 
ha d a b n or mal se me n a nal ysis res ults at  Visit 2 ( Da y 0) p ost -d ose, Visit 3 ( Da y 1 4) 
or Visit 4 ( Da y 2 8) c o m pare d t o baseli ne pre- d ose Visit 2 res ults.  
C ortic oster oi d usa ge will be d oc u me nte d a n d ma na ge d as necessar y. C ortic oster oi d 
ma na ge me nt  ca n occ ur eit her d uri n g  a sc he d ule d visit , u nsc he d ule d visit , or p h o ne-
call f oll o w- u p base d o n t he i n vesti gat or’s discreti o n. 
P h o ne c all  f oll o w-u p  ( A p pr o xi m atel y 2 a n d 4 m o nt hs after Visit 8 ( - D a y 8 4) 
T he  f oll o wi n g  assess me nts  will  be  perf or me d:  c o m pleti o n  of  A B Q O L 
q uesti o n naire ,  a d verse  e ve nt  assess me nt,  a n d c o nc o mita nt  me dicati o n. 
C ortic oster oi d usa ge will be d oc u me nte d a n d ma na ge d as necessar y.  
St u d y D ur ati o n  
St u d y d urati o n f or eac h patie nt (f oll o wi n g t he scree ni n g peri o d) will be u p t o 
a p pr o xi matel y 2 0 4 da ys   
Scree ni n g peri o d: 
U p t o 4 wee ks  
Treat me nt peri o d: 
2 8 da ys ( ±  2 da ys) 
F oll o w- u p peri o d: 
5 6 da ys ( ±  2 da ys)  or 9 0 da ys ( ±  2 da ys)  f or males w h o 
ha ve ha d a b n or mal s e me n a nal ysis res ults p ost -d ose Visit 
                                                 
a, b St u d y visits 3 t hr o u g h 9 ha ve a ± 2 da y wi n d o w. T he wi n d o w is calc ulate d fr o m t he act ual visit da y c o m pare d t o 
baseli ne ( Da y 0 ), (e. g., f or Visit  6 ( Da y 5 6) t he wi n d o w w o ul d be Da y 5 4 t o Da y 5 8) 
1 3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 4  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
2 ( Da y 0) , Visit 3  (Da y 1 4 ) or Visit 4 ( Da y 2 8) c o m pare d 
t o pre-d ose Visit 2 ( Da y 0) res ults; 2 a n d 4 m o nt hs 
f oll o w- u p p h o ne call after Visit 8 ( Da y 8 4) .   
 
N u m ber of 
P atie nts  
U p t o 1 5  patie nts are e x pecte d t o be e nr olle d i n t his st u d y. Recr uit me nt will  be 
c o m petiti ve.  
I ncl usi o n Criteri a 1.  Males or fe males, ≥ 6 0 years of a ge  
2.  Patie nts wit h a Kar n ofs y Perf or ma nce Stat us > 4 0 %  
3.  Eli gi ble patie nts are defi ne d as f oll o ws: 
a. I deall y, t h ose w h o ha ve n ot bee n pre vi o usl y treate d f or B P ( ne wl y 
dia g n ose d).  H o we ver, t he f oll o wi n g treat me nts are per mitte d:    
•  
S yste mic  oral  c ortic oster oi ds  ≤4 0. 0  m g/ da y  ( pre d nis o ne 
e q ui vale nt)  wit hi n  4  wee ks  pri or  t o  t he  first  treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0)  
•  
T o pical  c ortic oster oi ds  ot her  t ha n  t h ose  t hat  are  Class  1  or 
Class  2  ( See A p pe n di x  F ) wit hi n 2 wee ks  pri or  t o  t he first 
treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
b.  Pre vi o usl y  dia g n ose d  B P  patie nts,  w h o   are  resista nt  t o 
c ortic oster oi d  ta peri n g,  i n  w hic h  case  ot her  c ortic oster oi d 
re gi me ns are per mitte d. N o was h- o ut peri o d is re q uire d.  
c. All  patie nts,  m ust  be   dia g n ose d b y  t he  f oll o wi n g  assess me nts  
d uri n g t he scree ni n g peri o d: 
•  
Cli nical e val uati o n c o nfir mi n g B P  
•  
He mat o x yli n a n d e osi n ( H & E) stai ni n g of a s ki n p u nc h bi o ps y 
fr o m  t he  e d ge  of  a  lesi o n  t o  c hec k  t he  e osi n o p hil  ma ke- u p  
(i ncl u di n g e osi n o p hil c o u nt) of t he i nfla m ma t or y i nfiltrate 
•  
Ser u m testi n g f or a nti B P 1 8 0 a n d a nti B P 2 3 0 a ut oa nti b o dies 
•  
Direct i m m u n ofl u oresce nce ( DI F) o n salt s plit s ki n of a s ki n 
p u nc h  bi o ps y  fr o m  a  perilesi o nal  area  t o  c hec k  t he  li near 
de p ositi o n  of  I g G  a n d/ or  C 3  o n  t he  blister  r o of  (e pi der mal 
si de) 
•  
I n direct  i m m u n ofl u oresce nce  (II F)  of  t he  patie nt’s  ser u m  t o 
c hec k f or t he prese nce of I g G circ ulati n g a ut oa nti b o dies   
T h o u g h all of t hese assess me nts m ust be perf or me d, ulti mate deter mi nati o n of 
a p ositi ve B P dia g n osis, base d o n t he c o m p osite of t hese i nicat ors, is u p t o t he 
i n vesti gat or.  
I n ne wl y- dia g n ose d patie nts, if a n y of t hese assess me nts ha ve bee n perf or me d 
pre vi o usl y wit hi n 4 wee ks pri or t o first treat me nt a d mi nistrati o n, t he s pecific 
assess me nt will n ot ha ve t o be re peate d. I n patie nts r esista nt t o c ortic oster oi d 
ta peri n g,  if  eit her  DI F  or  II F  i m m u n ofl u oresce nce  assess me nts  ha ve  bee n 
perf or me d pre vi o usl y, t he s pecific assess me nt will n ot ha ve t o be re peate d.   B P 
1 4

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
Disease Area I n de x ( B P D AI ) i ncl u di n g Pr urit us V A S , p h ysicia n’s assess me nt 
of lesi o ns a n d  A B Q O L s h o ul d  be  perf or me d  pri or  t o  a d mi nistrati o n  of 
c ortic oster oi ds if p ossi ble . 
4.  M o derate t o e xte nsi ve b ull o us pe m p hi g oi d is defi ne d b y t he mea n n u m ber of 
b ullae  a n d/ or  urticarial  pla q ues  t hat  ha ve  a p peare d o n  3  se parate  occasi o ns  
d uri n g scree ni n g as deter mi ne d b y t he i n vesti gat or, t he referri n g p h ysicia n or 
re p orte d b y t he patie nt or care gi ver. M o derate disease is defi ne d b y 2-1 0 b ullae 
a n d/ or ≥5 urticarial pla q ues. E xte nsi ve disease is defi ne d b y > 1 0 b ullae a n d/ or 
urticarial pla q ues [3 ].   
5.  S yste mic  c ortic oster oi ds  f or  reas o ns  ot her  t ha n  b ull o us  pe m p hi g oi d  ma y  be 
use d  wit h  a  was h o ut  peri o d  of  4  wee ks  pri or  t o  t he  first  treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0) .  
6.  A de q uate car diac, re nal a n d he patic f u ncti o n as deter mi ne d b y t he in vesti gat or 
a n d de m o nstrate d b y scree ni n g la b orat or y e val uati o ns, vital si g n meas ure me nt, 
E C G rec or di n g a n d p h ysical e xa mi nati o n res ults 
7.  Fe males w h o , i n t he o pi ni o n of t he i n vesti gat or, are of c hil d beari n g p ote ntial 
m ust ha ve  a  ne gati ve  ser u m  pre g na nc y  test  at  scree ni n g  a n d a gree  t o  use 
effecti ve  c o ntrace pti o n (h or m o nal  c o ntrace pti o n  or  t w o  f or ms  of  barrier 
c o ntrace pti o n) c o nsiste ntl y t hr o u g h o ut t he st u d y.    
8.  Males m ust ha ve ha d a vasect o m y or ha ve e x presse d t hat t he y ha ve n o i nterest 
i n fertilit y i n t he f ut ure. 
9.  Fertile males ( males wit h n o hist or y of i nfertilit y or vasect o m y) m ust a gree t o 
use  effecti ve  c o ntrace pti o n  (e. g. , c o n d o ms,  s per mici des)  c o nsiste ntl y 
t hr o u g h o ut  t he  st u d y  a n d  f or  a  peri o d  of  f o ur  m o nt hs  f oll o wi n g  t he  e n d  of 
treat me nt a d mi nistrati o n.   
1 0.  Patie nts m ust be w illi n g a n d a ble t o a d here t o t he st u d y visit sc he d ule a n d ot her 
pr ot oc ol re q uire me nts. 
1 1.  Patie nts  m ust  be  w illi n g  a n d  a ble  t o  pr o vi de  v olu ntar y  writte n  i nf or me d 
c o nse nt or writte n i nf or me d c o nse nt fr o m a le gall y a ut h orize d re prese ntati ve. 
E xcl usi o n criteri a  1.  Patie nts wit h se vere me dical or s ur gical c o n diti o n s at scree ni n g or Visit 2 ( Da y 
0) i ncl u di n g, b ut n ot li mite d t o, se vere de me ntia or me ntal i m pair me nt, se vere 
str o ke,  se vere  car diac  i ns ufficie nc y, se vere  arterial  h y perte nsi o n, se vere  or 
u nc o ntr olle d  re nal,  he patic,  he mat ol o gical,  gastr oi ntesti nal,  e n d ocri ne, 
p ul m o nar y, car diac, ne ur ol o gic, cere bral, ps yc hiatric, or a n y ot her se vere ac ute 
or  c hr o nic  me d ical  c o n diti o n  t hat,  i n  t he  o pi ni o n  of  t he  i n vesti gat or,  ma y 
i ncrease t he ris k ass ociate d wit h st u d y partici pati o n/treat me nt or ma y i nterfere 
wit h  t he  i nter pretati o n  of  st u d y  res ults  a n d  w o ul d  ma ke  t he  patie nt 
i na p pr o priate f or st u d y e ntr y  
2.  Prese nce  of  a n y  mali g na nc y  t hat  has  bee n  u n der  acti ve  treat me nt  (e. g., 
ra di ot hera p y or  c he m ot hera p y)  wit hi n  t he  2  years  pri or  t o b aseli ne  or  is 
a ntici pate d t o re q uire treat me nt d uri n g t he st u d y peri o d (i ncl u di n g f oll o w u p) 
wit h  t he  e xc e pti o n  of  patie nts  wit h  re m o val  of  u nc o m plicate d  basal  cell 
carci n o ma or c uta ne o us s q ua m o us cell carci n o ma, w h o ma y ta ke part i n t he 
st u d y 
1 5

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
3.  C o n ge nital  or  ac q uire d  i m m u n o deficie nc y  (e. g.,  c o m m o n  varia ble 
i m m u n o deficie nc y, or ga n tra ns pla ntati o n) 
4.  Cli nicall y si g nifica nt vital si g n meas ure me nts or E C G fi n di n gs as deter mi ne d 
b y t he i n vesti gat or  
5.  Cli nicall y si g nifica nt a b n or mal la b orat or y test res ults  at scree ni n g as defi ne d 
b y t he i n vesti gat or, i ncl u di n g, b ut n ot li mite d t o : 
•  
He m o gl o bi n le vel < 1 0
.
0 g/ d L 
•  
W hite bl o o d cell c o u nt < 3 x 1 0
3/ µ L 
•  
L y m p h oc yte c o u nt < 0. 5 x 1 0 3/ µ L 
•  
Platelet c o u nt < 1 0 0 x 1 0 3/ µ L or >1 2 0 0 x 1 0 3/ µ L 
•  
Ala ni ne a mi n otra nsferase ( A L T) or as partate  a mi n otra nsferase ( A S T) 
> 3  t he u p per li mit of n or mal ( U L N) 
•  
Al kali ne p h os p hatase > 3  U L N  
•  
Ser u m creati ni ne > 2  U L N  
6.  C o nc o mita nt s ki n c o n diti o ns  pre ve nti n g p h ysical e val uati o n of B P 
7.  Acti ve or rece nt h ist or y of cli nicall y si g nifica nt i nfecti o n wit hi n 1 m o nt h  of t he 
first treat me nt a d mi nistrati o n ( Visit 2 – Da y 0)  
8.  Patie nts w h o are p re g na nt or breast-fee di n g, or pla nni n g t o bec o me pre g na nt 
d uri n g t he st u d y 
9.  Partici pati o n  i n  a  cli nical  trial  of  a n  i n vesti gati o nal  ( u na p pr o ve d)  pr o d uct 
wit hi n 4 wee ks  pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 – Da y 0)   
1 0.  Patie nts w h o are k n o w n t o ha ve h y perse nsiti vit y t o bertili m u ma b or a n y of t he 
dr u g e xci pie nts 
1 1.  Use  of  a n y  pre vi o us  treat me nt  f or  b ull o us  pe m p hi g oi d  ( ot her  t ha n  t he 
oral/t o pical  c ortic oster oi d  re gi me ns  all o we d as  descri be d  a b o ve  i n i ncl usi o n 
criteria # 3a   a n d # 3 b, a n d ot her t ha n t h ose treat me nts descri be d i n e xcl usi o n 
criteria  # 1 3 -1 5 bel o w,  f or  w hic h  t he  a p pr o priate  was h -o ut  peri o ds  were 
a p plie d).  
1 2.  Treat me nt  wit h  s yste mic  c ortic oster oi ds  at  a n y  d ose  f or  reas o ns  ot her  t ha n 
b ull o us pe m p hi g oi d  wit hi n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n 
( Visit 2 - Da y 0)  
1 3.  Treat me nt wit h i m m u n os u p pressa nts (e . g., azat hi o pri ne, met h otre xate) wit hi n 
4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
1 4.  Treat me nt  wit h  bi ol o gics  (e . g., eta nerce pt,  a dali m u ma b,  uste ki n u ma b, 
i nfli xi ma b,  i ntra ve n o us  I g)  wit hi n 4 m o n t hs pri or  t o  t he  first  treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0) . Patie nts w h o ha ve recei ve d rit u xi ma b wit hi n 
1  year  pri or  t o  t he  first  treat me nt  a d mi nistrati o n  ( Visit  2 - Da y  0)  will  be 
e xcl u de d fr o m st u d y partici pati o n.  
1 6

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 5.  Treat me nt wit h a f ull c o urse of macr oli des or tetrac ycli nes  wit hi n 4 wee ks pri or 
t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)   
1 6.  S u bj ects w h o r ecei ve d a vacci ne or ot her i m m u n osti m ulat or wit hi n 4 wee ks 
pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) 
1 7.  S u bj ects w h o h a ve cli nical, ra di o gra p hic, or la b orat or y e vi de nce of acti ve or 
late nt m yc o bacteri u m t u berc ul osis ( T B)  i nfecti o n  
1 8.  E vi de nce of a n acti ve disease  of he patitis B  ( H Bs A g or H Bc A b p ositi ve) or  
he patitis   C ( H C V  A b  p ositi ve), C M V  (I g M  p ositi ve) 
or  h u ma n 
i m m u n o deficie nc y vir us ( HI V) i nfecti o n ( HI V 1/ 2 A b p ositi ve) 
1 9.  Acti ve a b use of alc o h ol or dr u gs  
2 0.  A n y ot her c o n diti o n, w hic h, i n t he o pi ni o n of t he in vesti gat or , w o ul d place t he 
patie nt at a n u nacce pta ble ris k if partici pati n g i n t he st u d y pr ot oc ol 
I n vesti g ati o n al 
P r o d uct R o ute 
a n d D os a ge F or m  
Bertili m u ma b  is  a  rec o m bi na nt  h u ma n i m m u n o gl o b uli n  G  (I g G4 ) m o n ocl o nal 
a nti b o d y t hat ne utralizes h u ma n e ota xi n -1 (e ota xi n); t he dr u g pr o d uct c o nsists of 
bertili m u ma b f or m ulate d i n p h os p hate b uffere d sali ne ( P B S) at a c o nce ntrati o n of 
1 0  m g/ m L,  prese nte d  as  a  sterile,  clear,  c ol orless  s ol uti o n  i n  1 0  m L  clear  glass 
vials.  
Bertili m u ma b 1 0 m g/ k g will be a d mi nistere d b y I V o ver 3 0 mi n utes  of i nf usi o n 
ti me at Visit 2 ( Da y 0), Visit 3 ( Da y 1 4), a n d Visit 4 ( Da y 2 8). T he wei g ht use d f or 
d ose calc ulati o n at all d osi n g da ys is t he wei g ht meas ure d at scree ni n g.  
S yste mic 
C ortic oster oi d 
Us a ge  
D ue t o t he p ote ntial effects of l o n g -ter m a n d/ or hi g h-d ose s yste mic c ortic oster oi d 
usa ge o n b ull o us pe m p hi g oi d, ne wl y dia g n ose d patie nts will be per mitte d t o ta ke 
s yste mic oral c ortic oster oi ds s pecificall y f or b ull o us pe m p hi g oi d o nl y f or a peri o d 
of 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) at d oses n o 
greater t ha n 4 0 m g/ da y pre d nis o ne e q ui vale nt.  S peci ficall y: 
Patie nts w h o are ne wl y dia g n ose d: 
•  
W h o ha ve ta ke n s yste mic c ortic oster oi d s f or b ull o us pe m p hi g oi d l o n ger 
t ha n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) 
or at d oses greater t ha n 4 0 m g/ da y pre d nis o ne e q ui vale nt at a n y ti me  are 
e xcl u de d fr o m t he st u d y.   
•  
F or patie nts w h o ha ve use d s yste mic c ortic oster oi ds f or reas o ns ot her t ha n 
b ull o us  pe m p hi g oi d,  a  was h o ut  peri o d  of  4  wee ks  pri or  t o  t he  first 
treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) is re q uire d. 
•  
F or ne wl y dia g n ose d patie n ts w h o are ta ki n g s yste mic c ortic oster oi ds at a 
dail y d ose bet wee n 4 0 m g/ da y a n d 3 0 m g/ da y pre d nis o ne e q ui vale nt f or 
B P wit hi n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 
0),  ta peri n g  of  s yste mic  c ortic oster oi ds  is  at  t he  discreti o n of  t he 
i n vesti gat or. H o we ver, t h ose patie nts m ust be o n 3 0 m g/ da y pre d nis o ne 
e q ui vale nt  f or  t he  first  treat me nt  a d mi nistrati o n  ( Visit  2 - Da y  0). F or 
ne wl y dia g n ose d patie nts w h o are ta ki n g less t ha n 3 0 m g/ da y pre d nis o ne 
e q ui vale nt pri or t o t he first a d mi n istrati o n da y ( Visit 2 - Da y 0), a sta ble 
1 7

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
d ose of s yste mic c ortic oster oi ds s h o ul d be mai ntai ne d u ntil Visit 2 ( Da y 
0).  
Patie nts w h o are resista nt t o c ortic oster oi d ta peri n g : 
•  
Are n ot re q uire d t o be was he d o ut fr o m oral c ortic oster oi d treat me nt 
pri or t o Visit 2 – Da y 0 .  
T he ta peri n g sc he d ule de picte d i n Ta ble 1 is rec o m me n de d f or all patie nts f or t he  
re mai n der of t he st u d y. 
T a ble 1: Rec o m me n de d C ortic oster oi d T a peri n g Re gi me n  
S yste mic c ortic oster oi d d ose 
( pre d nis o ne e q ui v ale nt) per d a y 
T a peri n g sc he d ule  
≥3 0. 0- 1 0. 1 m g/ da y 
Decrease b y 5 m g eac h wee k  
1 0. 0 – 0 m g/ da y 
Decrease b y 2. 5 m g eac h wee k  
C ortic oster oi d ma na ge me nt ca n occ ur eit her d uri n g a sc he d ule d visit, u nsc he d ule d 
visit, or p h o ne- call f oll o w- u p as per t he i n vesti gat or’s discreti o n.  
Resc ue T her a p y  
If  necessar y,  resc ue  t hera p y  is  per mitte d  at a n y  p oi nt  d uri n g  t he  st u d y at  t he 
discreti o n of t he i n vesti gat or.  T he patie nt ca n c o nti n ue i n t he st u d y as l o n g as t he 
resc ue t hera p y is clearl y d oc u me nte d.  
O utc o me 
Me as ures  
P RI M A R Y E N D P OI N T S 
S A F E T Y E N D P OI N T S  
Safet y will be e val uate d o n t he basis of t he f oll o wi n g para meters:  
•  
A d verse e ve nts ( A E)  
•  
I nf usi o n reacti o ns  
•  
I nj ecti o n site reacti o ns 
•  
P h ysical e xa mi nati o n  
•  
Vital si g ns ( bl o o d press ure, heart rate, te m perat ure)  
•  
E C G  
•  
C o nc o mita nt me dicati o ns  
•  
La b orat or y e val uati o n ( he mat ol o g y, bi oc he mistr y, a nti- bertili m u ma b 
a nti b o dies) 
S E C O N D A R Y E N D P OI N T S  
E F FI C A C Y E N D P OI N T S  
1 8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 1 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
•  
Pr o p orti o n of patie nts w h o ac hie ve a re d ucti o n i n t he T otal Acti vit y Sc ore 
of t he B P D AI sc ore of at least 5 0 %, 7 5 % a n d 9 0 %  at visits 5 ( Da y 4 2), 6 
( Da y 5 6), 7 ( Da y 7 0), or 8 ( Da y 8 4) c o m pare d t o: 
o  Scree ni n g , if patie nt is resista nt t o c ortic oster oi d ta peri n g 
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d .  
•  
Pr o p orti o n of patie nts w h o ha ve ta pere d t o pre d nis o ne d ose of ≤ 1 0 
m g/ d a y at V isit 8 ( Da y 8 4)  a n d/ or 2 a n d 4 m o nt hs after Visit 8 ( Da y 8 4) 
•  
Pr o p orti o n of patie nts w h o ac hie ve c o ntr ol of disease acti vit y at V isits 5 
( Da y 4 2), 6 ( Da y 5 6), 7 ( Da y 7 0), or 8  ( Da y 8 4)   
o  C o ntr ol of disease acti vit y is defi ne d as t he ti me w he n at least 
t w o of t he f oll o wi n g occ ur: ne w lesi o ns cease t o f or m, 
esta blis he d lesi o ns be gi n t o heal a n d / or pr uritic s y m pt o ms start t o 
a bate. C o ntr ol of disease acti vit y will be assesse d b y t he B P D AI  
a n d t he i n vesti gat or’s assess me nt of lesi o n heali n g.  
•  
Mea n ti me t o c o ntr ol of disease acti vit y fr o m: 
o  Scree ni n g, if patie nt is resista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d 
•  
C ha n ge i n B P D AI sc ore at eac h sc he d ule d meas ure me nt ti me p oi nt 
c o m pare d t o: 
o  Scree ni n g, if patie nt is resista nt t o c ortic oster oi d ta peri n g 
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d 
•  
C ha n ge i n B P D AI  pr uritis c o m p o ne nt ( Vis ual A nal o g ue Scale) at eac h 
sc he d ule d meas ure me nt ti me p oi nt c o m pare d t o: 
o  Scree ni n g, if patie nt is resista nt t o c ortic oster oi d ta peri n g 
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d 
•  C ha n ge i n A B Q O L  sc ore at eac h sc he d ul e d meas ure me nt ti me p oi nt 
c o m pare d t o : 
o  Scree ni n g, if patie nt is resista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n ose d 
P H A R M A C O KI N E TI C S ( P K ) E N D P OI N T S  
•  
P K a nal ysis f or bertili m u ma b c o nce ntrati o n : bl o o d sa m ples will be 
c ollecte d t hree ti mes o n d osi n g da ys :  pre - d ose,  at t he c o m pleti o n of 
treat me nt i nf usi o n(a p pr o xi matel y 3 0 mi n utes f oll o wi n g i nf usi o n 
i nitiati o n) a n d  at 2 h o urs f oll o wi n g i nitiati o n of st u d y dr u g i nf usi o n,  a n d 
o nce at t he re mai ni n g st u d y visits (e xcl u di n g scree ni n g). T he f oll o wi n g 
P K para meters will be calc ulate d, t o t he de gree p ossi ble gi ve n t he 
n u m ber of ti me p oi nts:  C ma x , Tma x , Ca v g, Cmi n  a n d t1/ 2. A d diti o nal sta n dar d 
a n d e x pl orat or y P K para meters will be calc ulate d if dee me d necessar y.  
1 9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
P H A R M A C O D Y N A MI C ( P D) E N D P OI N T S  
•  
C ha n ge i n B P 1 8 0 a n d B P 2 3 0 a ut oa nti b o d y titres at eac h sc he d ule d 
sa m pli n g ti me p oi nt c o m pare d t o Visit 2 ( Da y 0)  
•  
C ha n ge i n bl o o d e osi n o p hil c o u nt at eac h sc he d ule d sa m pli n g ti me p oi nt 
c o m pare d t o Visit 2 ( Da y 0)  
•  
C ha n ge i n tiss ue e osi n o p hil c o u nt assesse d o n bi o ps y at t he sc he d ule d 
ti me p oi nt ( Visit 5)  c o m pare d t o scree ni n g 
•  
C ha n ge i n ser u m e ota xi n- 1 le vel at eac h sc he d ule d sa m pli n g ti me p oi nt 
c o m pare d t o Visit 2 ( Da y 0)    
E X P L O R A T O R Y E N D P OI N T:  
•  
C ha n ge i n P B M C bi o mar kers at Visit 5  c o m pare d t o Visit 2 ( Da y 0)  
St atistic al 
Met h o ds   
 
T his is a n o pe n- la bel st u d y. T h us, o nl y descri pti ve statistics a n d narrati ves of 
i n di vi d ual patie nt case st u dies are pla n ne d.  All data c ollecte d o n t he case re p ort 
f or ms ( C R Fs) will be s u m marize d f or t he cli nical st u d y re p ort ( C S R). 
All c o nti n u o us para met ers will be s u m marize d usi n g sta n dar d s u m mar y statistics 
as a p pr o priate ( n, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, ma xi m u m, 2 5t h 
perce ntile a n d 7 5t h perce ntile).  S u m mar y statistics f or cate g orical varia bles will 
i ncl u de fre q ue nc y c o u nts a n d perce nta ges. S u m maries will be prese nte d f or all 
patie nts  a n d b y Treat me nt P hase a n d F oll o w- u p E val uati o n. 
2 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
T A B L E O F C O N T E N T S  
P R O T O C O L SI G N A T U R E P A G E  .............................................................................................. 2 
P R O T O C O L V E R SI O N HI S T O R Y  ............................................................................................ 3 
P R O T O C O L S Y N O P SI S  ............................................................................................................ 1 0 
T A B L E O F C O N T E N T S  ............................................................................................................ 2 1 
G L O S S A R Y .................................................................................................................................. 2 4 
1. 0  I N T R O D U C TI O N ............................................................................................................... 2 6 
1. 1  B ull o us Pe m p hi g oi d ..................................................................................................... 2 6  
1. 1. 1  T he R ole of E ota xi n a n d E osi n o p hils i n B ull o us Pe m p hi g oi d .......................... 2 6  
1. 2  I n v esti gati o nal T her a p y ................................................................................................ 2 7 
1. 2. 1  N o nc li nical St u dies............................................................................................ 2 7 
1. 2. 2  Cli nical St u dies .................................................................................................. 2 8 
1. 3  St u d y R ati o nale  ............................................................................................................ 2 8 
1. 3. 1  Rati o nale f or D ose Sel ecti o n  ............................................................................. 2 9 
2. 0  S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  ..................................................................... 2 9 
2. 1  St u d y O bjecti ves ........................................................................................................... 2 9 
2. 2  St u d y E n d p oi nts a n d O utc o mes ................................................................................... 3 0  
3. 0  S T U D Y D E SI G N  ................................................................................................................. 3 1 
4. 0  S T U D Y P O P U L A TI O N  ...................................................................................................... 3 3 
4. 1  I n cl usi o n Criteria .......................................................................................................... 3 3 
4. 2  E x cl usi o n Criteria  ......................................................................................................... 3 5 
4. 3  Patie nt I de ntifi cati o n  .................................................................................................... 3 6 
4. 4  Scree ni n g Fail ures  ........................................................................................................ 3 6 
4. 5  Re m o val, Re place me nt, or Earl y Disc o nti n uati o n of Patie nts fr o m T hera p y or 
Assess me nt  ................................................................................................................... 3 7 
4. 5. 1  Ha n dli n g of Earl y Disc o nti n uati o n.................................................................... 3 7  
4. 5. 2  S p o ns or's Ter mi nati o n of St u d y ........................................................................ 3 8  
5. 0  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S .............................................................. 3 8 
5. 1  Scree ni n g Peri o d ( Visit 1, Da y - 2 8 t o Da y - 1) ............................................................. 3 8  
5. 2  Pr oce d ures f or E nr oll me nt of Eli gi ble Patie nts  ............................................................ 3 8 
5. 3  Safet y Assess me nts  ...................................................................................................... 3 8 
5. 3. 1  A d verse E v e nts ( A Es)  ....................................................................................... 3 9 
5. 3. 2  Pri or a n d C o nc o mita nt Me dicati o ns .................................................................. 3 9  
5. 3. 3  Vital Si g ns  ......................................................................................................... 3 9 
5. 3. 4  E C G  ................................................................................................................... 3 9 
5. 3. 5  P h ysical E x a mi nati o n  ........................................................................................ 4 0 
5. 3. 6  I nf usi o n Reacti o ns ............................................................................................. 4 0 
5. 3. 7  Safet y La b or at or y Assess me nts ......................................................................... 4 0 
5. 4  Efficac y Assess me nts  ................................................................................................... 4 2 
5. 4. 1  B ull o us Pe m p hi g oi d Dis ease Area I n de x ( B P D AI) .......................................... 4 2  
5. 4. 2  Assess me nt of Lesi o n Heali n g .......................................................................... 4 2  
5. 4. 3  A ut oi m m u ne B ull o us Disease Q u alit y of Life ( A B Q O L) ................................. 4 2 
2 1

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
5. 4. 4  P h ot o gra p h y....................................................................................................... 4 2  
5. 5  P har mac o ki netic ( P K) Assess me nts  ............................................................................. 4 2 
5. 6  P har mac o d y na mic ( P D) Assess me nts  .......................................................................... 4 3 
5. 6. 1  E osi n o p hil C o u nt i n Bi o ps y Tiss ue ................................................................... 4 3  
5. 6. 2  E osi n o p hil c o u nt i n Bl o o d ................................................................................. 4 3  
5. 6. 3  B P 1 8 0 a n d B P 2 3 0 A ut oa nti b o dies .................................................................... 4 3  
5. 6. 4  Ser u m Le vel of E ota xi n - 1 ................................................................................. 4 4 
5. 7  Ot her Assess me nts  ....................................................................................................... 4 4 
5. 7. 1  B ull o us Pe m p hi g oi d Dia g n o sis ......................................................................... 4 4 
5. 7. 2  Assess me nt of B P Se verit y ................................................................................ 4 5 
5. 7. 3  Kar n ofs k y Perf or ma n ce Stat us Scale  ................................................................ 4 5 
5. 7. 4  Bi o m ar kers  ........................................................................................................ 4 5 
5. 8  Earl y Disc o nti n uati o n St u d y Visit  ................................................................................ 4 5 
5. 9  U nsc he d ule d Visit ........................................................................................................ 4 6  
5. 1 0  P h o ne Call F oll o w- u p ................................................................................................... 4 6  
5. 1 1  P O S T T R E A T M E N T P H O N E C A L L  ......................................................................... 4 6 
6. 0  I N V E S TI G A TI O N A L P R O D U C T .................................................................................... 4 6 
6. 1  I d e ntit y of I n vesti gati o nal Pr o d uct ............................................................................... 4 6 
6. 2  St u d y Dr u g A d mi nistrati o n a n d D osa ge ...................................................................... 4 6  
6. 3  Ma n ufact u ri n g of St u d y Me dicati o n ............................................................................ 4 6 
6. 4  Pac ka gi n g a n d La b elli n g of St u d y Me dicati o n ............................................................ 4 7  
6. 5  Distri b uti o n a n d S hi p me nt of St u d y Me dicati o n .......................................................... 4 7  
6. 6  St ora ge a n d I nstr u cti o ns f or Pre parati o n a n d I nf usi o n of t he I n vesti gati o nal 
Pr o d uct.......................................................................................................................... 4 7  
6. 7  Acc o u nta bilit y a n d C o m plia nce of I n v esti gati o nal Pr o d uct ......................................... 4 7  
6. 8  C o nc o mita nt T hera p y ................................................................................................... 4 8  
6. 8. 1  C o nc o mita nt C ortic oster oi d T hera p y ................................................................ 4 8  
6. 8. 2  Resc ue T hera p y  ................................................................................................. 4 9 
6. 8. 3  Pr o hi bite d Pri or a n d C o n c o mita nt Me dicati o n  .................................................. 4 9 
7. 0  S A F E T Y A N D P H A R M A C O VI GI L A N C E  ..................................................................... 5 0 
7. 1  A d verse E v e nt  .............................................................................................................. 5 0 
7. 2  Seri o us A d verse E v e nt ................................................................................................. 5 1  
7. 3  Defi niti o n of a n U ne x pecte d A d verse E ve nt ................................................................ 5 2  
7. 4  N otificati o n a b o ut Seri o us or U ne x pecte d A d verse E ve nts ......................................... 5 2  
8. 0  S T A TI S TI C A L A N A L Y SI S  ............................................................................................... 5 3 
9. 0  E T HI C S  ................................................................................................................................ 5 4 
9. 1  I nstit uti o nal Re vie w B oar d or I n de p e n de nt Et hics C o m mittee .................................... 5 4 
9. 2  Et hical C o n d uct of t he St u d y........................................................................................ 5 4  
9. 3  Pr ot oc ol Re visi o ns a n d/ or De viati o ns .......................................................................... 5 4  
9. 4  St u d y Patie nt I nf or mati o n a n d C o nse nt........................................................................ 5 4  
9. 5  St u d y Patie nt I ns ura nce ................................................................................................ 5 5  
9. 6  Pers o nal Data Pr otecti o n  .............................................................................................. 5 5 
1 0. 0  D A T A C O L L E C TI O N, M A N A G E M E N T A N D Q U A LI T Y A S S U R A N C E  ................. 5 5 
1 0. 1  A u dits a n d I ns p ecti o ns ................................................................................................. 5 5  
2 2

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 0. 2  St u d y M o nit ori n g ......................................................................................................... 5 5  
1 0. 2. 1  S o urce Data a n d Rec or ds  .................................................................................. 5 6 
1 0. 3  Q ualit y La b orat or y Sta n d ar ds  ...................................................................................... 5 6 
1 0. 4  Data C ollecti o n a n d Ma n a ge me nt  ................................................................................ 5 6 
1 0. 4. 1  Electr o nic Case Re p ort F or ms  ........................................................................... 5 6 
1 1. 0  S T U D Y A D MI NI S T R A TI O N  ............................................................................................ 5 7 
1 1. 1  Partici pati n g Ce nters  .................................................................................................... 5 7 
1 1. 2  Cli nical Trial S u p plies  .................................................................................................. 5 7 
1 1. 3  I n v esti gat or Site File .................................................................................................... 5 7 
1 1. 4  Fi nal Re p ort .................................................................................................................. 5 7  
1 1. 5  Rete nti o n of St u d y Rec or ds .......................................................................................... 5 7  
1 1. 6  C o nfi de ntialit y a n d P u blicati o n .................................................................................... 5 8  
1 2. 0  R E F E R E N C E S  .................................................................................................................... 5 9 
1 3. 0  A P P E N DI C E S  ..................................................................................................................... 6 1 
 
 
2 3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 4  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
G L O S S A R Y   
A b bre vi ati o n/ Ter m  
Defi niti o n  
β -h C G  
Beta -h u ma n c h ori o nic g o na d otr o p hi n  
μ g  
Micr o gra m  
A B Q O L  
A ut oi m m u ne B ull o us Disease Q ualit y of Life  
A E  
 
A d verse e ve nt 
A SI  
A p plicati o n Set u p I nstr ucti o ns  
B M Z  
Base me nt Me m bra ne Z o ne  
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 D M  
Cli nical Data Ma na ge me nt / Ma na ger  
C D M o P  
Cli nical Data M o nit ori n g Pla n  
C F R  
C o de of Fe deral Re g ulati o ns  
c G M P 
C urre nt G o o d Ma n ufact uri n g Practice  
C M V  
C yt o me gal o vir us  
C R F  
Case re p ort f or m (als o e C R F f or electr o nic C R F) 
C R O  
C o ntract researc h or ga nizati o n 
C S R  
Cli nical St u d y Re p ort  
C V %  
DI F  
C oefficie nt of varia nce  
Direct I m m u n ofl u oresce nce 
D M  
Data Ma na ge me nt  
D V P  
Data Vali dati o n Pla n  
E C G  
Electr ocar di o gra m  
E D C  
Electr o nic Data Ca pt ure  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
HI V  
H u ma n i m m u n o deficie nc y vir us  
H P F  
Hi g h P o wer Fiel d  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I F 
I m m u n ofl u oresce nce 
I g G 
Im m u n o gl o b uli n G  
I R B 
I nstit uti o nal Re vie w B oar d 
2 4

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
A b bre vi ati o n/ Ter m  
Defi niti o n  
I V 
I ntra ve n o us 
k g  
Kil o gra m  
Me d D R A
®  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  
m L  
Milliliter  
m M  
Milli m olar  
M O H  
Mi nistr y of Healt h  
P B M C  
Peri p heral Bl o o d M o n o n uclear Cell  
P B S  
P h os p hate  b uffere d sali ne  
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic  
P P D  
P urifie d Pr otei n Deri vati ve  
Q A  
Q ualit y Ass ura nce  
Q O L  
Q ualit y of life  
S A E  
Seri o us a d verse e ve nt 
S O P  
Sta n dar d o perati n g pr oce d ure  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o n  
T B  
T u berc ul osis  
W H O  
W orl d Healt h Or ga nizati o n  
 
 
2 5

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1. 0  I N T R O D U C TI O N 
1. 1  
B U L L O U S P E M P HI G OI D  
B ull o us  pe m p hi g oi d  ( B P)  is  a n  i nfla m mat or y , a ut oi m m u ne  blisteri n g  disease  of  t he  s ki n t hat 
mai nl y aff ects pe o ple  o v er 6 0 years of a ge . T h e o verall i nci de nce is i ncreasi n g i n E ur o pe a n d t he 
U S  wit h  a n  i nci de nce  r ate bet wee n  2 0 -3 0  ne w  cases  per milli o n  i n ha bita nt s per  year  a n d  a n 
i nci de nce r ate u p t o 3 5 0 ne w cases per milli o n i n ha bita nts per year a m o n g t he p o p ulati o n a ge d 8 0 
years a n d ol der  [4 , 5 ]. T o date, t he o nl y effecti ve treat me nt f or B P is hi g h d ose ster oi ds,  w hic h are 
ass ociate d wit h si de eff ects s uc h as i ncrease d m or bi dit y ris k, p artic ul arl y i n t he el derl y p o p ulati o n. 
It  is  t heref ore  necessar y  t o  de vel o p  a  s afe,  efficaci o us  treat me nt  f or  t his  rare  diseas e  a n d/ or 
treat me nt w hic h will e na ble ster oi d ta peri n g. 
B P is c h aracterize d b y de p osits of I g G a nti b o dies a n d/ or c o m ple me nt c o m p o ne nt 3 ( C 3) al o n g t he 
e pi der mal  bas e me nt  me m bra ne  z o ne  ( B M Z)  [6 , 7 , 8 ]. F oll o wi n g  a nti b o d y  bi n di n g  t o 
he mi des m o s o mal a nti ge ns ( B P 1 8 0 a n d B P 2 3 0) i n t he B M Z, c o m ple me nt acti vati o n occ urs a n d 
i nfla m mat or y cells i nfiltrate t he s u be pi der mis ca usi n g te nse blisters t o f or m mai nl y o n t he fl e x or 
s urfaces of ar ms a n d le gs, a xillae, gr oi n, a n d a b d o me n. T he blisters of B P are fille d wit h a clear 
fl ui d, w hic h te n d t o de vel o p o n t he e d ge of er yt he mat o us pla q ues a n d ma y be wi des prea d or l ocal, 
a n d i nte nse itc hi n g is c o m m o n  [9 ]. 
Hi g h d os e  or al c ortic ost er oi ds ( pr e d nis o ne, 1 m g/ k g/ da y) ha ve bee n c o nsi dere d t h e mai nsta y of 
treat me nt f or ma n y years. It has b ee n clearl y de m o nstrate d t hat t hes e hi g h d oses are del eteri o us 
a n d directl y r es p o nsi ble f or a hi g h rate of treat me nt si de effects a n d a hi g h m ortalit y rate [3 , 1 0 , 
1 1 ]. S u per p ote nt t o pical c ortic oster oi ds ha ve b ee n de m o nstrate d t o be m ore effecti ve a n d safer 
t ha n  hi g h  d ose oral c ortic oster oi ds ,  re d uci n g  t h e  fre q ue n c y  of ster oi d-relate d si de  effects a n d 
m ortalit y rate, w hile c o ntr olli n g B P lesi o ns i n bet wee n 9 5 % t o 1 0 0 % of patie nts i n t w o ra n d o mize d 
c o ntr olle d  st u dies  of  m ore  t ha n  7 0 0  p atie nts [3 , 1 2 ].  Des pite t heir hi g h  efficac y,  t o pical 
c ortic oster oi ds are ofte n  c o nsi dere d i nc o n ve nie nt, necessitati n g  t he  assista nce  of  relati ves  or  a 
n urse t o a p pl y t he crea m o n t he w h ole b o d y s urface f or e xte n de d peri o ds of ti me a n d t heir use is 
ass ociate d wit h p o or c o m plia nce i n a n el derl y p o p ulati o n [1 8 ]. 
I m m u n os u p pr essa nts ar e p oorl y t oler ate d i n el derl y B P patie nts. Ra n d o mize d c o ntr olle d st u dies  
ha ve faile d t o de m o nstrate a  c ortic oster oi d  s pari n g effect, b ut re veal e d a hi g her rate of treat me nt 
si de  eff ects i n  p atie nts recei vi n g c o m bi ne d  treat me nt  c o m pare d  wit h  t h ose  treat e d  wit h 
c ortic oster oi d  al o ne.  
A nti bi otics (tetrac ycli n e, da ps o ne) are c o nsi dere d  safer t ha n oral c ortic ost er oi ds. H o w e ver, t heir 
efficac y is c o ntr o v ersial a n d has n ot bee n clearl y de m o nstrate d. 
I n  s u m mar y,  alt h o u g h  B P  lesi o ns  ca n  be  a de q uatel y  a n d  ra pi dl y  c o ntr olle d  wit h  eit her  oral  or 
t o pical c ortic oster oi ds, d ue t o si g nifica nt ass oci ate d si de effects a n d p o or c o m plia nce wit h use of 
ster oi d  cr ea ms  o v er  l ar ge  b o d y  s urface  areas,  t h ere  is  a  si g nifica nt  nee d  f or  n o v el,  efficaci o us 
treat me nts. 
1. 1. 1  T he R ole of E ot a xi n a n d E osi n o p hils i n B ull o us Pe m p hi g oi d  
E ota xi n -1  is  a n  e osi n o p hil -selecti ve  c h e m o ki ne pr o d uce d  b y  a  v ariet y  of  cell  t y pes  i ncl u di n g 
e osi n o p hils,  e pit helial  cells,  fi br o blasts,  e n d ot helial  cells,  T -l y m p h o c yt es,  m o n oc ytes  a n d 
macr o p ha ges f oll o wi n g i n d ucti o n b y pr o- i nfla m m at or y m e diat ors [1 3 ]. E ota xi n is k n o w n t o pla y 
2 6

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
a si g nifi ca nt r ole i n t he tiss ue acc u m ulati o n of e osi n o p hils t hat acc o m pa nies aller gic i nfla m mati o n. 
W hile  e osi n o p hils  are  a n  i m p orta nt  c o m p o ne nt  of  i n nate  i m m u nit y,  t he  acc u m ulati o n  of 
e osi n o p hils i n  tiss ues  ca n  be  detri me ntal. E osi n o p hil  de gra n ul ati o n  pr o d ucts  ha ve  si g nifica nt 
c yt ot o xic  eff ects  o n  tiss ues,  a n d  c yt o ki n es  k n o w n  t o  be  releas e d  b y  e osi n o p hils  e n ha nce 
i nfla m mat or y si g nali n g. 
T he cell ular i nfiltrate t hat c haracterizes B P is c o m prise d mai nl y of e osi n o p hils, b ut als o i ncl u des 
mast cells a n d l y m p h o c yt es. Hi g h le vels of T h 2 c yt o ki nes are f o u n d i n B P tiss ue a n d blister fl ui d. 
E osi n o p hil i nfiltrati o n a n d T h 2 -ass ociate d c h e m o ki nes pla y a ke y r ole i n t he pat h o ge nesis of B P 
[1 4 ].  T he  prese nce  of  e osi n o p hils  i n  B P  s ki n  lesi o ns  is  well  d oc u me nte d,  a n d  t he  c he m otactic 
fact ors r es p o nsi ble f or e osi n o p hil recr uit me nt i nt o t he tiss ue ha ve bee n i de ntifie d.  
I m m u n or eacti vit y t o e ota xi n, l ocalize d t o t he e pi der mis a n d e osi n o p hil gra n ules, has bee n f o u n d 
i n  tiss ue  bi o psies  fr o m  B P  patie nts  a n d  i n  blister  fl ui d [7 , 1 4 -1 6 ],  c o nsiste nt  wit h  i ncrease d 
c he m ota xis  of  T h 2  cells  t o war d  t he blister  fl ui d .  E ota xi n  a n d  i nterle u ki n  (I L-5),  a n ot her  T h 2 
c yt o ki ne, c o o p erat e t o acti vate a n d recr uit e osi n o p hils, ulti matel y c o ntri b uti n g  t o t he tiss ue da ma ge 
c haracteristic of  B P [1 5 ]. 
C o m pare d t o s uc ti o n blister fl ui ds o btai ne d e x peri me ntall y i n h ealt h y i n di vi d uals, blister fl ui ds 
fr o m  B P  patie nts  c o ntai n  si g nifica ntl y  hi g h er  a m o u nts  of  e ota xi n- 1 [1 7 ],  i n dicati n g  s u bsta ntial 
pr o d ucti o n of e ot a xi n -1 at sites of tiss ue da ma ge a n d s u g gesti n g t hat e ota xi n -1 is res p o nsi ble f or 
c he m ota xis of b ot h e osi n o p hils a n d T h 2 cells. Fr o m earl y sta ges of t he disease via l ocal pr o d ucti o n 
a n d release of c yt o ki nes (s uc h a s  I L-4, I L -5) a n d e ota xi n -1 itself, t he i m m u n ol o gical pr o cesses 
u n derl yi n g blister f or mati o n are a m plifie d a n d mai ntai ne d [7 ].  
T hese st u dies pr o vi d e str o n g rati o nale f or t h e use of t hera p e utic a ge nts tar geti n g e osi n o p hils a n d 
m olec ules  t hat re g ulate e osi n o p hil f u ncti o n s uc h as e ota xi n-1 i n t he treat me nt of B P . 
1. 2  
I N V E S TI G A TI O N A L T H E RA P Y  
Bertili m u ma b  is a h u ma n m o n ocl o nal I g G4 a nti b o d y t hat ne utralizes h u ma n e ota xi n -1 a n d i n hi bits 
its f u ncti o n. T he pr o d uct is ma n ufact ure d i n a ma m malia n cell li ne e n gi neere d usi n g rec o m bi na nt 
D N A tec h n ol o g y t o pr o d uce t he a nti b o d y. 
1. 2. 1  N o nc li nic al St u dies 
A si n gle -d ose t o xicit y st u d y wit h b ertili m u ma b was c o n d u cte d i n R hes us m o n ke ys ( 6  per d ose 
gr o u p). M o n ke ys  were a d mi nistere d a si n gle I V i nf usi o n of b ertili m u ma b at a d os e of 1 0 or 1 0 0 
m g/ k g a n d  o bser v e d f or 2 8 a n d 7 d a ys, res pecti v el y. N o effects o n m or bi dit y or m ortalit y were 
o bser ve d. B o d y wei g hts a n d f o o d c o ns u m pti o n w ere n ot i m pac te d b y bertili m u ma b treat me nt a n d 
all cli nical c h e mistr y a n d he mat ol o gi cal para met ers e x a mi ne d were u n affecte d.  I n a re peat- d ose 
t o xicit y  st u d y, R h es us  m o n ke ys  ( 6  per  d os e  gr o u p)  were  a d mi nistere d  1 0,  3 0  or  1 0 0  m g/ k g 
bertili m u ma b  t wice  wee kl y  b y  I V  i nf usi o n  f or  2 8  da ys.  T here  were  n o  deat hs  or  si g nifica nt 
m or bi dit y  f oll o wi n g  tr eat me nt  wit h  bertili m u ma b.  N o  effects  o n  cli nical  c h e mistr y, 
o p ht hal m osc o pic or h e m at ol o gical par a meters or b o d y wei g ht  w ere o bser v e d. At s acrifi ce (e n d of 
st u d y  p eri o d),  t h ere  w ere  no  tr eat me nt -relate d  c ha n ges  i n or ga n  w ei g ht  or  macr osc o pi c/  
micr osc o pic o bser v ati o ns.  
F or detaile d i nf or mati o n o n pre-cli nical st u dies, please refer t o t he  I n vesti gat or’s Br oc h ure. 
 
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P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1. 2. 2  Cli nic al St u dies  
T hree  cli nical  st u dies  of  bertili m u ma b were  c o n d ucte d  i n   E ur o pe: a P hase  1 st u d y i n  healt h y 
v ol u nteers ( st u d y C A T - 2 1 3- 0 1 0 1), a n d P hase 2 st u dies i n patie nt s wit h aller gic r hi nitis a n d aller gi c 
c o nj u ncti vitis   (st u dies C A T - 2 1 3-0 1 0 3  a n d C A T - 2 1 3- 0 2 0 3,  res pecti vel y). Ni net y  ni ne  ( 9 9) 
i n di vi d uals ha ve recei ve d bertili m u ma b : 4 5 via t he I V ( 4 5/ 9 9, 4 5 %), ei g ht ( 8) via t he  i ntra n asal 
( 8/ 9 9,  8 %),  a n d  4 6  vi a  t he  t o pical oc ular ( 4 6/ 9 9,  4 6 %) r o utes of  a d mi nistrati o n . T hirtee n 
i n di vi d uals recei ve d I V bertili m u ma b at d oses ≥5 0 0 m g ( ma xi mu m d ose a d mi nistere d: 7 7 0 m g). 
I n th ese st u dies, bertili m u ma b was w ell t olerate d a n d n o d ose-relate d a d verse e ve nts ( A Es) w ere 
n ote d. T o date, n o cli nical st u dies of bertili m u ma b ha ve bee n c o n d uct e d i n patie nts wit h B P . 
F or a d diti o nal i nf or mati o n o n t hese cli nical st u dies, please refer t o t he I n vesti gat or’s Br o c h ure. 
1. 3  
S T U D Y R A TI O N A L E  
Bertili m u ma b  is  t he  first  m o n ocl o nal  a nti b o d y  t o  s pecific all y  n e utrali ze  h u ma n  e ot a xi n - 1. 
Bertil i m u ma b has bee n s h o w n t o i n hi bit e ota xi n-sti m ulate d mi grati o n of cells a n d ma y t heref ore 
be usef ul  i n t he treat me nt of h u ma n diseases s u c h as B P , w here e osi n o p hil acc u m ulati o n is an 
i m p orta nt feat ure. 
T he  p ur p ose of t his st u d y is t o pr o vi de pr o of of c o n ce pt f or t h e treat me nt of B P wit h bertili m u ma b. 
T his st u d y will pr o vi d e b ot h safet y a n d efficac y d ata  f or i nter nal d ecisi o n - m a ki n g re gar di n g f urt her 
de vel o p me nt of bertili m u ma b i n B P. A p ositi ve pr o of of c o n ce pt i n t his st u d y w o ul d b e s u p p orti ve 
of f urt her  d e vel o p me nt  via ra n d o mize d  c o ntr ol  trial(s) t o  de m o nstrate  t h at  bertili m u ma b  is  a n 
a de q uate ca n di dat e f or m ai nte na nce t hera p y i n  ne wl y dia g n ose d p atie nts a n d patie nts resista nt t o 
c ortic oster oi d ta p eri n g wit h m o derate t o e xte nsi ve B P. Its efficac y i n ne wl y dia g n os e d patie nts 
w o ul d be pr o ve n b y  all o wi n g re d u ce d i nitial d oses of c ortic oster oi ds a n d re d uce d  c u m ulati ve d ose  
of c ortic oster oi ds b y facilitati n g rapi d ta peri n g t o 1 0 m g pre d nis o ne e q ui vale nt or l o wer after i nitial 
c o ntr ol of B P lesi o ns.  Its efficac y i n patie nts resista nt t o c ortic oster oi d ta peri n g w o ul d be pr o v e n 
b y  all o wi n g  patie nts  t o  be  ta pere d  d o w n  fr o m  c ortic oster oi ds  wit h o ut  flari n g  a n d/ or  all o wi n g 
s maller d oses of or al c ortic oster oi ds t o c o ntr ol t he disease. 
T he st u d y  will  i n vesti gate ne wl y  dia g n ose d a d ult  patie nts a n d  a d ult patie nt s resista nt  t o 
c ortic oster oi d ta p eri n g wit h m o derate t o e xte nsi ve B P . T he treat me nt peri o d will i ncl u de t hree I V 
i nf usi o ns of 1 0 m g/ k g b ertili m u ma b o n st u d y Da ys 0 , 1 4 ( ± 2 da ys) a n d 2 8 ( ± 2 da ys) a n d a f oll o w-
u p peri o d u p t o Da y 8 4 ( or Da y 1 1 8 f or males w h o ha ve ha d a b n or mal se me n a nal ysis res ults o n 
Da y  0,  D a y  1 4  or  D a y  2 8 ) relati ve  t o  pre- d ose Visit  2 .  Patie nts  will  recei ve  c o nc o mita nt  oral 
ster oi ds d uri n g t he tr eat me nt a n d f oll o w- u p peri o d.  
It has bee n de m o nstr ate d t hat relati vel y  l o w d oses of c ortic oster oi ds (e. g., 3 0 m g/ da y)  are o nl y 
partiall y  effecti ve i n ac hi e vi n g diseas e c o ntr ol or c o m plete re missi o n . T he ra pi d o nset of ster oi d 
acti o n is desire d i n or der t o alle viate patie nt s y m pt o ms as q uic kl y as p ossi ble w hile t he sl o wer 
acti n g bi ol o gic t a kes  eff ect . A k e y f oc us i n t his treat me nt is t he g oal is t o ta per t he ster oi ds as 
ra pi dl y  as  p ossi ble,  a  diffic ult  feat  t o  ac hie ve  wit h  ster oi ds i n  is olati o n.  Initial  treat me nt  wit h 
pre d nis o ne  has t h eref or e bee n  a d de d  t o  b ertili m u ma b treat me nt. T his  st u d y  is  desi g ne d  t o 
de m o nstrate  t hat  t he s uccessf ul ta peri n g  of  c orti c oster oi ds  o ver  a  s h orter  peri o d  of  ti me  t ha n 
p h ysicia ns  ha ve  bee n  acc ust o me d  t o will  be  p ossi ble  wit h  t he  a d mi nistrati o n  of  bertili m u ma b , 
t here b y miti gati n g ris ks ass ociate d wit h l o n g ter m ster oi d use .   
2 8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 2 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1. 3. 1  R ati o n ale f or D ose Selecti o n 
I m m u ne P har mace uticals has c h ose n t o e val uate t he 1 0 m g/ k g  I V d ose of bertili m u ma b base d o n 
t he f oll o wi n g safet y, p har mac o ki netic a n d P D d ata:  
•  N o  safet y  c o ncer ns  wer e  i de ntifie d  i n St u d y  C A T - 2 1 3- 01 0 1 ,  i n  w hic h  s u bjects  recei v e d  a 
si n gle I V b ertili m u ma b d ose of u p t o 1 0 m g/ k g (c orres p o n di n g t o a bs ol ute d oses of 5 7 0 t o 7 7 0 
m g  i n  f o ur  patie nts),  or  i n  St u d y  C A T - 2 1 3-0 1 0 3,  i n  w hic h  patie nts  recei ve d  a  si n gle  I V 
bertili m u ma b d ose of u p t o 5 0 0 m g. 
•  T he  P D e n d p oi nt  i n St u d y  C A T - 2 1 3-0 1 0 1 ,  e ot a xi n-i n d uce d  e osi n o p hil  s ha pe  c h a n ge,  was 
i n hi bite d b y  ser u m i n all s u bjects w h o recei v e d b ertili m u ma b d oses of 1 m g/ k g a n d hi g h er, 
wit h nearl y 1 0 0 % i n hi biti o n i n t he 5 m g/ k g  a n d 1 0 m g/ k g d ose  gr o u ps. A s ha pe c ha n ge i n 
e osi n o p hils is c o nsi dere d a r e q uisite pr ocess i n c he m ota xis, a n d ca n b e ta k e n as e vi de nce of a n 
i m pe n di n g mi grat or y r es p o nse. Ma xi m u m i n hi biti o n occ urre d at c o n ce ntrati o ns of ~ 4 0 μ g/ m L. 
At 3 5 da ys p ost -d ose, hi g h le v els of i n hi biti o n w ere still o bser v e d des pite l o w c o nce ntrati o ns 
of  bertili m u ma b,  s u g gesti n g  t hat  t he  P D  res p o ns e  was  pr ol o n ge d  w he n  c o m pare d  wit h  t he 
bertili m u ma b plas ma c o nce ntrati o ns.  
•  I n St u d y C A T - 2 1 3- 0 10 1 , after a si n gle d os e of 5 m g/ k g, u n b o u n d bertili m u ma b ha d a mea n 
half -life of 2 1 1 h o urs ( C V % 3 0. 5); t he mea n half-life after a si n gl e 1 0 m g/ k g d ose was 1 9 4 
h o urs ( C V % 2 7. 1).  
o  T he  data  fr o m  t his  st u d y  als o  s u g gest  d ose  pr o p orti o nalit y  i n  bertili m u ma b  e x p os ure 
bet wee n t hes e t w o d oses.   
•  N o a nti b o dies t o bertili m u ma b wer e detect e d i n a n y of t h e t hree pre vi o us si n gle -d os e cli nical 
trials. 
I n t he healt h y v ol u nteer a n d patie nt st u dies perf or me d t o date, b ertili m u ma b d oses u p t o 1 0 m g/ k g 
ha ve n ot bee n ass ociate d wit h a n y d os e- relate d a d verse effects.  
2. 0  S T U D Y O B J E C TI V E S A N D  E N D P OI N T S  
2. 1  
S T U D Y O B J E C TI V E S  
Pri m ar y O bjecti ve   
•  T o e val uate t he saf et y of bertili m u ma b  i n ne wl y dia g n ose d patie nts a n d patie nts  resista nt 
t o c ortic oster oi d ta peri n g wit h m o derate t o e xte nsi ve B P   
Sec o n d ar y O bjecti ves  
•  T o  e val uate t he preli mi nar y  e vi de nce  of cli nical  efficac y a n d P K   a n d P D  effect  of 
bertili m u ma b  i n  ne wl y  dia g n ose d  a n d  patie nts   resista nt t o  cortic oster oi d ta peri n g wit h 
m o derate t o e xte nsi ve B P  
E x pl or at or y O bjecti ve: 
•  T o deter mi ne c h a n ge fr o m Visit 2 ( D a y 0 ) t o Visit 5 of P B M C bi o mar kers 
 
 
2 9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
2. 2  
S T U D Y E N D P OI N T S  A N D O U T C O M E S  
Pri m ar y  E n d p oi nts  
•  Safet y  E n d p oi nts 
Safet y will be e val uat e d o n t he basis of t he f oll o wi n g para meters: 
o  A d verse e ve nts ( A E)  
o  I nf usi o n reacti o ns  
o  I njecti o n site reacti o ns 
o  P h ysical e x a mi nati o n  
o  Vital si g ns ( bl o o d press ure, heart rate, t e m perat ure)  
o  E C G  
o  C o nc o mit a nt me dicati o ns  
o  La b orat or y e val uati o n ( h e mat ol o g y, bi oc h e mistr y, a nti- bertili m u ma b a nti b o dies)  
Sec o n d ar y E n d p oi nts  
Efficac y E n d p oi nts 
•  Pr o p orti o n of patie nts w h o ac hie ve a re d ucti o n i n t he T otal Acti vit y Sc ore of t he B P D AI 
sc ore of at least 5 0 %, 7 5 % a n d 9 0 %  at visits 5 ( Da y 4 2), 6 ( D a y 5 6), 7 ( Da y 7 0), or 8 
( Da y 8 4) c o m pare d t o: 
o  Scree ni n g, if patie nt is r esista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n os e d.  
•  Pr o p orti o n of patie nts w h o ha ve ta pere d t o pre d nis o ne d ose of ≤1 0 m g/ da y at Visit 8 ( Da y 
8 4) a n d/ or 2 a n d 4 m o nt hs after Visit 8 ( D a y 8 4) 
•  Pr o p orti o n of patie nts w h o ac hie v e c o ntr ol of disease acti vit y at Visits 5 ( D a y 4 2), 6 ( Da y 
5 6), 7 ( Da y 7 0), or 8  ( D a y 8 4)   
o  C o ntr ol of disease acti vit y is defi ne d as t he ti me w he n at  least t w o of t he f oll o wi n g 
occ ur:  ne w  l esi o ns  ceas e  t o  f or m,  esta blis he d  l esi o ns  be gi n  t o  heal  a n d/ or  pr uritic 
s y m pt o ms start t o a bate.  C o ntr ol of disease acti vit y will b e ass esse d b y t h e B P D AI a n d 
t he i n vesti gat or’s assess me nt of lesi o n heali n g. 
•  Mea n ti me t o c o ntr ol of disease acti vit y fr o m:  
o  Scree ni n g, if patie nt is r esista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n os e d 
•  C ha n ge i n B P D AI s c ore at eac h s c he d ule d meas ure me nt ti me p oi nt c o m pare d t o: 
o  Scree ni n g, if patie nt is r esista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n os e d 
•  C ha n ge  i n  B P D AI  pr uritis  c o m p o ne nt  ( Vis ual  A nal o g ue  Scale)  at  eac h  sc he d ule d 
meas ure me nt ti me p oi nt c o m pare d t o:  
3 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
o  Scree ni n g, if patie nt is r esista nt t o c ortic oster oi d ta peri n g  
o  Visit  2 ( Da y 0), if patie nt is ne wl y dia g n os e d 
•  C ha n ge i n A B Q O L sc or e at eac h s c he d ule d meas ure me nt ti me p oi nt c o m pare d t o:  
o  Scree ni n g, if patie nt is r esista nt t o c ortic oster oi d ta peri n g  
o  Visit 2 ( Da y 0), if patie nt is ne wl y dia g n os e d 
P h ar m a c o ki netic  ( P K) E n d p oi nts 
•  P K a nal ysis f or bertili m u ma b c o nce ntrati o n : bl o o d sa m ples will be c ollecte d t hree ti mes 
o n  d osi n g  da ys :  pr e- d os e,   at t he  c o m pleti o n  of  treat me nt  i nf usi o n  (a p pr o xi matel y  3 0 
mi n utes f oll o wi n g t he i nitiati o n) a n d at 2 h o urs f oll o wi n g i nitiati o n of st u d y dr u g i nf usi o n,  
a n d o nce at t he re mai ni n g st u d y visits (e x cl u di n g scree ni n g). T he P K para meters will be 
calc ulate d , t o t he de gr ee p ossi ble gi ve n t h e n u m ber of ti me p oi nts: Cma x , Tma x , Ca v g, Cmi n  
a n d t 1/ 2. A d diti o nal sta n dar d a n d e x pl orat or y P K para meters will be cal c ulate d if d ee me d 
necessar y.  
P h ar m a c o d y n a mi c ( P D) E n d p oi nts  
•  C ha n ge  i n  B P 1 8 0  a n d  B P 2 3 0  a ut oa nti b o d y titers at eac h  sc he d ule d  sa m pli n g  ti me p oi nt 
c o m pare d t o Visit 2 ( D a y 0) 
•  C ha n ge i n bl o o d e osi n o p hil c o u nt at eac h sc h e d ule d sa m pli n g  ti me p oi nt c o m pare d t o Visit 
2 ( D a y 0)  
•  C ha n ge i n  tiss ue e osi n o p hil c o u nt assesse d o n bi o ps y at t he s c he d ule d ti me p oi nt  ( Visit 5) 
c o m pare d t o scree ni n g 
•  C ha n ge i n s er u m e ota xi n -1 le vel at eac h sc h e d ule d ti me p oi nt c o m pare d t o Visit 2 ( Da y 0)  
E x pl or at or y E n d p oi nt  
•  C ha n ge i n P B M C bi o mar kers at Visit 5  c o m pare d t o Visit 2 ( D a y 0 ) 
3. 0  S T U D Y D E SI G N  
T his is a n o pe n -la b el, pr o of- of-c o nce pt, si n gle gr o u p st u d y i n ne wl y di a g n ose d a d ult patie nts a n d 
a d ult patie nts resista nt t o c ortic oster oi d ta peri n g wit h m o derate t o e xte nsi ve  B P.  
Eli gi ble patie nts  ar e t h ose w h o : 
a. I d eall y,  ha v e  n ot  bee n  pre vi o usl y  treate d  f or  B P.  H o we ver,  t he  f oll o wi n g  treat me nts  are 
per mitte d  f or ne wl y dia g n ose d patie nts: 
•  S yste mic oral c ortic oster oi ds ≤4 0. 0 m g/ da y ( pre d nis o ne e q ui vale nt) wit hi n 4 wee ks pri or 
t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
•  T o pical c ortic oster oi ds ot her t ha n t h ose t hat are Class 1 or Class 2 ( See A p pe n di x  F) wit hi n 
2 wee ks pr i or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0).  
b.  Are c o nsi der e d b y t he i n vest i gat or t o be resista nt t o c ortic oster oi d ta peri n g, i n w hic h case ot her 
c ortic oster oi d r e gi me ns are per mitte d .  N o w as h o ut peri o d is re q uire d 
 
3 1

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
c.  Ha ve b ee n dia g n os e d  b y t he f oll o wi n g ass ess me nts :  
•  Cli nical e val uati o n c o nfir mi n g B P  
•  He mat o x yli n a n d e osi n ( H & E) stai ni n g of a s ki n p u nc h bi o ps y fr o m t he e d ge of a lesi o n 
t o c hec k t he e osi n o p hil ma ke- u p (i ncl u di n g e osi n o p hil c o u nt) of t he i nfla m mat or y 
i nfiltrate 
•  Ser u m testi n g f or a nti B P 1 8 0 a n d a nti B P 2 3 0 a ut o a nti b o dies 
•  Direct i m m u n ofl u oresce nce ( DI F) o n salt s plit s ki n of a s ki n p u nc h bi o ps y fr o m a 
perilesi o nal ar ea t o c h ec k t he li near de p ositi o n of I g G a n d/ or C 3 o n t he blister r o of 
(e pi der mal si de) 
•  I n dir ect i m m u n ofl u oresce nce (II F) of t he p atie nt’s ser u m t o c hec k f or t he prese nce of I g G 
circ ulati n g a ut oa nti b o d ies   
Alt h o u g h  all  of  t hese  assess me nts  m ust  be  perf or me d,  ulti mate  deter mi n ati o n  of  a  p ositi ve  B P 
dia g n osis bas e d o n t he c o m p osite of t hese i n d icat ors is u p t o t he i n vesti gat or. 
I n ne wl y dia g n ose d patie nts, if a n y of t hes e assess me nts ha ve bee n perf or me d wit hi n 4 wee ks pri or 
t o first treat me nt a d mi nistrati o n, t he s pecific assess me nt will n ot ha ve t o be re peate d. I n patie nts 
resista nt t o c ortic oster oi d ta peri n g, if eit her DI F or II F i m m u n ofl u ores ce nce assess me nts ha ve b ee n 
perf or me d pre vi o usl y, t he s pecific assess me nt will n ot ha ve t o be re p eate d.  
M o derate  t o  e xte nsi ve  b ull o us  pe m p hi g oi d  is  defi ne d  b y  t h e  mea n  n u m ber  of 
b ullae  a n d/ or  
urticarial pla q u es  t hat ha ve a p peare d o n 3 s e parat e occasi o ns d uri n g s cree ni n g as d eter mi ne d b y 
t he i n vesti gat or, t he ref errin g p h ysicia n or re p ort e d b y t he patie nt or care gi ver. M o derate disease 
is defi ne d b y 2- 1 0 b ullae a n d/ or ≥5 urticarial pla q ues. E xte nsi ve disease is defi ne d b y > 1 0 b ullae 
a n d/ or urticari al pla q ues [3 ].  
T he st u d y will c o nsist of t hree peri o ds:  
•  A scree ni n g p eri o d of u p t o 4 wee ks  
•  A n o pe n -la bel tr eat me nt peri o d lasti n g 4 w ee ks c o nsisti n g of I V i nf usi o n of bertili m u ma b 
at Visit 2 ( Da y 0), Visit 3 ( Da y 1 4) a n d Visit 4 ( Da y 2 8) 
•  A saf et y a n d efficac y f oll o w-u p peri o d of a p pr o xi matel y 5 6 da ys  ( or 9 0 d a ys f or m ales w h o 
ha ve ha d a b n or mal se me n a nal ysis res ults f or p ost - d ose Visit 2 ( Da y 0 ), Visit 3 (Da y 1 4 ) 
or Visit 4 ( Da y 2 8 ) c o m pare d t o pre - d ose Visit 2 ( Da y 0 ) results ); pl us a f oll o w-u p p h o ne  
call 2 a n d 4  m o nt hs f oll o wi n g Visit 8 ( Da y 8 4)  
D ue t o t he p ote ntial effects of l o n g -ter m a n d/ or hi g h-d ose s yste mic c ortic ost er oi d usa ge o n b ull o us 
pe m p hi g oi d, ne wl y  dia g n ose d patie nts  will  be  p er mitte d  t o  ta ke  s yste mi c oral c ortic oster oi ds 
s pecificall y  f or  b ull o us  pe m p hi g oi d  o nl y  f or  a  peri o d  of  4  wee ks  pri or  t o  t he  first  treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0) at d oses n o great er t ha n 4 0 m g/ da y pre d nis o ne e q ui vale nt.  
Ne wl y  dia g n ose d  p atie nts  w h o  ha ve  ta ke n  s yste mic oral c ortic oster oi d  f or  b ull o us  pe m p hi g oi d 
l o n ger t ha n 4 w ee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) or at d oses greater 
t ha n 4 0 m g/ da y pr e d nis o ne e q ui vale nt at a n y ti me are e x cl u de d fr o m t he st u d y.   
3 2

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
F or  n e wl y dia g n ose d  patie nts w h o ha v e use d s yst e mic oral  c ortic oster oi ds f or reas o ns ot her t ha n 
b ull o us pe m p hi g oi d, a was h o ut peri o d of 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 
2 - Da y 0) is r e q uire d. 
F or  n e wl y dia g n ose d  p atie nts w h o are ta ki n g s yste mic oral c ortic oster oi ds at a d ail y d ose b et wee n 
4 0 m g/ da y a n d 3 0  m g/ d a y pre d nis o ne e q ui vale nt f or B P wit hi n 4 wee ks pri or t o t he first treat me nt 
a d mi nistrati o n  ( Visit  2 - Da y  0),  ta peri n g  of  s yste mic  c ortic oster oi ds will  be  c o n d ucte d  at  t he 
discreti o n of t he i n vesti gat or. H o we v er, p atie nts m ust be o n 3 0  m g/ da y pre d nis o ne e q ui vale nt f or 
t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0). F or ne wl y dia g n ose d p atie nts w h o are ta ki n g 
less t ha n 3 0 m g/ da y pre d nis o ne e q ui vale nt pri or t o t he first a d mi nistrati o n d a y ( Visit 2 - D a y 0), a 
sta ble d ose of s yste mic c ortic oster oi ds s h o ul d be mai ntai ne d u ntil Visit 2 ( Da y 0).  
Patie nts w h o are resista nt t o c ortic oster oi d ta p eri n g are n ot re q uire d t o be was he d o ut fr o m oral 
c ortic oster oi d treat me nt pri or t o Visit 2 – Da y 0 . 
T he ta peri n g sc h e d ule de picte d i n  Ta ble 1  is  rec o m me n de d f or t he re mai n der of t he st u d y.  
T a ble 1: Rec o m me n de d C ortic oster oi d T a peri n g Re gi me n  
S yste mic c ortic oster oi d d ose 
( pre d nis o ne e q ui vale nt) p er da y 
Ta peri n g sc h e d ule  
≥3 0. 0 -1 0. 1  m g/ da y  
Decrease b y 5  m g eac h wee k  
1 0. 0 –  0  m g/ da y  
Decrease b y 2. 5  m g eac h wee k  
 
C ortic oster oi d ma na ge m e nt ca n occ ur eit her  d uri n g a sc h e d ule d visit, u nsc h e d ule d visit, or p h o n e -
call f oll o w- u p base d o n t he i n vesti gat or’s discreti o n. 
4. 0  S T U D Y P O P U L A TI O N  
T he st u d y will be c o n d ucte d i n patie nts a ge d ≥6 0 years dia g n os e d wit h  m o derate t o e xte nsi ve  
B P. Patie nts w h o meet all t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria will be 
e nr olle d.  
4. 1  
I N C L U SI O N C RI T E RI A 
1.  Males or fe m ales, ≥6 0 years of a ge  
2.  Patie nts wit h a Kar n ofs y Perf or ma nce Stat us  > 4 0 % 
3.  Eli gi ble patie nts ar e  defi ne d as f oll o ws: 
a. I d eall y, t h ose w h o ha ve n ot bee n pre vi o usl y treat e d f or B P. H o w e ver, t he f oll o wi n g 
treat me nts ar e per mitte d f or ne wl y dia g n os e d patie nts:  
•  S yste mic or al c ortic oster oi ds ≤4 0. 0 m g/ da y ( pre d nis o ne e q ui vale nt) wit hi n 4 wee ks 
pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
•  T o pical c ortic os ter oids ot her t ha n t h os e t hat are Class 1 or Class 2 ( See A p pe n di x  
F ) wit hi n 2 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
3 3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 4  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
b.  T h ose patie nts c o nsi dere d b y t he i n vesti gat or t o be resista nt t o c ortic oster oi d ta peri n g, 
i n w hic h case ot her c orti c oster oi d re gi me ns are p er mitte d  i ncl u di n g oral a n d t o pical 
c ortic oster oi ds.  N o w as h - o ut peri o d is re q uire d.  
c. Ha ve bee n dia g n ose d b y t he f oll o wi n g ass ess me nts .  
•  Cli nical e val uati o n c o nfir mi n g B P 
•  He mat o x yli n a n d e osi n ( H & E) stai ni n g of a s ki n p u nc h  bi o ps y fr o m t he e d ge of a 
lesi o n  t o  c hec k  t he  e osi n o p hil  ma ke- u p   (i ncl u di n g  e osi n o p hil  c o u nt)  of  t he 
i nfla m mat or y i nfiltrat e  
•  Ser u m testi n g f or a nti B P 1 8 0 a n d a nti B P 2 3 0 a ut o a nti b o dies  
•  Direct i m m u n ofl u oresce nce ( DI F)  o n salt s plit s ki n of a s ki n p u nc h bi o ps y fr o m a 
perilesi o nal area t o c hec k t he  li near de p ositi o n of I g G a n d/ or C 3 o n t he blister r o of 
(e pi der mal si de) 
•  I n dir ect i m m u n ofl u ores ce nce (II F) of t h e patie nt’s ser u m t o c hec k f or t he prese nce 
of I g G cir c ulati n g a ut oa nti b o dies  
Alt h o u g h all of t hese assess me nts m ust be perf or me d, ulti mate deter mi nati o n of a p ositi ve B P 
dia g n osis bas e d o n t he c o m p osite of t hese i n d icat ors is u p t o t he i n vesti gat or. 
I n ne wl y dia g n os e d patie nts, if a n y of t hese assess me nts ha ve b ee n p erf or me d wit hi n 4 wee ks 
pri or t o fir st tr eat me nt a d mi nistrati o n, t he s pecific assess me nt will n ot ha ve t o be re p eate d. I n 
patie nts  resista nt  t o  c ortic oster oi d  ta peri n g,  if  eit her  DI F  or  II F  i m m u n ofl u oresce n ce 
assess me nts  ha ve  bee n  perf or me d  pre vi o usl y,  t he  s pecific  assess me nt  will  n ot  ha ve  t o  be 
re peat e d.  B P Disease Area I n de x ( B P D AI ) i ncl u di n g Pr urit us V A S a n d M D assess me nt of lesi o ns 
a n d A B Q O L s h o ul d be p erf or me d pri or t o a d mi nistrati o n of c ortic oster oi ds if p ossi ble. 
4.  Patie nts  w h o  ha ve  m o d erate t o  e xte nsi ve b ull o us  pe m p hi g oi d  is  defi n e d  b y  t he  mea n 
n u m ber  of b ullae  a n d / or urticarial  pla q ues  t hat  ha ve  a p p eare d  o n  3  se p arate  o ccasi o ns 
d uri n g scr ee ni n g as deter mi ne d b y t he i n vesti gat or , t he referri n g p h ysicia n or re p orte d b y 
t he patie nt or care gi ver. M o derate dis ease is defi ne d b y 2- 1 0  b ullae  a n d/ or ≥5 urticarial 
pla q ues. E xte nsi ve disease is defi ne d b y > 1 0 b ullae a n d/ or urticarial pla q ues [3 ]. 
5.  S yste mic c ortic oster oi ds f or reas o ns ot her t ha n b ull o us pe m p hi g oi d ma y be use d wit h a 
was h o ut peri o d of 4 w ee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0) .   
6.  A de q uate  car diac,  re n al  a n d  h e patic  f u ncti o n  as  deter mi ne d  b y  t he i n vesti gat or a n d 
de m o nstrate d b y s cree ni n g l a b orat or y e val u ati o ns, vital si g n meas ure m e nt, E C G rec or di n g 
a n d p h ysi cal e x a mi nati o n res ults.  
7.  Fe males w h o, i n t he o pi ni o n of t he i n vesti gat or, are of c hil d be ari n g p ot e ntial , m ust ha ve a 
ne gati ve  ser u m  pre g n a n c y  t est  at  scree ni n g  a n d a gree  t o  use  effecti ve  c o ntrace pti o n 
(h or m o nal c o ntrace pti o n or t w o f or ms of barrier c o ntrace pti o n) c o nsiste ntl y t hr o u g h o ut t he 
st u d y.    
8.  Males m ust ha ve ha d a v asect o m y or h a ve e x presse d t hat t he y ha v e n o i nterest i n fertilit y 
i n t he f ut ure. 
3 4

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
9.  Fertile males ( m ales wit h n o hist or y of i nfertilit y or vasect o m y) m ust a gree t o use effecti ve 
c o ntrace pti o n  ( e. g.,.  c o n d o ms,  s per mici des)  c o nsiste ntl y  t hr o u g h o ut  t he  st u d y  a n d  f or  a 
peri o d of f o ur m o nt hs f oll o wi n g t he e n d of treat me nt a d mi nistrati o n .   
1 0.  Patie nts m ust be willi n g  a n d a ble t o a d here t o t he st u d y visit sc he d ule a n d ot her pr ot oc ol 
re q uire me nts. 
1 1.  Patie nts m ust be w illi n g a n d a ble t o pr o vi de v ol u ntar y writte n i nf or me d c o nse nt or writte n 
i nf or me d c o nse nt fr o m a le gall y a ut h orize d re pres e ntati ve wit h asse nt fr o m t he patie nt. 
4. 2  
E X C L U SI O N C RI T E RI A  
1.  Patie nts  wit h  se vere  me dical  or  s ur gical  c o n diti o ns  at  scree ni n g  or  Visit  2  ( Da y  0)  
i ncl u di n g, b ut n ot li mite d t o, se vere d e me ntia or m e ntal i m pair me nt, se vere str o ke, se vere 
car diac i ns ufficie nc y, se vere arterial h y p erte nsi o n, se vere or u nc o ntr olle d re nal, he patic, 
he mat ol o gical,  gastr oi ntesti nal,  e n d ocri ne,  p ul m o nar y,  car diac,  ne ur ol o g ic,  cere bral, 
ps yc hiatric, or a n y ot her se vere ac ut e or c hr o nic me dical c o n diti o n t hat, i n t he o pi ni o n of 
t he i n vesti gat or, ma y i ncr ease t he ris k ass ociate d wit h st u d y partici pati o n/treat me nt or ma y 
i nterfer e wit h t he i nter pr etati o n of st u d y res ults a n d w oul d ma ke t he patie nt i na p pr o priate 
f or st u d y e ntr y  
2.  Prese nce  of  a n y  mali g na nc y  t h at  has  bee n  u n d er  acti ve  treat me nt  (e. g.,  ra di ot hera p y  or 
c he m ot hera p y) wit hi n t h e 2 years pri or t o baseli ne or is a ntici pate d t o re q uire treat me nt 
d uri n g t he st u d y peri o d (i ncl u di n g f oll o w u p) wit h t he e x ce pti o n of patie nts wit h re m o val 
of u nc o m plicate d basal cell carci n o ma or c uta n e o us s q ua m o us cell carci n o ma, w h o ma y 
ta ke part i n t he st u d y 
3.  C o n ge nital  or  ac q uire d  i m m u n o deficie nc y  (e. g.,  c o m m o n  varia ble  i m m u n o deficie nc y, 
or ga n tra ns pla ntati o n) 
4.  Cli nicall y  si g nifica nt  vital  si g n  meas ure me nts  or  E C G  fi n di n gs  as  deter mi ne d  b y  t h e 
i n vesti gat or 
5.  Cli nicall y  si g nifica nt  a b n or mal  la b orat or y  t est  res ults   at  scree ni n g  as  d efi ne d b y  t he 
i n vesti gat or, i ncl u di n g, b ut n ot li mite d t o:  
•  He m o gl o bi n le v el <
0
1 0.  g/ d L  
•  W hite bl o o d cell c o u nt < 3 x 1 0
3/ µ L 
•  L y m p h oc yte c o u nt < 0. 5 x 1 0 3/ µ L 
•  Platelet c o u nt < 1 0 0 x 1 0 3/ µ L or > 1 2 0 0 x 1 03/ µ L 
•  Ala ni ne a mi n otra nsferas e ( A L T) or as partate a mi n otra nsferase ( A S T) > 3  t he u p per 
li mit of n or mal ( U L N) 
•  Al kali ne p h os p hatase > 3  U L N  
•  Ser u m creati ni ne > 2  U L N  
6.  C o nc o mita nt s ki n c o n diti o ns pre ve nti n g p h ysical e val uati o n of B P . 
7.  Acti ve  or  rece nt  hist or y  of  cli nicall y  si g nifica nt  i nfecti o n  wit hi n  1  m o nt h  of t he  first 
treat me nt a d mi nistrati o n ( Visit 2 – Da y 0).  
3 5

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
8.  P atie nts w h o are pre g na nt  or breast -fee di n g, or pla n ni n g t o bec o me pre g na nt d uri n g t he 
st u d y 
9.  Partici pati o n i n a cli nical trial of a n i n vesti gati o nal ( u na p pr o ve d) pr o d u ct wit hi n 4 wee ks 
pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 – Da y 0)   
1 0.  Patie nts w h o  are  k n o w n  t o  ha v e  h y perse nsiti vit y  t o  bertili m u ma b  or  a n y  of  t he  dr u g 
e x ci pie nts 
1 1.  Use  of  a n y  pre vi o us  tr eat me nts  f or  b ull o us  pe m p hi g oi d  ( ot her  t h a n  t he  or al/t o pic al 
c ortic oster oi d  re gi me ns  all o we d  as  descri be d  a b ove  i n  i ncl usi o n  criteri a  # 3 a, # 3 b,  a n d 
o t her t h a n t h ose tre at me nts descri be d i n excl usi o n criteri a # 1 3-1 5 bel o w, f or w hic h t he 
a p pr o pri ate w as h- o ut peri o ds were a p plie d).  
1 2.  Treat me nt  wit h  s yste mi c  c ortic oster oi ds  at  a n y  d ose  f or  reas o ns  ot her  t ha n  b ull o us 
pe m p hi g oi d wit hi n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0 )  
1 3.  Treat me nt wit h i m m u n os u p pressa nts (e. g., azat hi o pri ne, met h otre x ate) wit hi n 4 wee ks 
pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
1 4.  Treat me nt wit h bi ol o gics (e. g., eta n erce pt, a dali m u ma b, uste ki n u ma b, i nfli xi ma b, 
i ntra ve n o us I g) wit hi n 4 m o nt hs pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y 
0).  Patie nts w h o ha ve r ecei ve d rit u xi ma b wit hi n 1 year pri or t o t he first treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0)  will be e x cl u de d fr o m st u d y partici pati o n  
1 5.  Treat me nt wit h a f ull c o urse of macr oli des or tetrac ycli nes  wit hi n 4 wee ks pri or t o t he 
first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)   
1 6.  S u bjects w h o r ecei ve d a vacci ne or ot her i m m u n osti m ulat or wit hi n 4 wee ks pri or t o t he 
first treat me nt a d mi nistrati o n ( Visit 2 - Da y 0)  
1 7.  S u bjects w h o ha ve cli nical, ra di o gra p hi c, or la b orat or y e vi de nce of acti ve or late nt 
m yc o b acteri u m t u berc ul osis ( T B) i nfecti o n  
1 8.  E vi de nce of a n acti ve disease of h e patitis B ( H Bs A g or H Bc A b p ositi ve) or he patitis C 
( H C V A b p ositi ve), C M V (I g M p ositi ve) or h u m a n i m m u n o deficie nc y vir us ( HI V) 
i nfecti o n ( HI V 1/ 2 A b p ositi ve) 
1 9.  Acti ve a b use of alc o h ol or dr u gs  
2 0.  A n y ot her c o n diti o n, w hic h , i n t he o pi ni o n of t he i n vesti gat or, w o ul d place t he patie nt at 
a n u nacce pta ble ris k if partici pati n g i n t he st u d y pr ot oc ol 
4. 3  
P A TI E N T  I D E N TI FI C A TI O N  
At  scree ni n g,  all patie nts  w h o si g ne d i nf or me d c o nse nt will be i de ntifie d b y  a  s u bject n u m ber, 
t heir i nitials a n d birt h date.  
4. 4  
S C R E E NI N G F AI L U R E S  
Patie nt s w h o fail t o meet t he eli gi bilit y criteria at a n y sta ge pri or t o a d mi nistrati o n of t he first d ose 
of st u d y dr u g (Visit 2 - D a y 0 ) ar e defi ne d as scree n fail ures. All scree n fail ures will be d oc u me nte d 
o n  t he  scree ni n g  l o g,  w hic h  d oc u me nts  t he  scree ni n g  n u m ber, patie nt ’s  i nitials,  birt h  date,  a n d 
reas o n(s) f or scree n fail ure. T he scree ni n g l o g will be ke pt i n t he I n vesti gat or’s Site File.  
3 6

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
If  s u bjects  f ail  scr ee ni n g,  t he y  m a y  be  re-s cree ne d  o nce  at  t he  discreti o n  of  t he  i n vesti gat or. 
S u bjects  will  get  a  ne w  st u d y  i de ntificati o n  n u m ber  o n  re -scree ni n g.  A  la b  res ult d uri n g  t he 
scree ni n g peri o d ma y be re peat e d at t he discreti o n of t he i n vesti gat or if dee me d s p uri o us wit h o ut 
re peati n g t h e e ntir e set of scree ni n g r e q uireme nts.  I n t his partic ular case, t he s u bject will n ot get a 
ne w st u d y i d e ntificati o n n u m ber.   
4. 5  
R E M O V A L, R E P L A C E M E N T, O R E A R L Y DI S C O N TI N U A TI O N  O F P A TI E N T S 
F R O M T H E R A P Y O R A S S E S S M E N T  
Patie nt s are fr ee t o disc o nti n ue t heir partici pati o n i n t he st u d y at a n y ti me a n d wit h o ut prej u dice t o 
f urt her  treat me nt.    T he in vesti gat or  m ust  wit h dra w  a n y patie nt  fr o m  t he  st u d y  if  t hat p atie nt  
re q uests  t o  be  wit h dra w n,  or  if  it  is  deter mi ne d  t hat  c o nti n ui n g  i n  t he  st u d y  w o ul d  res ult  i n  a 
si g nifica nt saf et y ris k t o t he patie nt .  Wit h dra w n patie nt s will n ot be re place d o nce treat me nt has 
bee n a d mi nistere d .   
T he f oll o wi n g  ar e  e x a m ples  of reas o ns  w h y a  patie nt 's  partici p ati o n  i n  t his  st u d y  ma y  be 
disc o nti n ue d: 
•  Patie nt  wit h dra ws c o nse nt 
•  I nt olera ble a d vers e e ve nt 
•  T he in vesti gat or  d eci des  t hat  c o nti n ui n g  i n  t he  st u d y  w o ul d  n ot  be  i n  t he patie nt ’s  best 
i nterest 
•  T he patie nt  is n o nc o m plia nt wit h t he pr ot oc ol  
•  T he patie nt  bec o m es pre g na nt 
•  U p o n  t he  decisi o n  of rele va nt Re g ulat or y  A ut h orities  a n d/ or  t he  I n stit uti o nal Re vie w 
B oar d/I n de pe n d e nt Et hics C o m mittee  (I R B/I E C). 
4. 5. 1  H a n dli n g of E arl y Disc o nti n u ati o n 
If  a patie nt  is  wit h dra w n  fr o m  t he  st u d y,  eit her  at  his  or  her  re q uest  or  at  t he i n vesti gat or’s 
discreti o n, or fails t o ret ur n, e ver y eff ort s h o ul d be ma de t o deter mi ne t he reas o n. T his i nf or mati o n 
will be rec or d e d o n t he patie nt ’s case re p ort f or m ( C R F). All patie nt s w h o wit h dra w fr o m t he st u d y 
pre mat urel y, r e gar dl e ss of ca use, s h o ul d u n der g o Earl y Disc o nti n uati o n St u d y Visit (see Secti o n  
5. 8 ). It is i m p orta nt t o o btai n f oll o w-u p data f or a n y patie nt  wit h dra w n d ue t o  a n A E or a b n or mal 
la b orat or y  test  fi n di n g.    I n  a n y  case,  e ver y  eff ort  m ust  be  ma de  t o  u n derta ke  safet y  f oll o w- u p 
pr oce d ur es.  
Pre mat ure wit h dra wal m a y o cc ur f or a n y of t he f oll o wi n g reas o ns: 
•  Deat h  
•  Pre g n a nc y  
•  A E  
•  Patie nt  re q uest 
•  I n v esti gat or re q u est 
•  S p o ns or re q uest 
3 7

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
A n y s eri o us A E ( S A E) m ust be e nter e d i nt o t he C R F a n d re p orte d t o t h e S p o ns or or S p o ns or's 
desi g nee b y e mail a n d/ or fa x wit hi n 2 4 h o urs a n d t o t he I R B/I E C acc or di n g t o site’s re g ulati o ns 
(f or S A E n otificati o n pr o ce d ures, ref er t o Secti o n 7. 4 ).  
I n  t he  e v e nt  of  a n y  A Es  c o nsi dere d  cli nicall y  si g nifica nt  b y  t he i n vesti gat or, p atie nt s  will  be 
pr o vi de d wit h  a p pr o priat e  me dical  ma na ge m e nt  u ntil  t he  o utc o me  is  deter mi ne d  or  sta bilize d, 
acc or di n g t o t he in vesti gat or’s cli nical j u d g me nt. All f oll o w -u p i nf or mati o n will be rec or de d i n 
t he patie nt's C R F u ntil t he cl ose of t he st u d y. S u bse q ue nt f oll o w-u p will be d oc u me nte d i n t he 
patie nt 's pers o nal file. 
Patie nt s w h o  fail t o res p o n d t o st u d y treat me nt or e x perie nce a flare will be a ble t o recei ve l ocal 
sta n dard- of- care at t he in vesti gat or’s discreti o n .  
4. 5. 2  S p o ns or's Ter mi n ati o n of St u d y  
T he S p o ns or r eser v es t he ri g ht t o disc o nti n ue t h e st u d y at a n y ti me at t h e partici pati n g ce nters f or 
a n y reas o n.  
Re g ulat or y A ut h orities als o ha ve t he ri g ht t o ter mi nate t he st u d y f or a n y reas o n. 
5. 0  S T U D Y P R O C E D U R E S A N D  A S S E S S M E N T S  
T he sc he d ule of e ve nts f or t his st u d y is s h o w n i n  A p pe n di x A . N o pr ot oc ol relate d pr oce d ures, 
i ncl u di n g cessati o n of pr o hi bite d c o nc o mita nt me dicati o ns, s h o ul d be perf or me d bef ore patie nt s 
pr o vi de  writte n  i nf or m e d  c o nse nt.  St u d y  relate d  e ve nts  a n d  acti vities  i ncl u di n g  s pecific 
i nstr ucti o ns,  pr oce d ur es,  c o nc o mita nt  me dicati o ns,  dis pe nsi n g  of  st u d y  me dicati o n,  a n d 
descri pti o ns of A Es s h o ul d be rec or de d i n t he a p pr o priate s o urce d oc u m e nts a n d C R F. 
5. 1  
S C R E E NI N G P E RI O D ( VI SI T 1, D A Y - 2 8 T O D A Y - 1) 
All patie nts or t heir le gall y a ut h orize d r e pres e ntati ve m ust si g n a n d dat e t he m ost c urre nt I R B/I E C-
a p pr o ve d writte n  i nf or m e d  c o nse nt bef ore a n y  st u d y s pecific assess me nts or  pr oce d ures  are 
perf or me d. A n ori gi n al si g ne d c o ns e nt f or m will be retai ne d b y t he i n vesti gat or a n d t he p atie nt 
will recei ve a c o p y t o ta k e h o me.    
Patie nts will be scree ne d acc o r di n g t o t he assess me nts a n d pr oce d ures i n t he S c he d ule of E ve nts 
i n A p pe n di x A.  T hese m ust be c o m plete d a n d e v al uate d f or patie nt eli gi bilit y pri or t o treat me nt 
a d mi nistrati o n. T he scr ee ni n g visit ma y b e c o n d ucte d o ver m ulti ple da ys. Patie nts w h o meet all 
t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria will be e nr olle d i n t he st u d y.  
5. 2  
P R O C E D U R E S F O R E N R O L L M E N T  O F E LI GI B L E P A TI E N T S 
O nl y  p atie nts  w h o  f ulfill  all  e ntr y  criteri a  are  eli gi ble  f or  e nr oll me nt  i nt o  t he  st u d y.  O n ce  t he 
scree ni n g pr ocess is c o m plete, t he site s h o ul d c o m plete t he Eli gi bilit y f or m i n t he C R F f or re vie w 
b y t he Me dical M o nit or . O nce t he Me dical M o nit or c o nfir ms eli gi bilit y i n t he C R F, s hi p me nt of 
I P will be tri g ger e d. 
5. 3  
S A F E T Y A S S E S S M E N T S  
Safet y assess me nts will be base d o n A Es, pri or a n d  c o nc o mita nt me dicati o n use, vital si g ns, E C G, 
p h ysical  e x a mi nati o n,  a n d  la b orat or y  ass ess me nts  ( he mat ol o g y,  bl o o d  c he mistr y, a n d a nti-
3 8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 3 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
bertili m u ma b a nti b o dies ,  etc.).   Meas ure m e nts  of  all  safet y  para meters  s h o ul d  be  perf or me d  as 
descri be d i n t he Sc h e d ule of E ve nts ( A p p e n di x A)  a n d t he f oll o wi n g secti o ns. 
5. 3. 1  A d verse E ve nts ( A E s) 
A d verse e v e nts will be assesse d b y t he i n vesti gat or t hr o u g h o ut t he st u d y. A n y A E t hat occ urs after 
t he i nf or me d c o nse nt is si g ne d b y t he p atie nt will b e rec or de d i n t he p atie nts’  me dical files as well 
as o n t he a p pr o priate C R F pa ge. (See S ecti o n 5. 3. 4 ). 
A Es s h o ul d be c hec ke d at eac h visit a n d rec or de d. Patie nts s h o ul d be i nstr ucte d t o re p ort a n y ne w 
A E t hat occ ur s b et wee n s c he d ule d visits . 
A E s  will  be  c o d e d  b y  Data Ma n a ge me nt  usi n g  Me dical  Dicti o nar y  f or  Re g ulat or y  Acti vities 
( Me d D R A® ) versi o n 1 7. 0 or hi g h er. 
5. 3. 2  Pri o r a n d C o nc o mit a nt Me dic ati o ns 
Rec or di n g of c o n c o mita nt me dicati o n use will be c o n d ucte d at all st u d y visits . All treat me nts use d 
b y  patie nts  wit hi n 9 0  da ys  pri or  t o  scree ni n g  s h o ul d  be  rec or de d.  A n y  d ose  m o dificati o n  of 
c o nc o mita nt me dicati o ns s h o ul d be c hec ke d at eac h visit a n d rec or de d. T h ere will be a se p arat e 
C R F pa ge s pecificall y f or t he e ntr y of oral c ortic oster oi d t hera p y f or b ull o us pe m p hi g oi d. 
5. 3. 3  Vit al Si g ns  
Vital si g ns will be meas ure d at all visits e x ce pt f or Visit 9 ( D a y 1 1 8) as i n di cate d i n t h e Sc he d ul e 
of E ve nts ( A p pe n di x A ). At treat me nt a d mi nistrati o n Visits 2  ( Da y 0), 3 ( D a y 1 4), a n d 4 ( Da y 2 8), 
vital si g ns will be ta ke n pre -d ose ( a n y ti me pri or t o t he i nitiati o n of treat me nt i nf usi o n ), at t he 
c o m pleti o n of treat me nt i nf usi o n (a p pr o xi matel y 3 0 mi n utes f oll o wi n g t he  i nitiati o n of treat me nt 
i nf usi o n), a n d a p pr o xi matel y 2 h o urs f oll o wi n g t he i nitiati o n of treat me nt i nf usi o n. All vital si g ns 
are t o be o btai n e d pri or t o a n y  bi o psies, treat me nt i nf usi o n, or la b orat or y/ P K sa m pli n g c ollecti o n 
if t hese pr oce d ures are s c he d ule d at t he sa me visit . 
Vital si g ns will i nc l u de bl o o d press ure, p ulse rate a n d  oral te m perat ure after at least 5 mi n utes of 
rest. Si g nifica nt fi n di n gs w hic h meet t he defi niti o n of a n A E m ust be rec or de d o n t he A E C R F 
m o d ule.  
5. 3. 4  E C G  
E C G  will  be  perf or me d  at S cree ni n g  a n d  Visit  8   (Da y  8 4 ) as i n dicate d i n A p pe n di x  A .  EC Gs 
s h o ul d be o btai ne d pri or t o a n y bi o psies or la b orat or y/ P K sa m pli n g c ollecti o n if t hese pr oce d ures 
are sc h e d ule d at t he s a me visit .   
T he  patie nt  s h o ul d  rest  f or  at  least  1 0  mi n utes  bef ore  meas ure me nt  is  ta ke n. T he  E C G  will  be 
e val uate d  b y  t h e i n vesti gat or  (si g ne d  a n d  date d)  a n d  t he  pri nt o ut  s h o ul d  be  ke pt  i n  t he  s o urce 
d oc u me ntati o n file.  
W he n p ote ntiall y cli nicall y si g nifica nt fi n di n gs are detect e d b y t h e site in vesti gat or, a car di ol o gist 
s h o ul d be c o ns ulte d f or a defi niti ve i nter pretati o n a n d treat me nt, if necessar y.  T he i n vesti gat or 
a n d l ocal  car di ol o gist ar e res p o nsi ble  t o  d eter mi ne  w het her  t he  E C G  fi n di n gs  are  of  cli nical 
si g nifica n ce. Si g nifica nt  fi n di n gs  ma d e  after  t h e i nf or me d  c o nse nt  is  si g ne d w hic h  meet  t he 
defi niti o n of a n A E m ust be rec or de d o n t he A E C R F.  All a b n or malities will be cl osel y m o nit ore d 
u ntil sta bilize d or res ol ve d.  
3 9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
5. 3. 5  P h ysic al E x a mi n ati o n 
P h ysical e x a mi nati o n will be perf or me d  at all st u d y visits  e x ce pt f or Visit 9 ( Da y 1 1 8) as i n dicate d 
i n t he Sc he d ule of E ve nts (A p pe n di x A ). O n treat m e nt a d mi nistrati o n Visits 2 ( Da y 0), 3 ( D a y 1 4), 
a n d 4 ( Da y 2 8), a p h ysical e x a mi nati o n will be p erf or me d pr i or t o t he i nitiati o n of t he treat me nt 
i nf usi o n. Hei g ht will be r ec or de d at Visit 1 (scree ni n g)  o nl y.  
P h ysical e x a mi nati o n will i ncl u de wei g ht  a n d hei g ht (at scree ni n g o nl y)  meas ure me nts, assess me nt 
of  hea d,  l u n gs,  car di o vasc ular  s yste m,  a b d o me n,  m usc ul os keletal  s yst e m,  s ki n,  l y m p h  n o des, 
ce ntral  n er v o us  s yste m  a n d,  w here  a p pr o pri ate,  ot her  b o d y  s yste ms  as  i n dicate d  i n  t he  st u d y 
sche d ule.  
I nf or mati o n a b o ut t he p h ysical e x a mi nati o n m ust be rec or de d i n t he s o urce d oc u me ntati o n at t he 
st u d y site. Si g nifica nt fi n di n gs t hat are prese nt pri or t o t he start of st u d y dr u g m ust b e i ncl u de d i n 
t he Rele va nt Me dical Hist or y/ C urr e nt Me dical C o n diti o ns C R F. Si g nifica nt fi n di n gs ma de after 
t he start of st u d y dr u g, w hic h meet t he defi niti o n of a n A E, m ust be rec or d e d o n t he A E C R F.  
5. 3. 6  I nf usi o n Re acti o ns  
I nf usi o n reacti o ns s h o ul d be assess e d o n treat me nt a d mi nistrati o n Visits 2 ( Da y 0), 3 ( Da y  1 4), 
a n d 4 ( D a y 2 8) as i n dicat e d i n t he Sc he d ul e of E v e nts ( A p pe n di x A ). At t h ese visits, e vi de nce f or 
i nf usi o n reacti o ns  will  b e  e val u ate d  at  t he  co m pl eti o n  of  treat me nt  i nf usi o n  (a p pr o xi matel y   3 0 
mi n utes f oll o wi n g t he i nitiati o n of treat me nt i nf usi o n) a n d at 2 h o urs f oll o wi n g t he i nitiati o n of 
treat me nt i nf usi o n. 
5. 3. 7  S af et y L a b or at or y Assess me nts 
Safet y la b orat or y assess me nts will be perf or me d acc or di n g t o t he Sc h e d ule of  E v e nts ( A p p e n di x  
A ). 
He mat ol o g y a n d Bi o ch e mistr y will be perf or m e d at all visit s wit h t he e x ce pti o n of Visits 6 ( Da y 
5 6), 7 ( Da y 7 0), a n d 9  ( D a y 1 1 8) as i n dicat e d i n t h e Sc he d ule of E v e nts (A p pe n di x A ). At treat me nt 
a d mi nistrati o n Visits 2 ( Da y 0) , 3 ( D a y 1 4), a n d 4 ( Da y 2 8), t hes e sa m ples  will be ta ke n pre - d os e 
(a n y ti me pri or t o t he i nitiatio n of treat me nt i nf usi o n). F or scree ni n g, he m at ol o g y  a n d c he mistr y 
will be e val uate d  l ocall y a n d at a ce ntral la b orat or y f or all ot her visits.  
Ser ol o g y will be e v al uate d  l ocall y o nl y at Scree ni n g. 
Pre g n a nc y will be e val uate d  l ocall y b y s er u m at Scree ni n g a n d l o call y b y uri ne testi n g at all ot her 
visit s wit h t he e x ce pti o n of Visits 6 ( Da y 5 6) a n d 7 ( Da y 7 0). 
A nti -bertili m u ma b a nti b o dies  will be e val uate d at all visits wit h t he e x ce pti o n of scree ni n g a n d 
Visit 9 ( Da y 1 1 8). At treat me nt a d mi nistrati o n Visits 2 ( Da y 0), 3 ( Da y 1 4), a n d 4 ( D a y 2 8), a nti-
bertil u ma m b  sa m ples  will  be c ollecte d pre -d ose  (a n y  ti me  pri or  t o  t he  i nitiati o n  of  treat me nt 
i nf usi o n). A nti-bertil u ma m b a nti b o dies will be e val uate d ce ntrall y.  
 
 
4 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
T he f oll o wi n g p ara m eters will be teste d f or eac h  assess me nt : 
E v al u ati o ns  
P ar a meters  
He m at ol o g y  
He mat ocrit, he m o gl o bi n, platelet c o u nt, re d bl o o d cell c o u nt, retic ul oc ytes, w hite 
bl o o d cell c o u nt wit h differe ntial c o u nt, m o n oc ytes 
Bi oc he mistr y  
Ala ni ne a mi n otra nsferase, al kali ne p h os p hatase, as partate a mi n otra nsferase, 
calci u m, c h olester ol, creati ni ne, ga m ma -gl uta m yl tra nsferase, gl uc ose, p otassi u m, 
s o di u m, t otal bilir u bi n, tri gl yceri des, urea or B U N  
I m m u n ol o g y 
A nti -bertili m u ma b anti b o dies  
P re g n a nc y test  
S er u m β -h C G   
Uri ne β -h C G   
Ser ol o g y  
F or H B V  ( H Bs A g or H Bc A b), H C V ( H C V A b), HI V ( HI V 1/ 2 A b), C M V (I g M) 
All  la b orat or y  tests  wit h a b n or mal val ues  w hic h  are  c o nsi dere d  cli nicall y  si g nifica nt  a n d  are 
detecte d after t he i nf or me d c o nse nt is si g ne d will b e re p eate d as cli nicall y i n dicate d u ntil t he v al ues 
ret ur n t o n or m al, or u ntil t he eti ol o g y has b ee n d eter mi ne d a n d t he c o n diti o n c o nsi dere d st a ble. 
A b n or mal la b orat or y test res ults t hat are c o nsi dere d cli nicall y i m p orta nt b y t h e in vesti gat or will 
b e re p ort e d as a n A E i n t he A E C R F.  
La b orat or y  res ults  will  be  re p orte d  t o  t he in vesti gat or  w h o  will  re vi e w  a b n or mal  la b orat or y 
fi n di n gs f or cli nical si g nifica nce. T he in vesti gat or will n ote a n y l a b orat or y test res ults of cli nical 
c o ncer n,  or  v al ues  t hat are o utsi de  n or mal  ra n ges  a n d  pr o vi de  d etails  of  t he  relati o ns hi p  t o 
i n vesti gati o nal pr o d uct a n d t he acti o n ta ke n. If a c ha n ge i n a la b orat or y v al ue re prese nts a me dical 
c o n diti o n, t he me dical c o n diti o n will be liste d i n t he A E C R F pa ge. If n o c orrelati o n i s deter mi ne d , 
t he directi o n of c h a n ge (i ncreas e or decrease) i n a d diti o n t o t he act ual val ue will be rec or de d.  
Refer t o t he La b orat or y Ma n ual f or m ore details. 
5. 3. 7. 1  Se me n a n al ysis testi n g 
Se me n testi n g will be perf or me d at Visits 2 ( Da y 0), 3 ( Da y 1 4), 4 ( D a y 2 8). Visit 9 ( Da y 1 1 8) 
will o nl y be re q uir e d  if a n y res ults fr o m t he pre vi o us visits are a b n or mal c o m pare d t o pre - d ose 
Visit 2 ( Da y 0) . At treat me nt a d mi nistrati o n Visits 2 ( Da y 0), 3 ( Da y 1 4), a n d 4 ( Da y 2 8), s e me n 
testi n g will be perf or me d  pre -d ose (a n y ti me wit hi n  4 8 h o urs pri or t o t he i nitiati o n of treat me nt 
i nf usi o n), a n d at t he c o m pleti o n of treat me nt i nf usi o n (a p pr o xi matel y 3 0 mi n utes f oll o wi n g t he 
i nitiati o n) or a s cl ose t o t his ti me as p ossi ble .  
Se me n a nal ysis will be perf or me d o n a ll male patie nts partici pati n g i n t his st u d y wit h t he e x ce pti o n 
of t he f oll o wi n g: 
•  I nfertile males  
•  Patie nts wit h  reli gi o us c o nstrai nts t hat pre ve nt t he m fr o m pr o vi di n g se m e n sa m ples 
5. 3. 7. 2  T u berc ul osis E v al u ati o n 
A n  e val uati o n  f or  acti ve/late nt  t u berc ul osis  will be  perf or me d  at  Scree ni n g  as  i n dicate d  i n  t he 
Sc he d ule  of  E ve nts  ( A p pe n di x  A ).  T he  e val uati o n  will  be  p erf or m e d  l o call y  eit her  cli nicall y, 
ra di o gra p hicall y,  or  b y  l a b orat or y  (i.e., P P D,  X -ra y,  or  Q ua ntifer o n  G ol d).  Q ua ntifer o n  G ol d 
testi n g will als o be a v aila ble ce ntrall y as a n o pti o n, w here a p plica ble. 
4 1

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
5. 4  
E F FI C A C Y A S S E S S M E N T S  
5. 4. 1  B ull o us Pe m p hi g oi d Dise ase Are a I n de x  (B P D AI ) 
T he B P D AI ( See A p pe n di x D ) will be c o m plete d  at all visits wit h t he e x c e pti o n of Visit 9  ( D a y 
1 1 8) as i n dicate d i n t he Sc he d ule of E ve nts ( A p pe n di x A ). At treat me nt a d mi nistrati o n Visits 2 
( Da y 0), 3 ( Da y 1 4), a n d 4 ( Da y 2 8), t h e B P D AI s h o ul d be c o m plete d pre -d ose (a n y ti me pri or t h e 
i nitiati o n of treat me nt i nf usi o n).  I n scree ni n g, t h e B P D AI s h o ul d b e perf or me d, if p ossi ble, pri or 
t o c o m me nceme nt of c ortic oster oi d re gi me n.  
T he B P D AI Pr urit us C o m p o ne nt Vis ual A nal o g u e Scale  ( V A S) will be c o m plete d b y t h e patie nt 
or t heir le gall y a ut h orize d re prese nt ati ve a n d all ot her secti o ns f or t he B P D AI will be c o m plete d 
b y t he i n vesti gat or.  Patie nts a n d i nvesti gat ors will be as ke d t o c o m plete t h eir res pecti ve secti o ns 
o n t he c orres p o n di n g w or ks heets, w hic h will ser ve as s o urce d oc u m e ntati o n f or t his meas ure me nt. 
T he st u d y s o ur ce d o c u me nts s h o ul d reflect a n y iss ues t hat ma y h a ve o cc urre d d uri n g c o m pleti o n.  
5. 4. 2  Assess me nt  of Lesi o n H e ali n g 
T he assess me nt of lesi o n heali n g will be c o m plete d at all visits wit h t he e x ce pti o n of Visit 9 ( Da y 
1 1 8) as i n dicate d i n t he Sc he d ule of E ve nts ( A p p e n di x A ). As part of t he assess me nt f or c o ntr ol 
of disease acti vit y, o ne of t he efficac y e n d p oi nts, i n vesti gat ors will be as k e d t o d oc u me nt w het her 
esta blis he d lesi o ns ha ve starte d t o heal.   
5. 4. 3  A ut oi m m u ne B ull o us Dise ase Q u alit y of Life ( A B Q O L)  
T he  A B Q O L  ( See A p pe n di x  E ) will  be  c o m plete d  at  all  visits  wit h  t he  e x c e pti o n  of  Visit  9 
( Da y 1 1 8) as i n dicate d i n t he Sc he d ule of E ve nts (A p pe n di x A ). At treat me nt a d mi nistrati o n Visits  
2 ( Da y 0), 3 ( D ay 1 4), a n d 4 ( Da y 2 8), t he A B Q O L s h o ul d be c o m plete d pre- d ose (a n y ti me pri or 
t he i nitiati o n of treat me nt i nf usi o n). I n s cree ni n g, t he A B Q O L s h o ul d be c o m plete d, if p ossi ble, 
pri or t o c o m me nce m e nt of c ortic oster oi d re gi me n.  
Patie nts or  t heir le gall y a ut h orize d re prese ntati ve will be as ke d t o c o m plete t he A B Q O L o n t he 
w or ks heets, w hi c h will s er ve  as s o ur ce d o c u me nt ati o n f or  t his meas ure me nt. T he st u d y s o urce 
d oc u me nts s h o ul d reflect a n y iss ues t h at ma y h a ve occ urre d d uri n g c o m pleti o n.  
5. 4. 4  P h ot o gr a p h y 
P h ot o gra p hs will be ta ke n at all visits wit h t he e xce pti o n  of Visit 9 ( Da y 1 1 8) as i n dicate d i n t he 
Sc he d ule of E ve nts ( A p p e n di x A ). At  treat me nt a d mi nistrati o n Visits 2 ( Da y 0 ), 3 ( D a y 1 4), a n d 
4 ( Da y  2 8),  t he  p h ot o gr a p hs  s h o ul d  be  c o m plete d  pre-d os e  (a n y  ti me  pri or t o t he i nitiati o n of 
treat me nt  i nf usi o n). I n  s cree ni n g,  the  p h ot o gra p h y  s h o ul d  be  c o n d ucte d,  if  p ossi ble,  pri or  t o 
c o m me nce me nt of c ortic oster oi d re gi me n.  
Refer t o  t he P h ot o gra p h y User Ma n u al f or m ore d etails.  
5. 5  
P H A R M A C O KI N E TI C ( P K) A S S E S S M E N T S  
P K  will be meas ure d at all visits wit h t he e x ce pti o n of Scree ni n g  a n d Visit 9 ( Da y 1 1 8) as i n dicate d 
i n t he Sc he d ule of E ve nts (A p pe n di x A ). At treat me nt a d mi nistrati o n Visits 2 ( Da y 0), 3 ( Da y 1 4), 
a n d 4 ( Da y 2 8), P K  sa m ples will be c ollecte d  pre -d ose ( wit hi n 3 0 mi n utes pri or t o t he i nitiati o n of 
treat me nt i nf usi o n), at t h e c o m pleti o n of treat me nt i nf usi o n (a p pr o xi matel y 3 0 mi n utes f oll o wi n g 
4 2

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
t he i nitiatio n of treat me nt i nf usi o n), a n d 2 h o urs f oll o wi n g t he i nitiati o n of treat me nt i nf usi o n . All 
P K  sa m ples s h o ul d be  c ollecte d  aft er  vital  si g ns,  p h ysical  e x a mi nati o n,  a n d  E C G  if  t hese 
pr oce d ur es ar e sc he d ul e d  at t he sa me visit .   
P K o utc o me ref ers t o st u d y dr u g ( bertili m u ma b) c o nce ntrati o n i n t he ser u m. P K para meters ma y  
i ncl u de: 
C ma x   
Ma xi m u m bertili m u ma b ser u m c o nce ntrati o n  
T ma x  
Ti me t o C ma x  ( pea k e x p os ure) 
C a v g 
A vera ge bertili m u ma b ser u m c o nce ntrati o n  
C mi n  
Mi ni m u m bertili m u ma b ser u m c o nce ntrati o n  
λ z 
Eli mi nati o n rate c o nsta nt  
t1/ 2  
Eli mi nati o n half -life, calc ulate d as 0. 6 9 3/λ z 
A d diti o nal P K para meters ma y be calc ul ate d if dee me d necessar y.  
Refer t o t he La b orat or y Ma n ual f or m ore details.  
5. 6  
P H A R M A C O D Y N A MI C  ( P D) A S S E S S M E N T S  
5. 6. 1  E osi n o p hil C o u nt i n Bi o ps y Tiss ue 
E osi n o p hil c o u nt i n t he s ki n bi o ps y tiss ue will be e val uate d at Scree ni n g a n d V isit 5 ( Da y 4 2) as 
i n dicate d i n t he Sc he d ule of E ve nts (A p pe n di x A ). T his assess me nt will be e val uate d ce ntrall y , 
w here feasi ble .  
T his bi o ps y s h o ul d be c ollecte d usi n g a 4 - 6 m m p u nc h at t h e e d ge of a lesi o n or blister a n d s h o ul d 
i ncl u de s o me a djace nt u n affecte d  s ki n, as t h e sa m ple m ust c o ntai n i ntact e pit heli u m.  At Scree ni n g  
a n d at Visit 5 ( Da y 4 2), t he sa me bi o ps y s a m ple will be use d t o deter mi ne e osi n o p hil c o u nt a n d 
t he e osi n o p hil ma ke u p of t he i nfla m mat or y i nfiltrate wit h he mat o x yli n a n d e osi n stai ni n g.  T he 
Visit 5 ( Da y 4 2) bi o ps y s h o ul d be ta ke n fr o m a p pr o xi matel y t he s a me l o cati o n as t he o ne fr o m 
Scree ni n g.  
Refer t o t he La b orat or y Ma n ual f or m ore details. 
5. 6. 2  E osi n o p hil c o u nt i n Bl o o d  
E osi n o p hil c o u nt i n t he bl o o d will be e val uate d as part of t he he mat ol o g y assess me nt at all visits 
wit h t he e x ce pti o n of Visits 6 ( Da y 5 6), 7 ( Da y 7 0), a n d 9 ( Da y 1 1 8) as i n dicate d i n t he Sc h e d ule 
of E ve nts ( A p pe n di x A ). T his assess me nt will be e val uate d ce ntrall y.  
5. 6. 3  B P 1 8 0 a n d B P 2 3 0 A ut o a nti b o dies 
B P 1 8 0 a n d B P 2 3 0 a ut oa nti b o dies will be e val uate d at all visits wit h t he e xce pti o n of Visit 9 ( Da y 
1 1 8) as  i n dicate d  i n  t he  Sc he d ule  of  E ve nts  ( A p pe n di x  A ). T his assess me nt will  be  e val uate d 
ce ntrall y, w here f easi ble .  
Refer t o t he La b orat or y Ma n ual f or m ore details. 
4 3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 4  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
5. 6. 4  Ser u m Le v el of E ot a xi n- 1 
Ser u m le vels of e ota xi n -1 w ill be e v al uate d at all visits e x ce pt Scree ni n g a n d Visit 9 ( Da y 1 1 8) as 
i n dicate d i n t he Sc he d ule of E ve nts (A p pe n di x A ). T his assess me nt will be e val uate d ce ntrall y. 
Refer t o t he La b orat or y Ma n ual f or m ore details. 
5. 7  
O T H E R A S S E S S M E N T S  
5. 7. 1  B ull o us Pe m p hi g oi d Di a g n osis 
I n or d er t o dia g n ose pati e nts wit h b ull o us pe m p hi g oi d f or t his st u d y, t he f oll o wi n g assess me nts 
will  be perf or me d at Scree ni n g. H o we v er, if a n y of t hese assess m e nts ha ve b ee n perf or me d wit hi n 
4 wee ks pri or t o scree ni n g , t he assess me nt will n ot ha ve t o be re p eate d. Wit h t he e x ce pti o n of t he 
cli nical e val uati o n, all of t hese  assess me nts, if perf or me d d uri n g scree ni n g, will be e v al uate d at 
t he  ce ntral cli nical la b or at or y, w h ere  feasi ble . T h o u g h  all  assess me nts  ha ve  t o  be  perf or me d, 
ulti mate deter mi n ati o n of a p ositi ve dia g n osis is u p t o t he i n vesti gat or. 
5. 7. 1. 1  Cli nic al E v al u ati o n 
Cli nical  e val uati o n  of  t he  patie nt  f or  dia g n osi n g  b ull o us  pe m p hi g oi d  will  be  perf or me d  at 
Scree ni n g.  
5. 7. 1. 2  He m at o x yli n a n d E osi n ( H& E) St ai ni n g  
H & E  of  t he  s ki n  bi o ps y  tiss ue  will  be  e val uate d  at  Scree ni n g  a n d  Visit  5  as  i n dicate d  i n  t he 
Sc he d ule of E ve nts ( A p p e n di x A ).  
H & E will be perf or me d i n or der t o deter mi ne t he e osi n o p hil ma ke u p of t he i nfla m mat or y i nfiltrat e. 
T his bi o ps y s h o ul d be ta ke n usi n g a 4 - 6 m m p u n c h at t he e d ge of a l esi o n or blister a n d s h o ul d 
i ncl u de s o me a djace nt u n affecte d s ki n as t he sa m ple m ust c o ntai n i ntact e pit heli u m. At Scree ni n g 
a n d Visit 5 t he sa me bi o ps y sa m ple will be use d t o deter mi ne e osi n o p hil c o u nt a n d t he e osi n o p hil 
ma ke - u p of t he i nfl a m mat or y i nfiltrate wit h he mat o x yli n  a n d e osi n stai ni n g.  
See t he La b or at or y Ma n u al f or m ore d etails.  
5. 7. 1. 3  Direct  I m m u n ofl u oresce nce ( DI F) a n d S alt S plit S ki n 
DI F  o n  salt  s plit  s ki n  of  s ki n  bi o ps y  tiss ue  will  be  e val uate d  at  Scree ni n g  as  i n dicate d  i n  t he 
Sc he d ule of E ve nts ( A p p e n di x A ).  
DI F o n salt  s plit s ki n will be perf or me d t o c h ec k  t he li near d e p ositi o n of I g G a n d/ or C 3 o n t he 
blister r o of (e pi der mal si de) as part of t he dia g n osis f or b ull o us pe m p hi g oi d. 
T he bi o ps y s h o ul d b e ta k e n usi n g a 4 -6 m m p u nc h of er yt he mat o u s p erilesi o nal s ki n , a p pr o xi matel y 
0. 5 t o 1 c m a wa y fr o m a fres h blister.  A v oi d er osi o ns, ulcers, a n d b ullae w hile o btai ni n g tiss ue 
a djace nt t o acti ve lesi o ns.  
See t he La b or at or y Ma n u al f or m ore d etails.  
4 4

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
5. 7. 1. 4  B P 1 8 0 a n d B P 2 3 0 A ut o a nti b o dies 
B P 1 8 0 a n d B P 2 3 0 a ut oa nti b o dies will be e val uat e d at Scree ni n g as i n dicate d i n t he Sc he d ule of 
E ve nts ( A p pe n di x A ).  
Patie nts will be teste d  f or t he prese nce of  B P 1 8 0 a n d B P 2 3 0 a ut oa nti b o dies. At Scree ni n g, t he 
sa me sa m ple  will  be  us e d  t o  test  f or  B P 1 8 0  a n d  B P 2 3 0  a ut oa nti b o dies  a n d  I g G  circ ulati n g 
a ut oa nti b o dies wit h II F.  
See t he La b or at or y Ma n u al f or m ore d etails.  
5. 7. 1. 5  I n direct I m m u nofl u o resce n ce (II F)  
II F of t he patie nt’s ser u m will be  e val uate d at Scree ni n g as i n dicate d i n t he Sc he d ule of E ve nts 
(A p pe n di x A ).  
II F  of  t he  patie nt’s  s er u m  will  be  perf or m e d  t o c hec k  f or  t he  prese n ce  of  I g G  circ ulati n g 
a ut oa nti b o dies .  At  Scree ni n g,  t he  s a me  sa m ple  will  be  use d  t o  test  f or  B P 1 8 0  a n d  B P 2 3 0 
a ut oa nti b o dies a n d t he II F.  
See t he  La b or at or y Ma n u al f or m ore d etails.  
5. 7. 2  Assess me nt  of B P Se verit y 
M o derate t o e xte nsi ve B P will be defi ne d b y t he n u m ber of b ullae a n d/ or urticarial pla q ues t hat 
ha ve a p peare d o n 3 occasi o ns  d uri n g t he scree ni n g peri o d. T he n u m ber of b ullae a n d/ or urticarial 
pla q ues ca n be m o nit ore d a t t he cli nical site a n d rec or de d b y t he i n v esti gat or or it ca n be re p orte d 
b y t he p atie nt or care gi v er. T he n u m ber of b ullae a n d/ or urticarial pla q u es s h o ul d be d oc u me nte d 
o n t he Assess me nt of B P Se verit y f or m (see A p p e n di x B ). T he assess me nt s h o ul d be perf or me d at 
a p pr o xi matel y t he sa me ti me eac h d a y.   
5. 7. 3  K ar n ofs k y Perf or m a nce S t at us Sc ale 
T he Kar n ofs k y Perf or ma nce Stat us  Scale , a n assess me nt t o ol f or f u ncti o nal i m pair me nt (A p pe n di x  
C ), will be e val uate d at Scree ni n g as i n dicate d i n t he Sc he d ule of E v e nts ( A p pe n di x A ).  
5. 7. 4  Bi o m ar kers  
Bi o mar ker sa m ple c ollecti o n will be perf or me d at Visit 2 ( Da y 0) a n d Visit 5 ( Da y 4 2) as i n dicate d 
i n t he Sc he d ule of E ve nts (A p pe n di x A ). At Visit 2 ( Da y 0), bi o mar kers will be c ollecte d pre - d os e 
(a n y ti me pri or t o t he i nitiati o n of treat me nt i nf usi o n).  
5. 8  
E A R L Y DI S C O N TI N U A TI O N S T U D Y VI SI T  
A n e arl y disc o nti n uati o n st u d y visit will be perf or me d f or p atie nt s w h o wit h dra w fr o m t he st u d y 
f or t he reas o ns s pecifie d i n Secti o n 4. 5. 1 . 
All reas o ns f or treat me nt disc o nti n uati o n will be d oc u me nte d i n t he s o urce d oc u me nts as well as 
t he C R F. O nl y o n e reas o n (t he m ost se vere) f or earl y disc o nti n uati o n s h o ul d be rec or de d i n t he  
C R F. If o n e of t he r eas o ns f or disc o nti n uati o n is a n A E – t his s h o ul d be c h ose n as t he reas o n. 
E ver y eff ort s h o ul d be m a de t o f oll o w- u p t hese p atie nt s f or res ol uti o n of t he A E.  
4 5

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
T he  re q uire d  assess me nts  t hat  are  t o  be  p erf or me d  d uri n g  a n  earl y  disc o nti n uat i o n  visit are  
i n dicate d i n t he Sc h e d ule of E ve nts (A p pe n di x A ), b ut assess me nts ma y b e a d de d at t h e discreti o n 
of t he i n vesti gat or. 
5. 9  
U N S C H E D U L E D VI SI T  
A n u nsc he d ule d visit ma y be perf or me d at a n y ti me d uri n g t he st u d y at t he patie nt ’s re q uest or as 
dee me d n ecess ar y  b y  t h e i n vesti gat or. T h e  dat e  a n d  reas o n  f or  t h e  u ns c he d ule d  visit  will  be 
rec or d e d. A E m o nit ori n g a n d c o nc o mita nt me dicati o n rec or di n g s h o ul d be perf or me d. A p pr o priate 
pr oce d ur es a n d e v al uati o ns will be c o m plete d as dee me d necessar y b y t he in vesti gat or a n d ma y 
i ncl u de ( b ut ar e n ot li mite d t o) la b orat or y t ests, vital si g ns a n d p h ysical e x a mi nati o n.  
C ortic oster oi d use ma y b e ma na ge d at a s c he d ule d visit, u nsc he d ule d visit, or p h o ne call f oll o w -
u p base d o n i n vesti gat or discreti o n. 
5. 1 0  P H O N E C A L L F O L L O W -U P  
S yste mic c ortic oster oi d usa ge ma y be ma n a ge d at a sc he d ule d visit, u nsc h e d ule d visit, or p h o ne 
call f oll o w-u p per t he dis creti o n of t he i n vesti gat or. If a p h o n e call f oll o w - u p f or c ortic oster oi d use 
ma na ge me nt is perf or me d, ot her c o nc o mita nt trea t me nt a n d A E data s h o ul d als o be c ollecte d. 
5. 1 1  P O S T T R E A T M E N T P H O N E  C A L L  
A p pr o xi matel y 2 a n d 4 m o nt hs after Visit 8 ( Da y 8 4), a f oll o w- u p p h o n e call will be place d  a n d 
t he f oll o wi n g ass ess me nts will be perf or me d: c o m pleti o n of A B Q O L q uesti o n naire, a d v erse 
e ve nt assess me nt, a n d  c o nc o mita nt me dicati o n  re p orti n g. C ortic oster oi d usa ge ( oral a n d t o pical) 
will be d oc u me nte d a n d ma na ge d as n ecess ar y.  
6. 0  I N V E S TI G A TI O N A L P R O D U C T 
6. 1  
I D E N TI T Y O F I N V E S TI G A TI O N A L P R O D U C T 
Bertili m u ma b  is a rec o m bi na nt h u ma n I g G4 m o n ocl o nal a nti b o d y t hat n e utralizes h u ma n e ota xi n-
1 (e ota xi n); t he dr u g pr o d uct c o nsists of bertili m u ma b  f or m ulate d i n p h os p hate b uffere d sali ne 
( P B S) at p H 7. 2 a n d at a c o nce ntrati o n of 1 0 m g/ m L , pres e nte d as a sterile, clear, c ol orless s ol uti o n 
i n 1 0 m L clear glass vials.  
T he f or m ula f or t he P B S  is so di u m c hl ori de 7 7 m M, m o n os o di u m p h os p hate 1 7 m M  a n d dis o di u m 
p h os p hate 5 0 m M. 
6. 2  
S T U D Y D R U G A D MI NI S T R A TI O N A N D D O S A G E  
Bertili m u ma b 1 0 m g/ k g  will be a d mi nistere d b y I V o ver 3 0 mi n utes of i nf usi o n ti me . T he w ei g ht 
use d f or d ose calc ulati o n at all d osi n g da ys is t he wei g ht meas ure d at scree ni n g. 
6. 3  
M A N U F A C T U RI N G O F S T U D Y M E DI C A TI O N  
Pat he o n  U K   a n d N o v a  La b or at ories  Lt d , c G M P  ve n d or s, will perf or m  t he  dr u g  pr o d uct 
ma n ufact uri n g a n d releas e .  
4 6

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
6. 4  
P A C K A GI N G A N D L A B E L LI N G O F S T U D Y M E DI C A TI O N  
Bertili m u ma b  vials  will  be  pac ka ge d  a n d  la b el e d i n  c o m plia nce  wit h G C P  a n d  l ocal  healt h 
a ut h orit y g ui deli nes.   
Site desi g nee(s)  will be r es p o nsi ble f or ha n dli n g a n d pre parati o n of t he st u d y test me dicati o n.  
Refer t o t he I P Ma n u al f or m ore details.  
6. 5  
DI S T RI B U TI O N A N D S HI P M E N T O F S T U D Y M E DI C A TI O N  
T he patie nt s’ i n vesti gati o nal dr u g s u p plies will b e pac k e d a n d s hi p pe d i n a p pr o priate b o x es. If, 
u p o n arri val at t he cli nical i n vesti gati o n site, st u d y dr u g s u p plies a p p ear t o be da ma ge d, t he st u d y 
m o nit or s h o ul d be c o ntacte d i m me diatel y.  
Eac h  s hi p me nt  of  st u d y  dr u g  s u p plies  f or  t he  st u d y  will  be  acc o m pa nie d  b y  a  s hi p me nt  f or m 
descri bi n g  t he  c o nte nts  of  t he  s hi p me nt,  ac k n o wle d ge me nt  of  recei pt  a n d  ot her  a p pr o priate 
d oc u me ntati o n.  T he  s hi p me nt  f or m  will  assist  i n  mai ntai ni n g  c urre nt  a n d  acc urate  i n ve nt or y 
rec or ds. T h e st u d y staff will c o nfir m t he recei pt of cli nical s u p pl y t o t he st u d y m o nit or.  
6. 6  
S T O R A G E  A N D I N S T R U C TI O N S F O R P R E P A R A TI O N A N D I N F U SI O N O F 
T H E I N V E S TI G A TI O N A L P R O D U C T 
T he st u d y m e di cati o n will be  st ore d at eac h site u n der refri gerati o n  at 2- 8° C.  
Rec or ds s h o ul d  be ke pt b y t he desi g nee(s)  as t o h o w m uc h st u d y dr u g w as use d b y eac h patie nt . 
T he  st u d y  m o nit ors  m ust  peri o dicall y  c h ec k  t he  st u d y  dr u g  s u p plie d  t o  e ns ure  e x pir y  date  a n d 
s ufficie nt a m o u nt of st u d y dr u g, e ns ure t h at dr u g acc o u nta bilit y is b ei n g p erf or me d at eac h visit 
a n d t hat dr u g acc o u nta bilit y l o gs are m ai ntai ne d.  
All i n vesti g ati o nal pr o d u cts m ust be ke pt i n a l oc k e d area wit h access t o t he st u d y dr u g li mite d t o 
desi g nat e d st u d y p ers o n n el.  
Pre parati o n of t he st u d y  dr u g d os e f or a d mi nistrati o n  m ust be carrie d o ut b y a trai ne d me dical 
pr ofessi o nal at t h e st u d y ce nter usi n g ase pt ic tec h ni q ue acc or di n g t o t he P har mac y M a n ual. T h e 
n u m ber of vi als use d as well as t he st u d y dr u g v ol u me dis pe nse d per d ose will be rec or de d i n t he 
st u d y l o g b o o k.  I nstr ucti o ns f or pre parati o n a n d a d mi nistrati o n of st u d y dr u g are detaile d i n t he I P 
Ma n ual.  
O nl y  trai n e d  pers o n nel  are  a ut h orize d  t o pre p are  a n d  a d mi nister  st u d y  dr u g t o  partici pati n g 
patie nts .  
6. 7  
A C C O U N T A BI LI T Y A N D C O M P LI A N C E O F I N V E S TI G A TI O N A L P R O D U C T  
Eac h deli ver y m ust be ac k n o wle d ge d b y t he st u d y tea m me m ber res p o nsi ble f or t he i n vesti gati o nal 
me dici nal pr o d uct b y filli n g i n t he recei pt rec or d f or m a n d ret ur ne d acc or di n g t o t he i nstr ucti o ns 
i ncl u de d i n t he I P s hi p me nt. Acc ur ate, c o m plete , a n d ti mel y d oc u me ntati o n f or all distri b uti o n t o 
t he  st u d y  staff  a n d  pati e nts  will  be  mai ntai ne d  b y  t h e site  desi g nee(s), w hic h  ma y  i ncl u de 
c o nfir mati o n of r ecei pts of cli nical s u p pl y, dr u g acc o u nta bilit y l o gs a n d ot her f or ms.  
T he site d esi g n ee(s) is r es po nsi ble f or e ns uri n g t he s u per visi o n of t he st ora ge a n d all ocati o n of 
t hese  s u p plies,  w hic h  will  be  f or war d e d  t o  t he in vesti gat or  or  desi g nee  at  t he  a p pr o priat e  ti me 
4 7

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
bef ore  a d mi nistrati o n. In vesti gati o nal  dr u g  will  b e  a d mi nistere d  o nl y  t o p atie nt s w h o  meet  t he 
eli gi bilit y criteria of  t h e st u d y.  
Dr u g acc o u nt a bilit y rec or ds m ust be mai ntai ne d b y t h e cli nical i n vesti gati o n site at all ti mes. All 
use d a n d u n use d i n vesti gati o nal dr u g will be c ollecte d a n d dr u g acc o u nta bilit y perf or m e d b y t he 
site desi g nee(s).  T h e st u d y m o nit or will c hec k t h ese re g ul arl y d uri n g m o nit ori n g visits.  
U n use d dr u g s u p plies will be ret ur n e d t o t he S p o ns or, u nless i nstr ucte d ot her wise. At t he e n d of 
t he st u d y, all t he cli nical s u p pl y a n d t he c orres p o n di n g acc o u nta bilit y f or ms m ust be ret ur ne d t o 
t he S p o ns or, t he st u d y m o nit or or desi g nee f or rec o nciliati o n a n d destr ucti o n. A p h ot oc o p y of t hese 
rec or ds m ust be k e pt at t he cli nical i n vesti gati o n site. 
T he i n ve nt or y will be ma de a vaila ble t o t he st u d y m o nit or w h o will verif y acc o u nta bilit y  a n d v erif y 
d ose d uri n g t h e c o urs e of t he st u d y. 
St u d y dr u g or ders, rec or ds of st u d y dr u g recei pts, dis pe nsi n g rec or ds, a n d i n ve nt or y f or ms l ocate d 
at t he site will be e x a mi ne d a n d rec o ncile d b y t he st u d y m o nit or peri o dicall y d uri n g a n d at t he e n d 
of t he st u d y.   
6. 8  
C O N C O MI T A N T T H E R A P Y  
At t he scree ni n g visit, r el e va nt treat me nts c urre ntl y recei ve d b y t he p atie nt  will be rec or de d i n t he 
patie nt’s file a n d  o n t he p atie nt ’s C R F i ncl u di n g treat me nt na me, i n dicati o n, d ose, t otal dail y d ose, 
a n d start a n d st o p dates.   
A n y me di cati o ns (i ncl u di n g pr escri pti o n, o ver -t he-c o u nter, her b al s u p ple me nts, a n d ot her healt h 
st ore-t y p e pr o d ucts) t o be ta ke n d uri n g t he st u d y m ust be rec or de d i n t he C R F. All c o nc o mita nt 
me dicati o ns use d t o treat A Es will als o be rec or de d .  
6. 8. 1  C o nc o mit a nt C orti c oster oi d T her a p y  
•  Ne wl y dia g n ose d p atie nts: 
D ue t o t he p ote ntial effects of l o n g -ter m a n d/ or hi g h-d ose s yste mic c ortic oster oi d usa ge o n 
b ull o us pe m p hi g oi d, patie nts will be per mitte d t o ta ke s yste mic oral c ortic oster oi ds s pecificall y 
f or bull o us pe m p hi g oi d o nl y f or a peri o d of 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n 
( Visit 2 - Da y 0) at d os es n o gr eater t ha n 4 0 m g/ da y pre d nis o ne e q ui vale nt.  
Patie nts  w h o  ha ve  ta k e n  s yste mic oral c ortic oster oi d  f or  b ull o us  pe m p hi g oi d  l o n ger  t ha n 4 
wee ks pri or t o t he first tr eat me nt a d mi nistrati o n ( Visit 2 - D a y 0) or at d oses greater t ha n 4 0 
m g/ da y pr e d nis o ne e q ui v ale nt at a n y ti me are e x cl u de d fr o m t he st u d y.   
F or patie nts w h o ha ve us e d s yste mic c ortic oster oi ds f or reas o ns ot her t ha n b ull o us pe m p hi g oi d, 
a was h o ut peri o d of 4 w ee ks pri or t o t he first treat me nt a d mi nistrati o n ( Visit 2 - Da y  0)  is 
re q uire d. 
F or patie nts w h o are ta ki n g s yst e mic oral c ortic oster oi ds at a dail y d os e bet wee n 4 0  m g/ da y 
a n d  3 0 m g/ da y  pr e d nis o ne  e q ui vale nt  f or  B P  wit hi n  4 wee ks  pri or  t o  t he  first  treat me nt 
a d mi nistrati o n ( Visit 2 - Da y 0), ta p eri n g of s yst e mic c ortic oster oi ds is t o be c o n d uct e d at t he 
discreti o n of t he i n vesti gat or. H o we ver, patie nts m ust be o n 3 0  m g/ da y pre d nis o ne e q ui vale nt 
f or t he first tr eat me nt a d mi nistrati o n ( Visit 2 - Da y 0). F or patie nts w h o are ta ki n g less t ha n 3 0  
m g/ da y pre d nis o ne e q ui vale nt pri or t o t he first a d mi nistrati o n da y ( Visit 2 - Da y 0), a sta bl e 
d ose of s yst e mic c ortic oster oi ds s h o ul d be mai ntai ne d u ntil Visit 2 ( Da y 0).  
4 8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 4 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
•  Patie nts resista nt t o c ortic oster oi d ta peri n g : 
 
N o was h - o ut peri o d is re q uire d. 
T he ta peri n g sc h e d ule de picte d i n  Ta ble 1  is reco m me n de d f or t he re mai n der of t he st u d y.  
T a ble 1 : Rec o m me n de d C ortic oster oi d T a peri n g Re gi me n 
S yste mic c ortic oster oi d d ose 
( pre d nis o ne e q ui vale nt) p er da y 
Ta peri n g sc h e d ule  
≥3 0. 0 -1 0. 1  m g/ da y  
Decrease b y 5  m g eac h wee k  
1 0. 0 –  0  m g/ da y  
Decrease  b y 2. 5  m g eac h wee k  
 
C ortic oster oi d ma na ge m e nt ca n occ ur eit her d uri n g a sc h e d ule d visit , u nsc h e d ule d visit, or p h o n e -
call f oll o w- u p per t h e i n vesti gat or’s discreti o n . 
T a ble 2 : C ortic oster oi d C o m p aris o n C h art  
 
A p pr o xi mate E q ui vale nt D ose, m g  
Relati ve P ote nc y  
C ortis ol  
2 0  
1. 0  
C ortis o ne  
2 5  
0. 8  
Pre d nis o ne  
5  
4. 0  
Pre d nis ol o ne  
5  
4. 0  
Tria mci n ol o ne  
4  
5. 0  
De x a met has o ne  
0. 7 5  
3 0 -1 5 0  
Refere nce: W els h G A, Ma nz ull o E F a n d Nie ma n L K T he s ur gical patie nt ta ki n g gl uc oc ortic oi ds.  
2 0 0 7 U p T o Date ®  w w w. u pt o date.c o m.  
O n  c o m pleti o n  of  t he  st u d y,  p atie nts  will  be  treate d  acc or di n g  t o  l ocal  practice  a n d  at  t he 
i n vesti gat or’s discreti o n. 
Ot her c ortic oster oi d re gi me ns ot her t h a n t h ose list e d i n Ta bl e 2  are per mitte d o nl y if t h e patie nt is 
c o nsi dere d, i n t h e o pi ni o n of t he i n vesti gat or, u na ble t o ta per d o w n c ortic oster oi d treat me nt. N o 
was h - o ut peri o d is r e q uir e d.  
6. 8. 2  Resc ue T her a p y  
If  necessar y,  r esc u e t her a p y  is  per mitte d  at a n y  p oi nt  d uri n g  t h e  st u d y  at  t he  discreti o n  of  t he 
i n vesti gat or.   T he  patie nt  ca n  c o nti n ue  i n  t he  st u d y  as  l o n g  as  t he  resc ue  t hera p y  is  clearl y 
d oc u me nte d. 
6. 8. 3  Pr o hi bite d Pri or a n d C o nc o mit a nt Me dic ati o n  
Me dicati o ns ha vi n g t h e p ote ntial t o i nterfere wit h t he st u d y assess me nts are e x cl u de d t hr o u g h o ut 
t he trial a n d i ncl u de:  
4 9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
•  S yste mic c ortic oster oi ds a d mi nistere d f or reas o ns ot her t han b ull o us pe m p hi g oi d wit h o ut 
a was h o ut p eri o d of 4 wee ks pri or t o t he first treat me nt a d mi nistra ti o n (Visit 2 - Da y 0)  or 
at a n y ti me d uri n g t h e st u d y f or ne wl y dia g n os e d p atie nts.   
•  S yste mic  c ortic oster oi ds  ta ke n  s pecificall y  f or  b ull o us  pe m p hi g oi d  at a n y d ose ( greater 
t ha n  4 0  m g/ d a y  pr e d nis o ne  e q ui vale nt) wit hi n  4  wee ks  pri or  t o  t he  first  treat me nt 
a d mi nistrati o n da y ( Visit 2 - Da y  0) or greater t ha n 4 0  m g/ da y pre d nis o n e e q ui vale nt at 
a n y ti me pri or t o t he first treat me nt a d mi nistrati o n da y  or at a n y ti me d uri n g t he st u d y  f or 
ne wl y di a g n ose d patie nts 
•  Treat me nt wit h  class 1 a n d 2 t o pical ster oi ds wit hi n 2 wee ks pri or t o t he first treat me nt 
a d mi nistrati o n da y ( Visit 2 – Da y 0)   or at a n y ti me d uri n g t he st u d y f or n e wl y dia g n os e d 
patie nts  
•  I m m u n os u p pr essi ve  dr u gs  ( e. g.,  met h otre x ate,  azat hi o pri ne,  m yc o p he n olate  m ofetil, 
da ps o ne) wit hi n 4 wee ks pri or t o t he first treat me nt a d mi nistrati o n da y ( Visit 2 – Da y 0) or 
at a n y ti me d uri n g t h e st u d y  
•  Bi ol o gical  t her a pies  ( e. g.,  i ntra v e n o us  I g,  eta nerce pt,  a d ali m u ma b,  uste ki n u ma b, 
i nfli xi ma b)  wit hi n  4  m o nt hs  a n d  rit u xi ma b  wit hi n 1 year pri or  t o  t he  first  treat me nt 
a d mi nistrati o n da y ( Visit 2 – Da y 0)  or at a n y ti me d uri n g t h e st u d y  
•  Treat me nt wit h a f ull c o urse of macr oli des or tetrac ycli nes  wit hi n 4 wee ks pri or t o t he first 
treat me nt a d mi nistrati o n da y ( Visit 2 – Da y 0)  or at a n y  ti me d uri n g t h e st u d y 
•  Use  of  vacci nes  or  ot her  i m m u n osti m ulat or  wit hi n  4  wee ks  pri or  t o t he  first  treat me nt 
a d mi nistrati o n da y ( Visit 2 – Da y 0)  or a t a n y ti me d uri n g t h e st u d y  
I n t he i nter ests of patie nt  safet y a n d acce pta bl e sta n dar ds of me dical care, t he i n vesti gat or ma y  
prescri be a d diti o nal treat me nt(s) at his/ her discreti o n, w hic h will be rec or d e d o n t he patie nt ’s C R F. 
7. 0  S A F E T Y A N D P H A R M A C O VI GI L A N C E  
7. 1  
A D V E R S E E V E N T  
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a  patie nt  or cli nical i n vesti gati o n  
s u bjecta n d w hic h d oes n ot necessaril y ha v e t o ha ve a ca us al relati o ns hi p wit h t his treat me nt. T his 
i ncl u des  a n y  s u bjecti ve  si g ns,  s y m pt o ms  or  dia g n osis,  cli nicall y si g nifica nt  de viati o n  fr o m 
baseli ne scr ee ni n g  la b or at or y v al ues or vital si g ns, or w orse ni n g ( m ore se v ere, m ore fre q ue nt or 
i ncreas e d  i n  d urati o n  d uri n g  t he  i n vesti gati o nal  pr o d uct  treat me nt)  of  t he  c o nc o mita nt  disease 
prese nt at Visit 2 ( D a y 0)  visit (after i nitiati o n of i n vesti gati o nal pr o d uct treat me nt). Sta ble c hr o ni c 
c o n diti o ns t hat are prese nt pri or t o st u d y e ntr y a n d  d o n ot w orse n d uri n g t he st u d y will n ot be 
c o nsi dere d A Es. Disease -relate d a d verse e ve nts will n ot be c o nsi dere d A Es u nless t he y w ors e n 
be y o n d w hat w o ul d be e x pecte d i n t h e n or mal pr o gressi o n of t he diseas e. I n al l cases, t he eti ol o g y 
s h o ul d, as m uc h as p ossi ble, be i de ntifie d a n d t he S p o ns or n otifie d. 
A n a b n or mal res ult of di a g n ostic pr oce d ures i ncl u di n g a b n or m al la b orat or y or vital si g n fi n di n gs 
will be c o nsi dere d a n A E if it:  
•  Res ults i n patie nt ’s wit h dra wal b y the i n vesti gat or 
•  Is ass ociate d wit h cli nical si g ns or s y m pt o ms 
5 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
•  Is c o nsi dere d b y t h e p h ysicia n t o be of cli nical si g nifica nce. 
A d verse e ve nts re p orte d b y t he p atie nt  or o bser v e d b y t he in vesti gat or will be i n di vi d uall y liste d 
o n a n A E  f or m i n t he C R F as f oll o ws: t he s pecific e ve nt or c o n diti o n, w het her t he e v e nt was 
prese nt pre-st u d y, t he dat es a n d ti mes of occ urre n ce, d urati o n, se verit y, li keli h o o d of relati o ns hi p 
t o st u d y me dicati o n, s pecific c o u nter meas ures, a n d o utc o me.  
T he i nte ns it y or s e verit y of t he A E will be c h aracterize d as: 
•  
Mil d:  
Tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o m e dical 
i nter ve nti o n/t hera p y re q uire d 
•  
M o derate:  
Mil d t o m o derate li mitati o n i n acti vit y - s o me assista nce ma y be n ee d e d; 
n o or mi ni mal m e dical i nter ve nti o n/t hera p y re q uire d  
•  
Se vere:   
Mar ke d li mitati o n i n acti vit y, s o me assista nce us uall y re q uire d; me dical 
i nter ve nti o n/t hera p y re q uire d; h os pitalizati o n p ossi ble 
T he  I n vesti gat or  will  d oc u me nt  his/ her  o pi ni o n re gar di n g t he  relati o ns hi p  of  t he A E  t o  t he 
i n vesti gati o nal pr o d u ct (st u d y me dicati o n) usi n g t he f oll o wi n g criteria: 
C ate g or y 
Defi niti o n  
U nrel ate d  
Clearl y d ue o nl y t o e xtra ne o us ca uses, a n d d oes n ot meet criteria liste d u n der 
p ossi ble or pr o ba ble. 
U nli kel y  
D oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n. Ma y ha ve 
bee n pr o d uce d b y t he patie nt ’s cli nical state or b y e n vir o n me ntal fact ors or ot her 
t hera pies a d mi nistere d. 
P ossi ble  
F oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n, b u t ma y ha ve 
bee n als o pr o d uce d b y t he patie nt’s cli nical state, e n vir o n me ntal fact ors or ot her 
t hera pies a d mi nistere d. 
P r o b a ble 
Clear -c ut te m p oral ass ociati o n wit h a d mi nistrati o n wit h i m pr o ve me nt o n 
cessati o n of i n vesti gati o nal me dici nal pr o d uct or re d ucti o n i n d ose. Rea p pears 
u p o n rec halle n ge. F oll o ws a k n o w n patter n of res p o nse t o t he i n vesti gati o nal 
me dici nal pr o d uct. 
7. 2  
S E RI O U S A D V E R S E E V E N T 
A seri o us a d vers e e v e nt ( S A E) is a n y a d v erse e v e nt occ urri n g  after si g ni n g i nf or me d c o nse nt  at 
a n y d ose t hat s u g gest s a si g nifica nt hazar d or si de effect, re gar dless of t he in vesti gat or or s p o ns or's 
o pi ni o n o n t he r elati o ns hi p t o t he i n vesti gati o nal pr o d uct a n d t h at res ults i n, b ut ma y n ot be li mite d 
t o, a n y of t he f oll o wi n g o utc o mes: 
•  D eat h (r e gar dl ess of t he ca use)  
•  L if e-t hreate ni n g a d verse dr u g e x perie nce 
•  In p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n (a n y i n p atie nt h os pital 
a d missi o n t hat i ncl u des a mi ni m u m of a n o ver ni g ht sta y i n a healt h care facilit y)  
•  P ersiste nt or si g nifica nt disa bilit y/i nca pacit y  
•  C o n ge nital a n o mal y or birt h defect. 
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Fe br uar y 2 8, 2 0 1 8  
I m p ort a nt me dical e v e nts t hat ma y n ot be fatal,  life t hreate ni n g, or re q uire h os pitalizati o n ma y be 
seri o us w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he y ma y je o p ar di ze t he patie nt  a nd ma y 
re q uire me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve. 
H os pitalizati o n f or electi ve treat me nt of a pre -st u d y c o n diti o n t hat di d n ot w orse n w hile o n st u d y 
a n d h os pitalizati o ns f or tr eat me nt of n o n -a d v erse e ve nts (e. g. , cos metic s ur ger y) are n ot c o nsi dere d 
seri o us a d vers e e ve nts. Sit uati o ns w here a n u nt o w ar d me dical occ urre n ce di d n ot occ ur ( e. g., s o cial 
a n d/ or c o n ve nie n ce a d missi o n t o a h os pital) are n ot c o nsi dere d as s eri o us a d verse e v e nts.  
T he u n derl yi n g m e dical c o n diti o n f or a n y s ur ger y perf or m e d s h o ul d be re p orte d  as t h e e v e nt ter m 
rat her t ha n t h e pr oce d ure itself. 
Si g nific a nt me dic al  e ve nts  are t h ose w hic h ma y n ot be i m me diatel y life  t hreate ni n g,  b ut ma y 
je o par dize t he patie nt  a n d ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her seri o us o utc o mes 
liste d a b o ve. E x a m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me 
f or aller gic br o nc h os pas m; bl o o d d ys crasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; 
res ulti n g i n a n a d vers e e v e nt w hic h w o ul d n or mall y be c o nsi dere d seri o us b y t his criteri o n. 
I n p atie nt  h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n refers  t o h os pital  i n patie nt 
a d missi o n a n d/ or pr ol o n gati o n of h os pital sta y re q uire d f or treat me nt of A E, or w hic h occ urre d as 
a c o nse q ue n ce of t h e e ve nt. H os pitalizati o n f or electi ve treat me nt of a pre -st u d y c o n diti o n t hat di d 
n ot w orse n w hile o n st u d y a n d h os pitalizati o ns f or treat me nt of n o n -a d verse e ve nts (e. g. , c os metic 
s ur ger y or dia g n ostic pr o ce d ure) ar e n ot c o nsi dere d seri o us a d vers e e v e nts. 
A n y  ne w  S A E  t hat  o cc urs u p  t o  3 0  da ys after  t he  st u d y  p eri o d  a n d is  c o nsi dere d  r elate d 
( p ossi bl y/ pr o ba bl y) t o t h e i n vesti gati o nal pr o d u ct or st u d y partici p ati o n s h o ul d be rec or d e d a n d 
re p orte d i m me diatel y. 
A lif e-t hre ate ni n g a d verse dr u g e x perie nce is a n y a d verse e ve nt t hat places t he patie nt , i n t he vie w 
of t he in vesti gat or, at i m me diate ris k of deat h fr o m t he  reacti o n as it occ urre d, i.e., it d oes n ot 
i ncl u de a reacti o n t hat, h a d it occ urr e d i n a m ore s e vere f or m, mi g ht h a ve ca use d deat h.  
E ver y atte m pt s h o ul d be ma de t o descri be t he A E/ S A E i n ter ms of a dia g n osis. H o we v er, if a n 
o bser ve d  or  re p orte d  si g n  or  s y m pt o m  is  n ot  c o nsi dere d  a  c o m p o ne nt  of  a  s pecific  disease  or 
s y n dr o me b y t he I n vestigat or, it s h o ul d be rec or d e d as a se parate A E/ S A E o n t he e C R F. O nce a 
clear dia g n osis has bee n ma de, i n di vi d ual si g ns a n d s y m pt o ms s hall n ot be rec or d e d u nless t he y 
re pres e nt  at y pical  or  e xtre me  ma nifestati o ns  of  t he  dia g n osis,  i n  w hic h  case  t he y  s h o ul d  be 
re p orte d as se parate e ve nts. If a clear dia g n osis ca n n ot be esta blis he d, eac h si g n a n d s y m pt o m m ust 
be rec or de d i n di vi d uall y. 
7. 3  
D E FI NI TI O N O F A N U N E X P E C T E D A D V E R S E E V E N T 
A n u ne x pecte d  a d verse dr u g e x perie nce (e ve nt) is a n y a d vers e e ve nt of s pecificit y or sev erit y n ot 
re p orte d i n t he c urr e nt I n vesti gat or’s Br oc h ure . 
7. 4  
N O TI FI C A TI O N A B O U T S E RI O U S O R U N E X P E C T E D  A D V E R S E E V E N T S  
All S A Es m ust be re p orte d  i m me di atel y t o t h e I m m u ne P har mace uticals  re prese ntati ve as s o o n as 
it bec o mes k n o w n t o t he in vesti gat or a n d n ot later t ha n wit hi n 2 4 h o urs of t heir k n o wle d ge of t he 
occ urr e nce of a n S A E.    
 
 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
I m m u ne P har mace uticals  Re prese ntati ve : 
 
Tele p h o ne:
 e xt  
 
M o bile:   
 
F a x: 
 
E- m ail:
 
T hese  preli mi nar y re p orts  will  be  f oll o we d  wit hi n  2 4  h o urs  b y  detaile d  descri pti o ns  t hat  will 
i ncl u de  a  c o m plete d  S A E  f or m,  c o pies  of  h os pital  case  re p orts,  a ut o ps y  re p orts,  a n d  ot h er 
d oc u me nts, w he n r e q uest e d a n d a p plica ble. 
I n  a d diti o n,  all  A Es/ S A Es/ S us pecte d  U ne x pecte d  Seri o us  A d verse  Reacti o n  (S U S A Rs)  will  be 
re p orte d t o t he l ocal E C a n d re g ul at or y a ut h orities as re q uire d b y l o cal re g ulati o ns a n d I C H-G C P 
g ui deli nes.  
Preli mi nar y Re p orts m ust i ncl u de: 
•  A n i de ntifia ble patie nt  (e. g., s u bject n u m ber) 
•  A n i de ntifia ble re p orti n g s o urce 
•  All relate d a d v erse e ve nts  
•  T he s us pect me dici nal pr o d uct 
•  F oll o w- u p of S A Es/ S U S A Rs  
F oll o w- u p of S A Es/ S U S A Rs t hat occ ur d uri n g t he st u d y will c o nti n ue  u ntil satisfact or y res ol uti o n 
or sta bilizati o n.  
If  a n d w he n  s u p ple me ntar y  i nf or mati o n  is  a vaila ble,  a  f oll o w -u p  S A E  Re p ort  F or m  m ust  be 
c o m plete d b y t he site a n d fa x e d wit hi n 2 4 h o urs t o S p o ns or. 
T he c o ntact i nf or mati o n f or f oll o w u p S A E re p orti n g is t he sa me as f or i nitial S A E re p orts (see 
S ecti o n 7. 4).  
O nce f a x e d, t he S A E f or m a n d acc o m pa n yi n g d oc u me ntati o n s h o ul d be place d i n t he S A E secti o n 
of t he in vesti gat or’s file. If s u p ple me nt ar y i nf or mati o n o n a S A E has t o be se nt, t he S A E f or m has 
t o be use d mar ke d as “F oll o w - U p Re p ort.” 
S A Es ma y be re p ort e d t hr o u g h a n E D C s yste m wit h a pa per f or m use d as b ac k u p.  
F oll o w- U p Re p orts o n n o n -seri o us A E 
All A Es m ust be f oll o we d u ntil res ol uti o n or sta bilizati o n. I n o utsta n di n g cases, it ma y be defi n e d 
as “ o n g oi n g wit h o ut f urt her f oll o w- u p ” b y t he i n vesti gat or a n d s p o ns or’s d ecisi o n.  
8. 0  S T A TI S TI C A L A N A L Y SI S  
T his is a n o pe n -la b el st u d y. T h us, o nl y d escri pti ve statistics are pla n ne d.  All data c ollect e d o n t he 
case r e p ort f or ms ( C R Fs) will be s u m marize d f or t he cli nical st u d y re p ort ( C S R).  
All c o nti n u o us par a meters will be s u m marize d usi n g sta n d ar d s u m mar y statistics as a p pr o priate 
( n, mea n, sta n dar d de viati o n, me dia n, mi ni m u m, ma xi m u m, 2 5t h perce ntile, a n d 7 5t h perce ntile).  
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 4  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
S u m mar y  statistics  f or  cate g orical  varia bl es  will  i ncl u de  fre q ue nc y  c o u nts  a n d  perce nta ges. 
S u m maries will be prese nte d f or all patie nts a n d b y Treat me nt P hase a n d F oll o w - u p E val uati o n. 
Details will be s pecifie d i n t he  statistical a nal ysis pla n. 
9. 0  E T HI C S  
9. 1  
I N S TI T U TI O N A L R E VI E W B O A R D O R I N D E P E N D E N T E T HI C S C O M MI T T E E  
Pri or t o i nitiati o n of t he st u d y, t he in vesti gat or will s u b mit t he st u d y pr ot oc ol a n d a me n d me nts, 
sa m ple  I nf or me d  C o nse nt  F or m  (I C F),  a n d  a n y  ot her  d oc u me nts  t hat ma y  be  re q ueste d  t o  t he 
I R B/I E C f or r e vie w a n d a p pr o val.  T he in vesti gat or will re q uest t hat t he I R B/I E C pr o vi de writte n 
a p pr o val of t he st u d y a n d will kee p o n file rec or ds of a p pr o val of all d oc u me nts pertai ni n g t o t his 
st u d y. T he in vesti gat or will n ot b e gi n t he st u d y u ntil t he pr ot oc ol a n d I C F h a ve bee n a p pr o ve d b y 
t he I R B/I E C. T he in v esti gat or m ust a gree t o ma ke a n y re q uire d pr o gress re p orts t o t he I R B, as 
well as re p orts of S A Es, life -t hreate ni n g c o n diti o ns, or deat h. 
9. 2  
E T HI C A L C O N D U C T O F T H E S T U D Y  
All c li nical w or k  c o n d ucte d u n der t his pr ot oc ol is s u bject  t o G C P g ui deli nes. T his i ncl u des a n 
i ns pecti o n b y S p o ns or or its desi g n ee, h ealt h a ut h orit y or I R B/I E C re prese ntati ves at a n y ti me.  
T he in vesti gat or  m ust  a gree  t o  t he  i ns pecti o n  of  st u d y -relate d  rec or ds  b y  healt h  a ut h orit y 
re pres e ntati ves a n d/ or S p o ns or or its desi g n ee.  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he f oll o wi n g g ui deli nes: 
•  G C P: C o ns oli date d G ui deli ne (I nter nati o nal C o nfere nce o n H ar m o nizati o n of Tec h nical 
Re q uire me nts f or t he Re gistr ati o n of P har m ace uti cals f or H u ma n Use, Ma y 1 9 9 6) 
•  Declar ati o n of Helsi n ki: Brazil , 2 0 1 3 
•  Israeli M O H g ui deli nes (Fe br u ar y 2 0 1 6)   
•  G ui deli nes fr o m t he c o u ntr y- s p ecific Nati o nal C o m pete nt A ut h orit y as a p pr o priate   
9. 3  
P R O T O C O L R E VI SI O N S A N D/ O R D E VI A TI O N S  
C ha n ges  t o t he pr ot oc ol ma y be m a de o nl y b y t h e S p o ns or. All pr ot oc ol m o dificati o ns m ust be 
s u b mitte d t o t he I R B/I E C i n acc or d a nce wit h l ocal re q uire m e nts a n d, if re q uire d, t o Re g ulat or y 
A ge ncies, eit her as a n a me n d me nt or a n otificati o n. A p pr o val f or a me n d me nts m ust be gra nt e d  
bef ore a n y c ha n ges ca n b e i m ple me nte d, e x ce pt f or c ha n ges n ecess ar y t o eli mi nate a n i m me diate 
hazar d t o trial st u d y p atie nt s, or w he n t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects 
of t he trial. N o a p pr o v al will be re q uire d f or n otificati o ns.  
9. 4  
S T U D Y P A TI E N T  I N F O R M A TI O N A N D C O N S E N T 
Pri or t o st u d y s cree ni n g, eac h st u d y patie nt will be i nf or me d i n detail a b o ut t he st u d y dr u g t o be 
a d mi nistere d a n d t h e nat ure of t h e cli nical i n v esti gati o n wit h its e x pecte d ris ks a n d disc o mf orts. 
T he basic ele me nts of i nf or me d c o ns e nt as s pecifie d b y t h e F D A ( 2 1 C F R 5 0. 2 5)  a n d I C H -G C P 
will  be  f oll o we d.  Writte n  c o nse nt  will  be  o btai ne d  fr o m  eac h st u d y  p atie nt or  t heir  le gall y 
a ut h orize d re prese ntati ve t o be i n v ol ve d i n t he cli nical trial b y usi n g t he I R B/I E C -a p pr o v e d I C F 
pri or t o t he c o n d uct of a n y st u d y -relate d acti vit y.  Eac h st u d y patie nt will be gi ve n a c o p y of t he 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
writte n I C F. T h e st u d y p atie nts will als o be i nstr u cte d t hat t he y are free t o wit h dra w t heir c o nse nt 
a n d disc o nti n ue t heir partici pati o n i n t he st u d y at a n y ti me wit h o ut prej u dice. Eac h st u d y patie nt ’s 
c hart will i ncl u de t he si g ne d I C F f or st u d y p artici pati o n. W he n t he st u d y treat me nt is c o m plet e d 
a n d t he C R F has bee n m o nit ore d, t he I C F will be ke pt i n t he in vesti gat or’s ce ntral st u d y f ile f or 
t he re q uire d peri o d. Re g ulat or y a ut h orities ma y c h ec k t he e xiste nce of t he si g ne d I C F i n t his ce ntral 
st u d y f ol der if n ot c o nfir me d  d uri n g t he st u d y.   
9. 5  
S T U D Y P A TI E N T  I N S U R A N C E 
T he S p o ns or has a n i ns ura nce p olic y f or t he t otal d urati o n of t he st u d y c o veri n g t he patie nt s a n d 
in vesti gat ors i n res p ect of t he ris ks i n v ol ve d i n c o n d ucti n g t his st u d y acc or di n g t o t his pr ot oc ol.  
T he certificate of i ns ura n ce  will be file d i n t he in vesti gat or's file or ca n be ma de a vaila ble t o t he 
i n vesti gat or a n d t o t he I R B/I E C u p o n re q u est. 
9. 6  
P E R S O N A L D A T A P R O T E C TI O N  
T he S p o ns or c o m plies wit h t he pri nci ple of st u d y patie nt 's ri g ht t o pr otecti on a gai nst i n vasi o n of 
pri vac y. T hr o u g h o ut t his trial, all data will be i de ntifie d o nl y b y a s u bject n u m ber  a n d st u d y p atie nt 
i nitials. T he i de ntif yi n g p atie nt data will be bli n de d i n all data a n al ys es. H o we ver, t h e patie nt  m ust 
be  i nf or me d  a n d  c o nse nt  is  re q uire d  t hat  a ut h orize d  pers o n nel  of  t he  S p o ns or  a n d/ or  desi g n ee 
( St u d y M o nit or, A u dit or, etc.) a n d  rele v a nt healt h re g ulat or y  a ge n c y will  ha ve  direct  access  t o 
pers o nal me dical data t o ass ure a hi g h q u alit y sta n dar d of t he st u d y.  
1 0. 0  D A T A C O L L E C TI O N, M A N A G E M E N T A N D Q U A LI T Y  A S S U R A N C E  
1 0. 1  A U DI T S A N D I N S P E C TI O N S  
T he in vesti gat or s h o ul d u n dersta n d t hat s o urce d oc u me nts f or t his trial s h o ul d be ma de a vaila ble 
t o a p pr o priatel y q ualifie d pers o n nel fr o m t he S p o ns or or its desi g nees or t o re g ulat or y a ut h orit y 
i ns pect ors  after  a p pr o pri ate  n otificati o n.  T h e  verificati o n  of  t he C R F  data  m ust  be  b y  direct 
i ns pecti o n of s o urce d oc u me nts. T hese a u dits or ins pecti o ns ma y ta ke pl ace at a n y ti me, d uri n g or 
after t he st u d y, a n d ar e b ase d o n t he nati o nal re g ulati o ns, as well as I C H g ui deli nes.  
1 0. 2  S T U D Y M O NI T O RI N G  
M o nit ori n g of t he st u d y is t he res p o nsi bilit y of t h e S p o ns or a n d ma y b e  dele gate d t o a C R O or a 
c o ntract m o nit or. T he st u d y m o nit or will a d vise t he in vesti gat or re gar di n g t he practical c o n d uct of 
t he  st u d y  a n d  mai ntai ni n g  c o m plia nce  wit h  t he  pr ot oc ol,  G C P  a n d  all  a p plica ble  re g ulat or y 
re q uire me nts.  T hr o u g h o ut t he c o urs e of t he st u d y, t he st u d y m o nit or will o versee t he c o n d uct a n d 
t he pr o gr ess of t he st u d y b y fre q ue nt c o ntacts wit h t he in vesti gat or.  T his will i ncl u de tele p h o ne 
calls a n d o n -site visits.  D uri n g t he o n-site visits, t he C R F will be re vie we d f or c o m plete ness wit h 
c orres p o n di n g  s o urce  d o c u me nts.    As  part  of  t he  data  a u dit,  s o urce  d oc u me nts  will  be  ma de 
a vaila ble f or re vie w b y t he st u d y m o nit or.  T he st u d y m o nit or will als o perf or m dr u g acc o u nta bilit y 
c hec ks a n d ma y peri o dicall y re q u est re vie w of t he in vesti gat or’s st u d y file t o e ns ure c o m plete ne ss 
of d oc u me ntati o n i n all r es pects of cli nical st u d y c o n d uct.  
U p o n c o m pleti o n of t he st u d y, t he st u d y m o nit or will arra n ge f or a fi nal re vie w of t he st u d y files 
after w hic h t he files s h o ul d be sec ure d f or t he a p pr o priate peri o d.  T he in vesti gat or or a p p o i nte d 
dele gate  will  recei v e  t he  st u d y  m o nit or  d uri n g  t hese  o n -site  visits,  c o o perate  i n  pr o vi di n g  t he 
d oc u me nts f or i ns pecti o n a n d res p o n d t o i n q uiries.   
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 0. 2. 1  S o urce D at a a n d Rec o r ds  
S o urce  data/r ec or ds  c o nt ai n  all  t he  i nf or mati o n  w hic h  is  necessar y  f or  t he  rec o nstr u cti o n  a n d 
e val uati o n of t he st u d y.  S o urce data/rec or ds are 1) ori gi nal rec or ds, 2) certifie d c o pies of ori gi nal 
rec or ds, 3) o bser vati o ns, 4) la b orat or y re p orts, 5) pa per Case Re p ort F or ms ( C R Fs) a n d/ or data 
s heets.  S o ur ce d ata/rec or ds are t o b e kept wit hi n t he c o ntr ol of t he in vesti gat or u ntil t he e n d of t he 
c o ntract ual  rete nti o n peri o d.  T he in vesti gat or will per mit st u d y -relate d m o nit ori n g, a u dit(s), I R B 
re vie w(s) a n d r e g ulat or y i ns pecti o n(s), wit h direct access t o all t he re q uire d s o urce rec or ds. 
1 0. 3  Q U A LI T Y L A B O R A T O R Y S T A N D A R D S  
La b orat or y t ests or e val u ati o ns descri be d i n t his pr ot oc ol will be c o n d uct e d i n acc or da nce wit h 
q ualit y la b orat or y sta n d ar ds as des cri be d i n t h e S O Ps of t he l ocal i nstit uti o n la b orat or y a n d ce ntral 
la b orat ories. 
1 0. 4  D A T A C O L L E C TI O N A N D M A N A G E M E N T  
All  as pects  of  t he  st u d y  will  be  m o nit ore d  b y  I m m u ne  P har mace utical s a n d  t heir  desi g n ees 
acc or di n g  t o  G o o d  Cli nical  Practi ces  ( G C P)  a n d  Sta n dar d  O perati n g  Pr oce d ures  ( S O Ps)  f or 
c o m plia nce  wit h  a p plica ble  g o v er n me nt re g ulati o n  (i.e.,  I nf orme d  C o nse nt  Re g ulati o ns  [ U S 
2 1 C F R, Part 5 0] a n d I nstit uti o nal Re vie w B oar d re g ul ati o ns [ U S 2 1 C F R, Part 4 5. 1 0 3]). Acc ess t o 
all rec or ds, b ot h d uri n g t he trial a n d after trial c o m pleti o n, s h o ul d be ma de a vaila ble t o I m m u n e 
P har mace uticals at a n y ti me f or re v i e w a n d a u dit t o e ns ure t he i nte grit y of t he data.  
T he i n vesti gat or m ust c o n d uct t he pr ot oc ol i n acc or da nce wit h a p plica ble G C P re g ulati o ns a n d 
g ui deli nes. E ver y atte m pt m ust be ma d e t o f oll o w t he pr ot oc ol a n d t o o btai n a n d rec or d all data 
re q ueste d f or eac h s u bject at t he s pecifie d ti mes. If data is n ot rec or de d p er pr ot oc ol, t he reas o ns 
m ust be clearl y d oc u m e nte d i n t he C R F a n d site rec or ds. 
Pri or t o t he st u d y , a n I m m u ne P har mace uticals re prese ntati ve will re vie w t he pr ot oc ol a n d st u d y 
pr oce d ur es  a n d  pr ocess es  t o  i ncl u de  I P  recei pt,  st ora ge,  a n d  acc o u nta bilit y;  i n vesti gat or 
res p o nsi bilities a n d staff a de q uac y; e ve nt re p orti n g ti meli nes; m o nit ori n g a n d a u dit re q uire me nts; 
st u d y  d o c u me ntati o n  res p o nsi bilities;  s u bject  e nr oll me nt  pr oce d ures;  a n d  C R F  re q uire me nts  t o 
i ncl u de s yste m trai ni n g wit h t he in vesti gat or a n d site staff. A d diti o nal tas ks a n d acti vities ma y b e 
c o m plete d as nee de d f or t he st u d y.  
D uri n g t he st u d y , all pr ot oc ol -s pecifie d data will be rec or d e d i n t he s o urce d oc u me nts a n d d ata 
will be e ntere d  o n t he C R F fr o m t he s o urce d o c u me nts. C hec ks will be perf or me d b y t he st u d y 
m o nit or a n d data ma na ge me nt t o e ns ure t he q ualit y, c o nsiste nc y, a n d c o m plete ness of t he data. 
I nsta n ces of missi n g or u n-i nter preta bl e data will be res ol ve d wit h t he site staff. Site pers o n nel will 
be res p o nsi ble f or pr o vi di n g r es ol uti o ns t o t he data q ueries a n d t o c orrect t he C R Fs, as a p pr o priate.  
1 0. 4. 1  Electr o nic C ase Re p ort F or ms  
Data  f or  t his  st u d y  will  be  r ec or d e d  usi n g  a n  electr o nic  C R F.  Sites  will  recei v e  trai ni n g  f or 
a p pr o priate C R F c o m pleti o n a n d sites will be res p o nsi ble f or data e ntr y i nt o t he e C R F. I n t he e ve nt 
of discre p a nt dat a, t he S p o ns or or d esi g n ee will re q uest clarifi cati o n fr o m t he sites. T he sites will 
res ol ve discre p a nt data el ectr o nicall y i n t he C R F. A n I m m u ne P har mace uticals re prese ntati ve, or 
a  desi g nee,  will  perf or m  fi nal  dat a re vie w  a n d  e xter nal  data  rec o nciliati o ns  pri or  t o  all  maj or 
milest o nes,  i ncl u di n g  data base  cl ose  a n d  l oc k.  C R Fs  a n d  c orrecti o n  d oc u me ntati o n  will  be 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
mai ntai ne d i n t he C R F’s a u dit trail. Rec o r ds rete nti o n f or t he st u d y data will be c o nsiste nt wit h t he 
S O Ps of t he S p o ns or or desi g nee. 
A C R F m ust be c o m plete d f or eac h scr ee ne d s u bject. F or eac h scree n -faile d s u bject, t he reas o n f or 
scree n fail ure will als o be c ollecte d i n t he C R F. T he c orres p o n d i n g f or ms f or t he acti vities a n d 
assess me nts  perf or me d s h o ul d be e ntere d i nt o E D C f or scree n-faile d patie nts.  T he e ntire case b o o k 
of data m ust be re vi e we d a n d electr o ni call y si g n e d b y t he i n vesti gat or.   
1 1. 0  S T U D Y A D MI NI S T R A TI O N  
1 1. 1  P A R TI CI P A TI N G C E N T E R S 
U p t o  1 0 sites i n  Israel a n d U S  will partici pate i n t his st u d y. A d diti o nal sites ma y b e a d d e d as 
necessar y t o c o m plete e nr oll me nt. A list of t he Pri nci pal I n vesti gat ors will be  mai ntai ne d i n t h e  
trial master file. 
1 1. 2  C LI NI C A L T RI A L S U P P L I E S 
T he i n vesti gat or  a n d desi g nee(s)  will  be  res p o nsi ble  f or  a d mi nist eri n g,  i n ve nt or y,  a n d 
acc o u nta bilit y of all cli nical trial s u p plies, a n d e x ercisi n g acce pt e d me di cal  a n d p h ar mace utical 
practices. A n  acc urate  a n d  ti mel y  rec or d  of  t h e  dis p ositi o n  of  all  cli nica l  s u p plies  m ust  be 
mai ntai ne d. T he s u p plies a n d i n ve nt or y rec or d m ust be ma de a vaila ble f or i ns pecti o n u p o n re q ues t. 
U p o n  c o m pleti o n  or  ter mi nati o n  of  t he st u d y, t he in vesti gat or  will  kee p  t he  re mai ni n g  cli nical 
s u p plies al o n g wit h a c o p y of t he i n ve nt or y rec or d a n d a rec or d of the cli nical s u p plies ret ur ne d. 
U n der n o circ u mst a nces will t he in vesti g at or all o w t he st u d y dr u gs or ot her st u d y -rel ate d 
s u p plies t o be use d ot her t h a n as directe d b y t his pr ot oc ol. 
1 1. 3  I N V E S TI G A T O R SI T E FIL E  
All d oc u me nts re q uire d f or t he c o n d uct of t he  st u d y as s pecifie d i n t he I C H-G C P g ui deli nes will 
be mai ntai ne d b y t h e in v esti gat or i n a n or derl y m a n ner a n d ma d e a v aila ble f or m o nit ori n g a n d/ or 
a u diti n g b y t he S p o ns or a n d re g ulat or y a ge ncies. 
1 1. 4  FI N A L R E P O R T  
A fi nal st u d y re p ort will be pr e pare d after t he  st u d y h as bee n c o m plete d a n d data b ase h as b ee n 
clea ne d, l o c ke d a n d a nal yz e d . T he re p ort will be pre pare d acc or di n g t o t he I C H E 3 g ui d eli nes. 
1 1. 5  R E T E N TI O N O F S T U D Y R E C O R D S  
T he in vesti gat or  will  ret ai n  st u d y  d o c u me nts  u ntil  at  least  2  years  after  t he  last  a p pr o val  of  a 
mar keti n g a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at least 2 years h a ve el a pse d si nce t he f or mal disc o nti n uati o n of 
cli nical de vel o p me nt of t he i n vesti gati o nal pr o d u ct . H o we ver, t hese d o c u m e nts s h o ul d be retai ne d 
f or  a  l o n ger  peri o d  if  r e q uire d  b y  t he  a p plica ble  re g ul at or y  re q uire me nt(s)  or  if  nee de d  b y  t he 
S p o ns or. If  t he in vesti gat or is u na ble t o retai n t he st u d y d o c u me nts  f or t he  re q uire d a m o u nt of 
ti me,  S p o ns or  or  desi g nee  m ust  be  i nf or me d  of  t he  i n di vi d ual  w h o  will  be  ass u mi n g  t his 
res p o nsi bilit y. 
T hese  files  m ust  be  ma de  a vaila ble  f or  i ns pecti o n  u p o n  reas o na ble  re q uest  b y  a ut h orize d 
re pres e ntati ves of S p o ns or a n d / or t he rele va nt re g ulat or y a ge nci es. 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 1. 6  C O N FI D E N TI A LI T Y  A N D P U B LI C A TI O N  
St u d y  patie nt  me dical  i nf or mati o n  o btai ne d  b y  t h e  st u d y  is  c o nfi de ntial  a n d  discl os ure  t o  t hir d 
parties ot her t ha n t h ose n ote d bel o w is pr o hi bite d. T hr o u g h o ut t he st u d y, all data will be i de ntifie d 
o nl y b y t he s u bject n u m b er, a n d w h ere a p plica ble, t he st u d y patie nt’s i nitials a n d birt h date. 
At t he st u d y patie nt's re q uest, me dical i nf or mati o n ma y b e gi ve n t o his or her pers o nal p h ysicia n 
or ot her a p pr o pri ate me dical pers o n nel res p o nsi bl e f or his or her welfare. T he pers o nal p h ysicia n 
will be n otifie d b y site pers o n nel of st u d y p atie nt p artici pati o n i n t he st u d y.  
All i nf or mati o n s u p plie d b y  I m m u ne P har mace uti cals, I nc. i n ass ociati o n wit h t his st u d y a n d n ot 
pre vi o usl y p u blis he d, is c o nsi dere d c o nfi de ntial i nf or mati o n. T his i nf or mati o n i ncl u des, b ut is n ot 
li mite d  t o, t he  I n vesti gat or’s  Br o c h ure,  t he  pr ot o c ol,  C R Fs,  a n d  ot her  scie ntific  data.  A n y  data 
c ollecte d  d uri n g  t he  st u d y  ar e  als o  c o nsi dere d  c o nfi de ntial.  T his  c o nfi de ntial  i nf or mati o n  s hall 
re mai n  s ole  pr o pert y  of I m m u ne  P har m ace uticals, s hall  n ot  be  discl ose d  t o  ot hers  wit h o ut  t he 
writte n c o nse nt of  I m m u ne P har mace uticals, a n d s hall n ot be us e d e x ce pt i n t he perf or ma n ce of 
t his st u d y. 
T he i nf or m ati o n de vel o p e d d uri n g t h e c o n d uct of t his st u d y is als o c o nsi d ere d c o nfi de ntial, a n d 
will  be use d  b y  I m m u ne  P har mace uticals, I nc. T his  i nf or mati o n  ma y  b e  discl ose d  as  dee me d 
necessar y b y  I m m u ne P h ar mace uticals, I nc. T o all o w t he use of t his i nf or mati o n deri ve d fr o m t his 
st u d y, t he in vesti gat or is o bli ge d t o pr o vi de I m m u ne P h ar mace uticals  wit h c o m plete test res ults 
a n d all data de v el o pe d i n t his st u d y.  
5 8

 
 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 5 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 2. 0  R E F E R E N C E S  
1  M urrell D F , Da niel B S , J ol y P, B orra d ori L , A m a gai M , Has hi m ot o T , et al. Defi niti o ns a n d 
o utc o me  meas ures  f or  b ull o us  pe m p hi g oi d:  rec o m me n dati o ns  b y  a n  i nter nati o nal  pa nel  of 
e x perts. J A m Aca d Der mat ol. 2 0 1 2 Mar; 6 6( 3): 4 7 9- 8 5. 
2  Vailla nt L , B er n ar d P , J ol y P, Pr ost C , La beille B , Be da n e C , et al. E val uati o n of cli nical criteria 
f or  dia g n osis  of  b ull o us  pe m p hi g oi d.  Fre nc h  B ull o us  St u d y  Gr o u p. Arc h  Der mat ol.  1 9 9 8 
Se p; 1 3 4( 9): 1 0 7 5- 8 0. 
3  J ol y P, R o ujea u J C , Be nic h o u J , Picar d C , Dre n o B , Dela p orte E , et al.. A c o m paris o n of oral 
a n d  t o pical  c ortic oster oi ds  i n  patie nts  wit h  b ull o us  pe m p hi g oi d.  N  E n gl  J  Me d.  2 0 0 2  J a n 
3 1; 3 4 6( 5): 3 2 1- 7. 
4  La n ga n  S M, S meet h L, H u b bar d R, Fle mi n g K M, S mit h CJ, West J.  B ull o us pe m p hi g oi d a n d 
pe m p hi g us v ul garis --i nci de nce a n d m ortalit y i n t h e U K: p o p ulati o n base d c o h ort st u d y. B MJ 
2 0 0 8; 3 3 7: a 1 8 0. 
5  J ol y P, Barica ult S , S parsa A , Ber n ar d P , Bé da ne C , D u vert- Le he m bre S , et al. I n ci de nce a n d 
m ortalit y of b ull o us pe m p hi g oi d i n Fra nce. J I n vest Der mat ol. 2 0 1 2 A u g; 1 3 2( 8): 1 9 9 8- 2 0 0 4. 
6  K or ma n  NJ. B ull o us  pe m p hi g oi d.  T he  l atest  i n  dia g n osis,  pr o g n osis,  a n d  t hera p y.  Arc h 
Der mat ol. 1 9 9 8 Se p; 1 3 4( 9): 1 1 3 7- 4 1. 
7  A meri o P, Frezz oli ni A, Felicia ni C, Ver d oli ni R, Te of oli P, De Pità O, et al. E ota xi ns a n d 
C C R 3  rece pt or  i n  i nfla m mat or y  a n d  aller gic  s ki n  diseases:  t hera p e utical  i m plicati o ns.  C urr 
Dr u g Tar gets I nfla m m Aller g y. 2 0 0 3 M ar; 2( 1): 8 1- 9 4. 
8  Wals h  S R , H o g g  D , M y dlars ki  P R .  B ull o us  pe m p hi g oi d:  fr o m  be n c h  t o  be dsi de.  Dr u gs. 
2 0 0 5; 6 5( 7): 9 0 5- 2 6. 
9  Ber n ar d P. B ull o us pe m p hi g oi d ( Or p ha N u m ber O R P H A 7 0 3) Or p ha n et ( T he P ortal f or Rare 
Diseases  a n d  Or p ha n  Dr u gs)  [serial  o n  t he  I nter net].  2 0 0 6:  A vaila ble  fr o m: 
htt p:/ / w w w. or p ha. net//c o ns or/c gi- bi n/ O C _ E x p. p h p? L n g = G B & E x pert = 7 0 3 Date  accesse d: 
2/ 2 2/ 2 0 1 3. 
1 0  R o ujea u J C, L o k C, Bast uji -Gari n S, M halla S, E n gi n ger V, Ber n ar d P. Hi g h ris k of deat h i n 
el derl y patie nts wit h e xte nsi ve b ull o us pe m p hi g oi d.  Arc h D er mat ol. 1 9 9 8 A pr; 1 3 4( 4): 4 6 5- 9. 
1 1  J ol y P, Be nic h o u J, L o k C, Hell ot M F, Saia g P, T a ncre d e-B o hi n E, et al. Pre dicti o n of s ur vi val 
f or  patie nts  wit h  b ull o us  pe m p hi g oi d:  a  pr os pecti ve  st u d y. Arc h  Der mat ol.  2 0 0 5 
J u n; 1 4 1( 6): 6 9 1- 8. 
1 2  J ol y P, R o ujea u J C , Be nic h o u J , Dela p orte E , D'I n ca n M , Dre n o B , et al. A c o m paris o n  of t w o 
re gi me ns  of  t o pical  c orti c oster oi ds  i n  t he  treat me nt  of  patie nts  wit h  b ull o us  pe m p hi g oi d:  a 
m ultice nter ra n d o mize d st u d y. J I n vest D er mat ol . 2 0 0 9 J ul; 1 2 9( 7): 1 6 8 1- 7. 
1 3  Di n g  C,  Li  J,  Z h a n g  X.  Bertili m u ma b  Ca m bri d ge  A nti b o d y  Tec h n ol o g y  Gr o u p.  C urr  O pi n 
I n v esti g Dr u gs. 2 0 0 4 N o v; 5( 1 1): 1 2 1 3- 8. 
1 4  G o u n ni  A b delila h  S,  Welle ma ns  V,  A g o uli  M,  G ue n o u n o u  M,  Ha mi d  Q,  Bec k  L A,  et  al. 
I n crease d e x pressi o n of T h 2-ass ociate d c h e m o ki nes i n b ull o us pe m p hi g oi d disease. R ole of 
e osi n o p hils  i n  t he  pr o d ucti o n  a n d  rel ease  of  t hese  c h e m o ki nes.  Cli n  I m m u n ol.  2 0 0 6 
A u g; 1 2 0( 2): 2 2 0- 3 1. 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 5  S hri k ha n de M, H u nzi ker T, Braat h e n L R, Pic hler WJ, Da hi n de n C A, Ya wal kar N. I ncreas e d 
c oe x pressi o n of e ot a xi n a n d i nterle u ki n 5 i n b ull o us pe m p hi g oi d. Acta D er m Ve n ere ol. 2 0 0 0 
J ul- A u g; 8 0( 4): 2 7 7- 8 0. 
1 6  Wa k u ga w a M, Na k a m ur a K, Hi n o H, T o ya ma K, Hatt ori N, O k oc hi H, et al. Ele vate d le vels 
of  e ota xi n  a n d  i nterle u ki n -5  i n  blister  fl ui d  of  b ull o us  pe m p hi g oi d:  c orrelati o n  wit h  tiss ue 
e osi n o p hilia. Br J Der mat ol. 2 0 0 0 J ul; 1 4 3( 1): 1 1 2- 6. 
1 7  G u nt her C, W ozel G, Me urer M, Pf eiffer C. U p -re g ulati o n of C C L 1 1 a n d C C L 2 6 is ass o ciate d 
wit h acti vate d e osi n o p hils i n b ull o us pe m p hi g oi d. Cli n E x p I m m u n ol. 2 0 1 1 N o v; 1 6 6( 2): 1 4 5 -
5 3. 
1 8  I n ge n- H o usz-Or o S , V ale yri e -Alla n ore L , Ort o n n e N , R o ujea u J C , W ol ke nstei n P , C h osi d o w 
O . Ma na ge m e nt of b ull o us pe m p hi g oi d wit h t o pical ster oi ds i n t he cli nical practice of a si n gle 
ce nter: o utc o me at 6 a n d 1 2 m o nt hs.  Der mat ol o g y . 2 0 1 1; 2 2 2( 2): 1 7 6- 9. 
1 9  Se barat na m  D F,  Ha n n a  A M,  C hee  S N,  Fre w  J W,  Ve n u g o pal  S S,  Da niel  B S , et  al. 
De vel o p me nt  of  a  Q u alit y - of-Life  I nstr u m e nt  f or  A ut oi m m u ne  B ull o us  Disease:  T h e 
A ut oi m m u ne  B ull o us  Disease  Q ualit y  of  Life  Q uesti o n naire.  J A M A  Der mat ol.  2 0 1 3  Oct 
1; 1 4 9( 1 0): 1 1 8 6- 9 1. 
 
 
 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
1 3. 0  A P P E N DI C E S   
 
A p pe n di x A: Sc he d ule of Acti vities .............................................................................................. 6 2  
A p pe n di x B: Assess me nt of B P Se verit y *..................................................................................... 6 4  
A p pe n di x C: Kar n ofs k y Perf or ma nce Stat us ................................................................................. 6 5  
A p pe n di x D: B ull o us Pe m p hi g oi d Disease Area I n de x [ 1] ........................................................... 6 6  
A p pe n di x E: A ut oi m m u ne B ull o us Diseas e Q ualit y of Life  ......................................................... 6 9 
A p pe n di x F: T o pical Ster oi ds P ote nc y Class Ta ble ...................................................................... 7 2  
 
 
6 1

 
 
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
A p pe n di x A : Sc he d ule of Acti vities  
 
St u d y Pr oce d ures  
Scree n
i n g 
Tre at me nt 
Peri o d  
F oll o w -u p Peri o d a 
E arl y 
Disc o nti n u
ati o n b 
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9 o  
P h o n
e c all 
- 
St u d y D a y ( visit wi n d o w 
+/ - 2 d a y)  
-2 8  t o -
1 
0   
1 4  
( +/-
2)  
2 8  
( +/-
2)  
4 2  
( +/-
2)  
5 6  
( +/-
2)  
7 0  
( +/-
2)  
8 4  
( +/-
2)  
1 1 8  
( +/-
2)  
A p pr
o x. 
d a ys 
1 4 4 
a n d 
2 0 4   
- 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
 
 
 
 
 
 
 
De m o gra p hic & me dical 
hist or y  
X  
 
 
 
 
 
 
 
 
 
 
Kar n ofs k y perf or ma n ce 
stat us 
X  
 
 
 
 
 
 
 
 
 
 
P h ysical e xa mi n ati o n c 
X c 
X * 
X * 
X *  
X  
X  
X  
X  
 
 
X  
Vital si g ns  
X  
X d  
X d 
X d 
X  
X  
X  
X  
 
 
X  
E C G  
X  
 
 
 
 
 
 
X  
 
 
X  
He mat ol o g y (i n cl u di n g 
e osi n o p hil c o u nt) a n d 
bi oc he mistr y e 
X f 
X * 
X * 
X * 
X  
 
 
X  
 
 
X  
Ser u m e ota xi n -1  
 
X * 
X * 
X * 
X  
X  
X  
X  
 
 
X  
Scree n f or acti ve/late nt 
t u berc ul osis, g 
X  
 
 
 
 
 
 
 
 
 
 
S ki n p u nc h bi o ps y  f or H & E 
a n d e osi n o p hil c o u nt  
X  
 
 
 
X  h  
 
 
 
 
 
 
S ki n p u nc h bi o ps y f or DI F 
o n salt s plit s ki n  
X  
 
 
 
 
 
 
 
 
 
 
II F a n d B P 1 8 0 & B P 2 3 0 a ut o 
a nti b o dies 
X j 
X *  
X * 
X * 
X  
X  
X  
X  
 
 
X  
Assess me nt of B P se verit y  
X  
 
 
 
 
 
 
 
 
 
 
Ser ol o g y ( HI V, H B V, H C V, 
C M V)  e  
X  
 
 
 
Uri ne β -h C G i 
 
X * 
X * 
X * 
X  
 
 
X  
 
 
 
A nti -bertili m u ma b a nti b o dies  
 
X * 
X * 
X * 
X  
X  
X  
X  
 
 
X  
P K ( bertili m u ma b) bl o o d 
sa m pli n g 
 
X k 
X  k 
X k 
X  
X  
X  
X  
 
 
X  
P B M C bi o mar ker bl o o d 
sa m pli n g 
 
X * 
 
 
X 
 
 
 
 
 
 
Se me n a nal ysis  
 
X l 
X l 
X l 
 
 
 
 
X  
 
X m  
Bertili m u ma b i nf usi o n  
 
X  
X  
X  
 
 
 
 
 
 
 
B P D AI (i ncl u di n g Pr urit us 
e val uati o n) a n d lesi o n 
heali n g assess me nt  
X * *  
X * 
X * 
X * 
X  
X  
X  
X  
 
 
X  
 A B Q O L q uesti o n n aire  
X * *   
X * 
X * 
X * 
X  
X  
X  
X  
 
 
X  
C ortic oster oi d ma n a ge me nt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Pri or a n d c o nc o mita nt 
me dicati o ns   
X  
X * n 
X * n 
X * n 
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X * n 
X * n 
X * n 
X  
X  
X  
X  
X  
X  
X  
I nf usi o n reacti o n assess me nt 
 
X  o 
X  o 
X  o 
 
 
 
 
 
 
 
P h ot o gra p h y  
X  
X *  
X *  
X *  
X  
X  
X  
X  
 
 
X  
 
N ote:  A bilit y t o ta p er ster oi ds d uri n g sc h e d ule d or u nsc h e d ule d visits will b e d eter mi n e d b y t h e in vesti gat or b ase d o n  p atie nt 
6 2

 
 
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 3  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
res p o nse. 
* D e n otes assess me nt will b e d o ne pre -d ose  
* *  T o be perf or me d if p ossi ble pri or t o c o m me n ce me nt of c ortic oster oi d re gi me n 
a Visit s 3 t hr o u g h 9 h a ve a ± 2 d a y wi n d o w . T h e wi n d o w is calc ulate d fr o m t h e act u al visit d a y c o m p ar e d t o b aseli n e ( Da y 0 ), (e. g.,. 
f or Visit 6 ( Da y 5 6) t h e wi n d o w w o ul d b e Da y 5 4 t o Da y 5 8). 
b At t his visit , t h e acti vities t o b e p erf or me d will relate t o t h e st u d y p eri o d at w hic h ti me t h e p atie nt disc o nti n u e d. 
c P h ysical e xa mi n ati o n i n cl u di n g  wei g ht; h ei g ht meas ure me nt at scree ni n g  o nl y.  
d Vital si g ns will b e meas ure d pre -d ose  (a n y ti me pri or t o t h e i nitiati o n of treat me nt i nf usi o n), i m me diatel y at t h e c o m pleti o n of 
treat me nt  i nf usi o n  (a p pr o xi matel y 3 0  mi n utes  after  i nitiati o n ) a n d a p pr o xi matel y 2  h o u rs f oll o wi n g  i nitiati o n  of treat me nt 
i nf usi o n. 
e Cli nical la b orat or y assess me nts will b e p erf or me d b y a l o cal la b orat or y f or t h e scree ni n g visit a n d a ce ntral la b orat or y f or e ver y 
s u bse q ue nt visit. 
f Bi oc he mistr y will i n cl u d e ser u m β -h C G at scree ni n g  f or fe mal es of c hil d b eari n g p ote ntial o nl y. 
g T he patie nt s h o ul d b e e val u ate d f or acti ve/late nt T B as a p plica ble ( e. g.,. P P D, QF T, a n d/ or c h est x -ra y)  
h T he Visit 5 ( Da y 4 2) p u n c h bi o psies  s h o ul d b e ta ke n i n t h e area of t h e pre vi o us bi o psies, as m u c h as p ossi ble. 
i Fe males of c hil d b eari n g p ote ntial o nl y.  
j II F o nl y at scr ee ni n g 
k Bl o o d  sa m ples  f or  b ertili m u ma b  ( P K  a n al ysis)  will  b e  c ollecte d  pre -d ose  a n d  at  t h e  c o m pleti o n  of  treat me nt  i nf usi o n 
(a p pr o xi matel y 3 0 mi n utes after t h e i nitiati o n ) a n d 2 h o urs f oll o wi n g t h e i nitiati o n of treat me nt i nf usi o n. P K sa m ples 3 0 mi n utes 
p ost -i nf usi o n s h o ul d b e ta ke n as cl ose t o t his ti me as p ossi ble.  
l Se me n a nal ysis will  b e p e rf or me d f or males pre-d ose  a n d cl ose t o t h e c o m pleti o n of i nf usi o n as p ossi ble. Pre-d osi n g sa m ples ca n 
be ta ke n u p t o 2 d a ys pri or t o d osi n g.  
m O nl y f or males wit h a b n or mal s e me n a n al ysis r es ults fr o m D a y 0, Da y 1 4 or Da y 2 8  c o m p are d t o pre- d ose val u e at  Visit 2 ( Da y 
0) 
n A d verse e ve nts a n d c o n c o mita nt me dicati o n i nf or mati o n t o b e rec or d e d pre -d ose a n d 2 h o urs after t h e i nit iati o n of i nf usi o n. 
o I nf usi o n reacti o ns s h o ul d b e assesse d at t h e c o m pleti o n of  i nf usi o n (a p pr o xi matel y 3 0 mi n utes aft er t h e i nitiati o n) a n d 2 h o urs 
f oll o wi n g t he i nitiati o n of treat me nt i nf usi o n. 
 
 
 
 
 
6 3

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 5  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
A p pe n di x C : K ar n ofs k y Perf or m a nce St at us 
 
 
 
 
6 5

 
 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 6  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
A p pe n di x D: B ull o us Pe m p hi g oi d Dise ase Are a I n de x  [ 1] 
6 6

 
 
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Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 7  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
 
6 7

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 8  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
 
 
 
6 8

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 6 9  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
A p pe n di x E : A ut oi m m u ne B ull o us Dise ase Q u alit y of Life 
A B Q O L Q uesti o n n aire  
N ot D o ne, s pecif y reas o n:  
Date of Ass ess me nt   
 
 
( d d M o nt h y y y y) 
 
1.  I n re gar ds t o y o ur blisteri n g 
disease, d oes y o ur s ki n b ur n, sti n g 
or h urt i n a n y wa y? 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
2.  I n re gar ds t o y o ur blisteri n g 
disease, d oes y o ur s ki n it c h? 
 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
3.  Ha ve y o u ha d t o c ha n ge y o ur 
cl ot hi n g beca use of y o ur blisteri n g 
disease?  
 
 
o  3 I h a ve t o be v er y caref ul wit h h o w ti g ht m y 
cl ot hi n g is a n d w hat mat erials t he y are ma de of – I 
ha ve ha d t o c h a n ge w h at I wear all t he ti me  
o  2 I h a ve ha d t o c ha n ge m ost of t he t hi n gs I w ear  
o  1 I h a ve ha d t o c ha n ge s o me of t he t hi n gs I wear 
o  0 I h a ve ne v er h a d t o c ha n ge w hat I w ear  
 
4.  D o y o u n otice y o ur s ki n heals 
sl o wl y? 
 
o  3 I n otice t his all t he ti me  
o  2 I n otice t his s o meti mes  
o  1 I n otice t his occasi o nall y  
o  0 I h a ve ne v er h a d t his pr o ble m 
 
5.  D o y o u h a ve diffi c ult y b at hi n g or 
s h o weri n g beca use of y o ur 
blisteri n g diseas e?  
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
6.  I n re gar ds t o y o ur blisteri n g 
disease, d oes y o ur m o ut h ha ve 
er osi o ns w hic h ar e pai nf ul? 
 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
 
 
 
 
6 9

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 7 0  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
7.  I n re gar ds t o y o ur blisteri n g 
disease, d o y o ur g u ms bl ee d easil y?  
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
8.  D oes y o ur blisteri n g disease res ult 
i n y o u ha vi n g t o a v oi d f o o d or 
dri n ks t hat y o u e nj o y?  
 
o  3 I ca n n o l o n ger eat a n y of t he f o o ds I use d t o e nj o y 
o  2 I ca n eat s o me of t he f o o ds I e nj o y  
o  1 I ca n eat m ost of t he f o o ds I e nj o y 
o  0 I ca n eat a n yt hi n g I li ke  
 
 
9.  As  a res ult of y o ur blisteri n g 
disease, ar e y o u e m barrasse d a b o ut 
y o ur a p peara n ce?  
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
1 0.  D o y o u feel d e presse d or a n gr y 
beca use of y o ur blisteri n g diseas e?  
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
1 1.  D o y o u feel a n xi o us or ca n n ot rela x 
as a res ult of y o ur blisteri n g 
disease?  
 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
1 2.  D o y o u w orr y t hat frie n ds a n d 
fa mil y fi n d y o ur blisteri n g s ki n 
c o n diti o n tires o me? 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
1 3.  Is y o ur blisteri n g disease ca usi n g 
se x ual diffic ulties? 
 
o  3 All t he ti me  
o  2 S o meti mes  
o  1 Occasi o nall y  
o  0 Ne ver  
 
 
 
7 0

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 7 1  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
1 4.  D oes y o ur blisteri n g disease affect 
relati o ns hi ps wit h frie n ds or l o ve d 
o nes? 
o  3 I h a ve ha d t o e n d a relati o ns hi p beca use of m y 
disease O R I ca n n ot ha ve a relati o ns hi p beca use of 
m y diseas e  
o  2 Relati o ns hi ps are ver y diffic ult 
o  1 Relati o ns hi ps are a little diffic ult  
o  0 T his has n ot affecte d m y relati o ns hi ps 
 
 
1 5.  D oes y o ur blisteri n g disease affect 
y o ur s o cial life?  
 
o  3 I ca n n ot g o o ut t o s ocialize a n y m ore 
o  2 I ca n o nl y g o t o s o me s ocial e ve nts 
o  1 I ca n g o t o m ost s ocial e ve nts  
o  0 M y s ocial life is n ot affecte d  
 
 
1 6.  D oes y o ur blisteri n g disease affect 
y o ur w or k or st u d y? 
 
o  3 Yes, I ca n n o l o n ger w or k or st u d y 
o  2 Yes, I fi n d it diffic ult t o w or k or st u d y 
o  1 Yes, it is a little har der t ha n bef ore t o w or k or 
st u d y 
o  0 N o, I a m n ot affecte d O R  N/ A  
 
 
1 7.  D o e m pl o yers discri mi nate a gai nst 
y o u beca use of y o ur blisteri n g 
disease?  
 
o  3 I ca n n ot fi n d a j o b d u e t o m y blisteri n g disease  
o  2 I h a ve ha d t o c ha n ge j o bs d ue t o m y blisteri n g 
disease  
o  1 I still ha ve m y j o b b ut it is m ore diffic ult t ha n 
bef ore  
o  0 M y e m pl o yers are c o m pletel y u n d ersta n di n g O R  
N/ A  
 
 
 
 
 
7 1

 
 
P RI VI L E G E D &  C O N FI D E N TI A L  
 
Pr ot oc ol: I m m u ne/ B R T/B P -0 1  
P a ge 7 2  of 7 2  
Fi nal Versi o n 8. 0  
 
 
Fe br uar y 2 8, 2 0 1 8  
 
A p pe n di x F : T o pic al Ster oi ds P ote nc y Cl ass T a ble 
 
 
7 2