Clinical trial NCT04656418
Conditions: Hereditary Angioedema
Sponsor: CSL Behring
Start date: 2021-01-27; Completion date: 2022-06-07
Enrollment: 64 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, double-blind, randomized, placebo-controlled, parallel-arm study to investigate the efficacy and safety of subcutaneous administration of CSL312 (garadacimab) in the prophylactic treatment of hereditary angioedema.

Detailed description:

Arms: arm 1: Participants received a CSL312 loading dose of 400 mg as two 200 mg SC injections in Month 1 along with CSL312 of 200 mg subcutaneous (SC) injections, once monthly from Months 2 to 6. arm 2: Participants received a CSL312 matched loading dose of placebo as two SC injections in Month 1 along with CSL312 matched placebo SC injections, once monthly from Months 2 to 6.
Interventions: intervention 1: CSL312 intervention 2: Placebo
Intervention descriptions: intervention 1: Fully human immunoglobulin G subclass 4/lambda recombinant monoclonal antibody intervention 2: Buffer without active ingredient

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
And 
Clinical Study Protocol Administrative Amendment #1 
 
 
 
 
Study Number: 
CSL312_3001 
Study Title: 
A Multicenter, Double-Blind, Randomized, Placebo-
Controlled, Parallel-Arm Study to Investigate the Efficacy 
and Safety of Subcutaneous Administration of CSL312 
(garadacimab) in the Prophylactic Treatment of Hereditary 
Angioedema 
Version and Date of Protocol: 
FINAL (Original), 04 August 2020 
 
Administrative Amendment #1, 08 December 2020 
NCT Number: 
NCT04656418 
EudraCT Number: 
2020-000570-25 
 


 
 
 
C S  -S  O P -0 4 -T 0 4  
C o nfi d e nti al   
Versi o n   3 . 0 
Eff e cti v e   D at e:    We e k  c o  m  m e n ci n g  2 2 -O ct  -2 0 1 8      
 
P a g e  1  of  3 
 
Cli ni c al  St u d y  P r ot o c ol    
A d  mi nist r ati v e   A  m e n d  m e nt   
A  D   MI  NI S  T  R  A TI  V  E   A   M  E  N  D   M  E  N  T   # 1 
 
St u d y   N u  m b e r:  
C S L 3 1 2 _  3 0 0 1  
St u d y  Titl e : 
A   M ulti c e nt er,   D o u bl e  -Bli n d,   R a n d o  mi z e d, 
Pl a c e b o -  C o ntr oll e d,  P ar all el-  Ar  m  St u d y t o 
I n v esti g at e t h e  Effi c a c y  a n d S af et y  of 
S u b c ut a n e o us   A d  mi nistr ati o n  of   C S L 3 1 2 
( g ar a d a ci  m a b) i n t h e  Pr o p h yl a cti c  Tr e at  m e nt  of 
H er e dit ar y   A n gi o e d e  m a   
Ve rsi o n  a n d   D  at e  of  P r ot o c ol:     
FI  N  A L (  Ori gi n al),  0 4   A u g ust  2 0 2 0  
E u d r a  C  T   N u  m b e r:   
2 0 2 0 -0 0 0 5 7 0 -2 5  
I  N  D   N u  m b e r:  
 
A d  mi nist r ati v e   A  m e n d  m e nt   D  at e:     0 8  D e c  e  m b er  2 0 2 0  
 
 
T his  a  m e n d  m e nt is  a p pli c a bl e f or  all  st u d y sit es.   All  c h a n g es  ar e  d es cri b e d  h er ei n.  
 
C o  m  m e r ci al i n   C o nfi d e n c e  .  T his  d o c u  m e nt  a n d t h e i nf or  m ati o n  c o nt ai n e d  h er ei n  ar e  pr o pri et ar y  a n d 
c o nfi d e nti al.  T his  d o c u  m e nt  a n d t h e  c o nt ai n e d i nf or  m ati o n  ar e i nt e n d e d f or  dis cl os ur e t o  a n d  us e  b y t h os e 
p ers o n n el   w h o  ar e  u n d er  a n  o bli g ati o n  of  c o nfi d e nti alit y  b y  a si g n e d  a gr e e  m e nt   wit h  S p o ns or ( “  C S L   B e hri n g ”). 
T his  d o c u  m e nt  a n d t h e  c o nt ai n e d i nf or  m ati o n   m a y  b e  dis cl os e d  a n d  us e d  o nl y t o t h e  e xt e nt  n e c ess ar y t o  c o n d u ct 
t h e  cli ni c al st u d y.   R e pr o d u cti o n  or  dis cl os ur e  of t his  d o c u  m e nt  or its  c o nt ai n e d i nf or  m ati o n is f or bi d d e n  u nl ess 
a t t h e  e x pr ess r e q u est  or   wit h t h e   writt e n  c o ns e nt  of C S L   B e hri n g  .
C CI


C S L   B e hri n g   
C S L 3 1 2 _ 3 0 0 1   
C S L 3 1 2 ( F a ct or   XII a I n hi bit or   M o n o cl o n al   A nti b o d y)   
A d  mi nistr ati v e   A  m e n d  m e nt  #  1 
C o nfi d e nti al   
C S  -S  O P -0 4 -T 0 4  
Versi o n   3 . 0 
Eff e cti v e   D at e:    We e k  c o  m  m e n ci n g  2 2 -O ct  -2 0 1 8     
 
P a g e  2  of  3  
P  U  R P  O S  E   O F   A   M  E  N  D   M  E  N  T  
T h e  p ur p os e  of t his  a d  mi nistr ati v e   pr ot o c ol  a  m e n d  m e nt is t o   m a k e t h e f oll o  wi n g r e visi o ns t o 
t h e C S L 3 1 2 _ 3 0 0 1   cli ni c al  pr ot o c ol (  Ori gi n al),  d at e d  0 4  A u g  ust  2 0 2 0:  
1.     Cl arifi c ati o n  of t h e   c o ntr a c e pti o n r e q uir e  m e nt :  ali g n  m e nt  of t h e ti  m e  p eri o d   wit h 
S e cti o n  9. 6. 6  (f or 3   m o nt hs  aft er l ast  d os e  of i n v esti g ati o n al  pr o d u ct). 
    
R e as o n  : S u bj e cts s h o ul d  n ot  b e c o  m e  pr e g n a nt ( n or s h o ul d t h e  p art n er  of  a s u bj e ct 
b e c o  m e  pr e g n a nt) f or  at l e ast  3   m o nt hs  aft er t h e l ast  d os e  of i n v esti g ati o n al  pr o d u ct 
( S e cti o n  9. 6. 6). It   w as  n ot e d t h at  S e cti o n  4. 1. 2  a n d  S e cti o n  7. 4 i n a d v ert e ntl y st at e t h at 
t h e  c o ntr a c e pti o n r e q uir e  m e nt is  3 0  d a ys,   w hi c h is i n c o nsist e nt   wit h t h e  h alf-lif e  of t h e 
i n v esti g ati o n al  pr o d u ct  a n d t h e i nf or  m ati o n  pr o vi d e d i n  S e cti o n  9. 6. 6. 
    
A p pli c a bl e s e cti o ns  : S e cti o n  4. 1. 2 ( e x cl usi o n  c rit eri o n  1 2)  a n d  S e cti o n  7. 4. 
 
 


C S L   B e hri n g   
C S L 3 1 2 _ 3 0 0 1   
C S L 3 1 2 ( F a ct or   XII a I n hi bit or   M o n o cl o n al   A nti b o d y)   
A d  mi nistr ati v e   A  m e n d  m e nt  #  1 
C o nfi d e nti al   
C S  -S  O P -0 4 -T 0 4  
Versi o n   3 . 0 
Eff e cti v e   D at e:    We e k  c o  m  m e n ci n g  2 2 -O ct  -2 0 1 8     
 
P a g e  3  of  3  
A p p e n di x  1:      
Si g n at u r e  of  P ri n ci p al I n v esti g at o r  
St u d y  Titl e:     
A   M ulti c e nt er,   D o u bl e  -Bli n d,   R a n d o  mi z e d,  Pl a c e b o  -C o ntr oll e d, 
P ar all el -  Ar  m  St u d y t o I n v esti g at e t h e  Effi c a c y  a n d  S af et y  of 
S u b c ut a n e o us   A d  mi nistr ati o n  of   C S L 3 1 2 ( g ar a d a ci  m a b) i n t h e 
Pr o p h yl a cti c  Tr e at  m e nt  of   H er e dit ar y   A n gi o e d e  m a  
P r ot o c ol   N u  m b e r:     C S L 3 1 2 _ 3 0 0 1   
Ve rsi o n  a n d   D at e  of t h e  P r ot o c ol:      
FI  N  A L (  Ori gi n al),  0 4   A u g ust  2 0 2 0  
A d  mi nist r ati v e   A  m e n d  m e nt   N u  m b e r:      1  
A d  mi nist r ati v e   A  m e n d  m e nt   D at e:      
0 8  D e c  e  m b er  2 0 2 0  
Sit e   N u  m b e r:     
 
T o  b e  c o  m pl et e d  b y t h e st u d y sit e:   
I  a c k n o  wl e d g e r e c ei pt  of t his  a d  mi nistr ati v e  a  m e n d  m e nt. I  h a v e r e a d  a n d  u n d erst o o d its 
c o nt e nts. 
 
 
 
( Si g n at ur e) 
 
 
D at e   (  D  D   MM  M   Y  Y  Y  Y)   
( Pri nt e d  n a  m e) 
 
 
 
( Titl e) 
 
 
 


V er si o n: 1. 0
Si g n at ur e P a g e 1  of 1
--- D o N ot D et a c h T hi s Si g n at ur e P a g e ---
gl b d ct m p
Pri nt D at e: 2 8- J ul- 2 0 2 2 1 2: 1 1: 0 8 G M T- 0 4: 0 0
Si g n at ur e P a g e
C S L 3 1 2 _ 3 0 0 1 - Pr ot o c ol A m e n d m e nt -
A d mi ni str ati v e A m e n d m e nt 1 - 0 8 D e c 2 0 2 0
Si g n e d B y
D at e ( G M T)
A p pr o v e d-
 A p pr o v al
0 8- D e c- 2 0 2 0 2 2: 2 7: 2 3
A p pr o v e d-
 A p pr o v al
0 9- D e c- 2 0 2 0 1 3: 4 4: 1 5
P P D
P P D
P P D
P P D


 
  
  
 
Pr ot oc ol versi o n:  Ori gi nal  
 
Pa ge 1 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A M ultice nter, D o u ble -Bli n d, R a n d o mize d, Pl ace b o -C o ntr olle d, P ar allel -Ar m St u d y 
t o I n vesti g ate t he Effic a c y a n d S afet y of S u bc ut a ne o us A d mi nistr ati o n of C S L 3 1 2 
( g ar a d aci m a b) i n t he Pr o p h yl actic Tre at me nt of Here dit ar y A n gi oe de m a 
St u d y  
N u m ber:  
C S L 3 1 2 _ 3 0 0 1  
St u d y  
Pr o d uct:  
C S L 3 1 2  ( Fact or XIIa I n hi bit or M o n ocl o nal A nti b o d y)  
De vel o p me nt 
P h ase:  
P hase 3  
S h ort Title:  
St u d y of t he efficac y a n d safet y of C S L 3 1 2 ( g ara d aci ma b ) i n t he 
pre ve nti o n of here ditar y a n gi oe de ma attac ks 
S p o ns or:  
C S L Be hri n g, L L C  
1 0 2 0 First Ave n ue  
Ki n g of Pr ussia, Pe n ns yl va nia  
1 9 4 0 6 
U nite d States of A merica  
Pr ot oc ol 
V ersi o n: 
Ori gi nal  
E u dr a C T 
N u m ber:  
2 0 2 0 -0 0 0 5 7 0 -2 5  
I N D N u m ber:  
1 3 9 9 3 6  
Pr ot oc ol D ate:  
0 4  A u g ust  2 0 2 0  
C o m pli a nce:  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h sta n dar ds of G o o d 
Cli nical Practice (as d efi ne d b y t he I nter n ati o nal C o u ncil f or 
Har m o nisati o n ) a n d all a p plica ble nati o nal a n d l o cal re g ulati o ns.  
 
C o m m erci al i n C o nfi de nce . T his d oc u me nt a n d t he i nf or mati o n c o ntai ne d herei n are pr o prietar y a n d 
c o nfi de ntial.  T his d oc u me nt a n d t he c o ntai ne d i nf or mati o n are i nte n de d f or discl os ure t o a n d use b y t h ose 
pers o n nel w h o are u n der a n o bli gati o n of c o nfi de ntialit y b y a si g ne d a gree me nt wit h S p o ns or (“ C S L Be hri n g”).  
T his d oc u me nt a n d t he c o ntai ne d i nf or mati o n ma y be discl ose d a n d use d o nl y t o t he e xte nt necessar y t o c o n d uct 
t he cli nical st u d y.  Re pr o d ucti o n or discl os ure of t his d oc u me nt or its c o ntai ne d i nf or mati o n is f or bi d de n u nless 
at t he e x press re q uest or wit h t he writte n c o nse nt of C S L Be hri n g. 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
LI S T O F P E R S O N N E L A N D O R G A NI Z A TI O N S R E S P O N SI B L E F O R C O N D U C T 
O F T H E S T U D Y  
A list of pers o n nel a n d or ga nizati o ns res p o nsi ble f or t he c o n d uct of t h e st u d y will be s u p plie d 
t o st u d y sites as part of t he I n vesti gat or’s St u d y File . T his list will be u p date d b y 
C S L  Be hri n g, L L C ( or dele gate) a n d pr o vi de d t o t he st u d y sites as nee de d.  
 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
R E VI SI O N HI S T O R Y  
D ate  
Versi o n  
S u m m ar y of C h a n ges  
0 4  A u g ust  2 0 2 0  
Ori gi nal  
N ot a p plica ble  
 
 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Cli nic al St u d y Pr ot oc ol S y n o psis 
Title  
A M ultice nter, D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, 
Parallel - Ar m St u d y t o I n vesti gate t he Efficac y a n d Safet y of 
S u bc uta ne o us A d mi nistrati o n of C S L 3 1 2 ( g ara daci ma b ) i n t he 
Pr o p h ylactic Treat me nt of Here ditar y A n gi oe de ma  
St u d y  N u m ber  
C S L 3 1 2 _ 3 0 0 1 
S p o ns or  
C S L Be hri n g, L L C 
De vel o p me nt P h ase  3 
St u d y  Pr o d uct  
C S L 3 1 2  (Fact or XIIa I n hi bit or M o n ocl o nal A nti b o d y)  
I n dic ati o n 
Pr o p h yla xis t o pre ve nt here ditar y a n gi oe de ma ( H A E) attac ks  
St u d y S u m m ar y 
a n d O ver vie w  
T his is a m ultice nter, d o u ble- bli n d, ra n d o mize d, pl ace b o-c o ntr olle d, 
parallel - ar m, p hase 3 st u d y t o i n vesti gate t he effi cac y a n d safet y of 
2 0 0 m g  C S L 3 1 2 (als o k n o w n as gara daci ma b ) a d mi nistere d 
s u bc uta ne o usl y ( S C) o nce a m o nt h f or t he pr o p h yl a xis t o pre ve nt 
H A E attac ks i n a d ol esce nt ( 1 2  t o 1 7 years, i ncl usi ve) a n d a d ult 
s u bjects wit h C 1 -esterase i n hi bit or ( C 1-I N H) H A E. T his st u d y will 
be c o n d ucte d gl o b all y.  
F oll o wi n g i nf or me d c o nse nt, s u bjects will u n der g o a Scree ni n g 
Peri o d of u p t o 1 m o nt h t o deter mi ne eli gi bilit y f or e nr oll me nt i nt o 
t he st u d y. Scree ne d s u bjects w h o meet all t he i ncl usi o n a n d n o ne of 
t he e xcl usi o n criteri a will e nter a R u n-i n Peri o d t o c o nfir m t he 
re q uire d b aseli ne H A E attac k rate of ≥ 1 attac k p er m o nt h. S u bjects 
m us t c o m plete at least 1 m o nt h of t he R u n-i n Peri o d. A d diti o nall y, 
s u bjects m ust e x perie nce at least 2 H A E attac ks d uri n g t he R u n-I n 
Peri o d t o be eli gi ble t o e nter t he Treat me nt Peri o d. S u bjects w h o 
e x perie n ce at least 2 attac ks d uri n g t he re q uire d first m o nt h of t he 
R u n- I n Peri o d ma y e nter t he Treat me nt P eri o d if t he y als o meet all 
ot her criteri a as state d i n Secti o n  4. 1. 3.  


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
S u bjects w h o d o n ot meet t he scree ni n g criteria f or e nteri n g t he 
R u n-i n Peri o d wit hi n 3 0 da ys ma y be a ble t o rescree n wit h 
c o nfir mati o n fr o m t he s p o ns or. S u bjects w h o d o n ot meet t he 
mi ni m u m H A E attac k  rat e d uri n g t he R u n-i n Peri o d a n d / or all 
ot her crite ria f or e nteri n g t he Treat me nt Peri o d  will be c o nsi dere d 
R u n-i n fail ures a n d will n ot be all o we d t o res cree n. 
Eli gi ble s u bjects will be ra n d o mize d 3: 2 t o eit her t he C S L 3 1 2 
Acti ve Ar m ( C S L 3 1 2 S C o nce a m o nt h) or t h e Place b o  Ar m. T he 
d urati o n of treat me nt is 6 m o nt hs. Ra n d o mizati o n will ta ke a ge 
( ≤ 1 7 years, > 1 7 years ) a n d, f or a d ults, baseli ne attac k rate 
o bser ve d d uri n g t he R u n-i n Peri o d ( 1 t o < 3 attac ks / m o nt h, a n d 
≥ 3 attac ks / m o nt h) i nt o acc o u nt.  
F oll o wi n g t he Treat me nt Peri o d , s u bjects will eit her e nter a 
2- m o nt h F oll o w- u p Peri o d (ie, 3 m o nt hs after last i n vesti gati o nal 
pr o d uct a d mi nistrati o n) or ma y  r oll- o ver i nt o a n o pe n-la bel p has e 
3 b st u d y ( C S L 3 1 2 _ 3 0 0 2).   
Pri m ar y 
O bjecti ve(s)  
T he pri mar y o bjecti ve of t his st u d y is  t o e val uate t he efficac y of S C 
a d mi nistrati o n of C S L 3 1 2  as pr o p h yla xis t o pre ve nt H A E attac ks i n 
s u bjects wit h H A E. 
Pri m ar y 
E n d p oi nt(s)  
T he pri mar y e n d p oi nt is t he ti me- n or malize d n u m ber of H A E 
attac ks d uri n g treat me nt fr o m Da y 1 t hr o u g h D a y 1 8 2. 
Sec o n d a r y 
O bjecti ve(s)  
T he sec o n d ar y o bjecti ves of t he st u d y are: 
1.  To c har acteri ze t he cli nical effi cac y of S C C S L 3 1 2  i n t he 
pr o p h ylactic treat me nt of H A E. 
2.  To e val uate t he s afet y of S C C S L 3 1 2 i n t he pr o p h ylactic 
treat me nt of H A E. 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Sec o n d ar y 
E n d p oi nt(s)  
T he sec o n d ar y e n d p oi nts of t he st u d y are: 
•  T he re d u cti o n i n t he attac k rate d uri n g t he Treat me nt Peri o d 
c o m pare d t o t he R u n- i n Peri o d. 
•  T he ti me - n or malize d n u m ber of H A E attac ks re q uiri n g 
o n- de ma n d treat me nt . 
•  T he ti me - n or malize d n u m ber of m o derate a n d / or se vere H A E 
attac ks. 
•  T he ti me - n or malize d n u m ber of H A E attac ks at v ari o us ti me 
p oi nts d uri n g t he treat me nt peri o d. 
•  S u bject Gl o bal Assess me nt of Res p o nse t o Treat m e nt ( S G A R T). 
•  A d verse e ve nts ( A Es) .  
•  A d verse e ve nts of s pecial i nterest ( A E SI s).  
•  Seri o us a d vers e e ve nts ( S A Es) . 
•  C S L 3 1 2 i n d uce d a nti- C S L 3 1 2 a nti b o dies. 
•  Cli nicall y si g nifica nt a b n or malities i n la b orat or y assess me nts 
(ie, la b orat or y a b n or malities re p orte d as A Es). 
St u d y D ur ati o n  
T he d urati o n of t he st u d y f or a n i n di vi d ual s u bject is e x pecte d t o be 
a p pr o xi matel y 7 t o 1 1 m o nt hs. T his esti mati o n is base d o n: 
•  A Scree ni n g Peri o d of u p t o 1 m o nt h. 
•  A R u n -i n Peri o d of 1 t o 2 m o nt hs ( R u n-i n ca n occ ur o n t he 
sa me da y as Scree ni n g). 
•  A 6 - m o nth Treat me nt Peri o d . 
•  A F oll o w- u p Peri o d of 2 m o nt hs  (ie, 3 m o nt hs after last 
i n vesti gati o nal pr o d uct a d mi nistrati o n). 
T he o ver all st u d y d urati o n (ie, first s u bject’s Scr ee ni n g Visit t o last 
s u bject’s E n d of St u d y Visit) will be a p pr o xi matel y 1 9 m o nt hs.  
N u m ber of 
S u bjects  
T his st u d y will tar get t o ra n d o mize 6 0  s u bjects wit h C 1 -I N H H A E 
t y pe 1 or t y pe 2 t o be i ncl u de d i nt o t he Treat me nt Peri o d. T he 
a p pr o xi mate sa m ple size  i ncl u des a tar g ete d n u m b er of 5 a d ol esce nt 
s u bjects 1 2 t o 1 7 (i ncl usi ve) years of a g e . 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
St u d y P o p ul ati o n 
a n d M ai n Criteri a 
f or Eli gi bilit y 
 
T he mai n eli gi bilit y criteria t o e nter t he st u d y are:  
1.  Ca pa ble of pr o vi di n g writte n i nf or me d c o nse nt a n d willi n g 
a n d a ble t o a d h ere t o all pr ot oc ol re q uire m e nts a n d / or t he 
s u bject’s pare nt(s) or le g all y acce pta ble re pres e ntati ve(s) 
ca pa ble of pr o vi di n g writte n i nf or me d c o nse nt / asse nt as 
a p pr o priate. 
2.  Male or fe m ale.  
3.  A ge d ≥ 1 2 years at t he ti me of pr o vi di n g writte n i nf or me d 
c o nse nt or asse nt f or mi n ors.  
4.  Dia g n ose d wit h cli nicall y c o nfir me d C 1- I N H H A E 
a. D oc u me nte d cli nical hist or y c o nsiste nt wit h H A E 
(s u bc uta ne o us or m u c osal, n o n pr uritic s welli n g e pis o des 
wit h o ut acc o m pa n yi n g urticaria), a n d 
b.  C 1 -I N H a nti ge n a n d/ or f u ncti o nal acti vit y ≤ 5 0 % of 
n or mal as d oc u me nte d i n t he s u bject’s me dical rec or d, 
a n d  
c. C 4 a nti ge n c o nce ntrati o n bel o w t he l o wer li mit of t he 
refere nce ra n ge as d o c u me nte d i n t he s u bject’s me dical 
rec or d. 
5.  E x perie nce d ≥ 3 H A E attac ks d uri n g t he 3 m o nt hs bef ore 
Scree ni n g, as d o c u me nte d i n t he s u bject's me dical rec or d.  
N ote: F or s u bjects ta ki n g a n y pr o p h ylactic H A E t hera p y 
d uri n g t he 3 m o nt hs bef ore Scree ni n g, ≥3 H A E att ac ks 
ma y be d oc u me nte d o v er 3 c o nsec uti ve m o nt hs bef ore 
c o m me nci n g t he pr o p h yl actic t hera p y.   
St u d y  Pr o d uct  
D ose, D osi n g 
Re gi me n  a n d 
A d mi nistr ati o n   
S u bjects ra n d o mize d t o t he Acti ve Ar m will recei ve C S L 3 1 2 S C 
o nce m o nt h l y f or 6 m o nt hs. T he first d ose of C S L 3 1 2 will be a 
4 0 0 m g l oa di n g d ose a d mi nistere d S C  as 2 se parate i njecti o ns o n 
t he sa me da y at t he st u d y site (ie, M o nt h 1). S u bse q ue nt d oses of 
C S L 3 1 2 will be 2 0 0 m g a d mi nistere d S C  o nce m o nt hl y f or 
5 c o nsec uti ve m o nt hs (ie, M o nt hs 2 t hr o u g h 6). 
C o m p ar at or 
Pr o d uct,  D ose, 
D osi n g Re gi me n 
a n d A d mi nistr ati o n  
S u bjects ra n d o mize d t o t he Place b o  Ar m will recei ve 
v ol u me- matc he d place b o. T he first d ose of pl ace b o i n t he Place b o  
Ar m will be v ol u me -mat c he d place b o a d mi nistere d S C as 
2 se parat e i njecti o ns (ie, M o nt h 1). S u bjects will t he n recei ve 
v ol u me- matc h e d place b o S C o nce a m o nt h f or 5 c o nsec uti ve 
m o nt hs (ie, M o nt hs 2 t hr o u g h 6).  


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Effic ac y 
Assess me nts  
Efficac y will be assess e d b y t he n u m ber of H A E attac ks ( per m o nt h 
a n d a n n ualize d) i n s u bjects treate d o nce m o nt h l y wit h eit her 
C S L 3 1 2 ( Acti ve Ar m) or place b o ( Place b o Ar m) d uri n g t he effi cac y 
e val uati o n peri o d fr o m D a y 1 t hr o u g h Da y 1 8 2 ( 6 m o nt hs). 
S u bjects will rec or d rele va nt i nf or mati o n i n a n el ectr o nic diar y 
(e Diar y).  
S afet y Ass ess me nts  
Safet y will be assesse d b y treat me nt-e mer ge nt a d verse e v e nts 
( T EA Es ), vital si g ns, p h ysical e xa mi nati o ns, he mat ol o g y, 
bi oc he mistr y, uri nal ysis, c oa g ulati o n para meters, a n d a nti- dr u g 
a nti b o dies. 
P h ar m ac o ki netics  
Plas ma sa m ples will be c ollecte d f or assess me nt of C S L 3 1 2  
c o nce ntr ati o ns. 
P h ar m ac o d y n a mics 
Plas ma sa m ples will be c ollecte d f or assess me nt of Fact or XII 
(F XII ) c o n ce ntrati o n a n d acti vate d F XII ( F XIIa )-me diate d 
kalli krei n acti vit y.  
Ot her Assess me nts  
Q ualit y of life data will b e o btai ne d usi n g t he A n gi oe de ma Q u alit y 
of Life  (A E -Q o L ) q u esti o n naire, E ur o Q o L Gr o u p 5- Di me nsi o n 
5- Le vel ( E Q - 5 D-5 L ) q uesti o n naire, t he Wor k Pr o d ucti vit y a n d 
Acti vit y I m pair me nt: Ge neral Healt h  (W P AI: G H ) q uesti o n naire, t he 
I n vesti gat or Gl o bal Assess me nt of Res p o nse t o Treat me nt 
(I G A R T), a n d t he S u bject Gl o bal Assess me nt of R es p o nse t o 
Treat me nt ( S G A R T). 


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
St atistic al A n al yses  
F ort y s u bjects wit h  C 1 -I N H H A E t y pe 1 a n d 2 c o m pleti n g 
6 m o nt hs of treat me nt are nee d e d t o ac hie v e a p o wer of 
a p pr o xi matel y 9 0 % f or a t w o- si de d Wilc o x o n Test (al p ha of 5 %). 
S u bjects will be ra n d o mize d t o t he A cti ve Ar m a n d t he Place b o  
Ar m wit h a rati o of 3: 2. A n attac k rate per m o nt h of 0. 3 1 2 5 f or 
C S L 3 1 2-treate d s u bjects a n d of 1. 3 f or s u bjects recei vi n g place b o 
are ass u me d. T he m o nt hl y attac k rat es of place b o a n d of C S L 3 1 2 
are ass u me d t o b e P oiss o n distri b ute d. 
 
It is tar gete d t o ra n d o mize a p pr o xi matel y 5 a d ol es ce nts i nt o t he 
treat me nt peri o d wit h a ra n d omizati o n rati o of 3: 2 ( acti ve: place b o ). 
To all o w f or s ufficie nt safet y data, i ncreas e t he li keli h o o d of 
a d olesce nts  e nt eri n g t he st u d y, a n d t o ha ve at least 4 0 s u bjects 
reac hi n g t he e n d of t he st u d y, a n a d diti o nal 2 0 s u bjects are pl a n ne d 
f or ra n d o mizati o n. 
T he pri mar y esti ma n d , i n li ne wit h t he pri mar y i nterest of t he st u d y, 
f oll o ws t he treat me nt p olic y strate g y a n d is des cri be d as f oll o ws: 
•  P o p ulati o n: t he tar get patie nt p o p ulati o n defi ne d b y eli gi bilit y 
criteria a n d w h o were ra n d o mize d ( i nte nt-t o-treat [I T T]). 
•  Varia ble: ti me - n or m alize d n u m ber of H A E attac ks d uri n g 
treat me nt fr o m D a y 1 t hr o u g h Da y 1 8 2. 
•  I nterc urre nt e v e nts: T he occ urre nce of a n i nterc urre nt e ve nt is 
irrele va nt. All o bser ve d v al ues will be use d re g ar dl ess of 
occ urr e nce of a n y of t he f oll o wi n g i nterc urre nt e v e nts: 
o  ad mi nistrati o n of o n- de m a n d  me di cati o n i n a d diti o n t o 
pr o p h ylactic treat me nt wit h C S L 3 1 2 
o  n o n- c o m plia nce t o treat me nt  
o  earl y ter mi nati o n 
•  P o p ulati o n- le vel s u m mar y: me dia n ti me- n or malize d n u m ber of 
H A E attac ks p er m o nt h d uri n g treat me nt fr o m D a y 1 t hr o u g h 
Da y 1 8 2 b y treat me nt.  
T he pri mar y e n d p oi nt will be a nal yze d usi n g t he I T T a n d 
Per  Pr ot oc ol ( P P) P o p ulati o ns. T he I T T p o p ulati o n will be use d as 
t he pri mar y a n al ysis a n d t he P P will be use d as t he sec o n dar y 
a nal ysis. 
T he pri mar y e n d p oi nt “ti me- n or malize d n u m b er of H A E attac ks per 
m o nt h d uri n g treat me nt fr o m Da y 1 t hr o u g h Da y 1 8 2 ” is calc ulate d 
per s u bject as:  


C S L Be hri n g, L L C  
 
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)  
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0  of 1 1 7  
Date: 0 4  A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
[t he n u m ber of H A E attac ks / le n gt h of s u bject treat me nt i n 
da ys] * 3 0. 4 3 7 5 
w here t he l e n gt h of s u bject treat me nt is calc ul ate d as:  
[t he date of St u d y Visit D a y 1 8 2 or t he date of st u d y 
disc o nti n uati o n [ w hate ver is first] – t he date of St u d y Visits 
Da y 1  + 1].  
To test f or a differe nce i n t he pri mar y efficac y e n d p oi nt bet wee n 
C S L 3 1 2 a n d place b o, a c o m paris o n of t he ti me- n or malize d 
n u m bers of H A E attac ks i n t he 6 m o nt hs of t he Acti ve Ar m a n d i n 
t he 6- m o nt h Place b o Ar m p eri o d will be perf or me d b y usi n g a 
t w o-si de d Wilc o x o n Test (al p ha  = 5 %).  
T he ti me - n or malize d n u m ber of H A E attac ks per m o nt h a n d 
a n n ualize d  will be s u m m arize d d escri pti vel y f or t he 6 m o nt hs of t he 
Acti ve Ar m a n d t he 6 -m o nt h Place b o Ar m  peri o d b y me dia n a n d 
mea n wit h c orres p o n di n g 9 5 % c o nfi de n ce i nter v als ( CIs). 
 
 
 
 




C S L Be hri n g, L L C  
 
 St u d y N u m ber: C S L 3 1 2 _ 3 0 0 1  
 
 St u d y Pr o d uct:  C S L 3 1 2 
( Fact or XIIa I n hi bit or 
 
 
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A b bre vi ati o ns:  C 1-I N H = C 1-esterase i n hi bit or; C 4 = c o m ple me nt C 4 ; C S L  = C S L Be hri n g; e Diar y = electr o nic diar y; H A E  = here ditar y a n gi oe de ma; I R T = i nteracti ve res p o nse 
tec h n ol o g y 
F o ot n otes t o t he Sc he d ule of Assess m e nts: Scree ni n g a n d R u n -i n Peri o d [ All S u bjects] 
A: 
T he first d a y of t h e R u n -i n Peri o d ma y o cc ur o n t h e sa me d a y as t he Scree ni n g Visit f or s u bjects meeti n g t h e eli gi bilit y criteria f or t he R u n-i n Peri o d.  
B: 
S u bjects m ust c o m plete at least 1 m o nt h  of  t h e R u n-i n Peri o d. S u bjects ma y e nter t h e Treat me nt Peri o d o n ce t h e y e x perie nce at least 2 H A E attac ks.  
C: 
If a s u bject is u n a ble t o e nter t h e Treat me nt Peri o d after Da y 6 0, t he n C S L a p pr o v al is re q uire d f or t h e s u bject t o e nter t he Treat me nt Peri o d. Da y 6 0 will c o ncl u de t he 
st u d y f or a s u bject w h o h as e ntere d t h e R u n-i n Peri o d a n d is s u bse q u e ntl y n ot eli gi ble t o b e ra n d o mize d. Eli gi ble s u bjects will pr ocee d t o t he Da y 1 visit of t he 
Treat me nt Peri o d.  
D:  
Writte n i nf or me d c o nse nt m ust be pr o vi d e d b ef ore a n y st u d y -s p ecific assess me nts or pr o ce d ures are p erf or me d. 
E:  
Eli gi bilit y t o b e c o nfir me d b ef ore a n y st u d y ass ess me nts are p erf or me d.  Th e start of t h e R u n -i n Peri o d s h o ul d b e rec or de d i n t he I R T after rec o nfir mi n g eli gi bilit y. 
F:  
Tele p h o n e c o ntact is n ot a p plica ble w h e n t h e first d a y of t h e R u n -i n Peri o d o cc urs o n sa me d a y as t he Scree ni n g Visit. 
G:  
I ncl u de C 1 -I N H f u n cti o n al acti vit y a n d a nti g e n, a n d C 4 a nti g e n c o nce ntrati o n hist or y, rec or di n g of o v erall h ealt h wit hi n t he 6 m o nt hs bef ore Scree ni n g ; H A E hist or y 
i ncl u di n g t y p e, a g e of dia g n osis, me dical rec or ds t o s u p p ort dia g n osis (ie, attac k fre q u e n c y, hist ory of lar y n g eal attac ks, p ri or pr o p h yla xis t hera p y a n d o n-de ma n d 
treat me nt me dicati o n) wit hi n t h e 6 m o nt hs b ef ore Scree ni n g , a n d c o ntrace pti o n met h o d (f or fe male s u bjects of c hil d beari n g p ote ntial o nl y). 
H:  
A uri ne test f or b eta -h u ma n c h ori o nic g o n a d otr o pi n  will b e p erf or me d f or se x u all y acti v e w o me n of c hil d b eari n g p ote ntial ( o nl y). A ser u m pre g na nc y test will be 
perf or me d b y t h e site if t h e uri n e res ult is i nc o n cl usi v e.  
I: 
A p h ysical e x a mi n ati o n will b e c o n d u cte d p er t h e i n v esti g at or’s sta n d ar d pr o ce d ure a n d will als o i ncl u d e assess me nt of u nilateral pai n a n d  / or s welli n g of t he l o wer 
e xtre mities f or t h e p ur p ose of scree ni n g f or d ee p v ei n t hr o m b osis.  
J:  
Bl o o d sa m ple f or C 1 -I N H f u n cti o n al acti vit y a n d  a nti g e n, a n d C 4 a nti g e n c o n ce ntrati o n will b e c ollecte d d uri n g t h e Scree ni n g Peri o d f or c o nfir mati o n of hist orical 
la b orat or y v al u es c o ntai n e d i n t h e s u bject’s me dical rec or d. If a s u bject re q uires t h e use of o n -d e ma n d me dicati o n t o treat a n H A E attac k wit hi n 1 2 0 h o urs (ie, 5 da ys  
after C 1 -I N H a d mi nistrati o n) b ef ore Scree ni n g, t h e n t h at s u bject ma y ret ur n t o t h e st u d y site wit hi n t h e first 2 wee ks of t he R u n-i n Peri o d f or a sec o n d bl o o d dra w t o 
assess C 1- I N H a nti g e n c o n ce ntrati o n a n d f u n cti o n al acti vit y , a n d C 4 a nti g e n c o n ce ntrati o n . 
K:  
A n i n di vi d u al a c ute treat me nt pla n will b e d e v el o p e d b y t h e i n v esti g at or t o e ns ure t h at p artici p ati n g s u bjects are ca pa ble of ma na gi n g t heir  H A E attac ks d uri n g t he 
st u d y a n d c o nfir mati o n of s u bject’s access t o o n -d e ma n d H A E me dicati o n t o treat H A E attac ks . T h e acti o n plan will be re vie we d wit h s u bjects.  
L:  
Re peat  re m ote trai ni n g is re q uire d if 3 0 d a ys h a v e ela pse d b et wee n trai ni n g at t h e Scree ni n g Visit 
M:   
Refer t o A p p e n di x 2  f or i nstr u cti o ns o n H A E attac k d o c u me ntati o n a n d assess me nt.  
N:  
Access t o t h e e Diar y s h o ul d b e cl ose d at t h e Da y 6 0 Tele p h o n e C o ntact f or s u bjects w h o are n ot eli gi ble t o e nter  t he Treat me nt Peri o d.  e Diar y s h o ul d be ret ur ne d.  
O:  
Beri nert is t h e s u g g este d o n -d e ma n d  me dicati o n f or use d uri n g t his st u d y. H o we v er, s u bjects ma y use t h e o n -d e ma n d me dicati o n of t heir c h oice t o treat H A E attac ks  
e x perie n ce d d uri n g t h e st u d y if t hat me dicati o n h as pre vi o usl y b ee n s h o w n t o b e effecti v e.  






C S L Be hri n g, L L C  
 
 St u d y N u m ber: C S L 3 1 2 _ 3 0 0 1  
 
 St u d y Pr o d uct:  C S L 3 1 2 
( Fact or XIIa I n hi bit or 
 
 
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
N:   
T he f oll o wi n g p atie nt relate d o utc o mes will b e e ntere d at s p ecifie d st u d y site visits b ef ore a n y ot h er i nteracti o n wit h t he s u bject a b o ut t heir healt h stat us a n d bef ore 
re vie w of t h e electr o nic diar y: A E-Q o L, E Q -5 D -5 L, W P AI: G H, a n d S G A R T.  
O :  
I n vesti gat or c o m pletes I G A R T i n R A V E. S u bjects c o m plete S G A RT.  
P:   
O nl y a p plica ble f or s u bjects n ot r olli n g o v er t o St u d y C S L 3 1 2 _ 3 0 0 2.  
Q:  
T he e Diar y will be c ollecte d a n d deacti vate d o n Da y 1 8 2 f or s u bjects r olli n g o ver t o St u d y C S L 3 1 2 _ 3 0 0 2 a n d o n Da y 2 4 2 f or all ot h er s u bjects. F or s u bjects 
w h o ter mi nate t he st u d y  earl y, t he e Diar y s h o ul d be deacti vate d a n d c ollecte d eit her o n date of earl y t er mi nati o n or at t he F oll o w -u p V isit as a p plica ble. If 
t he F oll o w-u p Visit is c o n d ucte d re m otel y, t he de vice s h o ul d be ret ur ne d t o t he site.  
R:  
Beri nert is t h e s u g g este d o n -d e ma n d  me dicati o n f or use d uri n g t his st u d y. S u bjects ma y use t h e o n -d e ma n d me dicati o n of t heir c h oice t o treat H A E attac ks e x perie nce d 
d uri n g t he st u d y if t h at me dicati o n h as pre vi o usl y b ee n s h o w n t o be effecti v e.  
S:   
T he first d ose of i n v esti g ati o n al pr o d u ct will b e a l o a di n g d ose c o nsisti n g of eit h er 2 S C i njecti o ns of 2 0 0 m g C S L 3 1 2  eac h f or a t otal of 4 0 0 m g C S L 3 1 2  ( Acti ve Ar m) 
or 2  S C i njecti o ns of v ol u me -matc h e d place b o ( Place b o  Ar m) a d mi nistere d b y t h e i n v esti g at or or d ele g ate at t h e st u d y site.  
T:   
I n vesti gati o n al pr o d u ct a d mi nistrati o n c o nsisti n g of eit h er o n e 2 0 0 m g C S L 3 1 2  S C i njecti o n ( Acti v e Ar m) or o n e S C  i njecti o n of v ol u me-matc he d place b o ( Place b o  
Ar m) ma y b e self -a d mi n istere d b y t h e s u bject u n d er t h e s u p er visi o n of t h e i n v esti g at or or d ele g ate at t h e st u d y site.  
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble of C o nte nts  
Sc he d ule of Assess me nts: Scree ni n g a n d R u n- i n Peri o d ( All S u bjects) ................................. 1 1  
Sc he d ule of Assess me nts: Treat me nt Peri o d  ........................................................................... 1 3 
Ta ble of C o nte nts ..................................................................................................................... 1 6  
List of A b bre viati o ns  ............................................................................................................... 2 2 
List of C o n ve nti o ns .................................................................................................................. 2 4  
1  
I ntr o d ucti o n .......................................................................................................... 2 5 
1. 1  
Bac k gr o u n d ...................................................................................................... 2 5  
1. 1. 1  
Fact or XII  ..................................................................................................... 2 5 
1. 1. 2  
Fact or X II a n d t he K alli krei n- ki ni n Pat h wa y ............................................... 2 5 
1. 1. 3  
Bac k gr o u n d of Disease ................................................................................. 2 5  
1. 1. 4  
Bac k gr o u n d o n C S L 3 1 2 a n d Rati o nale f or Treat m e nt of Here ditar y 
A n gi oe de ma .................................................................................................. 2 7  
1. 1. 5  
U n met Me dical Nee d  .................................................................................... 2 8 
1. 2  
I nf or mati o n o n C S L 3 1 2 ................................................................................... 2 9 
1. 2. 1  
O ver vie w  ...................................................................................................... 2 9 
1. 2. 2  
N o ncli nical E val uati o n  ................................................................................. 2 9 
1. 2. 3  
Cli nical E x perie nce  ...................................................................................... 2 9 
1. 3  
St u d y O ver vie w ................................................................................................ 3 1  
1. 4  
P ote ntial Ris ks a n d Be nefits  ............................................................................. 3 1 
2  
St u d y O bjecti ves a n d E n d p oi nts ........................................................................... 3 3  
2. 1  
Pri mar y O bjecti ve a n d E n d p oi nt ...................................................................... 3 3  
2. 1. 1  
Pri mar y Efficac y O bjecti ve  .......................................................................... 3 3 
2. 1. 2  
Pri mar y Efficac y E n d p oi nt ........................................................................... 3 3  
2. 2  
Sec o n dar y O bj ecti ves a n d E n d p oi nts ............................................................... 3 3  
2. 2. 1  
Sec o n dar y O b j ecti ves ................................................................................... 3 3 
2. 2. 2  
Sec o n dar y E n d p oi nts .................................................................................... 3 4  
2. 3  
E x pl orat or y O bjecti ve a n d E n d p oi nts .............................................................. 3 6  
2. 3. 1  
E x pl orat or y O bjecti ve .................................................................................. 3 6  
2. 3. 2  
E x pl orat or y E n d p oi nts .................................................................................. 3 7  
3  
St u d y Desi g n a n d O versi g ht ................................................................................. 3 7  
3. 1  
O verall Desi g n  .................................................................................................. 3 7 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
3. 1. 1  
Scree ni n g  ...................................................................................................... 3 8 
3. 1. 2  
R u n- I n Peri o d ............................................................................................... 3 8 
3. 1. 3  
Treat me nt Peri o d  .......................................................................................... 3 9 
3. 1. 4  
F oll o w- U p Peri o d / O pe n-la bel P hase 3 b St u d y E ntr y ................................. 3 9  
3. 2  
D ose a n d D osi n g Re gi m e n ............................................................................... 3 9  
3. 3  
Scie ntific Rati o nale  .......................................................................................... 4 0 
3. 3. 1  
St u d y Desi g n Rati o nale ................................................................................ 4 0  
3. 3. 2  
D ose Rati o nale  ............................................................................................. 4 0 
3. 4  
Pla n ne d St u d y D urati o n ................................................................................... 4 1  
3. 5  
Pla n ne d N u m ber of S u bj ects ............................................................................ 4 1  
3. 6  
Defi niti o n of Start of t he Cli nical St u d y  .......................................................... 4 1 
3. 7  
Defi niti o n of E n d of t he Cli nical St u d y ........................................................... 4 2  
3. 8  
St u d y O versi g ht ................................................................................................ 4 2  
3. 8. 1  
I n de pe n de nt Data M o nit ori n g C o m mittee .................................................... 4 2 
3. 9  
Halti n g Criteria  ................................................................................................. 4 2 
3. 9. 1  
St u d y Halti n g Criteria  .................................................................................. 4 2 
4  
Selecti o n a n d Wit h dra wal of S u bjects .................................................................. 4 3  
4. 1  
Eli gi bilit y Criteria  ............................................................................................ 4 3 
4. 1. 1  
I ncl usi o n Criteria f or E ntr y i nt o t he R u n-i n Peri o d ...................................... 4 4 
4. 1. 2  
E xcl usi o n Criteria f or E ntr y i nt o t he R u n-i n a n d Treat me nt Peri o ds ........... 4 4  
4. 1. 3  
Criteria f or E ntr y i nt o t he Treat me nt Peri o d  ................................................ 4 6 
4. 2  
Scree n Fail ures  ................................................................................................. 4 6 
4. 2. 1  
R u n-i n Peri o d Fail ures .................................................................................. 4 7  
4. 3  
Disc o nti n uati o n of St u d y Treat me nt a n d S u bject Wit h dra wal ......................... 4 7  
4. 3. 1  
Disc o nti n uati o n of St u d y Treat me nt ............................................................. 4 7  
4. 3. 2  
S u bject Wit h dra wal  ...................................................................................... 4 7 
4. 3. 3  
Pr oce d ures f or H a n dli n g Wit h dra wals .......................................................... 4 8 
4. 3. 4  
S u bjects L ost t o F oll o w- u p ........................................................................... 4 8  
4. 3. 5  
Re place me nt P olic y  ...................................................................................... 4 8 
5  
St u d y I nter ve nti o ns ............................................................................................... 4 9  
5. 1  
I n vesti gati o nal Pr o d ucts ................................................................................... 4 9 
5. 1. 1  
Descri pti o n of C S L 3 1 2 ................................................................................. 4 9  
5. 1. 2  
Descri pti o n of Place b o  ................................................................................. 4 9 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
5. 1. 3  
D osi n g a n d A d mi nistrati o n  ........................................................................... 5 0 
5. 1. 4  
Pac ka gi n g, La beli n g, S u p pl y a n d St ora ge .................................................... 5 1  
5. 2  
Acc o u nta bilit y a n d Destr ucti o n ........................................................................ 5 1  
5. 2. 1  
C o nc o mita nt St u d y- relate d T hera pies .......................................................... 5 2 
5. 3  
Access t o I n v esti gati o nal Pr o d uct After t he E n d of St u d y ............................... 5 2  
6  
All ocati o n t o Treat me nt  ........................................................................................ 5 2 
6. 1  
S u bject Assi g n me nt  .......................................................................................... 5 2 
6. 2  
Ra n d o mizati o n Pr oce d ures ............................................................................... 5 3  
6. 3  
Bli n di n g Pr oce d ures ......................................................................................... 5 3  
6. 3. 1  
Bli n di n g Met h o d ........................................................................................... 5 3  
6. 3. 2  
Brea ki n g t he Bli n d f or a n E mer ge n c y .......................................................... 5 4  
6. 3. 3  
Pla n ne d U n bli n di n g Pr oce d ures ................................................................... 5 4  
6. 3. 4  
A d -h oc Saf et y U n bli n di n g ............................................................................ 5 4  
7  
C o ntrai n dicati o ns, Per mitte d T hera pi es a n d Pr o hi bite d T hera pi es ...................... 5 5  
7. 1  
C o ntrai n dicati o ns a n d Preca uti o ns t o F urt her D osi n g ...................................... 5 5  
7. 2  
Per mitte d T hera pies  .......................................................................................... 5 5 
7. 3  
Pr o hi bite d T hera pies ......................................................................................... 5 5  
7. 4  
Lifest yle Restricti o ns  ........................................................................................ 5 6 
8  
St u d y Pr oce d ures a n d Visit Sc he d ule ................................................................... 5 6  
8. 1  
Cli nical Pr oce d ures  .......................................................................................... 5 6 
8. 1. 1  
De m o gra p hics a n d Safet y Assess me nts  ....................................................... 5 7 
8. 1. 2  
P har mac o ki netic a n d P har mac o d y na mic Assess me nts ................................ 6 0  
8. 1. 3  
Efficac y Assess me nts  ................................................................................... 6 1 
8. 2  
Ot her Ass ess me nts  ............................................................................................ 6 2 
8. 2. 1  
O utc o me Researc h Assess me nts  .................................................................. 6 2 
8. 2. 2  
Electr o nic Diar y a n d Electr o nic Cli nical O utc o me Assess me nts  ................. 6 5 
8. 3  
Bl o o d Sa m ples .................................................................................................. 6 6  
8. 4  
Rete nti o n of Sa m ples ....................................................................................... 6 6  
8. 4. 1  
Rete nti o n Sa m ple f or H A E Bi o mar kers ....................................................... 6 6  
8. 5  
Pri or a n d C o nc o mita nt T hera pies ..................................................................... 6 7  
8. 6  
Electr ocar di o gra ms  ........................................................................................... 6 7 
8. 7  
Visit Sc he d ule  ................................................................................................... 6 7 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
8. 7. 1  
Assess me nt Ti me Wi n d o ws  .......................................................................... 6 7 
8. 7. 2  
Scree ni n g Visit  .............................................................................................. 6 8 
8. 7. 3  
R u n-i n Peri o d ............................................................................................... 6 9  
8. 7. 4  
Treat me nt Peri o d  .......................................................................................... 7 1 
8. 7. 5  
F oll o w- u p Tele p h o ne C o ntact or Fi nal Visit ................................................ 7 7  
8. 7. 6  
E n d of St u d y ................................................................................................. 7 7  
9  
A d verse E v e nts  ..................................................................................................... 7 7 
9. 1  
Defi niti o ns  ........................................................................................................ 7 7 
9. 1. 1  
A d verse E v e nt  .............................................................................................. 7 7 
9. 1. 2  
Seri o us A d vers e E ve nt  .................................................................................. 7 9 
9. 1. 3  
A d verse E v e nt of S pecial I nterest  ................................................................ 7 9 
9. 2  
Se verit y of A d v erse E v e nts  .............................................................................. 8 0 
9. 3  
Ca usalit y of A d vers e E ve nts ............................................................................ 8 0  
9. 4  
O bser vati o n Peri o d f or A d verse E ve nts ........................................................... 8 1  
9. 5  
F oll o w- u p of A d vers e E v e nts ........................................................................... 8 1  
9. 6  
A d verse E v e nt Re p orti n g ................................................................................. 8 2  
9. 6. 1  
A d verse E v e nts  ............................................................................................. 8 2 
9. 6. 2  
A d verse E v e nts of S peci al I nterest  ............................................................... 8 2 
9. 6. 3  
Seri o us A d vers e E ve nts  ................................................................................ 8 2 
9. 6. 4  
Ot her Si g nifica nt E ve n ts .............................................................................. 8 3 
9. 6. 5  
O ver d ose ....................................................................................................... 8 3  
9. 6. 6  
Pre g na nc y a n d Breastfee di n g  ....................................................................... 8 4 
9. 7  
I R B / I E C Re p orti n g Re q uire me nts ................................................................. 8 4 
1 0  
Statistics  ................................................................................................................ 8 5 
1 0. 1  
Sa m ple Size  Esti mati o n  .................................................................................... 8 5 
1 0. 2  
Descri pti o n of St u d y A nal ysis Sets .................................................................. 8 5  
1 0. 2. 1  
Scree ne d A n al ysis Set  .................................................................................. 8 5 
1 0. 2. 2  
I nte nt-t o-Treat A nal ysis Set  .......................................................................... 8 5 
1 0. 2. 3  
Safet y A n al ysis  Set  ....................................................................................... 8 6 
1 0. 2. 4  
Per -pr ot oc ol A nal ysis Set  ............................................................................. 8 6 
1 0. 2. 5  
P har mac o ki netic A nal ysis Set  ...................................................................... 8 6 
1 0. 2. 6  
P har mac o d y na mic A nal ysis Set  ................................................................... 8 6 
1 0. 3  
Statistical A nal y ses a n d Met h o ds ..................................................................... 8 6 
1 0. 3. 1  
S u bject Dis p ositi o n a n d C haracteristics  ....................................................... 8 7 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0. 3. 2  
Efficac y A nal yses  ......................................................................................... 8 8 
1 0. 3. 3  
Safet y A n al yses  ............................................................................................ 9 3 
1 0. 3. 4  
P har mac o ki netics A nal ys es  .......................................................................... 9 4 
1 0. 3. 5  
P har mac o d y na mic A nal yses  ......................................................................... 9 5 
1 0. 3. 6  
P har mac o ki netic / P har m ac o d y na mic Relati o ns hi ps  ................................... 9 5 
1 0. 3. 7  
Ot her A n al yses  ............................................................................................. 9 5 
1 0. 3. 8  
I nteri m A nal ysis ........................................................................................... 9 5 
1 1  
Q ualit y Ass ura n ce  ................................................................................................. 9 5 
1 2  
Re g ulat or y a n d Et hics C o nsi derati o ns .................................................................. 9 6  
1 2. 1  
Re g ulat or y C o nsi derati o ns ............................................................................... 9 6  
1 2. 2  
I nstit uti o nal Re vie w B oar d / I n de pe n d e nt Et hics C o m mittee .......................... 9 6 
1 2. 3  
S u bject I nf or mati o n a n d I nf or me d C o nse nt ..................................................... 9 6  
1 2. 4  
S u bject C o nfi de ntialit y  ..................................................................................... 9 7 
1 2. 5  
I n de m nit y a n d C o m pe nsati o n ........................................................................... 9 7 
1 3  
A d mi nistrati ve C o nsi derati o ns  ............................................................................. 9 7 
1 3. 1  
Cli nical Trial Researc h A gree me nt  .................................................................. 9 7 
1 3. 2  
Cli nical St u d y Re gistrati o n a n d Res ults Discl os ure ......................................... 9 8  
1 3. 3  
I m ple me ntati o n of t he Cli nical St u d y Pr ot oc ol a n d A me n d me nt(s) ................ 9 8 
1 3. 4  
Pr ot oc ol De viati o ns .......................................................................................... 9 9  
1 3. 5  
D oc u me ntati o n a n d Rec or d Kee pi n g ............................................................... 9 9  
1 3. 5. 1  
Data C ollecti o n  ............................................................................................. 9 9 
1 3. 5. 2  
Data Q ualit y Ass ura nce  .............................................................................. 1 0 0 
1 3. 5. 3  
Rec or d Rete nti o n  ........................................................................................ 1 0 1 
1 3. 6  
St u d y a n d Site Cl os ure ................................................................................... 1 0 1  
1 3. 7  
Cli nical St u d y Re p ort ..................................................................................... 1 0 1  
1 3. 8  
Use of Dat a a n d P u blicati o ns ......................................................................... 1 0 2  
1 4  
Refere n ces  .......................................................................................................... 1 0 3 
1 5  
A p pe n dices ......................................................................................................... 1 0 7  
A p pe n di x 1  
Si g nat ures ....................................................................................................... 1 0 8  
A p pe n di x 2  
Here ditar y A n gi oe d e ma Attac k Ass ess me nt  a n d Re p orti n g I nstr ucti o ns 
f or St u d y C S L 3 1 2- 3 0 0 1 ................................................................................. 1 1 0  
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
List of Ta bles  
Ta ble 1  
Descri pti o n of C S L 3 1 2 .................................................................................... 4 9  
Ta ble 2  
Descri pti o n of Place b o  ..................................................................................... 5 0 
Ta ble 3  
I n vesti gati o nal Pr o d uct D osi n g C haracteristics ............................................... 5 0 
Ta ble 4  
St u d y Pr oce d ures: De m o gra p hics a n d Safet y Ass ess me nts ............................. 5 8  
Ta ble 5  
Cli nical Pr oce d ures: P har mac o ki netic a n d P har m ac o d y na mic Ass ess me nts  .. 6 1 
Ta ble 6  
Ti me Wi n d o ws f or Ass ess me nts  ...................................................................... 6 8 
 
List of Fi g ures  
Fi g ure 1  
Fact or XII a n d its R ole i n t he C oa g ulati o n, Fi bri n ol ytic, a n d Kalli krei n- Ki ni n 
S yste ms  ............................................................................................................ 2 8 
Fi g ure 2  
St u d y O ver vie w ............................................................................................... 3 8  
 
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
L ist of  Ab bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A C E  
A n gi ote nsi n c o n verti n g e nz y me 
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nteres t 
A E -Q o L  
A n gi oe de ma Q u alit y of Life  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
B K  
Bra d y ki ni n 
CI  
C o nfi de nce i nter v al  
C 1 -I N H 
C 1 -esterase i n hi bit or  
C S L  
C S L Be hri n g 
e C O A  
Electr o nic cli nical o utc o mes assess me nt  
e C R F 
Electr o nic case re p ort f or m  
e Diar y  
Electr o nic diar y  
E Q -5 D -5 L  
E ur o Q o L -Gr o u p 5 -Di me nsi o n 5 -Le vel  
E- R 
E x p os ure-res p o nse 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F XI  
Fact or XI  
F XII  
Fact or XII  
F XIIa  
Acti vate d Fact or XII  
G C P  
G o o d Cli nical Practice  
G M P  
G o o d Ma n ufact uri n g Practice 
H A E  
Here ditar y a n gi oe d e ma  
H M W K  
Hi g h m olec ular wei g ht ki ni n o ge n 
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h ni cal 
Re q uire me nts f or P har m ace uticals f or H u ma n Us e 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I E C 
I n de pe n de nt Et hics C o m mittee  
I G A R T 
I n vesti gat or’s Gl o bal Ass ess me nt of Res p o nse t o T hera p y 
I g G 4 
H u ma n i m m u n o gl o b uli n G s u bclass 4  
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A b bre vi ati o n  
Ter m  
I S R 
I njecti o n site reacti o n 
I T T 
I V 
I nte nti o n-t o- Treat 
I ntra ve n o us 
m A b  
M o n ocl o nal a nti b o d y 
n C 1 -I N H 
N or mal C 1 -esterase i n hi bit or 
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic  
P P  
Per pr ot oc ol 
P R O  
Patie nt re p orte d o utc o me 
P T  
Preferre d ter m  
Q o L  
Q ualit y of Life  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S C  
S u bc uta ne o us 
S G A R T  
S u bject’s Gl o bal Assess me nt of Res p o nse t o T hera p y  
S O C  
S yste m or ga n class  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nts  
T E E  
T hr o m b oe m b olic e ve nt 
T P 1  
Treat me nt peri o d 1  
T P 2  
Treat me nt peri o d 2  
W P AI -G H  
Wor k Pr o d ucti vit y a n d A cti vit y I m pair me nt – Ge n eral Healt h  
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
List of C o n ve nti o ns  
•  T he a b br e viati o n “ C 1-I N H H A E” is use d i n t his cli nical st u d y pr ot oc ol t o i ncl u de 
here ditar y a n gi oe de ma t y pe 1 ( q ua ntitati ve decrease i n C 1- esteras e i n hi bit or plas ma 
c o nce ntr ati o ns) a n d here ditar y a n gi oe de ma t y p e 2 ( d ysf u ncti o nal C 1- esterase i n hi bit or 
prese nt i n n or mal or hi g h plas ma c o nce ntrati o ns). 
•  C S L 3 1 2 has bee n gi ve n t he Worl d H ealt h Or g a nizati o n I nter nati o nal N o n pr o prietar y 
Na mes  i de ntificati o n of g ara daci ma b.  
•  T he st u d y ar ms a n d peri o ds are defi ne d as f oll o ws: 
o  Acti ve Ar m : a d mi nistrati o n of C S L 3 1 2 f or 6 m o nt hs. 
o  Pl ace b o  Ar m : a d mi nistrati o n of v ol u me- matc he d place b o  f or 6 m o nt hs. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1  Intr o d ucti o n  
1. 1  B ac k gr o u n d  
1. 1. 1  F act or XII  
Fact or XII ( Ha g e ma n f act or, F XII) is pr o d uce d i n t he li ver a n d is s ecrete d i nt o t he plas ma; 
t he gl yc os ylate d 8 0 kil o dalt o n ( k Da) z y m o ge n circ ulates wit h a c o n ce ntrati o n of ~ 3 0 µ g / m L 
a n d a half -life of 5 0 t o 7 0 h o urs [Bj ör k q vist et al, 2 0 1 4 ].  
Fact or XII is t he pri nci pal i nitiat or of t he plas ma c o ntact s yste m [ Re n né et a l, 2 0 1 2]. T he 
c o ntact s yste m is a pr otease cas ca d e i n v ol vi n g t he pr otei ns F XII, fact or XI ( F XI), plas ma 
pre kalli krei n, a n d t h e n o ne nz y matic c ofact or hi g h m olec ular wei g ht ki ni n o ge n ( H M W K). 
U p o n c o ntact wit h a n e gati vel y- c har g e d s urface F XII is c o n verte d t o  acti vate d F XII ( F XII a). 
Se veral bi ol o gic s u bsta nces ha ve bee n s h o w n t o s u p p ort F XII acti vati o n i n vi v o, i ncl u di n g 
he pari n r elease d fr o m mast cells, misf ol de d pr otei n a g gre gat es, ri b o n ucleic aci d, a n d platelet 
p ol y p h os p hates [ Ke n n e et al, 2 0 1 5 ]. F XIIa tri ggers fi bri n f or mati o n t hr o u g h acti vati o n of 
F XI, a n d als o lea ds t o t he pr o d ucti o n of t he i nfla m mat or y me diat or bra d y ki ni n ( B K) t hr o u g h 
t he kalli krei n- ki ni n pat h wa y. F urt her clea v a ge of F XIIa releases t he 3 0 k D a li g ht c hai n 
c o ntai ni n g t he catal ytic d o mai n ( β F XIIa), w hic h ca n acti vate t he classical c o m ple me nt 
pat h wa y. T h us, acti vate d f or ms of F XII ha v e pr oi nfla m mat or y a n d pr o c oa g ula nt acti vities. 
1. 1. 2  F act or XII a n d t he K alli krei n -ki ni n P at h w a y  
Acti vati o n of F XII (t o F XIIa) als o lea ds t o t he pr o d ucti o n of B K t hr o u g h t he kalli krei n- ki ni n 
pat h wa y. I n t his pat h wa y, pre kalli krei n is c o n verte d t o kalli krei n b y F XIIa. Kalli krei n pla ys a 
n u m ber of r oles. First, it acti vates F XII z y m o ge ns b y a p ositi ve fee d b ac k mec ha nis m t o 
a m plif y t he casca de. Sec o n d, kalli krei n clea v es H M W K t o release t he p ote nt i nfla m mat or y 
me diat or B K. T he bi n di n g of B K t o B K t y pe 2 rece pt ors acti vates v ari o us i ntracell ular 
si g nali n g pat h wa ys t hat dilate vessels, i n d uce c h e m ota xis of ne utr o p hils, a n d i ncreas e 
vasc ular p er mea bilit y a n d fl ui d effl u x [ Bj ör k q vist et al, 2 0 1 3 ]. Bra d y ki ni n pr o d ucti o n is 
i ncreas e d d uri n g ac ut e here ditar y a n gi o e de ma ( H A E) attac ks a n d is t he m e diat or of s welli n g 
i n H A E [N uss ber ger et al, 1 9 9 8 ; N uss ber ger et al, 1 9 9 9 ]. 
1. 1. 3  B ac k gr o u n d of Dise ase  
Here ditar y a n gi oe d e ma is a rar e ge netic dis or d er classifie d i nt o 3 disease t y pes 
[R ose n  et al, 1 9 6 5; B or k et al, 2 0 0 0 ], i ncl u di n g H A E t y pe 1, H A E t y pe 2, a n d H A E wit h 
n or mal C 1-esteras e i n hi bit or ( n C 1- I N H). 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Here ditar y a n gi oe d e ma t y pe 1 a n d t y pe 2 are ca us e d b y m utati o ns of t he S E R PI N G 1 ge ne, 
a n d are c haract erize d b y a q ua ntitati ve decreas e i n C 1 -esterase i n hi bit or ( C 1 -I N H) pl as ma 
c o nce ntr ati o ns (t y pe 1) a n d d ysf u ncti o nal C 1-I N H prese nt i n n or mal plas m a c o nce ntrati o ns 
(t y pe 2) [Z ur a w  et al, 2 0 1 0; Cicar di  et al, 2 0 1 4]. To get her, H A E t y pe 1 a n d t y pe 2 are 
gr o u pe d as H A E wit h C 1- I N H deficie nc y ( C 1-I N H H A E). 
A lar ge n u m ber of diff ere nt S E R PI N G 1 m utati o ns ha ve bee n ass ociat e d wit h H A E t y pe 1, 
i ncl u di n g misse nse, n o nse nse, fr a mes hift, deleti o n, a n d i nserti o n m utati o ns 
[Kal mar  et al, 2 0 0 5]. I n g eneral, H A E t y pe 1 is ca use d b y m utati o ns i n t he C 1- I N H ge n e t hat 
res ults i n eit her tr u ncat e d or misf ol de d pr otei ns t hat ca n n ot be secrete d [Ver p y et al, 1 9 9 5 ]. I n 
H A E t y pe 1, a n i m pair e d s y nt hesis of n or mal a n d f u ncti o nall y acti ve C 1-I N H occ urs, ca usi n g 
a re d ucti o n i n t he a v aila bilit y of f u ncti o nall y acti ve C 1-I N H le v els t o bet wee n 5 % a n d 3 0 % 
of n or mal [ R ose n et al, 1 9 6 5 ]. A p pr o xi matel y 8 5 % of s u bjects wit h C 1-I N H H A E ha v e H A E 
t y pe 1 [L o n g h urst a n d B or k, 2 0 0 6 ].  
M ost S E R PI N G 1 m utati o ns ass ociate d wit h H A E t y pe 2 i n v ol ve resi d ues at or near t he acti ve 
site o n t he reacti ve m o bile l o o p of t he C 1-I N H pr otei n t hat res ult i n a pr otei n t hat is secrete d 
b ut is d ysf u ncti o nal [ Wa ge naar - B os a n d Hac k, 2 0 0 6]. I n H A E t y pe 2, n or mal le vels of a 
f u ncti o nall y i m paire d C 1-I N H m olec ul e are s y nt hesize d, b ut t he n or mal f or m of C 1-I N H is 
c o nsi dera bl y r e d uce d i n t he circ ulati o n [ R ose n et al, 1 9 6 5 ]. A p pr o xi matel y 1 5 % of s u bjects 
wit h C 1 -I N H H A E ha v e H A E t y pe 2 [L o n g h urst a n d B or k, 2 0 0 6 ].  
C 1 -esterase i n hi bit or is a seri ne pr otease i n hi bit or t hat re g ulates t he g e nerati o n of B K b y t he 
plas ma c o ntact s yste m, a n d is t he maj or i n hi bit or of a n u m ber of plas ma c o ntact s yste m 
pr oteases i ncl u di n g F XII a n d kalli krei n [ D a vis et al, 2 0 1 0 ]. E xcessi ve B K f or mati o n d ue t o 
pat h ol o gical acti vati o n of t he F XII- dri ve n pl as ma c o ntact s yste m is a c o nsiste nt fi n di n g i n 
ac ute e pis o des of H A E [ Bj ör k q vist et al, 2 0 1 3].  
Here ditar y a n gi oe d e ma wit h n or mal C 1 -I N H is a n i n herite d dis or der n ot ass ociate d wit h 
C 1 -I N H defi cie nc y, b ut misse nse m utati o ns, deleti o ns or i nserti o ns of base pairs of t he F XII 
ge ne [ Cicar di et al, 2 0 1 4 ], a misse nse m utati o n of t he plas mi n o ge n ge ne [B or k et al, 2 0 1 8 ; 
De wal d, 2 0 1 8 ], or ca us e d b y a n u n k n o w n ge netic defect [Cicar di  et al, 2 0 1 4]. A defecti ve 
m uci n -t y pe T hr 3 0 9-li n ke d gl yc os ylati o n ma y lea d t o i ncrease d c o ntact-m e diate d 
a ut oacti vati o n of z y m o ge n F XII, res ulti n g i n e xcessi ve acti vati o n of t he B K-f or mi n g 
kalli krei n - ki ni n pat h wa y [Bj ör k q vist et al, 2 0 1 5]. A Lys 31 1 Gl u s u bstit uti o n is a 
disease -ca usi ng plas mi n o ge n m utati o n w hic h ma y ca use a n irre g ular clea va ge b y F XII a a n d 
kalli krei n, t he seri ne pr oteases of t he ki ni n- f or mi n g casca d e [D e wal d, 2 0 1 8 ]. F or ot her f or ms 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
of H A E wit h C 1 -I N H, t h e u n derl yi n g pat h o p h ysi ol o g y is p o orl y u n derst o o d 
[B or k  et al, 2 0 0 0].  
Cli nicall y, H A E attac ks occ urri n g i n patie nts wit h C 1 -I N H H A E a n d H A E wit h n C 1-I N H are 
c haracteri ze d b y l ocal s w elli n g of t he s ki n (ie, e de ma of t he e xtre mities, facial e de ma, a n d 
e de ma of t he g e nitals), a b d o mi nal pai n, a n d, occasi o nall y, life -t hreate ni n g attac ks of 
lar y n geal e d e ma [B or k, 2 0 0 8 ]. T he esti mate d pre v ale nce of C 1-I N H H A E is c o m m o nl y 
re p orte d as 1: 5 0, 0 0 0, w hile t he pre val e nce of n C 1-I N H H A E is u n k n o w n [Cicar di et al, 2 0 1 0 ; 
Nasr et al, 2 0 1 6 ]. 
1. 1. 4  B ac k gr o u n d o n C S L 3 1 2  a n d R ati o n ale  f or T re at me nt of Here dit ar y 
A n gi oe de m a   
C S L 3 1 2 ( F XIIa i n hi bit or m o n ocl o nal a nti b o d y) is a f ull y h u ma n i m m u n o gl o b uli n G s u bclass 
4 (I g G 4) / la m b da rec o m bi na nt m o n ocl o nal a nti b o d y ( m A b) w hic h s pecificall y bi n ds t o t he 
catal ytic d o mai n of F XII a a n d p ote ntl y i n hi bits its catal ytic acti vit y. C S L 3 1 2 is a n 
affi nit y- mat ur e d varia nt of t he par e ntal a nti b o d y 3 F 7, w hic h was is olate d f oll o wi n g scree ni n g 
a gai nst t he β F XIIa . C S L 3 1 2 is pr o d uce d i n C hi nese ha mster o var y cells t h at ha ve bee n 
c haracteri ze d acc or di n g t o a p pl ica ble i nter n ati o nal g ui deli nes.  
Fact or XII is t he pri nci pal i nitiat or of t he plas ma c o ntact s yste m [ Re n né et al, 2 0 1 2 ], a 
pr otease casca de i n v ol vi n g t he pr otei ns F XII, F XI, plas ma pre k alli krei n, a n d t he n o n-
e nz y matic c ofact or H M W K. As s h o w n i n Fi g ure 1 , F XII is c o n verte d t o F XIIa  u p o n c o ntact 
wit h a ne gati vel y c h ar ge d s urface clea v i n g b ot h F XI a n d plas ma pre kalli krei n lea di n g t o 
se parat e pat h wa ys t hat e xert pr oc o a g ula nt a n d pr oi nfla m mat or y effects. F urt her clea va g e of 
F XIIa r eleases t he 3 0 k D a li g ht c hai n c o ntai ni n g t he catal ytic d o mai n ( β F XIIa), w hic h ca n 
acti vate t he cl assical c o m ple me nt pat h wa y.  
D uri n g ac ute H A E attac ks, B K pr o d ucti o n is i ncrease d a n d is t he me diat or of s welli n g i n 
H A E [ N uss ber ger et al, 1 9 9 8 ; N uss ber ger et al, 1 9 9 9 ]. Ac ut e a n d pr o p h ylactic treat me nts f or 
H A E ar e base d o n bl o c ki n g B K pr o d ucti o n t hr o u g h tar geti n g differe nt pr ot ei ns i n t he 
kalli krei n - ki ni n pat h wa y. Plas ma le vels of F XIIa h a ve bee n s h o w n t o i ncrease i n patie nts 
d uri n g ac ute H A E attac ks c o m pare d t o le v els d uri n g re missi o n [ Cs u ka et al, 2 0 1 5 ; 
C u g n o et al, 1 9 9 6]. Gi ve n t he i m p orta nce of F XIIa i n t he i nitiati o n of t he plas ma c o ntact 
s yste m, it is a n o vel tar get f or t he i n hi biti o n of t he kalli krei n- ki ni n pat h wa y a n d t he e xcessi ve 
pr o d ucti o n of bra d y ki ni n detecte d d uri n g H A E att ac ks. 


C S L Be hri n g, L L C
St u d y N u m ber:
C S L 3 1 2 _ 3 0 0 1
St u d y Pr o d uct:
C S L 3 1 2 ( Fact or XIIa I n hi bit or
M o n ocl o nal A nti b o d y)
Pr ot oc ol versi o n: Ori gi nal
Pa ge 2 8 of 1 1 7
Date: 0 4 A u g ust 2 0 2 0
C o nfi de ntial
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8
T he rati o nale f or e v al uati n g C S L 3 1 2 f or pr o p h yla xis t o pre ve nt H A E attac ks relies o n t he 
str o n g i n hi biti o n of F XIIa catal ytic acti vit y b y C S L 3 1 2 res ulti n g i n t he u pstrea m bl oc ki n g of 
t he c o ntact pat h w a y t hat pr o d uces B K w hic h fee ds t he ce ntral p at h o ge nic mec ha nis m of 
H A E. 
Fi g ure 1 
F act or XII a n d its R ole i n t he C o a g ul ati o n, Fi bri n ol ytic, a n d 
K alli krei n -Ki ni n S yste ms
H M W K = h i g h m olec ular wei g ht ki ni n o ge n
1. 1. 5
U n met Me dic al Nee d
I n s pite of t he gr o wi n g atte nti o n t o H A E patie nts b y t he me dical c o m m u nit y a n d 
sta ke h ol ders, t he b ur d e n of t his disease is ver y hi g h a n d q ualit y of life is still ne gati vel y 
i m pacte d. Her e ditar y a n gi oe de ma ne g ati vel y i m pacts a patie nt’s dail y-life, ps yc h o-social 
healt h, a n d pr o d ucti vit y b ot h d uri n g ti mes of attac k a n d d uri n g ti mes of re missi o n 
[Ay g ore n- P urs u n et al. 2 0 1 4 ].  
T he a vaila bilit y of pr o p h ylactic t hera pi es t hat re d uce t he fre q ue n c y a n d / or se verit y of 
attac ks has i m pr o ve d, h o we ver t here are li mitati o ns t o t he treat me nt ar ma me nt s uc h as a n 
u nfa v ora bl e si de effect pr ofile (ie, atte n uat e d a n dr o ge ns), a lac k of effect 
(ie, a nti-fi bri n ol ytics), or t he fre q u e nc y of a d mi nistrati o n (i ntra ve n o us [I V] or s u bc uta ne o us 
[S C ] C 1 -I N H). F urt her m ore, t her e are c urre ntl y n o t hera pies s pecificall y d e vel o pe d f or 
treat me nt or pr e ve nti o n of H A E attac ks d ue t o n C 1-I N H H A E. T here re mai ns a me dical nee d 
f or effecti ve a n d safe t hera pies t hat pre v e nt a n d re d uce t he diseas e b ur de n, i m pr o ve t he 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 2 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
q ualit y of life, a n d offer a c o n ve nie nt d osi n g re g i me n f or patie nts wit h H A E 
[Valerie v a  2 0 1 8]. 
C S L 3 1 2 ma y ha ve t he p ote ntial t o a d dress c urre nt u n met nee ds as a m A b wit h a n o vel 
mec ha nis m of acti o n tar g eti n g F XIIa, w hic h is ele vate d i n t he ser u m d uri n g ac ute H A E 
attac ks c o m pare d t o n or mal le vels o bser ve d d uri n g ti mes of re missi o n [ C u g n o et al. 1 9 9 6 ]. 
C S L 3 1 2 tar gets F XIIa t o i n hi bit t he kalli krei n- ki ni n pat h wa y, t here b y i n hi biti n g e xcessi ve 
pr o d ucti o n of B K, t he me diat or of s welli n g i n H A E attac ks. I n a d diti o n, t he S C r o u te of 
a d mi nistrati o n a n d o nce m o nt h l y d osi n g of C S L 3 1 2  ma y offer i m pr o ve d p atie nt c o n ve nie nce 
c o m pare d t o ot her pr o d u cts re gistere d f or pre ve nti o n of H A E attac ks. 
1. 2  I nf or m ati o n o n C S L 3 1 2  
1. 2. 1  O ver vie w  
C S L 3 1 2 (fact or XIIa i n hi bit or m o n ocl o nal a nti b o d y) is a f ull y h u ma n I g G 4 / la m b da 
rec o m bi na nt m o n ocl o nal a nti b o d y w hic h s pecificall y bi n ds t o t he catal ytic d o mai n of F XIIa 
a n d p ote ntl y i n hi bits its catal ytic acti vit y. C S L 3 1 2 is a n affi nit y- mat ure d varia nt of t he 
pare ntal a nti b o d y 3 F 7, w hic h was is olate d f oll o wi n g Scree ni n g  a g ai nst t he β F XIIa. C S L 3 1 2 
is pr o d uce d i n C hi nese h a mster o var y cells t hat ha ve bee n c haracterize d acc or di n g t o 
a p plica ble i nter n ati o nal g ui deli nes.  
A detaile d descri pti o n of t he c he mistr y, p har mac ol o g y, efficac y, a n d safet y of C S L 3 1 2 is 
pr o vi de d i n t he I n vesti gat or’s Br oc h ure. 
C S L 3 1 2 is n ot yet a p pr o ve d f or a n y i n dicati o n i n a n y c o u ntr y. 
1. 2. 2  N o ncli nic al E v al u ati o n  
T he n o n-cli nical pr o gra m c o n d ucte d t o s u p p ort de vel o p me nt of C S L 3 1 2 i ncl u de d 
p har mac ol o gical, p har mac o ki netic ( P K), a n d t o xic ol o gical st u dies perf or me d i n 
p har mac ol o gicall y rele va nt s pecies t hat are descri be d i n t he C S L 3 1 2i n vesti gat or’s br oc h ure.  
1. 2. 3  C li nic al E x perie nce  
1. 2. 3. 1  He alt h y S u bjects  
O ne ra n d o mize d, d o u ble- bli n d, place b o-c o ntr olle d, si n gle asce n di n g d ose, p hase 1 st u d y was 
c o n d ucte d i n healt h y v ol u nteers. D uri n g t his st u d y ( C S L 3 1 2 _ 1 0 0 1), t he safet y a n d 
t olera bilit y, a n d P K of escalati n g d oses of C S L 3 1 2 were assesse d after si n gle I V or S C 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
i njecti o ns of u p t o 1 0 m g / k g i n healt h y male s u bjects. C S L 3 1 2 ha d a n  acce pta ble safet y a n d 
t olera bilit y pr ofile. D uri n g t he st u d y t here were n o seri o us a d vers e e v e nts ( S A Es); n o 
wit h dra wals d ue t o a d v erse e ve nts ( A Es); n o t hr o m b oe m b olic e ve nts ( T E Es), blee di n g 
e ve nts, or cases of a na p h yla xis; n o cli nicall y si g nifica nt a b n or m al tre n ds i n he mat ol o g y or 
cli nical c he mistr y assess me nts. T he maj orit y of all A Es were of mil d i nte nsit y. I njecti o n site 
reacti o ns (I S Rs) were m ore c o m m o n wit h S C C S L 3 1 2 t ha n S C place b o, b ut t here was n o 
a p pare nt d os e de pe n d e nce. A d diti o nall y, C S L 3 1 2 e xhi bite d  li near P K wit h a half-life 
~ 1 9  da ys. T he st u d y r es ults are descri be d i n greater detail i n t he C S L 3 1 2 i n vesti gat or’s 
br oc h ure. 
1. 2. 3. 2  S u bjects wit h Here dit ar y A n gi oe de m a  
O ne  cli nical st u d y wit h C S L 3 1 2 is o n g oi n g i n s u bjects wit h H A E.  
C S L 3 1 2 _ 2 0 0 1 is a n o n g oi n g m ultice nter, ra n d o mize d, place b o- c o ntr olle d, parallel -ar m, 
p hase 2 , d ose r a n gi n g ( 7 5 m g, 2 0 0 m g, a n d 6 0 0 m g) st u d y t o i n vesti gate t he efficac y, P K, a n d 
safet y of C S L 3 1 2 S C a d mi nistere d e ver y 4 w ee ks  as pr o p h yla xis t o pre ve nt H A E attac ks i n 
s u bjects wit h C 1 -I N H H A E or F XII/ Plas mi n o ge n H A E. T he st u d y c o nsists of a Scree ni n g 
Peri o d, a R u n-i n Peri o d, 2 Treat me nt Peri o ds ( Treat me nt Peri o d 1 [ T P 1 ] 
[ 2 parts:  1 d o u ble- bli n d p art a n d 1 o pe n-la bel part] a n d o pe n-la b el Treat me nt Peri o d 2 
[T P 2 ]), a n d a F oll o w- up Peri o d. After t he R u n -i n Peri o d, eli gi ble s u bjects wit h  C 1 -I N H H A E 
were ra n d o mize d t o 1 of 4 treat me nt gr o u ps ( place b o, or 7 5 m g, 2 0 0 m g, or 6 0 0 m g C S L 3 1 2 ) 
i n d o u ble- bli n d T P 1. S u bjects recei ve d a si n gle I V l oa di n g d ose of i n vesti gati o nal pr o d uct 
f oll o we d 1 wee k later b y a si n gle S C i njecti o n of i n vesti gati o nal pr o d uct o n ce e v er y 4  wee ks 
f or 1 2 wee ks  (f or a t otal of 1 3 wee ks). I n o pe n-la bel T P2, s u bjects recei ve a si n gle 
S C  i njecti o n of eit her 2 0 0 m g or 6 0 0 m g C S L 3 1 2 e ver y 4 w ee ks (f or a t otal of 4 4 wee ks). 
C urre ntl y t he st u d y is o n g oi n g a n d t he ra n d o mize d, d o u ble- bli n de d part of T P 1 has bee n 
c o m plete d.  
A t otal of 3 2 patie nts wit h C 1 -I N H H A E t y pe 1 or t y pe 2 were e nr olle d i n t he ra n d o mize d 
d o u ble- bli n d treat me nt ar ms of T P 1 at 2 0 st u d y sites acr oss 5 c o u ntries. I nt eri m res ults fr o m 
T P 1 de m o nstrate t hat C S L 3 1 2 is safe a n d w ell t olerate d at all 3 d oses a n d has a n o verall 
fa v ora bl e saf et y pr ofile. All 3 d ose le vels of C S L 3 1 2 S C e ver y 4 wee ks ac hie ve d cli nicall y 
mea ni n gf ul re d u cti o n i n t he H A E attac k r at e c o m p are d t o place b o.  T h e m ost fre q ue nt A Es 
were n o n -seri o us I S Rs (i e, i njecti o n site er yt he ma, pr urit us, s welli n g, a n d disc o mf ort) t hat 
were mil d or m o der ate i n se verit y . N o S A Es or A Es of s pecial i nterest ( A E SIs , se vere 
h y perse nsiti vit y a n d a na p h yla xis, T E Es , blee di n g e ve nts) were re p orte d.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
N o differe nce i n t he P K of C S L 3 1 2 was n ote d bet wee n healt h y s u bjects i n 
St u d y C S L 3 1 2 _ 1 0 0 1 a n d s u bjects wit h H A E i n St u d y C S L 3 1 2 _ 2 0 0 1. 
All eli gi ble s u bjects w h o s uccessf ull y c o m plete St u d y C S L 3 1 2 _ 2 0 0 1 ma y ha ve t he 
o p p ort u nit y t o e nr oll i n a n o pe n-la bel p has e 3 b  st u d y of C S L 3 1 2 i n s u bjects wit h H A E 
( C S L 3 1 2 _ 3 0 0 2).  
1. 3  St u d y O ver vie w  
C S L 3 1 2 _ 3 0 0 1 is a m ultice nter, ra n d o mize d, place b o-c o ntr olle d, parallel-ar m, p hase 3 st u d y 
t o i n vesti gate t he cli nical efficac y a n d safet y of s u bc uta ne o usl y a d mi nistere d C S L 3 1 2 as 
pr o p h yla xis t o pre ve nt H A E attac ks i n s u bjects wit h C 1-I N H H A E t y pe 1 or t y pe 2. 
Secti o n  3. 1  prese nts a det aile d o ver vie w of t he st u d y.  
1. 4  P ote nti al R is ks a n d B e nefits  
C S L 3 1 2 is a f ull y h u ma n m A b  t hat i n hi bits F XII a acti vit y. C S L 3 1 2 is bei n g de vel o pe d f or 
r o uti ne pr o p h yla xis t o pr e ve nt H A E attac ks i n s u bjects wit h C 1 -I N H H A E t y pe 1 or t y pe 2, 
as well as t o assess t he b e nefit of I V i nf usi o n of C S L 3 1 2 i n patie nts wit h C O VI D 1 9 . I n t he 
c urre nt st u d y, C S L 3 1 2 will be s u bc uta ne o usl y ad mi nistere d o nce m o nt hl y t o s u bjects 
e x perie n ci n g rec urr e nt H A E attac ks.  
Be nefits  
A p ote ntial be nefit of t his st u d y is t he re d ucti o n i n fre q ue n c y of attac ks a n d pre ve nti o n of 
attac ks i n s u bjects wit h H A E b y i n hi biti n g t he attac k -ca usi n g defecti ve pat h wa ys. C S L 3 1 2 
tar gets t he i nitiati o n of t he kalli krei n- ki ni n pat h wa y b y acti n g as a n i n hi bit or t o F XIIa, 
aff ecti n g t he re g ul ati o n of B K f or mati o n a n d t h us i n hi biti n g e xcessi ve B K ge nerati o n 
res ulti n g i n t he pre ve nti o n of H A E attac ks.  
Ris ks  
T he f oll o wi n g ris ks ha ve n ot bee n o bser v e d i n t he de vel o p me nt pr o gra m of C S L 3 1 2, b ut are 
p ote ntial ris ks base d o n t he dr u g class a n d/ or t he m o de of acti o n :   
T hr o m b oe m b olic E ve nts a n d Blee di n g:  B y bl oc ki n g F XIIa wit h C S L 3 1 2, t here ma y be a 
p ote ntial ris k of blee di n g or T E Es d ue t o altere d h e m ostasis, u nsta ble cl ot f or mati o n, or 
i m paire d cl ot brea k d o w n. I n a d diti o n, beca us e of t he p har mac ol o gical acti o n of C S L 3 1 2, a 
pr ol o n gati o n of acti vate d partial t hr o m b o plasti n ti me (a P T T) is e x pecte d t o be o bser ve d i n a 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
d ose- de pe n d e nt ma n n er. Cli nical e x perie nce wit h C S L 3 1 2 wit h healt h y v ol u nteers i n t he 
p hase 1 st u d y C S L 3 1 2 _ 1 0 0 1 a n d s u bjects wit h H A E i n t he o n- g oi n g p hase 2 st u d y 
C S L 3 1 2 _ 2 0 0 1 di d n ot s h o w a n effect o n eit her pr ot hr o m bi n ti me or a b n or mal blee di n g . T his 
is c o nsiste nt wit h t he o bser vati o n t hat patie nts w h o ha ve c o n g e nital deficie nc y of F XII d o n ot 
e x hi bit a blee di n g p he n ot y pe, des pite ha vi n g a pr ol o n ge d a P T T [ La m mle et al, 1 9 9 1 ; Rat n off 
a n d C ol o p y, 1 9 5 5 ]. I n a d diti o n, n o ncli nical st u dies i n mice a n d ra b bits s h o we d n o i m pair me nt 
i n he m ostasis f oll o wi n g i n hi biti o n of F XIIa [Larss o n et al, 2 0 1 4 ]. Ne v ert hel ess, s u bjects will 
be m o nit ore d caref ull y f or si g ns of t hr o m b osis or blee di n g d uri n g t he st u d y.  
Se vere H y perse nsiti vit y / A n a p h yl actic -t y pe Re acti o ns: A d mi nist rati o n of t hera p e utic 
pr otei ns i ncl u di n g m A bs  s uc h as C S L 3 1 2 is p ote ntiall y ass ociate d wit h t he ris k of se vere 
h y perse nsiti vit y a n d a na p h ylactic reacti o ns, s o me of w hic h ca n be seri o us a n d life 
t hreate ni n g. A p pr o priat e preca uti o ns will be ta k e n w he n C S L 3 1 2 is a d mi nistere d at t he st u d y 
site, wit h vi gila nt m o nit ori n g f or p ote ntial se vere h y perse nsiti vit y a n d a na p h ylactic reacti o ns. 
A d mi nistrati o n of C S L 3 1 2 , at least t he first 2 t o 3 d oses, will be perf or me d at t he site u n der 
me dical s u per visi o n wit h i m me diate access t o e mer ge nc y e q ui p me nt a n d m e dicati o n f or 
treat me nt of se v ere h y p erse nsiti vit y a d verse reacti o ns i ncl u di n g a na p h yla xis. S u bjects will be 
i nf or me d of t he earl y si g ns of h y perse nsiti vit y reacti o ns i ncl u di n g hi ves, ge neralize d 
urticaria, ti g ht ness of t he c hest, w heezi n g, h y p ote nsi o n, a n d a na p h yla xis.  
I m m u n o ge nicit y ( a nti-dr u g a nti b o dies):  All pr otei n t hera pe utics are p ot e ntiall y 
i m m u n o ge nic. Beca use C S L 3 1 2 is a pr otei n, it has t he p ote ntial t o ca use t he de vel o p me nt of 
a nti- dr u g a nti b o dies. T he de vel o p me nt of a nti- dr u g a nti b o dies t hr o u g h o ut t he st u d y will be 
m o nit ore d.  
I n b ot h t he p hase 1 st u d y C S L 3 1 2 _ 1 0 0 1 a n d T P 1 of t he p hase 2 st u d y C S L 3 1 2 _ 2 0 0 1, n o 
S A Es were r e p orte d. A d diti o nall y, n o A E SIs were re p orte d  t he p h ase 2 st u d y C S L 3 1 2 _ 2 0 0 1. 
T here w ere n o d os e de p e n de nt safet y c o n cer ns i n eit her st u d y. 
Gi ve n t he p ote ntial be nefit of C S L 3 1 2 f or s u bjects wit h H A E, as well as t he fa v ora bl e safet y 
data of C S L 3 1 2 fr o m t he p hase 1 st u d y ( C S L 3 1 2 _ 1 0 0 1) a n d t he o n g oi n g p hase 2 st u d y 
( C S L 3 1 2 _ 2 0 0 1), t he ass ociate d be n efit-ris k assess me nt is c o nsi dere d acce pta ble f or s u bjects 
w h o partici pate i n st u d y C S L 3 1 2 _ 3 0 0 1. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2  S t u d y Objecti ves  a n d  En d p oi nts  
2. 1  Pri m ar y O bjecti ve a n d E n d p oi nt  
2. 1. 1  Pri m ar y Effic ac y O bjecti ve 
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he efficac y of S C a d mi nistrati o n of 
C S L 3 1 2 as pr o p h yla xis t o pre ve nt H A E attac ks i n s u bjects wit h H A E. 
2. 1. 2  Pri m ar y Effic ac y E n d p oi nt  
E n d p oi nt  
S u m m ar y Me as ure  
T i me-n or malize d n u m ber of here ditar y a n gi oe de ma (H A E ) attac ks 
d uri n g treat me nt fr o m Da y 1 t hr o u g h Da y 1 8 2  a 
T he ti me -n or malize d n u m ber of 
H A E attac ks  ( per m o nt h a n d 
a n n ualize d ) i n s u bjects treate d 
o nce a m o nt h wit h eit her C S L 3 1 2  
(Acti ve Ar m ) or  place b o (Pla ce b o  
Ar m ) d uri n g t he  peri o d fr o m Da y 
1 t hr o u g h Da y 1 8 2  ( 6 m o nt hs) . 
a 
O nl y i n vesti gat or -c o nfir me d H A E attac ks base d o n t he i n vesti gat or’s assess me nt of s u bject-re p orte d 
s y m pt o ms will be i ncl u de d i n t he a nal ysis of pri mar y efficac y e n d p oi nt . Descri pti o ns of  c o nfir me d H A E 
attac k are pr o vi de d i n  Secti o n  8. 1. 3  a n d A p pe n di x 2 . 
2. 2  Sec o n d ar y O bjecti ves  a n d E n d p oi nts  
2. 2. 1  Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bjecti ves of t he st u d y are: 
1.  To c har acteri ze t he cli nical effi cac y of S C C S L 3 1 2 i n t he pr o p h ylactic treat me nt of 
H A E.  
2.  To  e val uate t he s afet y of S C C S L 3 1 2 i n t he pr o p h ylactic treat me nt of H A E. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 2. 2  Sec o n d ar y E n d p oi nts  
Sec o n d ar y 
O bjecti ve  
E n d p oi nt  
S u m m ar y Me as ure (s) 
Efficac y E n d p oi nts  
1 
T he re d ucti o n i n t he attac k rate d uri n g t he 
Treat me nt Peri o d c o m pare d t o t he R u n -i n Peri o d  
T he perce nta ge re d ucti o n (at least ≥ 5 0 % 
≥ 7 0 %, ≥ 9 0 or e q ual t o 1 0 0 % [attac k 
free]) i n t he ti me-n or malize d n u m ber of 
H A E attac ks i n s u bjects treate d o nce a 
m o nt h wi t h eit her C S L 3 1 2 ( Acti ve Ar m) 
or place b o ( Place b o Ar m) d uri n g t he 
peri o d fr o m Da y 1 t hr o u g h Da y 1 8 2 
( 6 m o nt hs) c o m pare d t o t he R u n -i n 
Peri o d , as well as f or t he first 3-m o nt h 
ti me peri o d a n d f or t he sec o n d 3-m o nt h 
ti me peri o d of t he Acti ve a n d Place b o 
Ar ms  c o m pare d t o t he R u n -i n Peri o d. 
1 
T he ti me -n or malize d n u m ber of H A E attac ks 
re q uiri n g o n-de ma n d treat me nt  
T he ti me -n or malize d n u m ber ( per m o nt h 
a n d a n n ualize d) of H A E attac ks re q uiri n g 
o n -de ma n d treat me nt i n s u bjects treate d 
o nce a m o nt h wit h eit her C S L 3 1 2 ( Acti ve 
Ar m) or place b o ( Place b o Ar m) d uri n g t he 
peri o d fr o m Da y 1 t hr o u g h Da y  1 8 2 
( 6 m o nt hs) , as well as f or t he first 3-m o nt h 
ti me peri o d a n d f or t he sec o n d 3-m o nt h 
ti me peri o d of t he Acti ve a n d Place b o 
Ar ms . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Sec o n d ar y 
O bjecti ve  
E n d p oi nt  
S u m m ar y Me as ure (s) 
1 
T he ti me -n or malize d n u m ber of m o derate 
an d  / or se vere H A E attac ks  
T he ti me-n or malize d n u m ber ( per m o nt h 
a n d a n n ualize d) of m o derate a n d  / or 
se vere H A E attac ks i n s u bjects treate d 
o nce a m o nt h wit h eit her C S L 3 1 2 ( Acti ve 
Ar m) or place b o ( Place b o Ar m) d uri n g t he 
peri o d fr o m Da y 1 t hr o u g h Da y 1 8 2 
( 6 m o nt hs) , as well as f or t he first 3-m o nt h 
ti me peri o d a n d f or t he sec o n d 3-m o nt h 
ti me peri o d of t he Acti ve a n d Place b o 
Ar ms . 
1 
Ti me -n or malize d n u m ber of H A E attac ks at 
vari o us ti me p oi nts d uri n g t he treat me nt peri o d  
T he ti me -n or malize d n u m ber of H A E 
attac ks ( per m o nt h a n d a n n ualize d) i n 
s u bjects treate d o nce m o nt hl y wit h eit her 
C S L 3 1 2 ( Acti ve Ar m) or place b o 
( Place b o Ar m) d uri n g t he first 3-m o nt h 
ti me peri o d a n d t he sec o n d 3-m o nt h ti me 
peri o d of  C S L 3 1 2 ( Acti ve Ar m) a n d 
place b o ( Place b o Ar m).  
T he perce nta ge re d ucti o n will be 
calc ulate d f or t he ti me -n or malize d n u m ber 
of H A E attac ks bet wee n t he Acti ve Ar m 
a n d t he Place b o Ar m f or t he 6 -m o nt h 
treat me nt peri o d, as well as f or t he first 
3 m o nt hs a n d t he sec o n d 3 m o nt hs of t he  
treat me nt peri o d. 
1 
S u bject’s Gl o bal Assess me nt of Res p o nse t o 
T hera p y (S G A R T ) 
C o m paris o n of t he distri b uti o n of 
res p o nses t o t hera p y bet wee n C S L 3 1 2 a n d 
place b o at t he e n d of t he Treat me nt Peri o d 
( Da y 1 8 2 or Da y 9 1 if disc o nti n uati o n 
occ urs bef ore Da y 1 8 2) base d o n t he 
pr o p orti o ns of s u bjects wit h a " e xcelle nt, 
g o o d , fair, p o or or  n o ne " res p o nse t o 
t hera p y. 
Safet y E n d p oi nts  
2 
•  
A Es  
•  
A E SIs  
•  
S A Es   
•  
C S L 3 1 2 i n d uce d a nti-C S L 3 1 2 a nti b o dies  
•  
Cli nicall y si g nifica nt a b n or malities i n 
la b orat or y assess me nts (ie, la b orat or y 
a b n or malities re p orte d as A Es).  
T he n u m ber a n d perce nta ge of s u bjects 
e x perie nci n g t he s pecifie d safet y e ve nts 
o n treat me nt wit h C S L 3 1 2 or place b o 
d uri n g t he e ntire Treat me nt P eri o d u ntil 
F oll o w -u p or Fi nal Visit .  
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 3  E x pl or at or y O bjecti ve a n d E n d p oi nts  
2. 3. 1  E x pl or at or y O bjecti ve  
T he e x pl orat or y o bj ecti v e  of t his st u d y is t o f urt her e val uate t h e efficac y, 
P K  / p har mac o d y na mics ( P D ), a n d q ualit y of life ( Q o L ) ass ociat e d wit h t he use of C S L 3 1 2 i n 
s u bjects wit h H A E. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 3. 2   Ex pl or at or y E n d p oi nts  
E x pl orat or y e n d p oi nts i ncl u de t he f oll o wi n g: 
1.  T he ti me t o first attac k after Da y 1 a n d after Da y 1 5 . 
2.  C S L 3 1 2 c o nce ntrati o n s at sc he d ule d ti me p oi nts. 
3.  F XII c o nce ntrati o n a n d F XIIa -me diate d kalli krei n acti vit y  at sc he d ule d ti me p oi nts. 
4.  S u bject re p orte d o utc o m e meas ures:  
•  A n gi oe de ma Q u alit y of Life ( A E -Q o L ) 
•  E ur o Q o L- Gr o u p 5- Di me nsi o n  5-Le vel  ( E Q- 5 D-5 L )  
•  Wor k Pr o d ucti vit y a n d A cti vit y I m pair me nt: Ge neral Healt h  (  W P A I:G H ). 
5.  I n vesti gat or’s Gl o bal Ass ess me nt of Res p o nse t o T hera p y (I G A R T). 
3  St u d y Desi g n  a n d O versi g ht  
3. 1  O ver all  Desi g n  
T his is a m ultice nter, d o u ble- bli n d, ra n d o mize d, pl ace b o-c o ntr olle d, parallel-ar m, p hase 3 
st u d y t o i n vesti gate t he efficac y a n d safet y of a si n gle d ose of S C C S L 3 1 2 a d mi nistere d o nce 
m o nt h l y as pr o p h yla xis t o pre ve nt H A E attac ks i n a d olesce nt ( 1 2 t o 1 7 y ears, i ncl usi ve) a n d 
a d ult s u bjects wit h H A E.  T his st u d y will be c o n d ucte d gl o ball y. As s h o w n i n Fi g u re 2 , t he 
st u d y c o nsists of a Scree ni n g Peri o d ( u p t o 1 m o nt h), a R u n-i n Peri o d ( u p t o 2 m o nt hs), 
1 Treat me nt Peri o d ( 6 m o nt hs), a n d eit her a 2- m o nt h F oll o w- u p Peri o d ( ie, 3 m o nt hs after 
last i n vesti gati o nal pr o d uct a d mi nistrati o n ) or e ntr y i nt o t he o pe n-la bel P hase 3 b St u d y 
C S L 3 1 2 _ 3 0 0 2. 




C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 3 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
S u bjects are n ot per mitte d t o use r o uti ne pr o p h yla xis t o pre ve nt H A E attac ks d uri n g t he 
R u n-i n Peri o d ( Secti o n 7. 3 ); h o we ver, s u bj ects ma y use o n- de ma n d H A E t h era p y t o treat 
H A E attac ks if t hat me di cati o n has pre vi o usl y bee n s h o w n t o be effecti ve ( Secti o n  7. 2 ). 
S u bjects w h o d o n ot meet t he mi ni m u m H A E attac k rate d uri n g t he R u n-i n Peri o d or are 
ot her wise deter mi ne d t o be i neli gi ble d ue t o Scree ni n g  assess me nts, will be c o nsi dere d 
R u n-i n fail ures a n d will n ot be all o we d t o be rescree ne d f or partici pati o n i n t he st u d y. 
3. 1. 3  Tre at me nt Peri o d  
S u bjects meeti n g t he eli gi bilit y criteria ( Secti o n 4. 1. 3 ) will e nter t he Treat me nt Peri o d after 
t he R u n-i n Peri o d. If a s u bject is u na ble t o e nter t h e Treat me nt Peri o d b y D a y 6 0, t he n 
C S L  Be hri n g (C S L ) a p pr o val is re q uire d f or t he s u bject t o e nter the Treat me nt Peri o d.  
Eli gi ble s u bjects will be ra n d o mize d 3: 2 t o eit her t he C S L 3 1 2 Acti ve Ar m or t he Place b o  
Ar m. T he d ur ati o n of t he Treat me nt Peri o d is 6 m o nt hs. Ra n d o mizati o n will ta ke a ge 
( ≤ 1 7 years, > 1 7 years) a n d, f or a d ults, baseli ne atta c k rate obs er ve d d uri n g t he R u n-i n 
Peri o d ( 1 t o < 3 attac ks / m o nt h, a n d ≥ 3 attac ks / m o nt h) i nt o acc o u nt.  
3. 1. 4  F oll o w -U p Peri o d  / O pe n-l a bel P h ase 3 b  St u d y E ntr y  
S u bjects w h o s uccessf ull y c o m plete t he c urre nt st u d y ( C S L 3 1 2 _ 3 0 0 1) ma y ha ve t he o pti o n t o 
r oll o ver i nt o a n o pe n-la b el phase 3 b St u d y C S L 3 1 2 _ 3 0 0 2. S u bjects w h o c h o ose n ot t o 
partici pate i n St u d y C S L 3 1 2 _ 3 0 0 2 are re q uire d t o c o m plete t he F oll o w- u p Visit ( Da y 2 4 2, 
w hic h is a p pr o xi matel y 3◦m o nt hs after t he last d os e of i n vesti gati o nal pr o d uct). F or s u bjects 
w h o c h o ose t o partici p ate i n St u d y◦C S L 3 1 2 _ 3 0 0 2, assess me nts c ollecte d o n Da y 1 8 2 will be 
use d t o f ulfill a p plica ble assess me nts f or D a y◦1 of St u d y C S L 3 1 2 _ 3 0 0 2. 
Details of o pe n- la b el phase 3 b St u d y C S L 3 1 2 _ 3 0 0 2 are des cri be d i n a s e p arate pr ot oc ol.  
3. 2  D ose a n d D osi n g Re gi me n  
T he i n vesti gati o nal pr o d ucts i n t his st u d y are 2 0 0 m g C S L 3 1 2 a n d place b o.  
S u bjects ra n d o mize d t o t he Acti ve Ar m will recei ve C S L 3 1 2 S C o nce a m o nt h f or 6 m o nt hs. 
T he first d ose of C S L 3 1 2 will be a 4 0 0 m g l oa di n g d ose a d mi nistere d s u bc uta ne o usl y o n t he 
sa me da y as 2 s e par ate i njecti o ns at t he st u d y site (ie, M o nt h 1). S u bse q ue nt d oses of C S L 3 1 2 
will be 2 0 0 m g a d mi nistere d S C o nce m o nt h l y f or 5 c o nsec uti ve m o nt hs (ie, M o nt hs 2 
t hr o u g h 6). 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
S u bjects ra n d o mize d t o t he Place b o  Ar m will recei ve  v ol u me-matc he d place b o  o nce m o nt hl y 
f or 6 m o nt hs. T he first d ose of place b o i n t he Place b o  Ar m will be v ol u me -matc he d place b o 
a d mi nistere d S C  as 2 se parate i njecti o ns (ie, M o nt h 1). S u bjects will t he n recei ve 
v ol u me- matc he d place b o S C o nce a m o nt h f or 5 c o nsec uti ve m o nt hs (ie, M o nt hs 2 
t hr o u g h 6).  
3. 3  Scie ntific R ati o n ale  
3. 3. 1  St u d y Desi g n  R ati o n ale  
T his p hase 3, m ultice nter, d o u ble- bli n d, ra n d o mize d, place b o- c o ntr olle d, p arallel -ar m st u d y 
will i n vesti g ate t he efficac y a n d saf et y of o nce m o nt hl y S C d osi n g re gi me n of C S L 3 1 2 f or 
t he pre ve nti o n of H A E attac ks i n a d olesce nt (ie, 1 2 t o 1 7 years of a ge i ncl usi ve) a n d a d ult 
s u bjects wit h C 1 -I N H H A E t y pe 1 a n d t y pe 2. 
T he st u d y will i ncl u de a Scree ni n g Peri o d ( u p t o 1 m o nt h) t o assess s u bject eli gi bilit y, a 
R u n-i n Peri o d ( u p t o 2 m o nt hs) f or c o nfir m ati o n of disease acti vit y a n d det er mi nati o n of 
s u bjects’ baseli ne H A E attac k rate, 1 Treat me nt Peri o d ( 6  m o nt hs) f or c o nfir mati o n of t he 
safet y a n d effi cac y of t he 2 0 0 m g C S L 3 1 2 d ose, a n d a 2- m o nt h F oll o w- u p Peri o d ( 3 m o nt hs 
after t he l ast a d mi nistrati o n of i n vesti gati o nal pr o d uct).  
3. 3. 2  D ose  R ati o n ale  
T he pr o p ose d d ose of 2 0 0 m g was selecte d b ase d o n t he effi cac y a n d safet y o bser ve d i n T P 1 
of St u d y C S L 3 1 2 _ 2 0 0 1, C S L 3 1 2 P K, i n hi biti o n of F XIIa -m e diate d kalli krei n acti vit y, a n d 
e x p os ure- res p o nse ( E-R) m o deli n g.  
T he 2 0 0 m g d ose a d mi nistere d o nce e ver y 2 8 da ys ( ± 3 da ys) was hi g hl y effecti ve acr oss 
vari o us efficac y e n d p oi nts a n d ha d a fa v ora ble safet y pr ofile. I n a d diti o n, t he 2 0 0 m g d o se 
res ulte d i n ~ 5 0 % i n hi biti o n of F XIIa-m e diate d kalli krei n acti vit y.  
To s u p p ort p hase 3 d ose selecti o n, a n E- R m o del was use d t o si m ulate H A E attac k  rates o ver 
a wi de ra n g e of C S L 3 1 2 c o nce ntr ati o ns t hat w o ul d be e x pecte d aft er differe nt d osi n g 
re gi me ns. Base d o n t he E-R m o del, t he esti mate d dail y a vera g e c o n ce ntrati o ns t o ac hie ve 5 0, 
7 5, a n d 9 0 % rel ati ve attac k ris k re d ucti o n i n t he b aseli ne attac k rate w ere 1. 4, 3. 3, a n d 7. 8 
µ g/ m L, res pecti vel y. T he me dia n pre dicte d mi ni m u m dail y a vera g e C S L 3 1 2 c o nce ntrat i o ns 
at stea d y-state f oll o wi n g 2 0 0 m g S C o nce a m o nt h re gi me n c orres p o n ds t o t he 9 0 % rel ati ve 
attac k ris k re d u cti o n i n baseli ne attac k rate i n 7 3 % of patie nts.   


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A d diti o nall y, t he E- R m o del s h o we d a c u m ulati ve effect of C S L 3 1 2 c o nce ntrati o n is 
e vi de nce d i n  t he re d ucti o n i n t he e x pecte d n u m b er of H A E attac ks per m o nt h. T he 2 0 0 m g 
S C o nce a m o nt h re gi me n is pre dicte d t o re d u ce t he mea n attac k rat e b y a p pr o xi matel y 9 1 % 
c o m pare d t o  place b o. I n creasi n g t he d ose b e y o n d 2 0 0 m g is n ot pre dicte d t o res ult i n 
si g nifica nt f urt her re d ucti o ns i n H A E attac ks. 
Fi nall y, t he e x p os ures at t he 2 0 0 m g S C d ose a d mi nistere d m o nt hl y are n ot e x pecte d t o ca use 
a P T T pr ol o n gati o n i n t he maj orit y of s u bjects i n t he p hase 3 st u d y. 
Base d o n all t he fact ors ta ke n i nt o c o nsi derati o n i n selecti n g a d ose f or a d v a nci n g t he 
C L S 3 1 2 cli nical pr o gra m, t he 2 0 0 m g of C S L 3 1 2 S C a d mi nistere d o nce m o nt h l y is e x pecte d 
t o ac hie ve cli nicall y mea ni n gf ul treat me nt effect a n d o pti mal be nefit/ris k rati o i n s u bjects 
wit h C 1 -I N H H A E t y pe 1 a n d t y pe 2.  
3. 4  Pl a n ne d St u d y D ur ati o n  
T he d urati o n of t he st u d y f or a n i n di vi d ual s u bject is e x pecte d t o be a p pr o xi matel y 7 t o 
1 1  m o nt hs. T his esti mati o n is base d o n: 
•  A S creeni n g P eri o d of u p t o 1 m o nt h. 
•  A R u n -i n Peri o d of 1 t o 2 m o nt hs ( R u n-i n ca n occ ur o n t he sa me da y as Scree ni n g ). 
•  A T reat me nt P eri o d of 6  m o nt hs.  
•  A F oll o w- u p Peri o d of 2 m o nt hs (ie, 3 m o nt hs after t he last a d mi nistrati o n of 
i n vesti gati o nal pr o d uct). 
T he o ver all st u d y d urati o n (ie, first s u bject’s Scree ni n g V isit t o last s u bject’s E n d of St u d y 
V isit) will be a p pr o xi matel y 1 9 m o nt hs. 
3. 5  Pl a n ne d N u m ber of S u bjects  
T h is st u d y will ra n d o mize a p pr o xi matel y 6 0 s u bjects wit h C 1 -I N H H A E t y pe 1 or t y pe 2.  
3. 6  Defi niti o n of St art of t he Cli nic al St u d y  
T he start of t he cli nical st u d y is defi ne d as t he dat e of t he first act of recr uit me nt of a 
p ote ntial s u bject at a st u d y site.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
3. 7  Defi niti o n of E n d of  t he Cli nic al St u d y  
T he e n d of t he cli nical st u d y (ie, c o m pleti o n of t h e st u d y at all partici pati n g st u d y sites)  is 
defi ne d as eit her t he dat e of t he last visit of t he last s u bject at t heir F oll o w-u p Visit 
(ie, Da y  2 4 2) or t he date of t he last s u bject’s e nr oll me nt i nt o t he o pe n-la bel phase 3 b St u d y 
C S L 3 1 2 _ 3 0 0 2. 
3. 8  St u d y O versi g ht  
3. 8. 1  I n de pe n de nt D at a M o nit ori n g C o m mittee   
A n i n de pe n de nt dat a m o nit ori n g c o m mittee (I D M C)  will be esta blis he d t o m o nit or t he safet y 
a n d efficac y data g e ner ate d d uri n g t he st u d y. T he ID M C will c o nsist of a n i n de pe n de nt 
statisticia n a n d cli nical s pecialists i n t he fiel ds of H A E  ma na ge m e nt, w h o als o ha ve 
e x perie n ce i n cli nical trials. T he I D M C will re vie w acc u m ulati n g dat a fr o m t he o n g oi n g 
st u d y. Base d o n t hese re vie ws, t he I D M C will a d vise o n t he f urt her c o n d uct of t he st u d y. N o 
s uccess or f utilit y t hres h ol ds will be set f or t he ID M C re vie ws; C S L  will n ot st o p t he st u d y 
u nless a maj or saf et y iss ue has bee n i d e ntifie d. T h e c o m p ositi o n, acti vities, a n d 
res p o nsi bilities of t he ID M C will be descri be d se p aratel y i n t he ID M C c harter . 
3. 9  H alti n g Criteri a  
3. 9. 1  St u d y H alti n g  Criteri a  
I n di vi d u al S u bject 
If a s u bject meets a n y of t he f oll o wi n g criteria d uri n g partici pati o n i n t he st u d y, t he n f urt her 
a d mi nistrati o n of C S L 3 1 2  t o t hat s u bject will be halte d (i.e., te m p oraril y pa use d) u ntil a n 
assess me nt of t hat s u bject’s safet y is c o m plete d: Pr ol o n ge d s y m pt o m s of se vere 
h y perse nsiti vit y c o nsi der e d b y t he i n vesti gat or a n d/ or C S L t o be relate d wit h C S L 3 1 2 
a d mi nistrati o n; a c o nfir me d dia g n osis of T E E or a cli nicall y si g nifica nt a b n or mal blee di n g 
e ve nt, irres p ecti ve of C S L 3 1 2 ca usalit y; or a n y e v e nt or la b orat or y a b n or m alit y t hat is 
c o nsi dere d b y t he i n v esti gat or a n d/ or C S L t o p ose a n u nacce pta ble ris k t o t he s u bject i n t he 
st u d y.  
St u d y Le vel  
If a n y of t he f oll o wi n g criteria ar e met, t he n all f urt her a d mi nistrati o n of i n vesti gati o nal 
pr o d uct a n d f urt her e nr ol me nt of ne w s u bjects will be halte d (ie, te m p oraril y pa use d) u ntil a n 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
assess me nt of t he o verall  safet y of c o nti n ui n g t he st u d y is c o m plete d: 1 s u bject de vel o ps a n 
S A E t hat res ults i n deat h a n d is c o nsi dere d b y t he i n vesti gat or, I D M C a n d / or C S L t o be 
relate d to t he a d mi nistrati o n of C S L 3 1 2 ; or 1 s u bject de vel o ps a n y e ve nt t h at is dee me d t o 
p ose a n u nacce pta bl e ris k t o ot her s u bjects i n t he st u d y, a n d t hese e ve nts are c o nsi dere d b y 
t he i n vesti gat or, I D M C a n d / or C S L B t o be relate d t o t he a d mi nistrati o n of C S L 3 1 2. 
If a n y st u d y halti n g criteria are met a n d t he st u d y is halte d per I D M C rec o m me n dati o n, t he 
C S L Gl o bal Safet y C o m mittees will c o n d uct a safet y assess me nt t o esta blis h if t he st u d y 
s h o ul d be res u me d or if t he te m p orar y h alt s h o ul d c o nti n ue. T he st u d y ca n be res u me d o n t he 
rec o m me n dati o n of C S L’s Gl o bal Safet y C o m mittees, i n a gree me nt wit h t h e I D M C, if t he 
safet y assess me nt c o ncl u des t hat n o f urt her st u d y m o dificati o ns, pr ot oc ol a me n d me nts, or 
ris k miti gati o n meas ures are necessar y a n d it is safe t o res u me t he st u d y. Re g ulat ors ( o n a 
c o n diti o nal basis) a n d t he I n de pe n d e nt Et hics C o m mittee (I E C) will be n otifie d of t he 
te m p orar y halt a n d s u bs e q ue nt res u m pti o n of t he st u d y. A s u bsta ntial pr ot oc ol a me n d me nt 
will be s u b mitte d t o t he Re g ulat ors a n d t he I E C f or a p pr o val if t he s afet y assess me nt 
c o ncl u des t hat m o dificati o ns t o t he pr ot oc ol (i ncl u di n g a d diti o n of ne w ris k miti gati o n 
meas ures) are re q uir e d t o res u me t he st u d y. A d - h o c u n bli n di n g pr oce d ures ma y be i nitiate d as 
per C S L sta n dar d o p erati n g pr oce d ures f or f urt her safet y assess me nt, if n ee de d. If t he ris k 
assess me nt c o ncl u de d t h at c o nti n ue d d osi n g p oses a n u nacce pta ble ris k t o s u bjects a n d n o 
f urt her ris k miti gati o n ste ps ca n be a p plie d, th e C S L Gl o bal Safet y C o m mittees will be 
i n v ol ve d i n rec o m me n di n g a st u d y st o p.  Re g ulat ors a n d t he I E C will be n otifie d of a st u d y 
st o p. 
4  Selecti o n a n d W it h dr a w al of S u bjects  
4. 1  Eli gi bilit y C riteri a 
T he st u d y p o p ulati o n will be selecte d o n t he b asis of t he i ncl usi o n a n d e xcl usi o n criteria 
descri be d i n t he secti o ns bel o w. Eac h s u bject s h o ul d meet all of t he i ncl usi o n criteria a n d 
n o ne of t he e x cl usi o n criteria f or t his st u d y. S u bject eli gi bilit y s h o ul d be re vie we d a n d 
d oc u me nte d b y a n a p pr o priatel y me dicall y q ualifi e d me m ber of t h e i n vesti gat or’s st u d y tea m 
bef ore s u bjects ar e i ncl u de d i n t he st u d y. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
4. 1. 1  I ncl usi o n Criteri a f or E ntr y i nt o t he R u n-i n Peri o d 
To be e nr olle d i nt o t he R u n-i n Peri o d of t his st u d y, s u bjects m ust meet all of t he f oll o wi n g 
i ncl usi o n criteria: 
1.  Ca pa ble of pr o vi di n g writte n i nf or me d c o nse nt a n d willi n g a n d a b le t o a d h ere t o all 
pr ot oc ol re q uire m e nts a n d/ or t he s u bject’s pare nt(s) or le gall y acce pta bl e 
re pres e ntati ve(s) ca p a ble of pr o vi di n g writte n i nf or me d c o nse nt/asse nt as a p pr o priate. 
2.  Male or fe m ale.  
3.  A ge d ≥ 1 2 years at t he ti me of pr o vi di n g writte n i nf or me d c o ns e nt or asse nt f or mi n ors.  
4.  Dia g n os e d wit h cli nicall y c o nfir me d C 1 -I N H H A E:  
a. D oc u me nte d cli nical hist or y c o nsiste nt wit h H A E ( s u bc uta ne o us or m u c osal, 
n o n pr uritic s welli n g e pis o des wit h o ut acc o m pa n yi n g urticaria), a n d 
b.  C 1 -I NH a nti ge n a n d/ or f u ncti o nal acti vit y ≤ 5 0 % of n or mal as d oc u me nt e d i n t he 
s u bject’s me dical rec or d, a n d  
c. C 4 a nti ge n c o nce ntr ati o n bel o w t he l o wer li mit of t he refere n ce ra n ge as 
d oc u me nte d i n t he s u bject’s me dical rec or d. 
5.  E x perie nce d ≥ 3 H A E attac ks d uri n g t he 3 m o nt hs bef ore Scree ni n g, as d oc u me nte d i n 
t he s u bject's me dical r ec or d.  
N ote: F or s u bjects ta ki n g a n y pr o p h ylactic H A E t hera p y d uri n g t he 3 m o nt hs bef ore 
Scree ni n g, ≥ 3 H A E attac ks ma y be d oc u me nt e d o ver 3 c o nsec uti ve m o nt hs bef ore 
c o m me nci n g t he pr o p h yl actic t hera p y.   
4. 1. 2  E xcl usi o n C riteri a  f or E ntr y i nt o t he R u n-i n a n d Tre at me nt Peri o ds 
S u bjects m ust n ot be e nr olle d i nt o t he st u d y if t he y meet a n y of t he f oll o wi n g e xcl usi o n 
criteria:  
1.  C o nc o mita nt dia g n osis of a n ot her f or m of a n gi oe de ma, s uc h as i di o pat hic or ac q uire d 
a n gi oe de ma, r ec urre nt a n gi oe de ma ass oci ate d wit h urticarial or H A E t y pe 3.  
2.  A n y pre pla n n e d maj or s ur geries or pr oce d ures d uri n g t he cli nical st u d y. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
3.  F or a d ult s u bjects: Use of C 1-I N H pr o d u cts, a n dr o ge ns, a ntifi bri n ol ytics or ot her 
s mall m olec ule me dicati o ns f or r o uti ne pr o p h yla xis a gai nst H A E attac ks wit hi n  
2 wee ks pri or t o  t he R u n-i n Peri o d.  
4.  F or a d olesce nt s u bjects 1 2 t o 1 7 years of a ge, i ncl usi ve: Use of l o n g- ter m 
pr o p h ylactic t her a p y f or H A E bef ore S cree ni n g.  
5.  Use of m o n ocl o nal a nti b o dies s uc h as la na d el u ma b ( Ta k hz yr o ® ) wit hi n 3 m o nt hs 
pri or t o  t he R u n-i n Peri o d. 
6.  Use of estr o g e n -c o nt ai ni n g me dicati o ns wit h s yste mic a bs or pti o n (e g, oral 
c o ntracepti ve or h or m o n al re place me nt t hera p y), a n gi ote nsi n-c o n verti n g e nz y me 
( A C E) i n hi bit or wit hi n 4 wee ks pri or t o t he R u n- i n Peri o d, or c urre ntl y recei vi n g a 
t hera p y n ot per mitte d d uri n g t he st u d y as defi ne d i n Secti o n 7. 3 . 
7.  Partici pati o n i n a n ot her i nter ve nti o nal cli nical st u d y d uri n g t he 3 0 da ys bef ore 
Scree ni n g or wit hi n 5 half-li ves of t he fi nal d os e of t he i n vesti gati o nal pr o d uct 
a d mi nistere d d uri n g t he pre vi o us i nter ve nti o nal st u d y, w hic he ver is l o n ger. 
8.  K n o w n or s us pect e d h y p erse nsiti vit y t o m o n ocl o nal a nti b o d y t hera p y or 
h y perse nsiti vit y t o t he i n vesti gati o nal pr o d uct or t o a n y e xci pie nts of t he 
i n vesti gati o nal pr o d uct. 
9.  S u bject has a n y c o n diti o n t hat i n t he j u d ge me nt of t he i n vesti gat or or C S L, ma y 
c o m pr o mise t heir saf et y or c o m plia nce, i m pe d e s uccessf ul c o n d uct of t he st u d y, 
i nterfer e wit h i nter pret ati o n of t he res ults or w o ul d ot her wise re n der t he s u bject 
u ns uita ble f or partici p ati o n i n t he st u d y, e g, cli nicall y si g nifica nt blee di n g d ue t o 
c oa g ul o pat h y, t hr o m b otic dis or der, si g nifica nt ill nesses or maj or c o m or bi dities. 
1 0.  Pre vi o usl y a d mi nistere d C S L 3 1 2 i n a n ot her i nter ve nti o nal cli nical st u d y. 
1 1.  I nte nti o n t o bec o me pr e g na nt or t o fat her a c hil d at a n y ti me d uri n g t he st u d y. 
1 2.  Fe male of c hil d beari n g p ote ntial or male s u bjects w h o are fertile a n d s e x uall y acti ve  
eit her n ot usi n g or n ot willi n g t o use a n acce pt a ble met h o d of c o ntrace pti o n t o a v oi d 
pre g na nc y d uri n g t he st u d y a n d f or 3 0 da ys after r ecei pt of t he last d ose of 
i n vesti gati o nal pr o d uct. Acce pt a ble met h o ds of c o ntrace pti o n are defi ne d i n 
Secti o n  7. 4 . 
N ote:  All fe mal e s u bjects are ass u me d t o b e of c hil d beari n g p ote ntial e xce pt: 
•  S u bjects a ge d > 6 0 years. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  S u bjects a ge d 4 5 t o 6 0 years (i ncl usi ve) wit h a me n orr hea f or ≥ 1 year wit h 
d oc u me nte d e vi de n ce of f ollicle -sti m ulati n g h or m o ne le vel > 3 0 I U/ L. If t h e 
f ollicle-sti m ulati n g h or m o ne val ue is n ot a vaila ble bef ore  ra n d o mizati o n, a uri ne 
pre g na nc y t est is re q uire d. 
•  S u bjects w h o are s ur gicall y sterile f or at least 3 m o nt hs bef ore pr o vi di n g i nf or m e d 
c o nse nt. 
N ote:  All male s u bjects are ass u me d fertile e x ce pt s u bjects w h o are s ur gicall y 
sterile f or at least 3 m o nt hs bef ore pr o vi di n g i nf or me d c o nse nt 
1 3.  Pre g na n t, breastfee di n g , or n ot willi n g t o cease breastfee di n g. 
1 4.  I n v ol ve d i n t he pla n ni n g a n d / or c o n d uct of t h e st u d y (a p plies t o C S L staff, staff at 
t he st u d y site, a n d t hir d- part y ve n d ors). 
4. 1. 3  Criteri a f or E ntr y i nt o t he Tre at me nt Peri o d  
S u bjects will be eli gi ble t o e xit t he R u n -i n Peri o d a n d e nter t he Treat me nt Peri o d if t he y meet 
all t he f oll o wi n g criteria:  
1.  Partici pate d i n t he R u n -i n Peri o d f or at least 1 m o nt h. 
2.  E x perie nce d at least a n a vera ge of 1 H A E attac k p er m o nt h d uri n g t he R u n-i n Peri o d 
(e g, e x perie nce d a t otal of at least 2 H A E attac ks) .  
3.  D oes n ot ha ve la b orat or y cli nical a b n or malities assesse d as cli nicall y si g nifica nt b y 
t he i n vesti gat or i n res ults of he mat ol o g y, c he mistr y, or uri nal ysis assess me nts.  
4.  C 1 -I N H f u ncti o nal acti vit y a n d a nti ge n, a n d C 4 a nti ge n c o nce ntrati o n le vels ha ve 
bee n verifie d pri or t o r a n d o mizati o n. 
N ote : S u bjects wit h ≥ 2 ti mes t he u p per li mit of n or mal f or as p artate a mi n otra nsferase 
a n d / or ala ni ne a mi n otra nsferas e ma y be eli gi ble f or partici pati o n if t here is a n 
e x pla nati o n f or t his la b or at or y res ult a n d if t he res ults are n ot cli nicall y si g nifica nt. 
4. 2  Scree n F ail ures  
Scree n f ail ures are defi ne d as i n di vi d uals w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut 
w h o d o n ot meet t he eli gi bilit y criteria f or partici pati o n i n t he st u d y (see Secti o n  4. 1 ). A 
mi ni mal set of i nf or mati o n i ncl u di n g de m o gra p h y, eli gi bilit y criteria,  a n d scree n fail ure 
details  s h o ul d be rec or de d f or all i n di vi d uals c o nsi dere d scree n fail ures.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
If a p ote ntial s u bject is n ot eli gi ble f or e ntr y i nt o t he R u n-i n Peri o d wit hi n 3 0 da ys after 
pr o vi di n g i nf or me d c o ns e nt, t he n t he s u bject ma y rec o nse nt a n d ma y be scre e ne d a gai n (f or a 
ma xi m u m of 2 Scree ni n g Peri o ds per s u bject) after c o ns ultati o n wit h C S L . I n t he e ve nt t hat a 
p ote ntial s u bject is scree ne d t wice, all Scree ni n g  assess me nts m ust be re peate d d uri n g t he 
sec o n d Scree ni n g Peri o d. 
4. 2. 1  R u n -i n Peri o d F ail ures  
R u n-i n peri o d fail ures ar e defi ne d as s u bjects w h o are n ot eli gi ble t o e nter t he Treat me nt 
Peri o d. S u bjects w h o e nter t he R u n-i n Peri o d b ut are n ot eli gi ble t o e nter t he Treat me nt 
Peri o d will be c o nsi dere d R u n-i n fail ures a n d ca n n ot be rescree n e d. T he pri mar y reas o n f or 
R u n-i n failure m ust be d oc u me nte d f or s u bjects n ot eli gi ble t o e nter t he Treat me nt Peri o d.  
4. 3  Disc o nti n u ati o n of St u d y Tre at me nt a n d S u bject Wit h dr a w al  
4. 3. 1  Disc o nti n u ati o n of St u d y Tre at me nt  
S u bjects ma y disc o nti n ue st u d y treat me nt wit h C S L 3 1 2 at a n y ti me at t heir o w n re q u est, or at 
t he discreti o n of t he i n vesti gat or or C S L f or safet y, be ha vi oral, or a d mi nistrati ve reas o ns. 
S u bjects  w h o disc o nti n ue treat me nt wit h C S L 3 1 2 will be e nc o ura g e d t o re mai n i n t he st u d y 
u ntil Da y 1 8 2 i n or der t o c ollect st u d y assess me nts . Refer t o Secti o n 4. 3. 2  f or details o n 
ha n dli n g s u bject wit h dra wals.  
4. 3. 2  S u bject Wit h dr a w al  
S u bjects ma y wit h dra w fr o m t he st u d y at a n y ti me at t heir o w n re q u est, or at t he discreti o n of 
t he i n vesti gat or or C S L f or safet y, be ha vi oral, or a d mi nistrati ve reas o ns (e g, beca use of  a n 
A E, pr ot oc ol de viati o n, l oss t o f oll o w- u p, s u bject n o nc o m plia nce, st u d y ter mi nati o n). If 
disc o nti n uati o n occ urs bef ore D a y 1 8 2, s u bjects w h o disc o nti n ue i n vesti gati o nal pr o d uct will 
be e nc o ur a ge d t o r e mai n i n t he st u d y u ntil Da y 1 8 2 i n or de r t o c ollect st u d y assess me nts a n d 
c o m plete t he E n d of Tr eat me nt Peri o d V isit. If t he s u bject wit h dra ws fr o m t he st u d y, a n d als o 
wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or m ati o n, C S L ma y retai n a n d c o nti n ue t o use 
a n y data a n d s a m ples c ollecte d bef ore  wit h dra wal of c o nse nt. 
T he i n vesti gat or s h o ul d r ec or d i n t he el ectr o nic case re p ort f or m (e C R F ) a n d i n t he s u bject's 
me dical rec or ds t he r eas o n a n d date of s u bject wit h dra wal.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
I n acc or da n ce wit h t he I nter nati o nal C o u ncil f or H ar m o nisati o n of Tec h nical Re q uire me nts 
f or P har mace uticals f or H u ma n Use (I C H) pri nci ples of G o o d Cli nical Practice ( G C P), t he 
i n vesti gat or al wa ys has t he o pti o n t o a d vise a s u bject t o wit h dra w fr o m t he st u d y if t he 
s u bject's safet y or well bei n g is c o m pr o mise d b y his or her f urt her partici pati o n i n t he st u d y. 
C o ncer n f or t h e i nterests of t he s u bject m ust al wa ys pre vail o ver t he i nterests of t he st u d y.  
4. 3. 3  Pr oce d ures f or H a n dli n g Wit h dr a w als  
If a s u bject is wit h dra w n  fr o m t he st u d y, atte m pts will be ma de t o c o m plete a n d d oc u me nt t he 
E n d of Treat me nt Peri o d Visit  ( Da y 1 8 2) assess me nts . If t he s u bject is wit h dra w n fr o m t he 
st u d y after r ecei vi n g C S L 3 1 2 , e ver y eff ort will be ma de t o e ns ure t hat t he rele va nt safet y 
assess me nts are c o m plete d.  T he s u bject ma y als o be as ke d b y t he i n vesti gat or t o c o m plete 
ot her st u d y assess me nts.  
If t he s u bject wit h dr a ws fr o m t he st u d y a n d als o wit h dra ws c o nse nt f or discl os ure of f ut ure 
i nf or mati o n, C S L  ma y retai n a n d c o nti n ue t o use a n y data c ollecte d bef ore s uc h wit h dra w al 
of c o nse nt. 
4. 3. 4  S u bjects L ost t o F oll o w -u p  
If a s u bject re peate dl y fails t o ret ur n f or sc h e d ule d visits, t he site m ust atte m pt t o c o ntact t he 
s u bject a n d c o u nsel t he s u bject o n t he i m p orta nce of mai ntai ni n g t he assi g ne d visit sc he d ule 
a n d ascertai n w het h er or n ot t he s u bject wis hes t o a n d / or s h o ul d c o nti n ue i n t he st u d y. All 
atte m pts t o c o ntact t he s u bject s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or d.  
A s u bject will be c o nsi dere d l ost t o f oll o w- u p if he or s he re peat e dl y fails t o ret ur n f or 
sc he d ule d visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. S u bjects l ost t o f oll o w- u p 
will be c o nsi dere d t o ha v e wit h dra w n fr o m t he st u d y. 
4. 3. 5  Re pl ace me nt P olic y  
S u bjects wit h dra w n fr o m t he st u d y will n ot be re place d. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 4 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
5  St u d y I nter ve nti o ns  
5. 1  I n vesti g ati o n al Pr o d ucts 
5. 1. 1  Descri pti o n of C S L 3 1 2  
C S L 3 1 2 will be s u p plie d ( 1. 2 m L per prefille d s yri n ge ) as a sterile, pres er vati ve-free s ol uti o n 
f or i njecti o n, at p H 6. 1. C S L 3 1 2 is f or m ulate d i n b uffer c o ntai ni n g 2 0 m M L- histi di ne, 
1 5 0 m M ar gi ni ne m o n o h y dr oc hl ori de, 1 4 0 m M L- pr oli ne, 0. 0 2 % w / v p ol ys or bate 8 0, a n d 
h y dr oc hl oric aci d. Eac h vial c o ntai ns C S L 3 1 2 at a c o nce ntrati o n of 1 7 0 m g per 1 m L.  
Ta ble 1 
Descri pti o n of C S L 3 1 2 
S u bst a nce n a me  
C S L 3 1 2  
Acti ve s u bst a nce  
Fact or XIIa i n hi bit or m o n ocl o nal a nti b o d y 
Tr a de n a me  
N ot a p plica ble 
I nter n ati o n al n o n-pr o priet ar y 
n a me:  
Gara d aci ma b  
St or a ge  
T he rec o m me n de d st ora g e te m perat ure is + 2 t o +  8° C. 
D os a ge f or m 
1. 2 m L prefille d s yri n ge 2 0 0 m g C S L 3 1 2 at a 
c o nce ntrati o n of 1 7 0 m g per 1 m L. 
 
C S L 3 1 2 will be ma n ufact ure d b y C S L i n acc or d a nce wit h I C H G o o d Ma n ufact uri n g Practice 
( G M P) g ui deli nes a n d l o cal re g ulat or y re q uire me nts. 
5. 1. 2  Descri pti o n of  Pl ace b o  
Place b o will be s u p plie d ( 1. 2 m L per prefille d s yri n ge ) as a sterile, pres er vati ve-free s ol uti o n 
f or i njecti o n. Place b o c o ntai ns t he sa me f or m ulati o n b uffer as C S L 3 1 2, b ut d oes n ot c o ntai n 
t he acti ve s u bsta nce (ie, Fact or XII a i n hi bit or m A b ). 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble 2 
Descri pti o n of Pl ace b o  
S u bst a nce n u m ber  
N ot a p plica ble  
S u bst a nce  
Place b o  
Tr a de n a me  
N ot a p plica ble  
D os a ge f or m  
S ol uti o n f or i njecti o n  
M o de of a d mi nistr ati o n  
S u bc uta ne o us i njecti o n  
 
5. 1. 3  D osi n g a n d A d mi nistr ati o n  
T he i n vesti gat or ( or d ele gate) will a d mi nister or dis pe nse C S L 3 1 2 o nl y t o s u bjects i ncl u de d 
i n t his st u d y f oll o wi n g t he pr oce d ures set o ut i n t his st u d y pr ot oc ol. I nf or mati o n o n t he 
d osi n g c haracteristics of C S L 3 1 2 is pr o vi de d i n  Ta ble  3. 
Ta ble 3 
I n vesti g ati o n al Pr o d uct D osi n g C h ar acteristics 
A d mi nistr ati o n p ar a meter  
I n vesti g ati o n al Pr o d uct 
C S L 3 1 2  
Pl ace b o  
D ose  
2 0 0 m g 
N ot a p plica ble 
R o ute  
S u bc uta ne o us 
S u bc uta ne o us 
A n at o mic al L oc ati o n  
A b d o me n 
A b d o me n 
Tot al i nf usi o n v ol u me  
1. 2  m L  
1. 2 m L 
 
T he first d ose of C S L 3 1 2 or place b o will be a S C l oa di n g d ose c o nsisti n g of 2 se parat e 
i njecti o ns of 2 0 0 m g C S L 3 1 2 f or a t otal of 4 0 0 m g C S L 3 1 2 or v ol u me- matc he d place b o. 
After o btai ni n g t he a d mi nistrati o n trai ni n g, t he first 3 S C a d mi nistrati o ns will be 
self-a d mi nistrate d b y t he s u bjects or care gi vers u n der t he s u per visi o n of t he i n vesti gat or or 
dele gate d uri n g t he st u d y site visits (ie. Da y 1, 3 1, a n d 6 1). S u bse q ue nt d oses ca n be 
self-a d mi nistrate d wit h (if dee me d n ecess ar y b y t h e i n vesti gat or) or wit h o ut s u per visi o n of 
t he i n vesti gat or or dele g ate .  
Detaile d i nf or mati o n o n t he pre parati o n a n d a d mi nistrati o n of C S L 3 1 2 or place b o is pr o vi de d 
i n t he Site I n vesti gati o nal Pr o d uct Ma n ual.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
5. 1. 3. 1  D osi n g  M o dific ati o n  
D ose m o dificati o ns will n ot be per mitte d d uri n g t his st u d y.  
5. 1. 3. 2  Tre at me nt C o m pli a nce  
T he first d ose of i n vesti g ati o nal pr o d uct a n d all su bse q ue nt i njecti o ns will be a d mi nistere d b y 
S C i njecti o n b y t he s u bject at t he st u d y site u n der s u per visi o n b y t he i n vesti gat or or dele g ate. 
T he i n vesti g at or will rec or d t he d ose a n d d ate of i nvesti gati o nal pr o d uct a d mi nistrati o n i n t he 
e C R F. C o m plia nce will be assesse d usi n g t he a d mi nistrati o n details e ntere d i nt o t he e C R F.  
5. 1. 4  P ac k a gi n g , L a beli n g , S u p pl y a n d St or a ge 
5. 1. 4. 1  P ac k a gi n g a n d L a beli n g  
I n vesti gati o nal pr o d uct will be pac ka ge d a n d la bel e d acc or di n g t o c urre nt I C H G M P a n d 
G C P  g ui deli nes a n d nati o nal le gal re q uire me nts. S pecific det ails re gar di n g pac ka gi n g of 
C S L 3 1 2 are pr o vi de d i n t he Site I n vesti gati o nal Pr o d uct Ma n ual . 
5. 1. 4. 2  S u p pl y a n d St or a ge  
I n vesti gati o nal pr o d uct will be s u p plie d t o t he st u d y sites b y C S L or dele gat e .  
T he i n vesti gati o nal pr o d uct  m ust be st ore d u n der te m perat ure-c o ntr olle d a n d m o nit ore d 
c o n diti o ns fr o m + 2° C t o + 8° C i n a sec ure st ora ge area as s pecifie d i n t he Site I n vesti gati o nal 
Pr o d uct M a n ual.  
5. 2  Acc o u nt a bilit y a n d Destr ucti o n  
I n vesti gati o nal pr o d uct m ust be use d o nl y as directe d i n t he cli nical st u d y pr ot oc ol. 
T he i n vesti gat or or del e g ate will c o nfir m recei pt of all s hi p me nts of i n vesti gati o nal pr o d uct 
i n t he i nteracti ve r es p o ns e tec h n ol o g y (I R T) s yste m. 
All s u p plies of i n vesti gati o nal pr o d uct m ust be acc o u nte d f or t hr o u g h o ut t he st u d y. 
Rec or ds f or t h e deli ver y of i n vesti gati o nal pr o d uct t o t he st u d y site, t he i n ve nt or y at t he st u d y 
site, t he use b y eac h s u bject, a n d t he d estr ucti o n or ret ur n of i n v esti gati o nal pr o d uct t o 
C S L  / desi g nee m ust be mai ntai ne d b y t he i n vesti gat or or dele g ate  usi n g t he I R T s yste m. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he i n vesti gat or or del e g ate m ust pr o vi de reas o ns f or a n y discre pa n cies i n dr u g 
acc o u nta bilit y  i n t he I R T.  
F or Ja pa n sites o nl y, dr u g i n ve nt or y a n d acc o u nta bilit y l o gs / re p orts m ust be date d a n d 
si g ne d b y t he hea d of t h e me dical i nstit ute or t he st u d y dr u g st ora ge ma na g er (if assi g ne d b y 
t he hea d of t he m e dical i nstit ute). 
F urt her details re g ar di n g acc o u nta bilit y a n d destr u cti o n of i n vesti gati o nal pr o d uct are 
pr o vi de d i n t he Site I n vesti gati o nal Pr o d uct Ma n ual . 
5. 2. 1  C o nc o mit a nt St u d y -rel ate d T her a pies  
5. 2. 1. 1  O n- de m a n d  Me dic ati o n  
S u bjects m ust be assesse d b y t he i n vesti gat or t o be ca p a ble of ma n a gi n g t heir H A E attac ks 
d uri n g partici pati o n i n t he st u d y. A n i n di vi d ual acti o n pla n will be re vie we d wit h t he s u bject.  
Here ditar y a n gi oe d e ma  attac ks occ urri n g pri or t o ra n d o mizati o n (ie, d uri n g t he Scree ni n g a n d 
R u n-i n P eri o ds) or d uri n g t he st u d y s h o ul d be ma na ge d i n acc or da n ce wit h t he i n vesti gat or’s 
us ual sta n dar d of car e of t heir patie nts, i ncl u di n g use of o n- de ma n d attac k t hera pies t hat t he 
i n vesti gat or dee ms me dicall y a p pr o priate. Beri nert®  will be s u p plie d b y C S L i n c o u ntries 
w here Beri nert is lice nse d or w her e it meets t he l ocal re g ulati o n as a n o ni n vesti gati o nal 
pr o d uct t o t h ose s u bjects w h o elect t o use C 1- I N H f or o n- de ma n d  treat me nt of H A E attac ks. 
H o we ver, s u bjects ma y use ot her effect i ve o n- de m a n d me dicati o n of t heir c h oice t o treat 
H A E attac ks e x perie n ce d d uri n g t he st u d y as descri be d i n Secti o n 7. 2 . Use of I V C 1 -I N H 
will be per mitte d as a n o n - de ma n d attac k t hera p y, s h ort-ter m pr o p h yla xis use pri or t o 
me dicall y i n dicate d pr o ce d ures , b ut n ot as a l o n g-ter m pr o p h yla xis. 
5. 3  Access t o I n vesti g ati o n al Pr o d uct After t he E n d of St u d y  
S u bjects will n ot be pr o vi de d wit h i n vesti gati o nal pr o d u ct b y C S L after c o m pleti o n or 
disc o nti n uati o n fr o m t he st u d y. Eli gi ble s u bjects will  ha ve t he o pti o n t o r oll o ver i nt o t he 
o pe n- la bel phas e  3 b St u d y C S L 3 1 2 _ 3 0 0 2 s p o ns ore d b y C S L. 
6  All oc ati o n  t o Tre at me nt 
6. 1  S u bject Assi g n me nt  
After pr o vi di n g writte n i nf or me d c o ns e nt, t he s u bject will be iss ue d a st u d y-le vel u ni q ue 
s u bject i de ntificati o n n u m ber via a n I R T s yste m . T he s u bject i de ntificati o n n u m ber will be 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
use d t o i de ntif y t he s u bject f or t he d urati o n of t he st u d y. S u bject i de ntificati o n n u m bers will 
n ot be reassi g ne d or re us e d. 
6. 2  R a n d o miz ati o n Pr oce d ures  
S u bjects will be ra n d o mize d usi n g a bl oc k ra n d o mizati o n b y mea ns of ce ntralize d I R T t o 1 of 
2 treat me nt ar ms i n a 3: 2 rati o t o eit her t he Acti ve Ar m or t o t he Place b o  Ar m. Stratif yi n g 
varia bles  will be a g e ( ≤ 1 7 years, > 1 7 y ears) a n d, f or a d ults, t he s u bject’s baseli ne attac k rate 
( 1 t o < 3 attac ks/ m o nt h, a n d ≥ 3 attac ks/ m o nt h ).  
T he ra n d o mizati o n list will be ge nerate d acc or di n g t o t he a p pr o ve d ra n d o mizati o n 
s pecificati o ns, w hic h i ncl u des f urt her ra n d omizati o n details . T he I R T ser vice pr o vi der will 
kee p t he r a n d o mizati o n c o de o n file. 
6. 3  Bli n di n g  Pr oce d ures  
I n vesti gati o nal site staff, i ncl u di n g t he i n vesti gat ors, will be bli n de d t o treat me nt all ocati o n. 
S u bjects a n d C S L staff / desi g nates partici pati n g i n t he c o n d uct of t he st u d y will als o be 
bli n de d t o treat me nt all ocati o n ( d o u ble- bli n d). 
6. 3. 1  Bli n di n g Met h o d  
T he i n vesti gati o nal pr o d uct will be pac ka g e d a n d la belle d t o e ns ure bli n di n g is mai ntai ne d 
a n d C L S 3 1 2 P F S is n ot disti n g uis ha ble fr o m t he place b o. St u d y u n bli n di n g will ta ke place 
f oll o wi n g l oc ki n g of t he st u d y data base e x ce pt i n t he sit uati o ns as o utli ne d i n Secti o ns 6. 3. 2 , 
6. 3. 3 , a n d 6. 3. 4 . 
 
A de q uate pr o ce d ures are i n place t o e ns ure t he i nte grit y of t he bli n de d data wit hi n C S L. 
St u d y data will be pr o vi de d t o t he I D M C as bli n de d data. T he I D M C ma y re q uest t he 
u n bli n di n g of a n i n di vi d ual's treat me nt assi g n me nt f or reas o ns of safet y. T hese pr oce d ures 
will be o utli ne d i n t he I D M C C harter.  
T he i n vesti gati o nal pr o d uct will be pac ka g e d a n d la belle d t o e ns ure bli n di n g is mai ntai ne d. 
All bl o o d sa m ples c ollecte d f or P K / P D a nal yze d b y t he ce ntral la b orat or y will re mai n 
bli n de d u ntil data base l oc k. I n a d diti o n, res ults fr o m assess me nt of a P T T will n ot be a vaila ble 
t o s u bjects, st u d y site pers o n nel, or C S L a n d t heir dele gates w h o are bli n de d t o treat me nt 
assi g n me nt 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
St u d y u n bli n di n g will ta ke place f oll o wi n g l oc ki n g of t he st u d y data base e x ce pt i n t he 
sit uati o ns as o utli ne d i n Secti o ns 6. 3. 2 , 6. 3. 3 , a n d 6. 3. 4 . 
T he bi oa nal yst a n d p har mac o ki neticist res p o nsi ble f or t he sa m ple a nal ysis a n d P K  / P D, 
i m m u n o ge nicit y, a n d c oa g ulati o n e val uati o ns will be u n bli n de d. H o we v er, t he y will a gree n ot 
t o discl ose t he ra n d o mizati o n sc he d ule or a n y d ata.  
6. 3. 2  Bre a ki n g t he Bli n d  f or a n Emer ge nc y  
T he ra n d o mizati o n c o de f or i n di vi d ual s u bjects ma y be u n bli n de d t o a site d uri n g t he st u d y i n 
e mer ge n c y sit uati o ns f or reas o ns of s u bject safet y, if k n o wi n g treat me nt assi g n me nt will 
c ha n ge s u bject ma na ge m e nt. I n cas e of a n e mer g e nc y sit uati o n f or t he reas o n of s u bject 
safet y, t he in vesti gat or s h o ul d use t he I R T t o i de ntif y t he treat me nt all ocati o n f or a s u bject. 
W he ne v er p ossi ble, t he i n vesti gat or s h o ul d c o ns ult wit h C S L bef ore u n bli n di n g t he 
ra n d o mizati o n c o de. T he reas o n f or u n bli n di n g t he ra n d o mizati o n c o de m ust be f ull y 
rec or d e d i n t he s u bject’s s o urce d oc u m e nts, a n d t he i n vesti gat or m ust f oll o w t he defi ne d 
pr oce d ur es pr o vi de d i n t he st u d y refere n ce ma n u als. T he s u bject’s treat me nt all ocati o n 
s h o ul d n ot be rec or d e d i n t he s u bject’s s o urce d o c u me nt. 
6. 3. 3  Pl a n ne d U n bli n di n g Pr oce d ures  
N ot a p plica ble.  
6. 3. 4  A d -h oc S afet y U n b li n di n g 
C S L Be hri n g's Gl o bal Cli nical Safet y a n d P har m ac o vi gila nce pers o n nel ma y, o n a n a d- h oc 
basis, u n bli n d t he ra n d o mizati o n c o de directl y i n t he I R T at a n y ti me d uri n g t he st u d y, 
beca use of  a safet y c o n cer n . T he p ur p os e of t he u n bli n de d data re vie w is t o deter mi ne if t here 
is a ris k t o s u bject safet y t hat w o ul d re q uire f urt her acti o n eit her f or t he i n di vi d ual 
ma na ge me nt of a st u d y s u bject or f or t he o n g oi n g c o n d uct of t he st u d y. T he nee d t o u n bli n d a 
s u bject or gr o u p of s u bjects ma y n ot necessaril y arise beca use of a n S A E. T he nee d t o 
u n bli n d o n a n a d- h oc basis will be  deter mi ne d b y C S L’s Gl o bal Cli nical Safet y a n d 
P ha mac o vi gila nce se ni or lea ders hi p.  
T he I D M C, i n c o ns ultati o n wit h C S L a n d t he Me dical M o nit or, ma y re q uest t he u n bli n di n g 
of a s u bject's treat me nt assi g n me nt f or reas o ns of safet y. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
7  C o ntr ai n dic ati o ns, Per mitte d T her a pies  a n d  Pr o hi bite d T her a pies  
7. 1  C o ntr ai n dic ati o ns a n d P rec a uti o ns  t o F urt her  Dosi n g  
T here are n o c o ntrai n dicati o ns or preca uti o ns ass ociate d wit h C S L 3 1 2 a d mi nistrati o n. 
7. 2  Per mitte d T her a pie s 
T he f oll o wi n g me dicati o ns a n d t hera pies are P E R MI T T E D at a n y ti me d uri n g t he st u d y: 
•  Prescri be d me dicati o n(s) re q uire d f or t he ma n a ge me nt of ac ute or c h r o nic me dical 
c o n diti o ns.  
•  T hera pies t o tr eat a n y A Es t he s u bject e x peri e nces d uri n g t he st u d y, i ncl u di n g 
n o n pr o p h ylactic as piri n ( e g, t o treat a h ea dac he).  
T he f oll o wi n g o n- de ma n d H A E t hera pi es are P E R MI T T E D at a n y ti me d uri n g t he st u d y f or 
t he treat me nt of H A E att ac ks if t hat me dicati o n has pre vi o usl y bee n s h o w n t o be effecti ve or 
if use d acc or di n g t o t he pr o d uct la bel or wit h de vi ati o ns fr o m t he la bel as directe d b y a h ealt h 
care pr o vi der:  
•  Plas ma - deri ve d or rec o m bi na nt C 1-I N H (e g, B eri nert, Ci nr yze® , R uc o nest ® ). 
•  Firaz yr ®  (icati ba nt). 
•  Kal bit or ®  (ecalla nti de). 
T he use of me dicati o ns ( e g, I V C 1 -I N H) f or t he pre ve nti o n of H A E attac ks pri or t o a n y 
s ur gical pr oce d ur e is P E R MI T T E D at a n y ti me d uri n g t he st u d y. 
7. 3  Pr o hi bite d T her a pie s 
R o uti ne (l o n g-ter m) pr o p h yla xis t o pre ve nt H A E attac ks wit h t he use of C 1-I N H pr o d u cts, 
a n dr o ge ns, a ntifi bri n ol yti cs, Da naz ol ® , Ta k hzy r o®  or f ut ure a p pr o ve d me di cati o n are 
P R O HI BI T E D d uri n g t he e ntire st u d y.  
•  A C E i n hi bit ors. 
•  Use of Estr o ge n-c o ntai ni n g c o ntrace pti ve re gi me ns  or re place me nt t hera p y wit h 
s yste mic a bs or pti o n (e g, oral c o ntrace pti ve or h or m o nal re place me nt t hera p y). 
S u bjects are n ot t o be e nr olle d i nt o t he st u d y if t he y recei v e a n y pr o hi bite d t hera p y or a n y 
t hera p y i n a pr o hi bite d d osa ge t hat ca n n ot b e disc o nti n ue d or re d uce d t o a per mitte d d ose 
bef ore e nr oll me nt.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
7. 4  Lifest yle Restricti o ns  
Fe male s u bjects c o nsi der e d t o  be w o me n of c hil d beari n g p ote ntial1 a n d male s u bjects 2 m ust 
use a hi g hl y eff ecti ve f or m of c o ntrace pti o n d uri n g t he st u d y d urati o n a n d f or 3 0 da ys after 
t he last S C i nf usi o n of i n vesti gati o nal pr o d uct. A cce pta ble met h o ds of c o ntrace pti o n are: 
•  A bsti ne nce, w h ere a bsti ne nce is t he preferre d a n d us ual lifest yle of t he s u bject, 
i ncl u di n g refrai ni n g fr o m heter ose x u al i nterc o urs e d uri n g t he e ntire peri o d of ris k 
ass ociate d wit h t he i n vesti gati o nal pr o d uct. Peri o dic a bsti ne nce (cale n d ar, 
s y m pt ot her mal, p ost o v ulati o n met h o ds), wit h dra wal (c oit us i nterr u pt us), s per mici des 
o nl y, a n d lactati o nal a me n orr h oea m et h o d are n ot acce pta ble defi niti o ns of 
a bsti ne nce.  
•  Acce pt a ble h or m o nal met h o ds i ncl u de: pr o gesti n- o nl y oral c o ntrace pti ves, 
c o ntrace pti ve me dicati o n patc h, c o ntrace pti ve me dicati o n i njecti o n, va gi nal ri n g, or 
c o ntrace pti ve me dicati o n i m pla nt.  
•  Use of i ntra uteri ne de vice ( place d m ore t ha n 3 m o nt hs bef ore pr o vi di n g i nf or me d 
c o nse nt). 
•  Bilateral t u bal occl usi o n of fe male s u bjects ( 3 m o nt hs bef ore pr o vi di n g i nf or me d 
c o nse nt).  
•  Vasect o m y of male s u bj ects ( 3 m o nt hs bef ore pr o vi di n g i nf or me d c o nse nt). 
8  S t u d y P r oce d ures a n d Visit Sc h e d ule 
8. 1  Cli nic al P r oce d ures 
T he ti mi n g a n d fre q ue n c y of t he cli nical pr o ce d ures descri be d i n t he f oll o wi n g secti o ns are 
detaile d i n t he Sc he d ule of Assess me nts: Scree ni n g a n d R u n- i n Peri o d ( All S u bjects) a n d 
Sc he d ule of Assess me nts: Treat me nt Peri o d . M ore fre q ue nt assess me nts  ma y be perf or me d, if 
cli nicall y i n dicate d, at t h e discreti o n of t he i n vesti gat or. Refer t o t he pr o vi d e d st u d y ma n uals 
f or detaile d i nstr ucti o ns o n h o w t he assess me nts s h o ul d be perf or me d. 
 
1 Fe male s u bjects c o nsi dere d t o be w o me n of c hil d beari n g p ote ntial are t h ose w h o ha ve n ot e x perie nce d 
me n o pa use (ie, nat ural a me n orr hea f or > 1 2 m o nt hs), or are wit h o ut a hist or y of h ysterect o m y, bilateral 
o o p h orect o m y, bilateral sal pi n gect o me, or bilateral  t u bal li gati o n. 
2 Male s u bjects are c o nsi dere d fertile after p u bert y u nless per ma ne ntl y sterile b y bilateral orc hiect o m y, etc.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
8. 1. 1  De m o gr a p hics a n d S afet y  Assess me nts  
S u bject de m o gra p hics a n d safet y assess me nts t o b e c o n d ucte d d uri n g t his st u d y are pr o vi de d 
i n Ta ble 4 . Cli nical la b or at or y assess me nts are t o be perf or me d at ti me p oi nts as detaile d i n 
t he Sc he d ule of Assess m e nts: Scree ni n g a n d R u n- i n Peri o d ( All S u bjects) a n d Sc he d ule of 
Assess me nts: Treat me nt Peri o d . T he ti me wi n d o ws f or eac h t y pe of assess me nt are det aile d 
i n Secti o n  8. 7. 1 . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble 4 
St u d y Pr oce d ures: De m o gr a p hics a n d S afet y Assess me nts  
Assess me nt  
Descri pti o n  
De m o gr a p hics  
Year of birt h / a ge  
Se x  
Race a n d et h nicit y  
Me dic al hist or y  
Rele va nt me dical hist or y wit hi n t he 6 m o nt hs bef ore Scree ni n g wit h res pect t o 
t he o verall healt h of t he s u bject  
•  
Me dical hist or y of H A E:  
o  
t y pe 1 or t y pe 2  
o  
a ge of dia g n osis  
o  
an y hist or y of lar y n geal attac ks  
o  
fa mil y hist or y of H A E  
•  
La b val ues C 1- I N H f u n cti o n al acti vit y a n d a nti g e n / C 4 a nti g e n c o n ce ntrati o n 
me dical rec or ds t o s u p p ort dia g n osis  
•  
H A E attac ks i n t he last 3 m o nt hs  
o  
If o n pr o p h ylactic t hera p y 3 m o nt hs pri or t o scree ni n g, c ollect 
hist or y of n u m ber of H A E attac ks 3 m o nt hs pri or t o t he start o f 
pr o p h ylactic t hera p y  
•  
P ri or pr o p h yla xis t hera p y a n d o n-de ma n d treat me nt me dicati o n 
3 m o nt hs pri or t o scree ni n g   
•  
C o ntrace pti o n met h o d  
Pri or ( wit hi n 6 m o nt hs bef ore Scree ni n g) / c o nc o mita nt me dicati o ns a n d 
t hera pies 
Pre g n a nc y test  a 
Uri ne test f or C h ori o g o na d otr o pi n Beta ( beta -h u ma n c h ori o nic g o na d otr o pi n), f or 
w o me n of c hil d beari n g  p ote ntial  
P h ysic al e x a mi n ati o n  
As per t he i n vesti gat or’s sta n dar d pr oce d ure, i ncl u di n g assess me nt of u nilateral 
pai n a n d / or s welli n g of t he l o wer e xtre mities f or t he p ur p ose of scree ni n g f or 
dee p vei n t hr o m b osis  
A d verse e ve nts  
E val uati o n of all a d verse e ve nts (e g, ca usalit y/relate d ness, se verit y, seri o us ness)  
A d verse e ve nts of s pecial i nterest:  
•  
A b n or mal blee di n g e ve nts  
•  
T hr o m b oe m b olic e ve nts  
•  
Se vere h y perse nsiti vit y i ncl u di n g a na p h yla xis  
Vit al si g ns  
Bl o o d press ure (s yst olic a n d diast olic)  
Res pirat or y rate  
P ulse rate  
Te m perat ure  
Hei g ht a n d b o d y wei g ht  
C ar di ac f u ncti o n test  
1 2 -lea d electr ocar di o gra m 
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 5 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Uri n al ysis b 
 
Bilir u bi n  
Occ ult bl o o d  
Er yt hr oc ytes  
Gl uc ose  
Ket o nes  
Le u k oc yte esterase  
Nitrite  
p H  
Pr otei n  
S pecific gra vit y  
Ur o bili n o ge n  
 
He m at ol o g y b  
He m o gl o bi n  
He mat ocrit  
Er yt hr oc ytes (re d bl o o d cell c o u nt)  
Mea n c or p usc ular v ol u me  
Mea n c or p usc ular he m o gl o bi n  
Mea n c or p usc ular he m o gl o bi n c o nce ntrati o n 
Le u k oc ytes ( w hite bl o o d cell c o u nt)  
Ne utr o p hils, % a n d a bs ol ute  
L y m p h oc ytes, % a n d a bs ol ute  
M o n oc ytes, % a n d a bs ol ute  
E osi n o p hils, % a n d a bs ol ute  
Bas o p hils, % a n d a bs ol ute  
Platelet c o u nt  
 
Bi oc he mistr y b  
S o di u m  
P otassi u m  
C hl ori de  
B icar b o nate 
Al b u mi n  
A L P  
Direct Bilir u bi n  
Bilir u bi n, t otal  
A S T  
Pr otei n – t otal 
Calci u m  
A L T  
Creati ni ne  
P h os p hate  
B U N  or urea  
Gl uc ose  
 
 
C o a g ul ati o n b  
a P T T  d  
Pr ot hr o m bi n fra g me nt 
( pF 1 + 2 ) 
D- di mer  
P r ot hr o m bi n ti me  
I N R 
 
 
H A E bi o m ar k ers  c  A bl o o d sa m ple will be retai ne d f or p ote ntial assess me nt of H A E bi o mar ker assess me nt 
(rete nti o n sa m ple) 
I m m u n o ge nicit y b  Bi n di n g a nti b o dies (i n hi bit or y a n d n o n -i n hi bit or y) s pecific t o F XIIa i n hi bit or m o n ocl o nal 
a nti b o d y (a nti -C S L 3 1 2 ) 
Ot her  
C 1- I N H f u n cti o n al acti vit y a n d a nti g e n, a n d C 4 a nti g e n c o n ce ntrati o n 
A b bre vi ati o ns:  % = perce nta ge; a P T T = acti vate d partial t hr o m b o plasti n ti me; A L P = al kali ne p h os p hatase; 
A L T = ala ni ne a mi n otra nsferase; A S T = As partate a mi n otra nsferase; B U N = bl o o d urea nitr o ge n;  
C 1 -I N H = C 1 -esterase i n hi bit or ; F XIIa = acti vate d Fact or XII; H A E  = here ditar y a n gi oe de ma ; 
I N R = i nter nati o nal n or malize d rati o. 
F o ot n otes:  
a  
Uri ne pre g na nc y test will be c o n d ucte d at t he st u d y site. If t he uri ne pre g na nc y test is i nc o ncl usi ve, a 
ser u m pre g na nc y test will be perf or me d a n d a nal yze d at a l ocal la b orat or y. 
b  
A nal ysis will be c o n d ucte d at a ce ntral la b orat or y. A d diti o nal details will be pr o vi de d i n t he La b orat or y 
Ma n ual.   
c 
H A E bi o mar ker sa m ples will be s hi p pe d t o a ce ntral la b orat or y a n d st ore d at -7 0° C f or p ote ntial testi n g 
of H A E mar kers or use d f or researc h a n d will be destr o ye d wit hi n 5 years after c o m pleti o n of t he st u d y.  
F or a d ults o nl y.  
d  
Ce ntral la b orat or y will pr o vi de res ults i n a bli n de d ma n ner u ntil data base l oc k.  
 
Res ults of safet y la b orat or y tests ( he mat ol o g y, bi oc he mistr y, a n d uri nal ysis) c o m plete d at t he 
ce ntral  la b orat or y s h o ul d be si g ne d a n d date d a n d retai ne d at t he st u d y site as s o urce d ata. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he i n vesti gat or s h o ul d ma ke a n e v al uati o n of t h e a vaila ble s afet y- assess me nt res ults wit h 
re gar d t o cli nicall y rele v a nt a b n or malities. Refer t o Secti o n 9  f or i nf or mati o n o n h o w A Es 
base d o n la b or at or y tests s h o ul d be assesse d a n d re p orte d. 
L a b or at or y P ar a m eters 
Details relate d t o t he c ollecti o n, pre parati o n, a n d tra nsfer of bl o o d a n d uri n e sa m ples f or 
la b orat or y ass ess me nts will be pr o vi de d i n t he La b orat or y Ma n u al. 
Refer t o  Secti o n  9. 1. 1  f or assess me nt of a b n or m al la b orat or y val u es. Tests res ulti n g i n 
a b n or mal la b or at or y val u es d uri n g t he st u d y peri o d t hat ha ve bee n classifie d b y t he 
i n vesti gat or as cli nicall y si g nifica nt s h o ul d be f oll o we d u p after recei vi n g t he la b orat or y 
re p ort a n d ma y i n cl u de a n u nsc he d ule d re peat safet y sa m pli n g at t he discreti o n of t he 
i n vesti gat or. 
Vit al Si g ns  
Bl o o d press ure a n d h eart rate will be meas ure d wit h t he s u bject i n a s u pi ne or seate d p ositi o n 
after r esti n g f or at least 5 mi n utes. B o d y te m perat ure will be meas ure d eit h er s u bli n g uall y or 
t y m pa nicall y, a n d t he met h o d of meas ure me nt s h o ul d be c o nsiste nt t hr o u g h o ut t he st u d y f or a 
gi ve n s u bject. 
8. 1. 2  P h ar m ac o ki netic a n d P h ar m ac o d y n a mic  Assess me nts  
P har mac o ki netic a n d P D  assess me nts  t o be c o n d ucte d d uri n g t he st u d y are pr o vi de d i n 
Ta ble  5 . T he ti me wi n d o ws f or eac h t y pe of assess me nt are det aile d i n Secti o n  8. 7. 1 . Detail s 
relate d t o t he c ollecti o n, pre par ati o n, a n d tra nsfer of P K / P D sa m ples will be pr o vi de d i n a 
La b orat or y M a n ual.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble 5 
Cli nic al Pr oce d ures: P h ar m ac o ki netic a n d P h ar m ac o d y n a mic 
Assess me nts  
Pr oce d ure  
Descri pti o n  
P h ar m ac o ki netics 
e v al u ati o ns 
(ce ntr al l a b or at o r y) 
Plas ma sa m ples will be c ollecte d f or assess me nt of C S L 3 1 2 
c o nce ntrati o n . 
P h ar m ac o d y n a mics 
e v al u ati o ns 
(ce ntr al l a b or at o r y) 
Plas ma sa m ples will be c ollecte d f or assess me nt of F XII 
c o nce ntrati o n a n d F XIIa me diate d kalli krei n acti vit y. 
A b bre vi ati o ns:  F XII = Fact or XII; F XIIa = acti vate d Fact or XII . 
8. 1. 3  Effic ac y Assess me nts  
Efficac y assess me nts are t o be perf or m e d at ti me p oi nts as detaile d i n t he Sc he d ule of 
Assess me nts: Scree ni n g a n d R u n- i n Peri o d ( All S u bjects) a n d Sc he d ul e of Assess me nts: 
Treat me nt Peri o d . T he ti me wi n d o ws f or eac h t y p e of assess me nt are d etaile d i n 
Secti o n  8. 7. 1 . Here ditar y a n gi oe de ma  attac ks t hat are c o nfir me d b y i n vesti gat or or desi g nee 
will be use d f or t he efficac y a nal ysis a n d will be rec or de d o n t he e C R F. All H A E s y m pt o ms 
re p orte d b y t he s u bject will be dis pla ye d i n a b y-s u bject listi n g. T he i n vesti gat or will re vie w 
t he s y m pt o m(s) re p orte d b y t he s u bjects. T he i n vesti gat or s h o ul d c o nfir m if t he s y m pt o m(s) 
re pres e nt a n H A E attac k a n d, if n ot a n H A E attac k, t he n d oc u me nt t he s y m pt o m(s) as a n A E 
i n t he e C R F. A pr o dr o mal s y m pt o m b y itself or use of o n- de m a n d me dicati o n al o ne s h o ul d 
n ot be c o nsi dere d as a n attac k. A p pe n di x 2  c o ntai ns assess me nt criteria f or i n vesti gat or 
c o nfir mati o n of H A E attac ks. 
At eac h st u d y visit a n d p h o ne c o ntact d uri n g t he R u n-i n Peri o d, t he i n vesti gat or or desi g nee 
will re vie w t he s u bject’s electr o nic diar y (e Diar y) e ntries. T he i n vesti gat or will c o nsi der all 
a vaila ble me dical i nf or m ati o n a n d ma y as k clarif yi n g q uesti o ns t o assist i n t heir c o nfir mati o n  
of H A E attac k s. S u bjects will be e nc o ura g e d  t o c ontact t he st u d y site wit hi n 7 2 h o urs of t he 
o nset of si g ns or s y m pt o ms of a n H A E attac k. If t he s u bject is i nca pacitate d a n d u na ble t o 
c o ntact t he st u d y site, a f a mil y me m ber of  t he i n di vi d ual ma y c o ntact t he st u d y site t o 
pr o vi de details of t he e v e nt . T he f oll o wi n g i nf or m ati o n will be d oc u me nte d i n t he s u bject 
e Diar y:  
•  Date a n d ti me of H A E s y m pt o m o nset.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  Date a n d ti me of H A E s y m pt o m res ol uti o n ( ie, s u bject n o l o n ger e x p erie n ci n g 
s y m pt o ms of t he attac k). 
•  L ocati o n of H A E s y m pt o m(s). 
•  C o nfir mati o n  of i nterfer e nce of s y m pt o m(s) wit h t he s u bject’s dail y acti vities.  
•  If o n- de ma n d  m e dicati o n was use d t o treat H A E s y m pt o ms:  
o  Na me of me dicati o n.  
o  D ate a n d ti me of a d mi nistrati o n.  
•  C o nfir mati o n of me dical assista nce recei v e d f or t h e H A E s y m pt o ms . 
T he i n vesti gat or w ill c o nfir m a d diti o nal details wit h t he s u bject relate d t o t he sy m pt o ms: 
•  L ocati o n of H A E s y m pt o m(s). 
•  S tart/e n d date/ti me of s y m pt o m(s). 
•  D ose(s) of o n d e ma n d m e dicati o n(s) use d.  
•  R o ute(s) of A d mi nistrati o n of o n de ma n d me dicati o n(s) use d.  
•  S elf-a d mi nistere d o n de ma n d me dicati o n(s)? ( yes / n o). 
•  A d mi nistrati o n of o n de ma n d me dicati o n(s) at a st u d y site, h o me or e mer ge nc y 
r o o m.  
•  Ty pe of me dical assista nce or i nter v e nti o n pr o vi de d b y a healt hcare pr ofessi o nal 
d uri n g H A E s y m pt o ms, i ncl u di n g h os pitalizati o n or e mer g e nc y d e part me nt visits.  
•  Se verit y of t he attac k ( base d o n de gree of i nterfere nce i n dail y acti vities, a n d 
w het her or n ot t he us e of o n de ma n d me dicati o n a n d/ or me dical assista nc e was 
nee de d).  
8. 2  Ot her Assess me nts  
8. 2. 1  O utc o me Rese arc h Assess me nts  
Q ualit y of life data will b e o btai ne d usi n g t he S G A R T , A E - Q o L q u esti o n naire, E Q -5 D -5 L 
q uesti o n naire, W P AI :G H  q uesti o n naire (t o be c o m plete d b y t he s u bject i n t his or der), a n d 
I G A R T. Q ualit y of life d ata  will be ca pt ure d electr o nicall y  usi n g a pr o visi o ne d electr o ni c 
Cli nical O utc o me Assess me nt (e C O A) s ol uti o n . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he a ge c o nsi derati o ns f or t hese assess me nts are:  
•  E Q - 5 D-5 L:  all a g es 
•  S G A R T: all a ges 
•  I G A R T: all a ges 
•  W P AI: ≥ 1 6 years  
•  
A E -Q o L: ≥ 1 8 years  
8. 2. 1. 1  A n gi oe de m a Q u alit y of Life Q uesti o n n aire  
T he A E -Q o L  q u esti o n naire is a n i nstr u me nt t o ass ess q ualit y of life i m pair me nt i n s u bjects 
wit h rec urr e nt a n gi oe d e ma attac ks [ Weller et al, 2 0 1 2 ]. 
T he A E - Q o L is a q u esti o n naire t hat c o v ers 4 di me nsi o ns (f u ncti o ni n g, fati g ue / m o o d, 
fear / s ha m e, a n d n utriti o n), a n d c o nsists of 1 7 q uesti o ns wit h 5 le vels of res p o nse ( ne ver, 
rarel y, occasi o nall y, ofte n, a n d ver y oft e n). A li near tra nsf or mati o n of ra w sc ores res ults i n a 
ra n ge of p ossi ble t otal sc ores fr o m 0 ( mi ni m u m) t o 1 0 0 ( ma xi m u m). 
T he A E -Q o L will be c o m plete d usi n g a pr o visi o ne d e C O A s ol uti o n. 
F urt her details will be pr o vi de d i n t he statistical a nal ysis pla n  ( S A P). 
8. 2. 1. 2  E Q- 5 D - 5 L 
T h e E Q- 5 D- 5L is a sta n d ar dize d meas ure of healt h stat us t hat pr o vi des a si m ple, ge neric 
meas ure of h ealt h f or cli nical a n d ec o n o mic a p praisal. T he q uesti o n naire, w hic h is desi g ne d 
f or self- c o m pleti o n b y res p o n de nts, is a p plica ble t o a wi de ra n g e of h ealt h c o n diti o ns a n d 
treat me nts [E ur o Q ol Gr o u p, 1 9 9 0 ]. 
T he E Q - 5 D- 5 L c o nsists of 2 parts:  
•  A descri pti ve pr ofile, c o m prisi n g t he f oll o wi n g 5 di me nsi o ns: m o bilit y, self- care, 
us ual acti vities, pai n / disc o mf ort, a n d a n xi et y / de pressi o n. Res p o n de nts rate eac h 
di me nsi o n base d o n 5 le v els of se verit y (ie, n o pr o ble ms, sli g ht pr o ble ms, m o derate 
pr o ble ms, se ver e pr o ble ms, e xtre me pr o ble ms).  
•  A vertical, vis ual a nal o g scale, o n w hic h t he res p o n de nt rates t heir o v erall h ealt h fr o m 
‘ Best i ma gi na ble healt h state’ t o ‘ Worst ima gi na bl e healt h state .’ 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
S u bjects are t o c o m plete t he E Q - 5 D- 5 L usi n g a pr o visi o ne d e C O A s ol uti o n. A d diti o nal 
details will be pr o vi de d i n t he S A P. 
8. 2. 1. 3  Wor k Pr o d ucti vit y a n d Acti vit y I m p air me nt Q uesti o n n aire : 
Ge ner al He alt h   
T he W P AI :G H  q u esti o n naire is a n i nstr u me nt t o meas ure i m pair m e nts i n b ot h pai d a n d 
u n pai d w or k [ Reill y et al, 1 9 9 3 ]. 
T he W P AI :G H  meas ures a bse nteeis m, pres e nteeis m, as well as i m pair me nts i n u n pai d 
acti vit y beca use of healt h pr o ble ms d uri n g t he 7 da ys bef ore a d mi nistrati o n of t he 
q uesti o n naire. It has b ee n vali date d t o q ua ntif y w or k i m pair me nts f or n u mer o us diseases. T h e 
W P AI :G H  has bee n use d t o c o m pare w or k i m pair me nts bet wee n treat me nt gr o u ps i n cli nical 
st u dies or bet wee n s u bjects wit h differe nt disease se verit y le vels.  
W P AI :G H  o utc o mes are e x presse d as i m pair me nt perce nt a ges, wit h hi g her n u m bers 
i n dicati n g greater i m pair me nt a n d less pr o d ucti vit y (ie, w orse o ut c o mes).  
T he W P AI :G H  will be c o m plete d  usi n g a pr o visi o ne d e C O A s ol uti o n. 
F urt her details will be pr o vi de d i n t he S A P . 
8. 2. 1. 4  
S u bject’s Gl o b al Assess me nt of Res p o nse t o T her a p y  
T he o ver all res p o nse t o tr eat me nt wit h t he i n vesti gati o nal pr o d uct will be self -assesse d b y t he 
s u bject usi n g t he S G A R T. 
T he S G A R T will meas ur e t he s u bject’s o v erall treat me nt res p o nse t o t he i n vesti gati o nal 
pr o d uct usi n g t he f oll o wi n g rati n gs: 
•  ( 0) n o ne – w orse or n o r es p o nse at all, n ot acce pta ble 
•  ( 1) p o or – ver y little res p o nse, n ot acce pta ble  
•  ( 2) fair – s o m e res p o nse, acce pta ble b ut c o ul d be b etter  
•  ( 3) go o d – g o o d res p o ns e, acce pta ble 
•  ( 4) e xcelle nt – e xcelle nt r es p o nse, as g o o d as ca n b e i ma gi ne d 
T he S G A R T will re q uire s u bjects t o rate t he msel v es usi n g t he f oll o wi n g directi o n ( or a n 
a p pr o priate tr a nslati o n, as a p plica ble): “ C o nsi deri n g all of t he wa ys H A E affects y o u, please 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
rate y o ur r es p o nse t o t he st u d y me dicati o n y o u were gi ve n t o pre v e nt H A E attac ks d uri n g t his 
Treat me nt Peri o d .” 
T he S G A R T will be c o m plete d  usi n g a pr o visi o ne d e C O A s ol uti o n. 
F urt her details will be  pr o vi de d i n t he S A P . 
8. 2. 1. 5  
I n vesti g at or’s Gl o b al Assess me nt of Res p o nse t o T her a p y 
T he o ver all res p o nse t o tr eat me nt wit h t he i n vesti gati o nal pr o d uct will be assesse d b y t he 
i n vesti gat or usi n g t he I G A R T.  
T he I G A R T will meas ure t he s u bject’s o verall treat me nt r es p o nse t o t he i n vesti gati o nal 
pr o d uct usi n g t he f oll o wi n g rati n gs:  
•  ( 0) n o ne – w orse or n o r es p o nse at all, n ot acce pta ble  
•  ( 1) p o or – ver y little res p o nse, n ot acce pta ble  
•  ( 2) fair – s o m e res p o nse, acce pta ble b ut c o ul d be b etter  
•  ( 3) go o d – g o o d res p o ns e , acce pta ble  
•  ( 4) e xcelle nt – e xcelle nt r es p o nse, as g o o d as ca n b e i ma gi ne d  
T he I G A R T will re q uire t he i n vesti gat or t o rate s u bjects usi n g t he f oll o wi n g directi o n ( or a n 
a p pr o priate tr a nslati o n, as a p plica ble): “ C o nsi deri n g all of t he wa ys H A E affects y o ur patie nt, 
please r ate y o ur patie nt’s res p o nse t o t he st u d y me dicati o n pr o vi de d t o pre v e nt H A E attac ks 
d uri n g t his Treat me nt Peri o d.” W he n e ver p ossi ble, t he sa me i n vesti gat or will perf or m t he 
I G A R T f or eac h s u bject t hr o u g h o ut t he st u d y.  
T he I G A R T will be  c o m plete d i n t he e C R F.  
F urt her details will be pr o vi de d i n t he S A P . 
8. 2. 2  Electr o nic Di ar y a n d Electr o nic Cli nic al O utc o me Assess me nts  
T he st u d y will e m pl o y 3 r d- part y pr o visi o ne d e C O A s ol uti o n t o ca pt ure b ot h patie nt-re p ort e d 
o utc o me ( P R O) meas ur es a n d e Diar y i nf or mati o n.  
Patie nt -re p orte d o utc o m e assess me nts will be c o m plete d b y s u bjects usi n g t he e C O A s ol uti o n 
via a pr o visi o ne d electr o nic de vice ( e g, ta blet ) pr o vi de d at t he st u d y site. e Diar y e ntries will 
als o be c o m plete d via a pr o visi o ne d electr o nic d e vice (e g, h a n d hel d) a n d are t o be e ntere d b y 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
t he s u bject w hile at h o me. S u bjects will be f ull y trai ne d b y t he site staff i n t he use of t he 
e Diar y a n d t a blet . Refer t o Secti o n 8. 1. 3  f or e Diar y c o nte nt. 
T he f oll o wi n g assess me nts will be c o m plete d b y t he s u bject usi n g t he e C O A s ol uti o n at t he 
st u d y site: 
•  S G A R T  
•  A E -Q o L  
•  E Q - 5 D- 5 L 
•  W P AI :G H  
A we b p ortal will pr o vi de site staff wit h o n - d e ma n d, r ole-base d access t o all P R O data a n d 
e Diar y dat a. 
8. 3  Bl o o d S a m ples  
D uri n g t he st u d y, bl o o d will be ta ke n fr o m eac h s u bject f or la b orat or y safet y assess me nts a n d 
P K  / P D e val uati o ns. Detaile d i nf or mati o n o n t he v ol u me of bl o o d t o be sa m ple d f or eac h 
assess me nt will be a vaila ble i n t he la b orat or y ma n ual.  Re peat or u nsc h e d ul e d bl o o d sa m ples 
ma y be ta ke n f or saf et y r eas o ns or f or tec h nical iss ues wit h t he sa m ples.  
I nf or mati o n o n t he v ol u me of bl o o d t o be c ollect e d f or eac h visit will be a vaila ble i n t he 
i nf or me d c o nse nt f or m (I C F). 
Refer t o t he la b orat or y m a n ual  f or d etails a b o ut t he v ol u me, c ollecti o n, st ora ge, ha n dli n g a n d 
pr ocessi n g of bl o o d sa m ples. 
8. 4  Rete nti o n of S a m ples  
Refer t o t he la b orat or y m a n ual f or f urt her d etails a b o ut t he st ora ge a n d d estr ucti o n of 
rete nti o n sa m ples. 
8. 4. 1  Rete nti o n S a m ple f or H A E Bi o m ar kers  
Bl o o d sa m ples f or p ote ntial f ut ure assess me nt of H A E bi o mar kers will be o btai ne d d uri n g 
t he Treat me nt Peri o d at all visits, i ncl u di n g t he E n d of Treat me nt Visit ( D a y 1 8 2), as well as 
at t he F oll o w-u p Visit . T hese sa m ples will be st ore d f or p ote ntial testi n g of H A E bi o mar kers 
a n d will be destr o ye d wit hi n 5 years aft er c o m pleti o n of t he st u d y. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
8. 5  Pri or a n d C o nc o mit a nt T her a pie s 
All me dicati o ns a n d t her a pies t hat ha ve b ee n a d mi nistere d t o a s u bject wit hi n 6 m o nt hs 
bef ore si g ni n g i nf or me d c o nse nt ar e re g ar de d as pri or me dicati o ns a n d t hera pies a n d m ust be 
d oc u me nte d as s uc h i n t h e e C R F. 
All dr u gs a n d / or pr oce d ures c urre ntl y bei n g a d mi nistere d t o a s u bject at t he ti me of si g ni n g 
i nf or me d c o nse nt, a n d w hic h c o nti n ue t o be ta ke n i n a d diti o n t o i n vesti gati o nal pr o d uct 
d uri n g t he st u d y, are re g ar de d as c o n c o mita nt t hera pies. All c o n c o mita nt t hera pies will be 
rec or d e d i n t he s u bject’s e C R F. 
B ot h p har mac ol o gical ( e g, prescri pti o n a n d o ver-t he-c o u nter me dicati o ns, a n d her bal a n d 
vita mi n s u p ple me nts) a n d n o n p har mac ol o gical (e g, a n y s ur gical or di a g n ostic pr oce d ures) 
will be re p orte d. 
8. 6  Electr oc ar di o gr a ms  
A sta n dar d 1 2- lea d electr ocar di o gr a m (E C G ) will be perf or me d (si n gle rea di n g) acc or di n g t o 
t he Sc he d ule of Assess m e nts (Sc he d ule of Assess me nts: Treat me nt Peri o d ). T he date a n d 
ti me of eac h E C G will be rec or d e d i n t he s o urce d oc u me nts a n d t he e C R F. T he E C G  will be 
se nt t o a ce ntr al ve n d or f or rea di n g a n d assess me nt. 
8. 7  V isit S c he d ule  
8. 7. 1  Assess me nt Ti me Wi n d o ws  
T he ti mi n g a n d fre q ue n c y of t he st u d y visits  are descri be d i n t he Sc h e d ule of Assess me nts: 
Scree ni n g a n d R u n- i n Peri o d ( All S u bjects) a n d Sc he d ule of Assess me nts: Treat me nt Peri o d . 
Ti me wi n d o ws f or all ass ess me nts are d etaile d i n Ta ble 6 . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Ta ble 6 
Ti me Wi n d o ws f or Assess me nts  
Visit  / Pr oce d ure 
Ti m e wi n d o w  (rel ati ve t o sc he d ule d visit / 
pr oce d ure)  
Scree ni n g  
N ot a p plica ble  
R u n -i n Peri o d:  Visit Da ys 1 5, 3 0, 4 5, a n d 6 0  
± 4  da ys  
Treat me nt Peri o d: Visit Da ys 3 1 , 6 1 , 9 1 , 1 2 1 , 1 5 1 , 
1 8 2  
± 4  da ys  
F oll o w -u p : Visit Da y 2 4 2  
- 1 4  da ys  
Vital si g ns , p h ysical e xa mi nati o n, a n d pre g na nc y 
test 
Prei njecti o n  o n sa me da y  
 
8. 7. 2  Scree ni n g  Visit  
All s u bjects ( or t he s u bject’s a ut h orize d re pres e ntati ve) m ust pr o vi de writte n i nf or me d 
c o nse nt bef or e a n y st u d y- s pecific assess me nts or pr oce d ures are perf or me d. Writte n i nf or me d 
c o nse nt is n ot re q uire d f or assess me nts or pr o ce d ures p er f or me d acc or di n g t o sta n dar d of 
care (e g, f or dia g n osis or treat me nt); res ults fr o m s uc h assess me nts ma y be use d i n t he 
deter m i nati o n of st u d y eli gi bilit y. S u bjects will be all o we d t o be res cree ne d  (see Secti o n  4. 2 ). 
A scree ni n g e x a mi nati o n s h o ul d be perf or m e d wit hi n 3 0 da ys bef ore t he start of t he R u n-i n 
Peri o d .  
T he f oll o wi n g pr oce d ures will be c o n d ucte d a n d d oc u me nte d at t he S cree ni n g V isit: 
•  O btai n writte n i nf or me d c o nse nt a n d re gister t he s u bject via t he I R T.  
•  Re vi e w i ncl usi o n a n d e x cl usi o n criteria. 
•  O btai n rele va nt m e di cal hist or y i ncl u di n g o verall healt h f or at least t he 6 m o nt hs bef ore 
t he S cree ni n g V isit, H A E hist or y bef ore Scree ni n g , a n d c o ntrace pti o n met h o d (f or 
fe males of c hil d beari n g p ote ntial o nl y). 
•  Rec or d s u bject de m o gra p hics . 
•  C ollect uri ne f or pr e g na n c y test (f or se x uall y acti v e w o me n of c hil d beari n g p ote ntial).  
•  Perf or m p h ysical e x a mi nati o n . 
•  Rec or d  vital si g ns, i ncl u di n g hei g ht a n d b o d y wei g ht . 
•  C ollect uri ne  f or uri nal ysis. 
•  C ollect bl o o d f or: 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 6 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
o  He mat ol o g y 
o  Bi oc he mistr y  
o  C oa g ulati o n 
o  C 1 -I N H f u ncti o nal acti vit y a n d a nti ge n, a n d C 4 a nti ge n c o nce ntrati o n  f or 
c o nfir mati o n of hist orical la b orat or y val u es c o ntai ne d i n t he s u bject’s me di cal rec or d. 
•  De vel o p  a n i n di vi d ual ac ute acti o n pla n, i ncl u di n g assess me nt of s u bject’s a bilit y t o 
ma na ge H A E attac ks a n d c o nfir mati o n of s u bject’s access t o o n -d e ma n d H A E me dicati o n 
t o treat H A E attac ks. 
•  Perf or m e Diar y trai ni n g  
•  Rec or d pri or a n d c o nc o mita nt me dicati o ns a n d t h era pies (t y pe, d os e, r o ute, date, a n d 
ti me) i n t he last 6 m o nt hs. 
•  Be gi n t o m o nit or A Es. 
Re -scree ni n g: If a p ot e ntial s u bject is n ot eli gi ble f or e ntr y i nt o t he R u n-i n Peri o d wit hi n 
3 0 da ys after pr o vi di n g i nf or me d c o ns e nt, t he n t he s u bjects ma y re- c o nse nt a n d ma y be 
scree n e d a g ai n (f or a ma xi m u m of 2 Scree ni n g Peri o ds per s u bject) after c o ns ultati o n wit h 
C S L . I n t he e ve nt t hat a p ote ntial s u bject is scree ne d t wice, all Scree ni n g assess me nts m ust 
be re peate d d uri n g t he s ec o n d Scree ni n g Peri o d. If t he s u bject is n ot eli gi ble f or t he st u d y 
(ie, t he s u bject is a Scr ee n Fail ure), all eli gi bilit y criteria t hat are n ot met m ust be rec or d e d i n 
I R T.  
8. 7. 3  R u n -i n Peri o d 
8. 7. 3. 1  R u n -i n Peri o d : Visit D a y 1  
S u bjects w h o c o m plete all Scree ni n g  assess me nts a n d w h o f ulfill t he eli gi bilit y criteria 
(ie, eli gi ble s u bjects) will be e nr olle d i nt o t he st u d y.  T he first da y of t he R u n-i n Peri o d a n d 
Scree ni n g  ma y occ ur o n t he sa me da y. If t h e R u n-i n Peri o d be gi ns after Scree ni n g , t he n t he 
first da y of t he R u n-i n Peri o d be gi ns wit h a tele p h o ne c o ntact. 
T he f oll o wi n g pr oce d ures will be c o n d ucte d: 
•  Re -co nfir m s u bject eli gi bilit y . 
•  Rec or d start of R u n-i n Peri o d i n I R T. 
•  Tel e p h o ne co nt act f or all s u bjects ( n ot a p plica ble if perf or me d o n sa me d a y as Scree ni n g 
Visit) . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  e Diar y tr ai ni n g if i nitial trai ni n g was c o n d u cte d 3 0 da ys bef ore R u n-i n Peri o d. 
•  O pe n s u bject access t o e Diar y a n d re vie w diar y i nstr ucti o ns wit h s u bject. 
•  e Diar y c o m pleti o n b y s u bject. 
•  C o nfir m access t o o n - d e ma n d H A E me dicati o n. 
•  Rec or d pri or a n d c o nc o mita nt me dicati o ns a n d t hera pies (t y pe, d os e, r o ute, date, a n d 
ti me). 
•  Rec or d A Es.  
8. 7. 3. 2  R u n -i n Peri o d : Visit D a ys 1 5, 3 0, a n d 4 5 ± 4 d a ys  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at Visit Da ys 1 5, 3 0, a n d 4 5 d uri n g t he R u n-i n 
Peri o d: 
•  Tele p h o ne c o nt act f or all s u bjects.  
•  e Diar y c o m pleti o n b y s u bject. 
•  Re vie w of e Di ar y data.  
•  Assess / d oc u me nt H A E attac ks.  
•  C o nfir m acce ss t o o n- d e ma n d H A E me dicati o n. 
•  Rec or d c o n c o mita nt me dicati o ns a n d t hera pi es (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es . 
S u bjects m ust partici pate i n t he R u n -i n Peri o d f or at least 1 m o nt h. S u bjects ma y e xit t he 
R u n- i n Peri o d a n d e nter t he Treat me nt Peri o d w h e n t he y ha ve met t he criteria s pecifie d i n 
pr ot oc ol ( Secti o n 4. 1 ). Specificall y, s u bjects m ust ha ve e x p erie nce d a n a vera ge of 1 H A E 
attac k per m o nt h d uri n g t he 2- m o nt h R u n-i n Peri o d (ie, f or a mi ni m u m of 2 H A E attac ks if 
t he s u bject e nters t he Treat me nt Peri o d wit h 2 m o nt hs fr o m Da y 1 of R u n-i n).  
8. 7. 3. 3  R u n -i n Peri o d: D a y 6 0 ± 4 d a ys  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at Visit Da y  6 0 d uri n g t he R u n-i n Peri o d: 
•  Tele p h o ne c o nt act f or all s u bjects .  
•  e Diar y c o m pleti o n b y s u bject. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  Re vie w of e Di ar y data.  
•  Cl ose e Diar y access ( o nl y a p plica ble f or s u bjects n ot eli gi ble t o e nter t he Treat me nt 
Peri o d).  
•  C o nfir m acce ss t o o n- d e ma n d H A E me dicati o n. 
•  Rec or d c o n c o mita nt me dicati o ns a n d t hera pi es (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
S u bjects s h o ul d e nter t he Treat me nt Peri o d n o later t ha n 1 5 da ys after t he D a y 6 0 tele p h o ne 
c o ntact. If a s u bject is u n a ble t o e nter t he Treat me nt Peri o d wit hi n t he 1 5 da ys after t h e 
Da y  6 0 tele p h o ne c o ntact, t he n C S L a p pr o val is re q uire d f or t he s u bject t o e nter t he 
Treat me nt Peri o d. T h e D a y 6 0 tele p h o ne c o ntact will c o ncl u de t he R u n-i n Peri o d f or a 
s u bject w h o has e ntere d t he R u n-i n Peri o d a n d is s u bse q ue ntl y n ot eli gi ble t o be assi g ne d t o 
treat me nt wit h i n vesti gati o nal pr o d uct i n t he Treat me nt Peri o d. 
 
S u bjects w h o e nter t he R u n- i n Peri o d b ut are n ot eli gi ble t o e nter t he Treat me nt Peri o d will 
be c o nsi der e d R u n-i n fail ures. If a s u bject is n ot eli gi ble t o e nter t he Treat m e nt Peri o d, t he 
pri mar y reas o n f or R u n-i n fail ure m ust be d oc u me nte d. T hese s u bjects ma y n ot be 
rescr ee ne d. 
8. 7. 4  Tre at me nt Peri o d  
8. 7. 4. 1  Tre at me nt Peri o d: Visit D a y 1 
S u bjects w h o c o m plete all scree ni n g assess me nts , f ulfill t he eli gi bilit y criteria (ie, eli gi ble 
s u bjects), a n d meet t he Treat me nt Peri o d e ntr y criteria (Secti o n 4. 1. 3 ) will be ra n d o mize d t o 
i n vesti gati o nal pr o d uct. T he f oll o wi n g pr oce d ures are t o be c o n d ucte d a n d d oc u me nte d: 
•  C o nfir m eli gi bilit y f or Treat me nt Peri o d . 
•  Ra n d o mizati o n a n d assi g n me nt of i n vesti gati o nal pr o d uct via I R T. 
•  C ollect uri ne f or pr e g na n c y test (f or se x uall y acti v e w o me n of c hil d beari n g p ote ntial).  
•  Perf or m p h ysical e x a mi nati o n.  
•  Rec or d vital si g ns a n d b o d y wei g ht. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  Perf or m E C G  ( E C G ma y be perf or me d d uri n g t he R u n-i n Peri o d as a n alter nati ve). 
•  Uri ne c ollecti o n f or uri nal ysis * 
•  C ollecti o n of bl o o d t o assess: 
o  He mat ol o g y. *  
o  Bi oc he mistr y .* 
o  C oa g ulati o n.  * 
o  H A E bi o mar kers (ret e nti o n sa m ple) (a d ults o nl y). 
o  P K  / P D.  
o  I m m u n o ge nicit y. 
•  Rec or d  c o n c o mita nt me dicati o ns a n d t hera pi es (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
•  P R O / e C O A ta blet trai ni n g . 
•  S u bject t o c o m plete : 
o  A E -Q o L  (s u bjects ≥ 1 8 years). 
o  E Q - 5 D-5 L.  
o  W P AI: G H  (s u bjects ≥ 1 6 years). 
•  e Diar y c o m pleti o n b y s u bject. 
•  Re vie w e Diar y data, i ncl u di n g i n vesti gat or assess me nt of H A E s y m pt o ms a n d 
d oc u me ntati o n of H A E attac ks.  
•  C o nfir m access t o o n - d e ma n d H A E me dicati o n. 
•  O btai n  i n vesti gati o nal pr o d uct kit assi g n me nt i n I R T. 
•  S u bc uta ne o us a d mi nistrati o n of i n vesti gati o nal pr o d uct l oa di n g d ose b y i n vesti gat or or 
dele gate  ( after c o m pleti o n of pre g na n c y test, p h y sical e xa mi nati o n, vital si g ns, a n d 
c ollecti o n of bl o o d sa m ples). 
•  Acc o u nta bilit y of i n vesti gati o nal pr o d uct. 
* A ssess me nt ma y be o mitte d if Scree ni n g / R u n- i n Peri o d assess me nts occ urre d wit hi n t he 
pre vi o us 3 m o nt hs. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
8. 7. 4. 2  Tre at me nt Peri o d: Visit D a ys 3 1, 6 1, 1 2 1, a n d 1 5 1 ( ± 4 d a ys ) 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 6 1 a n d D a y 1 5 1 ( ± 4  da ys) site visits: 
•  C ollect uri ne f or pr e g na n c y test (f or w o m e n of c hil d beari n g p ote ntial a n d s e x uall y 
acti ve).  
•  Perf or m p h ysical e x a mi nati o n.  
•  Rec or d vital si g ns a n d b o d y wei g ht. 
•  C ollecti o n of bl o o d t o assess: 
o  P K / P D.  
o  H A E bi o mar kers (ret e nti o n sa m ple) (a d ults o nl y). 
•  Rec or d  c o n c o mita nt me dicati o ns a n d t hera pi es (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
•  S u bject t o c o m plete : 
o  A E -Q o L  (s u bjects ≥ 1 8 years). 
o  W P AI: G H  (s u bjects ≥ 1 6 years). 
•  e Diar y c o m pleti o n b y s u bject. 
•  Re vie w e Diar y data, i ncl u di n g i n vesti gat or assess me nt of H A E s y m pt o ms a n d 
d oc u me ntati o n of H A E attac ks.  
•  C o nfir m access t o o n - d e ma n d H A E me dicati o n. 
•  O btai n  i n vesti gati o nal pr o d uct kit assi g n me nt i n I R T. 
•  S u bc uta ne o us a d mi nistrati o n of i n vesti gati o nal pr o d uct b y s u bject u n der s u per visi o n 
(after c o m pleti o n of pre g na nc y test, p hysical e x a mi nati o n, vital si g ns , a n d bl o o d sa m ple 
c ollecti o n). 
•  Acc o u nta bilit y of i n vesti gati o nal pr o d uct. 
•  Offer s u bject o pti o n t o e nr oll i n St u d y C S L 3 1 2 _ 3 0 0 2 ( Da y 1 5 1 o nl y). 
8. 7. 4. 3  Tre at me nt Peri o d: Visit D a y 9 1 ± 4 d a ys  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 9 1 ± 4  da ys site visit: 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  C ollect uri ne f or pr e g na n c y test (f or w o m e n of c hil d beari n g p ote ntial a n d s e x uall y 
acti ve).  
•  Perf or m p h ysical e x a mi nati o n.  
•  Rec o r d vital si g ns a n d b o d y wei g ht. 
•  Uri ne c ollecti o n f or uri nal ysis.  
•  C ollecti o n of bl o o d t o assess: 
o  He mat ol o g y. 
o  Bi oc he mistr y.  
o  C oa g ulati o n. 
o  P K / P D . 
o  H A E bi o mar kers (ret e nti o n sa m ple) (a d ults). 
o  I m m u n o ge nicit y. 
•  D oc u me nt c o nc o mita nt me dicati o ns a n d t hera pies (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
•  S u bject t o c o m plete:  
o  S G A R T.  
o  A E -Q o L  (s u bjects ≥ 1 8 years). 
o  E Q - 5 D- 5 L. 
o  W P AI: G H  (s u bjects ≥ 1 6 years). 
•  I G A R T. 
•  e Diar y c o m pleti o n b y s u bject. 
•  Re vie w e Diar y data, i ncl u di n g i n vesti gat or assess me nt of H A E s y m pt o ms a n d 
d oc u me ntati o n of H A E attac ks.  
•  C o nfir m access t o o n - d e ma n d H A E me dicati o n. 
•  O btai n  i n vesti gati o nal pr o d uct kit assi g n me nt i n I R T. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  S u bc uta ne o us a d mi nistrati o n of i n vesti gati o nal pr o d uct b y s u bject u n der s u per visi o n 
(after c o m pleti o n of pre g na nc y test, p hysical e x a mi nati o n, vital si g ns , a n d bl o o d sa m ple 
c ollecti o n). 
•  Acc o u nta bilit y of i n vesti gati o nal pr o d uct. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
8. 7. 4. 4  E n d of Tre at me nt Peri o d: Visit D a y 1 8 2  ± 4 d a ys  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t he Da y 1 8 2 ± 4  da ys site visit: 
•  C ollect uri ne f or pr e g na n c y test (f or se x uall y acti v e w o me n of c hil d beari n g p ote ntial).  
•  Perf or m p h ysical e x a mi nati o n.  
•  Rec or d vital si g ns a n d b o d y wei g ht. 
•  Perf or m  E C G . 
•  Uri ne c ollecti o n f or uri nal ysis. 
•  C ollecti o n of bl o o d t o assess: 
o  He mat ol o g y. 
o  Bi oc he mistr y.  
o  C oa g ulati o n. 
o  H A E bi o mar kers (ret e nti o n sa m ple) (a d ults o nl y). 
o  P K / P D.  
o  I m m u n o ge nicit y. 
•  D oc u me nt c o nc o mita nt me dicati o ns a n d t hera pies (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
•  S u bj ect t o c o m plete:  
o  S G A R T.  
o  A E -Q o L  (s u bjects ≥ 1 8 years). 
o  E Q - 5 D- 5 L. 
o  W P AI: G H  (s u bjects ≥ 1 6 years). 
•  I G A R T. 
•  e Diar y c o m pleti o n b y s u bject. 
•  Re vie w e Diar y data, i ncl u di n g i n vesti gat or assess me nt of H A E s y m pt o ms a n d 
d oc u me ntati o n of H A E attac ks.  
•  De vice d eacti vati o n ( e g, e Diar y a n d Ta blet) (f or s u bjects e nteri n g St u d y C S L 3 1 2 _ 3 0 0 2). 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  C o nfir m access t o o n - d e ma n d H A E me dicati o n. 
8. 7. 5  F oll o w -u p Tele p h o ne C o nt act or  Fi n al Visit  
F oll o w- u p is o nl y a p plica ble t o s u bjects n ot e nteri n g t he p hase 3 b  St u d y C S L 3 1 2 _ 3 0 0 2. T hi s 
visit ma y be wai ve d i n place of a tele p h o n e c o ntact. If t he visit is t o be c o n d ucte d i n pers o n, 
t he f oll o wi n g pr oce d ur es will be perf or me d b y t h e i n vesti gat or or dele gat e at F oll o w- u p : Visit 
Da y 2 4 2 (- 1 4) da ys; 3 m o nt hs after t he last i n vesti gati o nal pr o d uct a d mi nistrati o n  or u p o n a 
s u bject’s earl y ter mi nati o n fr o m t he st u d y: 
•  C ollecti o n of bl o o d t o assess: 
o  H A E bi o mar kers (ret e nti o n sa m ple) (a d ults o nl y). 
o  P K  / P D.  
•  D oc u me nt c o nc o mita nt me dicati o ns a n d t hera pies (t y pe, d ose, r o ute, d ate, a n d ti me). 
•  Rec or d A Es.  
•  Re vie w e Diar y data, i ncl u di n g i n vesti gat or assess me nt of H A E s y m pt o ms a n d 
d oc u me ntati o n of H A E attac ks.  
•  De vice d eacti vati o n ( e g, e Diar y a n d Ta blet)  (f or s u bjects n ot e nteri n g 
St u d y C S L 3 1 2 _ 3 0 0 2 ). 
8. 7. 6  E n d of St u d y  
T he  sc he d ule d e n d of st u d y partici pati o n f or a n i n di vi d ual s u bject occ urs wit h c o m pleti o n of 
Da y 2 4 2 (- 1 4 d a ys ) or u p o n e ntr y i nt o t he phase 3 b  st u d y at Da y 1 8 2, after w hic h n o f urt her 
st u d y-relate d pr o ce d ur es will be perf or me d.  
9  A d verse E ve nt s 
9. 1  D efi niti o ns  
9. 1. 1  A d verse E ve nt  
As per t he I C H  To pic E 2 A ( Cli nical Safet y Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or 
E x pe dite d Re p orti n g) , a n A E is a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har m ace utical pr o d uct a n d w hic h d oes n ot necessaril y 
ha ve a ca usal r elati o ns hi p wit h t his treat me nt . A n A E ca n, t heref ore, be a n y u nfa v ora bl e a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal, cli nicall y si g nifica nt la b orat or y fi n di n g), s y m pt o m, 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
or disease te m p or all y ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct, 
w het her or n ot c o nsi dere d relate d t o t he me dici n al (i n vesti gati o nal) pr o d uct.  
T he peri o d of o bs er vati o n f or A Es e xte n ds fr o m t he ti me t he s u bject gi ves i nf or me d c o nse nt 
u ntil t he e n d of st u d y (see Secti o n 9. 4  f or f urt her details). 
 A d vers e e ve nts ma y i n cl u de:  
•  E xacer bati o n (ie, a n i n cr ease i n t he fre q ue n c y or s e verit y) of a pre -e xisti n g c o n diti o n. 
Ill ness pr ese nt bef ore st u d y e ntr y s h o ul d be rec or d e d i n t he me dical hist or y secti o n of t he 
e C R F a n d o nl y be re p ort e d as a n A E if t here is a n i ncreas e i n t he fre q ue nc y or se verit y of 
t he c o n diti o n d uri n g t he st u d y.  
•  A cli nical e ve nt o cc urri n g after c o nse nt b ut bef ore i n vesti gati o nal pr o d uct a d mi nistrati o n. 
•  I nterc urre nt ill nesses wit h a n o nset after a d mi nistrati o n of i n vesti gati o nal pr o d uct. 
A d verse e ve nts d o n ot i ncl u de: 
•  E ve nts i de ntifie d at Scree ni n g  t hat meet e xcl usi o n criteria. 
•  Me dical or s ur gical pr oce d ures (t he c o n diti o n t hat lea ds t o t he pr oce d ure is t he A E). 
•  Sit uati o ns w here a n u nt o war d me dical occ urre n ce has n ot ta ke n place. F or e xa m ple:  
o  Pla n ne d h os pitalizati o ns d ue t o pre-e xisti n g c o n diti o ns, w hic h ha ve n ot w orse ne d. 
o  H os pitalizati o ns t hat occ ur f or pr o ce d ures n ot d ue t o a n A E (e g, c os metic s ur ger y). 
o  H os pitalizati o ns f or a dia g n ostic pr oce d ure w here t he h os pital sta y is less t ha n 
2 4 h o urs i n d urati o n or f or n or mal ma na g e me nt pr oce d ures (e g, c he m ot hera p y). 
o  O ver d ose of i n vesti gati o nal pr o d uct or a n y c o nc o mita nt t hera p y t hat d oes n ot res ult i n 
a n y a d vers e si g ns or s y m pt o ms.  
F or la b orat or y safet y par a meters, a n y i nsta n ces of a bs ol ute val ues bei n g o utsi de t he refere n ce 
ra n ge or c ha n g es at a n y visit after st u d y start t hat are c o nsi dere d b y t he i n vesti gat or as 
cli nicall y si g nifica nt m ust be rec or de d i n t he e C R F  as A Es. I n a d diti o n, at t he i n vesti gat or’s 
discreti o n, a n y c h a n ges or tre n ds o ver ti me i n la b orat or y para meters ca n b e rec or d e d i n t he 
e C R F as A Es if s uc h c h a n ge s or tre n ds are c o nsi dere d t o be cli nicall y rele v a nt, e ve n if t he 
a bs ol ute val ues ar e wit hi n t he ref ere n ce ra n ge.  
La b orat or y fi n di n gs d o n ot nee d t o be re p orte d as A Es i n t he f oll o wi n g cas es: 
•  La b orat or y p ara m eters alrea d y be y o n d t h e refere n ce ra n g e at Scre e ni n g, u nless a f urt her 
i ncreas e / decr eas e ca n b e c o nsi dere d a n e x acer bati o n of a pre -e xisti n g c o n diti o n.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 7 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  A b n or mal la b orat or y p ar a meters ca use d b y mec ha nical or p h ysical i nfl ue n ces o n t he 
bl o o d sa m ple (e g, i n vitr o he m ol ysis) a n d fla g ge d as s uc h b y t he la b orat or y i n t he 
la b orat or y r e p ort. 
•  A b n or mal par a meters t hat are o b vi o usl y bi ol o gicall y i m pla usi ble (e g, val ues t hat are 
i nc o m pati ble wit h life or o utsi de t he meas uri n g ra n ge). 
•  A n a b n or mal la b or at or y val ue t hat ca n n ot b e c o nfir me d after re p eat a nal ysis, prefera bl y 
i n t he sa me la b orat or y (ie, t he pre vi o us res ult c o ul d be mar ke d as n ot vali d a n d s h o ul d n ot 
necessaril y be re p orte d as a n A E).  
9. 1. 2  Seri o us A d verse E ve nt  
A S A E is defi ne d a s a n y u nt o war d me dical o cc urre nce t hat at a n y d ose: 
•  Res ults i n de at h  – T he e ve nt m ust be t he ca use of deat h f or t he S A E t o meet t his seri o us 
criteri o n.  
•  Is life-t hre at e ni n g – T he ter m “life -t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject 
was at ris k of  deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it ha d b ee n m ore s e vere. 
•  Re q uires i n - p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n – C S L 
c o nsi ders “ h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n” f or at least 
2 4 h o urs as t he defi ni n g criteri o n f or a n S A E. H os pital a d missi o ns f or pla n ne d s ur ger y or 
f or n or mal diseas e ma na ge me nt pr oce d ures (e g, c he m ot hera p y) are n ot c o nsi dere d as 
defi ni n g criteria f or S A Es.  
•  Res ul ts i n persiste nt or si g nific a nt dis a bilit y or i nc a p acit y. 
•  Is a c o n ge nit al a n o m al y or birt h defect. 
•  Is m e dic all y si g nific a nt – A me dicall y si g nifica nt e ve nt is defi ne d as a n e v e nt t hat d oes 
n ot necessaril y meet a n y of t he S A E criteri a, b ut w hic h is j u d ge d b y a p h ysicia n t o 
p ote ntiall y je o par dize t he s u bject or re q uire me dical or s ur gical i nter v e nti o n t o pre ve nt 
o ne of t he a b o v e o utc o m es liste d as a n S A E criteri o n. 
A d verse e ve nts t hat d o n ot fall i nt o t he a b o ve cat e g ories are d efi ne d as n o nseri o us A Es. 
9. 1. 3  A d vers e E ve nt of S peci al I nterest  
T here are s e ver al A Es t h at will be m o nit ore d as A E SIs  t o e na ble a n a d e q uate ris k- be nefit 
e val uati o n of C S L 3 1 2.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he f oll o wi n g e ve nts will be c o nsi dere d A E SIs : 
•  T hr o m b oe m b olic e ve nts. 
o  A n y s yste mic T E E is c o nsi dere d a n S A E a n d s h o ul d be re p orte d as s uc h. 
A d diti o nall y, a n y n o n- s yste mic T E E (e g, a T E E ass ociate d wit h vasc ular 
access) t hat meets t he seri o us criteria m ust be re p orte d as a n S A E.  
o  A n y n o n- seri o us access-relate d t hr o m b osis s h o ul d be e ntere d as a n A E o n t he 
e C R F a n d will  be part of t he re g ular re vie w of A Es of s pecial i nterest b y t he 
I D M C. 
•  Blee di n g e ve nts.  
o  All blee di n g e ve nts t hat are a b n or m al a n d, i n t he o pi ni o n of t he i n vesti gat or, 
are c o nsi d ere d S A Es s h o ul d be re p orte d as s uc h. 
•  Se vere H y p erse nsiti vit y  / A na p h yla xis.  
o  All e ve nts of se vere h y perse nsiti vit y/a na p h yla xis are c o nsi dere d S A Es a n d 
s h o ul d be re p orte d as s uc h. 
T he re p orti n g r e q uire me nts f or A E SIs are detaile d i n Secti o n 9. 6. 2 . 
9. 2  Se verit y of A d verse E ve nts  
T he se verit y of eac h A E  (ie, n o n-seri o us a n d seri o us A Es) is t o be assess e d b y t he 
i n vesti gat or as f oll o ws: 
Se verit y  
Defi niti o n  
Mil d  
A t y pe of A E  t hat is us uall y tra nsie nt a n d ma y re q uire o nl y mi ni mal 
treat me nt or t her a pe utic i nter ve nti o n. T he e ve nt d oes n ot ge nerall y i nterfere 
wit h us ual acti vities of dail y li vi n g.  
M o derate  
A t y pe of A E  t hat is us uall y alle viate d wit h a d diti o nal s pecific t hera pe utic 
i nter ve nti o n. T he e v e nt i nterferes wit h us ual acti vities of dail y li vi n g, 
ca usi n g disc o mf ort b ut p oses n o si g nifica nt or per ma ne nt ris k of har m t o t h e 
s u bject. 
Se vere  
A t y pe of A E  t hat i nterr u pts us ual acti vities of dail y li vi n g, or si g nifica ntl y 
aff ects cli nical stat us, or ma y re q uire i nte nsi ve t h era pe utic i nter v e nti o n.  
S o urce: C DI S C S D T M Se verit y I nte nsit y Scale f or A d verse E ve nt Ter mi n ol o g y . 
9. 3  C a us alit y of A d verse E ve nts  
T he ca us al relati o ns hi p of a n A E t o i n vesti gati o nal pr o d uct , t he me dical d e vice (c o nstit ue nt), 
or t he c o m bi nati o n of de vice a n d i n vesti gati o nal pr o d uct, m ust  al w a ys be assesse d b y t he 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
i n vesti gat or. All A Es  will be classifie d as eit her rel ate d  or n ot rel ate d  t o i n vesti gati o nal 
pr o d uct, t he me dical d e vice (c o nstit ue nt), or t he c o m bi nati o n of de vice a n d i n vesti gati o nal 
pr o d uct. If a ca us alit y assess me nt is n ot pr o vi de d f or a n A E (i ncl u di n g a n S A E), t hat A E will 
be c o nsi der e d relat e d t o i n vesti gati o nal pr o d uct, t he me dical de vice (c o nstit ue nt), or t he 
c o m bi nati o n of de vice a n d i n vesti gati o nal pr o d uct.  
T he de gr ee of cert ai nt y wit h w hic h a n A E is attri b ute d t o i n vesti gati o nal pr o d uct or a n 
alter nati ve ca use ( e g, nat ural hist or y of t he u n derl yi n g disease, c o nc o mita nt t hera p y) will be 
deter mi ne d b y h o w w ell t he e ve nt ca n be u n d erst o o d i n ter ms of: 
•  K n o w n p har mac ol o g y of i n vesti gati o nal pr o d uct. 
•  Cli nicall y a n d  / or pat h o p h ysi ol o gicall y pla usi ble c o nte xt. 
•  Reacti o n of a si milar nat ure pre vi o usl y o bser ve d wit h si milar pr o d ucts, or re p orte d i n t he 
literat ure f or si milar pr o d ucts as bei n g pr o d uct relate d (e g, hea dac h e, facial fl us hi n g, 
pall or). 
•  Pla usi bilit y s u p p orte d b y t he te m p oral relati o ns hi p ( e g, t he e v e nt bei n g rel ate d b y ti me t o 
a d mi nistrati o n or ter mi nati o n of treat me nt wit h i n vesti gati o nal pr o d uct, dr u g wit h dra wal 
or re pr o d u ce d o n r ec h alle n ge). 
9. 4  O bser v ati o n Peri o d f or A d verse E ve nts  
T he o bser vati o n peri o d f or t he re p orti n g of A E s (a n d S A Es) f or a n i n di vi dual s u bject will 
start at t he ti me of gi vi n g writte n i nf or me d c o ns e nt f or partici pati o n i n t he c urre nt st u d y a n d 
fi nis h u p o n t he s u bject’s fi nal visit. 
If t he i n vesti gat or bec o m es a ware of a n S A E t hat has starte d after t he o bs er vati o n peri o d has 
fi nis he d, a n d t here is at least a p ossi ble ca us al rel ati o ns hi p wit h t he  i n vesti gati o nal pr o d uct or 
me dical de vice c o nstit ue nt, t he e ve nt m ust be re p orte d t o C S L f oll o wi n g t he sa me ti meli nes 
a n d pr oce d ures des cri be d f or S A Es occ urri n g d uri n g t he st u d y (see Secti o n 9. 6. 3 ). 
9. 5  F oll o w -u p of A d verse E ve nts  
E ver y eff ort s h o ul d be m a de t o f oll o w A Es u ntil res ol uti o n or sta bilizati o n. O n g oi n g, 
n o n-seri o us A Es t h at ha v e n ot res ol ve d or sta bilize d will be f oll o we d u ntil t he s u bject 
c o m pletes t he st u d y. Seri o us a d verse e ve nts will be f oll o we d u ntil t he A E res ol ves, sta bilizes, 
or t he s u bject is l ost t o f oll o w - u p. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
9. 6  A d verse E ve nt R e p orti n g 
9. 6. 1  A d verse E ve nts  
At eac h cli nical e val uati o n, t he i n vesti gat or ( or del e gate) will deter mi ne w h et her a n y A Es 
ha ve occ urr e d. All A Es are t o be r ec or d e d i n t he e C R F. If k n o w n, t he me dical dia g n osis of a n 
A E s h o ul d be rec or de d i n prefere nce t o t he listi n g of i n di vi d ual si g ns, la b orat or y fi n di n gs, 
a nd / or s y m pt o ms. T he i n vesti gat or m ust f oll o w u p o n t he c o urse of a n A E u ntil res ol uti o n or 
sta bilizati o n. If a n A E  is o n g oi n g after t he e n d of st u d y visit, t he A E will c o nti n ue t o be 
f oll o we d u p u ntil res ol uti o n, sta bilizati o n, or t he s u bject is l ost t o f oll o w- u p. 
If, d uri n g t he st u d y peri o d, a s u bject pres e nts wit h a pre-e xisti n g c o n diti o n t hat was n ot n ote d 
at t he ti me of st u d y e ntr y, t he c o n diti o n s h o ul d be retr os pecti vel y rec or d e d i n t he Me dic al 
Hist or y e C R F. 
9. 6. 2  A d verse E ve nts of S peci al I nterest  
A d verse e ve nts of s pecial i nterest s h o ul d be re p ort e d f oll o wi n g e x pe dite d re p orti n g 
pr oce d ur es, as des cri be d f or S A Es ( Secti o n  9. 6. 3 ). See Secti o n 9. 1. 3  f or a list of A E SIs.  
9. 6. 3  S eri o us A d verse E ve nt s 
T his st u d y will c o m pl y wit h all a p plica ble re g ulat or y re q uire m e nts a n d a d h ere t o t he f ull 
re q uire me nts of I C H To pic E 2 A ( Cli nical Safet y Data Ma na ge me nt: Defi niti o ns a n d 
Sta n dar ds f or E x p e dite d Re p orti n g). 
F or S A Es occ urri n g d uri n g t he st u d y, t he i n vesti gat or or dele g ate will e nter all rele v a nt 
i nf or mati o n i n t he e C R F. 
All S A Es t h at occ ur d uri n g t he c o urse of t he st u d y, w het her or n ot c a us all y rel ate d t o 
i n vesti g ati o n al pr o d uct, must be e ntere d i nt o t he e C R F i m me di atel y  ( wit hi n 2 4 h o urs of 
t he i n vesti g at or bec o mi n g a w are of t he e ve nt). F or J a p a n sites o nl y, t he i n vesti g at or 
m ust als o i nf or m t he he a d of t he me dic al i nstit uti o n of t he S A E a n d rel ate d i nf or m ati o n 
i n acc or d a nce wit h t he J a p a nese re g ul at or y re q uire me nt a n d I C H G C P. 
A d verse e ve nts occ urri n g i n t he peri o d bet wee n t he ti me t he s u bject ga ve writte n i nf or me d 
c o nse nt a n d t he first e x p os ure t o i n vesti gati o nal pr o d uct, a n d t hat meet 1 or m ore of t he 
seri o us ness criteria, m ust be e nter e d i nt o t he e C R F i n t he sa me ma n ner as ot her S A Es a n d 
will be i ncl u de d i n t he cli nical st u d y data base.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A n y S A E t hat occ urs after t he E n d of St u d y V isit t hat is c o nsi dere d t o be ca usall y relate d t o 
i n vesti gatio nal pr o d uct m ust be re p orte d i m me di atel y (ie, wit hi n 2 4 h o urs of t he 
i n vesti g at or bec o mi n g a w are of t he e v e nt) t o C S L. S uc h e ve nts are n ot e ntere d i nt o t he 
e C R F. F or Ja pa n sites o nl y, t he i n vesti gat or m ust als o i nf or m t he hea d of t h e me dical 
i nstit uti o n of t he S A E a n d relate d i nf or m ati o n i n acc or da n ce wit h t he J a pa n ese re g ul at or y 
re q uire me nts a n d I C H G C P. 
T he mi ni m u m re p orti n g re q uire me nts f or re p orti n g of S A Es i ncl u de: 
•  S u bject  i de ntificati o n n u m ber. 
•  S us pecte d me dici nal pr o d uct a n d / or pr oce d ure.  
•  E ve nt ter m. 
•  Re p orti n g s o urce i de ntifi cati o n. 
If t he mi ni m u m re q uire m e nts f or re p orti n g are f ulfille d, t he i n vesti gat or s h o ul d n ot wait t o 
recei v e a d diti o nal i nf or m ati o n t o f ull y d oc u me nt t he e ve nt.  
I n a d diti o n, t he i n vesti gat or m ust: 
•  R e p ort all S A Es t o t he rele va nt I nstit uti o nal Re vie w B oar d (I R B) / I E C wit hi n t he 
ti mefra me s pecifie d b y t he I R B / I E C. 
•  If t he s u bject is a n acti ve partici pa nt i n t he st u d y: 
o  E nter f oll o w- u p i nf or m ati o n i n t he e C R F u ntil t he S A E has res ol ve d, or, i n t he case of 
per ma ne nt i m pair me nt, u ntil sta bilize d .  
o  E ns ure t hat t he ca usalit y assess me nt f or all S A Es is e ntere d i n t he e C R F. 
•  If t he s u bject is n o l o n ger partici pati n g i n t he st u d y, re p ort t he f oll o w- u p i nf or mati o n t o 
C S L.  
I n cases of deat h, t he i n v esti gat or s h o ul d s u p pl y C S L  a n d t he I E C / I R B (as a p plica ble) wit h 
a n y a d diti o nal i nf or mati o n as it bec o mes a v aila ble (e g, a ut o ps y re p orts a n d detaile d me dical 
re p orts). 
9. 6. 4  Ot her Si g nific a nt E ve nt s 
N ot a p plica ble.  
9. 6. 5  O ver d ose  
O ver d ose is defi ne d as t h e i nf usi o n or i n gesti o n of a n y d ose (si n gle or c u m ulati ve) of a 
pr o d uct t hat is c o nsi dere d e xcessi ve. T h e effects of a n y p ote ntial o ver d os e wit h C S L 3 1 2 ha ve 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
n ot bee n st u die d. I n case of o ver d ose, t h e s u bject s h o ul d be cl osel y m o nit ore d, a n d 
s u p p orti ve treat me nt s h o ul d be a d mi nistere d, as n ee de d. 
A n y o ver d ose t hat o cc urs i n ass ociati o n wit h a n a d verse si g n or s y m pt o m m ust be e ntere d 
i nt o t he e C R F as a n A E; if t he A E meets a n y seri o us ness criteria, t he e ve nt m ust be re p orte d 
as a n S A E (see Secti o n 9. 6. 3 ).  
Details (ie, v ol u me, l ocati o n of i njecti o n, i njecti o n rate) of o v er d ose of i n vesti gati o nal 
pr o d uct ( defi n e d i n Secti o n  9. 6. 5 ) m ust be rec or de d i n t he st u d y t reat me nt ad mi nistrati o n 
e C R F. Details of o ver d os e of a n y c o n c o mita nt t hera p y m ust be rec or de d i n t he C o n c o mita nt 
Me dicati o n e C R F. 
9. 6. 6  Pre g n a nc y a n d Bre astfee di n g  
A fe male s u bject or fe male part ner of a male s u bj ect w h o bec o mes pre g na nt w hile 
partici pati n g i n t he st u d y, or u p t o a n d i ncl u di n g 3 m o nt hs after t he last d ose of 
i n vesti gati o nal pr o d uct, m ust n otif y t he i n vesti gat or i m me diatel y.   
If a f e male s u bject bec o mes pre g na nt, s he m ust disc o nti n ue treat me nt wit h i n vesti gati o nal 
pr o d uct, b ut ma y c o nti n ue ot her st u d y pr oce d ures at t he discreti o n of t he i n vesti gat or.  
C S L m ust be n otifie d wit hi n 5 da ys of t he i n vesti gat or bec o mi n g a w are of t he pre g na n c y.  
W he ne v er p ossi ble, a pr e g na nc y i n a s u bject or i n a fe male p art ner of a mal e s u bject e x p ose d 
t o i n vesti gati o nal pr o d uct s h o ul d be f oll o we d t o ter m s o as t o assess a n y p ote ntial occ urre nce 
of c o n ge nital a n o m alies or birt h defects.  A n y f oll o w- u p i nf or mati o n, i ncl u di n g pre mat ure 
ter mi nati o n a n d t he stat us of t he m ot her a n d c hil d after d eli ver y, s h o ul d be re p orte d b y t he 
i n vesti gat or t o C S L  usi n g a Pre g na nc y R e p orti n g / O utc o me F or m.  
9. 7  I R B / I E C Re p orti n g Re q uireme nts  
T he ti me fra me wit hi n w hic h a n I R B  / I E C m ust be n otifie d of deat hs a n d i n vesti gati o nal 
pr o d uct- rel ate d u ne x p ect e d S A Es is sti p ulate d b y eac h I R B / I E C. It is t he i n vesti gat or’s (f or 
Ja pa n sites o nl y: t he hea d of t he me dical i nstit uti o n’s) res p o nsi bilit y t o c o m pl y wit h t he 
re q uire me nts f or I R B / I E C n otificati o n. C S L will pr o vi de i n vesti gat ors (f or Ja pa n sites o nl y: 
t he hea d of t he m e dical i nstit uti o n’s) wit h all details of all S A Es re p orte d t o healt h  
a ut h orities.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0  St atistics 
1 0. 1  S a m ple S ize E sti m ati o n 
I n t otal, 6 0 s u bjects are pla n ne d t o be ra n d o mize d. 
F ort y s u bjects wit h C 1 -I N H H A E t y pe 1 a n d t y pe 2 c o m pleti n g t he 6- m o nt h Treat me nt 
Peri o d are n ee de d t o ac hi e ve a p o w er of a p pr o xi m atel y 9 0 % f or a t w o- si de d Wilc o x o n Test 
(al p ha of 5 %). S u bjects will be ra n d o mize d t o t he Acti ve Ar m or t he Place b o  Ar m wit h a rati o 
of 3: 2. A n attac k rate p er m o nt h of 0. 3 1 2 5 f or C S L 3 1 2- treate d s u bjects a n d of 1. 3 f or s u bjects 
recei vi n g place b o are ass u me d. T he m o nt hl y attac k rates of place b o a n d of C S L 3 1 2 are 
ass u me d t o be P oiss o n distri b ute d. 
 
It is tar gete d t o r a n d o mize a p pr o xi matel y 5 a d ol es ce nts i nt o t he treat me nt p eri o d wit h a 
ra n d o mizati o n rati o of 3: 2 (acti ve: place b o ).  
To all o w f or s ufficie nt safet y data, t o i ncrease t h e li keli h o o d of a d olesce nts e nteri n g t he st u d y 
a n d, t o ha ve at least 4 0 s u bjects reac hi n g t he e n d of t he st u d y, a n a d diti o nal 2 0 s u bjects are 
pla n ne d t o be ra n d o mize d. 
I n case it is n ot be f easi ble t o ra n d o mize t he t ar get e d n u m ber of a d olesce nts, t he tar gete d t otal 
sa m ple size will be ac hie ve d b y ra n d o mizi n g t he n ee de d n u m ber of a d ult s u bjects. 
1 0. 2  D escri pti o n of St u d y A n al ysis Sets  
1 0. 2. 1  Scree ne d  A n al ysis Set  
T he scree ne d a nal ysis set c o m prises all s u bjects w h o pr o vi de writte n i nf or me d c o nse nt a n d 
w h o u n der g o st u d y scr ee ni n g pr oce d ures.   
1 0. 2. 2  I nte nt-t o-Tre at A n al ysis Set  
T he i nte nt-t o-treat (I T T) a nal ysis set  c o m prises all s u bjects i n t he s cree ne d a nal ysis set w h o 
were ra n d o miz e d. T he I T T a nal ysis set  will be a nal yze d usi n g t he treat me nt t o w hic h t he 
s u bject was ra n d o mize d, re gar dl ess of t he treat me nt act uall y recei ve d.  
A n y s u bject w h o recei ves a treat me nt ra n d o mizati o n n u m ber will be c o nsi d ere d t o ha v e bee n 
ra n d o mize d. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0. 2. 3  S afet y A n al ysis Set  
T he safet y a nal ysis set  c o m prises all s u bjects i n t he I T T a n al ysis set  w h o recei ve d at least 
1 d ose of i n vesti gati o nal pr o d uct a n d will be a n al yze d usi n g  t he act u al treat me nt recei v e d. 
1 0. 2. 4  Per - pr ot oc ol A n al ysis S et 
T he per - pr ot oc ol ( P P) a n al ysis set  c o m prises all s u bjects i n t he I T T a n al ysis set w h o recei ve 
at least 1 d ose of i n vesti g ati o nal pr o d uct a n d w h o c o m pl y wit h t he pr ot oc ol. Decisi o ns 
re gar di n g e xcl usi o n fr o m t he P P a nal ysis will be ma de a n d d oc u m e nte d bef ore t he st u d y data 
are u n bli n de d. 
1 0. 2. 5  P h ar m ac o ki netic A n al ysis Set  
T he P K a nal ysis set  c o m prises all s u bjects i n t he safet y a n al ysis set w h o recei ve a n i njecti o n 
of i n vesti gati o nal pr o d uct wit h at least 1 meas ura ble c o nce ntrati o n of C S L 3 1 2. 
1 0. 2. 6  P h ar m ac o d y n a mic A n al ysis Set  
T he P D a nal ys is set is defi ne d as s u bjects i n t he safet y a nal ysis set  p o p ulati o n f or w h o m at 
least 1 P D meas ure me nt was o btai ne d. 
1 0. 3  St atistic al A n al yses a n d M et h o ds 
C o nti n u o us varia bles will be descri be d b y usi n g mea n v al ues wit h t heir res pecti ve 
9 5 % c o nfi de n ce i nter v als ( CIs); S D; ra n ge; 2 5t h, 5 0t h ( me dia n), a n d 7 5t h p erce ntiles; a n d 
c o u nts of missi n g a n d n o n- missi n g val ues.  
T he ge o metric c oefficie nt of variati o n will be e x presse d as a p erce nta ge f or P K a n d P D data. 
T he ge o metric mea n a n d its res pecti ve 9 0 % CI will be calc ulate d f or P K a n d P D data. T he 
9 0 % CI f or t he g e o metric mea n will be calc ulate d b y l o g tra nsf or mi n g t he d ata, cal c ulati n g 
t he l o wer a n d u p p er li mits of t he 9 0 % CI of t he m ea n of t he l o g-tra nsf or m e d data, a n d 
s u bse q ue ntl y bac k tra nsf or mi n g t he l o wer a n d u p per li mits.  
Cate g orical val ues will be descri b e d usi n g c o u nts a n d perce nta ges. 
All data will be dis pla ye d i n b y -s u bject listi n gs. T he listi n gs will be s orte d b y treat me nt ar m, 
st u d y site, s u bject, ti me p oi nt, a n d ite m n u m ber (if a p plica ble).  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
As it is e x pecte d t hat  t he c or o na vir us disease 2 0 1 9 ( C O VI D- 1 9) pa n de mic is still o n g oi n g 
d uri n g t he c o n d uct of t he st u d y, it will be assesse d f or s u b jects w h o are affecte d b y 
C O VI D - 1 9 d uri n g t heir p artici pati o n i n t he st u d y if t he y will be e xcl u de d fr o m s o me 
a nal yses. Reas o ns f or a n e xcl usi o n will be d oc u me nte d. A d v erse e ve nts  a n d earl y 
disc o nti n uati o ns ca use d b y C O VI D- 1 9 will be fla g ge d. Pr ot oc ol de viati o ns ca use d b y 
C O VI D - 1 9 will be d oc u me nte d a n d liste d. 
A c o m plete descri pti o n of t he statistical a nal yses a n d met h o ds will be a vaila ble i n a n S A P , 
w hic h will be fi nalize d b ef ore t h e data b ase is l oc k e d. 
1 0. 3. 1  S u bject Dis p ositi o n a n d C h ar acteristics  
1 0. 3. 1. 1  S u bject Dis p ositi o n  
S u bject dis p ositi o n will be s u m marize d usi n g all s u bjects.  
S u m mar y ta bles b y treat me nt ar m a n d t otal p o p ulati o n will prese nt: 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o u n d er we nt Scree ni n g. 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o e ntere d t he R u n-i n Peri o d. 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o disc o nti n ue d fr o m t he st u d y d uri n g t he 
R u n-i n Peri o d wit h reas o n f or disc o nti n uati o n ( perce nta ges b ase d o n t he n u m ber w h o 
disc o nti n ue d). 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o w ere n ot assi g ne d t o st u d y treat me nt.  
•  T he n u m ber a n d p erce nta ge of s u bjects w h o c o m plete d t he t reat me nt. 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o c o m plete d t he st u d y. 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o disc o nti n ue d t he st u d y d uri n g t he 
Treat me nt wit h reas o n f or disc o nti n uati o n ( perce nta ges base d o n t he n u m b er w h o 
disc o nti n ue d). 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o pre mat urel y disc o nti n ue treat m e nt. 
Reas o ns f or disc o nti n ui n g t he i n vesti gati o nal pr o d uct a n d wit h dra wi n g a s u bject fr o m t he 
st u d y will be liste d b y s u bject. 
1 0. 3. 1. 2  S u bject C h ar acteristics  
De m o gra p hic a n d s u bject c haracteristics will be s u m marize d usi n g t he I T T a n d P P sets.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
At mi ni m u m, s u bject c haracteristics  will be prese nte d i n s u m mar y ta bles.  A ge will be 
descri be d as b ot h a c o nti n u o us a n d a discrete vari a ble. S u p p orti ve da ta will be liste d b y 
s u bject. 
T he f oll o wi n g s u m maries will be pr o vi de d: 
•  De m o gra p hic c har acteristics: se x, race, et h nicit y, a ge, hei g ht a n d b o d y w ei g ht at 
Scree ni n g, a n d b o d y mass i n de x.  
•  H A E hist or y: H A E t y pe ( C 1- I N H t y pe 1, C 1-I N H t y pe 2), n u m ber of H A E attac ks 
bef ore Scree ni n g f or s u bj ects wit h o ut pr o p h ylactic H A E t hera p y, n u m ber a n d 
perce nt a ge of s u bjects w h o t o o k pr o p h ylactic H A E t hera p y, n u m ber of H A E attac ks 
bef ore t h e start of pr o p h ylactic t hera p y .  
•  Me dical hist or y b y s yste m or ga n class (S O C ) a n d preferre d t er m  ( P T). 
•  C o nc o mita nt diseases b y S O C a n d P T . 
•  Stratificati o n fact ors: a g e ( ≤1 7 year, > 1 7), bas eli ne attac k rate o bser ve d d uri n g t he 
R u n-i n Peri o d ( 1 t o < 3 attac ks / m o nt h, a n d ≥ 3 attac ks/ m o nt h). 
1 0. 3. 2  Effic ac y A n al yses  
1 0. 3. 2. 1  Pri m ar y Esti m a n d  
T he pri m ar y i nter est is t o assess t he treat me nt effect of C S L 3 1 2 d uri n g treat me nt fr o m Da y 1 
t hr o u g h Da y 1 8 2 w hile s u bjects are all o we d t o treat H A E attac ks wit h o n- de ma n d  
me dicati o ns, a d mi nistere d acc or di n g t o Secti o n 5. 2. 1. 1 . 
T he pri mar y esti ma n d i n li ne wit h t he pri mar y i nterest of t he st u d y f oll o ws t he treat me nt 
p olic y strate g y a n d is des cri be d as f oll o ws: 
•  P o p ulati o n: t he tar get patie nt p o p ulati o n defi ne d b y eli gi bilit y criteria a n d w h o were 
ra n d o mize d (I T T). 
•  Varia ble: ti me - n or m alize d n u m ber of H A E attac ks d uri n g treat me nt fr o m D a y 1 t hr o u g h 
Da y 1 8 2. 
•  I nterc urre nt e v e nts: T he occ urr e nce of a n i nterc urre nt e ve nt is irrele va nt. All o bser ve d 
val ues will be use d re g ar dless of occ urre nce of a n y of t he f oll o wi n g i nterc urre nt e v e nts: 
o  a d mi nistrati o n of o n- de m a n d  me dicati o n  i n a d diti o n t o pr o p h ylactic treat me nt wit h 
C S L 3 1 2. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 8 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
o  n o n- c o m plia nce t o tr eat me nt . 
o  earl y disc o nti n uati o n. 
•  P o p ulati o n- le vel s u m mar y: me dia n ti me- n or malize d n u m ber of H A E attac ks per m o nt h 
d uri n g treat me nt fr o m D a y 1 t hr o u g h Da y 1 8 2 b y treat me nt .  
S u bjects will be f oll o we d  after f ail ure t o a d mi nister or t o c o nti n ue C S L 3 1 2 treat me nt u ntil 
t heir c o m pleti o n of t he st u d y, ie, Visit Da y 1 8 2 or Earl y Ter mi nati o n Vis it (w hic he ver o cc urs 
first).  
1 0. 3. 2. 2  S u p ple me nt ar y A n al ysis  Pri m ar y Esti m a n d  
T he pri mar y esti ma n d d escri be d a b o v e is c o m ple me nte d b y a n a d diti o nal s u p ple me ntar y 
esti ma n d a n d a nal ysis.  
O nl y s u bjects i n t he P P a nal ysis set will be i ncl u de d. T he i nterest is t o assess t he treat me nt 
eff ect of C S L 3 1 2 d uri n g treat me nt fr o m D a y 1 t hr o u g h Da y 1 8 2 w hile s u bj ects are all o we d t o 
treat H A E attac ks wit h o n -de ma n d  me dicati o ns, a d mi nistere d acc or di n g t o Secti o n  5. 2. 1. 1 , 
b ut e xcl u di n g s u bjects w h o d o n ot c o m pl y wit h t he pr ot oc ol. 
T he a d diti o nal esti ma n d i n li ne wit h t he i nterest of t he st u d y f oll o ws t he treat me nt p olic y 
strate g y a n d is descri be d as f oll o ws: 
•  P o p ulati o n: t he tar get s u bject p o p ulati o n defi ne d b y eli gi bilit y criteria, w h o were 
ra n d o mize d, r ecei ve d at l east 1 d ose of C S L 3 1 2 a n d w h o c o m pl y wit h t he pr ot oc ol ( P P). 
•  Varia ble: ti me - n or m alize d n u m ber of H A E attac ks d uri n g treat me nt fr o m D a y 1 t hr o u g h 
Da y  1 8 2. 
•  I nterc urre nt e v e nts: T he occ urr e nce of a n i nterc urre nt e ve nt is irrele va nt. All o bser ve d 
val ues will be use d re g ar dless of occ urre nce of a n y of t he f oll o wi n g i nterc urre nt e v e nts:  
o  a d mi nistrati o n of o n- de m a n d  me dicati o n  i n a d diti o n t o pr o p h ylactic treat me nt wit h 
C S L 3 1 2. 
o  earl y disc o nti n uati o n. 
•  P o p ulati o n- le vel s u m mar y: descri pti ve statistics of t he ti me- n or malize d n u m ber of H A E 
attac ks d uri n g treat me nt fr o m Da y 1 t hr o u g h D a y 1 8 2 b y treat me nt . 
1 0. 3. 2. 3  Pri m ar y Effic ac y A n al ysis  
T he  pri mar y e n d p oi nt will be a nal yze d usi n g t he I T T a n d P P P o p ulati o ns. T he I T T p o p ulati o n 
will be use d as t he pri mar y a nal ysis a n d t he P P will be use d as t he sec o n d ar y a nal ysis. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
F oll o wi n g t he esti ma n d descri be d i n Secti o n 1 0. 3. 2. 1 , t he pri mar y e n d p oi nt “ti me-n or malize d 
n u m ber of H A E attac ks p er m o nt h d uri n g treat me nt fr o m Da y 1 t hr o u g h D a y 1 8 2 ” is 
calc ulate d p er s u bject as:  
[t he n u m ber of H A E attac ks / le n gt h of s u bject treat me nt i n da ys] * 3 0. 4 3 7 5 
w here t he l e n gt h of s u bject treat me nt is calc ul ate d as:  
[t he date of St u d y Visit D a y 1 8 2 or t he date of st u d y disc o nti n uati o n [ w hate ver is 
first]– t he date of St u d y Visits Da y 1 + 1].  
To test f or a differ e nce i n t he pri mar y e fficac y e n d p oi nt bet wee n C S L 3 1 2 a n d place b o, a 
c o m paris o n of t he ti me- n or malize d n u m bers of H A E attac ks i n t he 6 m o nt h s of t he A cti ve 
Ar m a n d i n t he 6- m o nt h Place b o Ar m peri o d  will be perf or me d b y usi n g a t w o-si de d 
Wilc o x o n Test (al p h a  = 5 %).  
T he ti me - n or malize d n u m ber per m o nt h a n d p er year of H A E attac ks will be s u m marize d 
descri pti vel y f or t he 6 m o nt hs of t he Acti ve Ar m a n d t he 6- m o nt h P lace b o Ar m p eri o d b y 
me dia n a n d mea n wit h c orres p o n di n g 9 5 % CIs b y treat me nt. 
As a se nsiti vit y a nal ysis, t he ti me - n or malize d n u m ber of H A E attac ks will be c o m pare d f or 
t he 6 m o nt hs of t he Acti v e Ar m a n d t he 6 m o nt hs of Place b o Ar m  usi n g a P oiss o n Re gressi o n 
m o del. T he ti me - n or mali ze d n u m ber of H A E attac ks of t he R u n-i n Peri o d a n d a ge as 
c o variates a n d t he l o garit h m of t he le n gt h of s u bject treat me nt as a n offs et varia ble will be 
i ncl u de d. T he m o del will acc o u nt f or o ver dis persi o n. 
1 0. 3. 2. 4  Sec o n d ar y Effic ac y A n al yses  
T he sec o n d ar y efficac y e n d p oi nt of t he perce nta ge re d ucti o n i n t he ti me- n or malize d n u m ber 
o f H A E attac ks is calc ulate d wit hi n a s u bject as: 
1 0 0 * [ 1 – (ti me- n or mali ze d n u m ber of H A E attac ks per m o nt h d uri n g treat me nt / 
ti me- n or malize d n u m ber of H A E attac ks per m o nt h d uri n g R u n-i n)]  
f or t he e ntire 6- m o nt hs of t he A cti ve Ar m a n d f or t he 6- m o nt h Place b o Ar m p eri o d a n d will 
be teste d via a t w o -si de d Wilc o x o n Test usi n g t he i n di vi d ual perce nta g e re d ucti o n bet wee n 
treat me nt gr o u ps. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
T he n u m ber a n d p erce nta ge of res p o n d ers a n d n o n-res p o n ders will be pres e nte d wit h 
c orres p o n di n g 9 5 % CIs . A s u bject is classifie d as a res p o n der if t he perce nt a ge re d u cti o n i n 
H A E attac ks is ≥ 5 0 %. I n a d diti o n, t he n u m ber a n d perce nt a ge of s u bjects wit h perce nta g e 
re d ucti o ns of ≥ 7 0 %, a n d ≥ 9 0 % will be prese nte d wit h c orres p o n di n g 9 5 % CIs.  
T he n u m ber a n d p erce nta ge of s u bjects wit h a perce nta ge re d ucti o n of 1 0 0 %, ie, w h o d o n ot 
e x perie n ce a H A E attac k a n d s o are attac k -free, will be prese nte d a n d s u m marize d wit h 
c orres p o n di n g 9 5 % CI f or t he 6- m o nt h Acti ve Ar m peri o d a n d f or t he 6-m o nt h Place b o Ar m 
peri o d, a Fis her-Test w ill be perf or me d t o asses f or differe nce s bet wee n treat me nts. 
T he per ce nta g e re d u cti o n i n t he ti me -n or malize d n u m ber of H A E attac ks f or t he 6- m o nt hs of 
t he Acti ve Ar m will als o be calc ul ate d as perce nt a ge re d ucti o n c o m p are d t o t he 6- m o nt h of 
t he Place b o Ar m ( be t w ee n s u bjects) as 
1 0 0 * [ 1 – ( me dia n ti me- n or malize d n u m ber of H A E attac ks per m o nt h d uri n g 6 m o nt hs 
of t he A cti ve Ar m / me dia n ti me - n or malize d n u m ber of H A E attac ks p er m o nt h d uri n g 
6- m o nt hs Place b o Ar m p eri o d)]  
a n d will be teste d  as e x pl orat or y via a t w o -si de d Wilc o x o n Test usi n g t he i n di vi d ual 
perce nt a ge r e d ucti o n bet wee n treat me nt gr o u ps. 
T he sec o n d ar y efficac y e n d p oi nt of ti me- n or malize d n u m ber of H A E attac ks per m o nt h 
re q uiri n g o n- de ma n d treat me nt is calc ulate d as: 
1 0 0 * [ 1 – ( n u m ber of H A E attac ks re q uiri n g o n- de ma n d treat me nt d uri n g treat me nt / 
le n gt h of s u bject treat me nt i n da ys)] * 3 0. 4 3 7 5 
A n H A E attac k re q uiri n g o n- de ma n d treat me nt is defi ne d as a n attac k f or w hic h t he date of 
a d mi nistrati o n of a n o n- d e ma n d  treat me nt is betw ee n t he start (i n cl u di n g) a n d e n d date 
(i ncl u di n g) of a H A E attac k. Diff ere n ces bet w ee n t he 6 - m o nt hs of t he A cti ve Ar m a n d t he 
6- m o nt h Place b o Ar m p eri o d will be teste d i n a n e x pl orat or y ma n ner vi a a t w o-si de d 
Wilc o x o n Test.  
F or t he a nal ysis of t he ti me- nor malize d n u m b er of m o derate a n d/ or se v ere H A E attac ks , a n 
a nal o g ue calc ulati o n will be d o ne usi n g all H A E attac ks classifie d as m o derate or se v ere.  
T he S G A R T  will be pres e nte d descri pti vel y. C o m paris o n of t he distri b uti o n of res p o nses t o 
t hera p y bet w ee n C S L 3 1 2 a n d place b o at t he e n d of Treat me nt Peri o d ( Da y 1 8 2) will be d o ne. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
To test f or a differ e nce i n S G A R T bet wee n C S L 3 1 2  a n d place b o, a c o m paris o n of t he 
distri b uti o n of res p o nses at t he e n d of Treat me nt Peri o d  ( Da y 1 8 2) will be perf or me d b y 
usi n g a t w o- si de d Wilc o x o n Test (al p ha = 5 %). 
I n a d diti o n, t he sec o n dar y e n d p oi nts descri be d a b o ve (e xce pt t he S G A R T) will be 
s u m marize d f or t h e first 3 m o nt hs ( Da y 1 t o Da y 9 1), as well as t he s ec o n d 3 m o nt hs of t he 
Acti ve a n d Place b o Ar ms. F urt her, t he f oll o wi n g e n d p oi nts will be c o m pare d bet wee n t he 
Acti ve Ar m a n d t he Place b o Ar m usi n g t he first 3 m o nt hs ( Da y 1 t o Da y 9 1), as well as t he 
sec o n d 3 m o nt hs ( Da y 9 2 t o Da y 1 8 2) i n a n e x pl orat or y ma n ner usi n g t he s a me tests as f or 
t he res pecti ve mai n a nal yses: 
•  Ti me - n or malize d n u m ber of H A E attac ks per m o nt h. 
•  Perce nta g e re d u cti o n i n t he ti me - n or malize d n u m ber of H A E attac ks. 
•  Perce nta g e of s u bjects wit h a perce nta ge re d ucti o n of 1 0 0 %. 
•  H A E attac ks p er m o nt h r e q uiri n g o n- de ma n d treat me nt.  
1 0. 3. 2. 5  M ulti plicit y  
Iss ues relate d t o m ulti plicit y arisi n g fr o m testi n g t he pri mar y e n d p oi nt a n d t he sec o n dar y 
e n d p oi nts: perce nta g e re d ucti o n i n t he ti me- n or malize d n u m ber of H A E attac ks, perce nta g e 
of s u bjects wit h a per ce nt a ge re d u cti o n of 1 0 0 %, a n d t he S G A R T .  
T he 4 e n d p oi nts will be teste d i n a hierarc hical or der wit h a n al p ha of 5 % eac h. 
F o ur n ull h y p ot heses are defi ne d, o ne f or t he pri m ar y e n d p oi nt ( H 0 1) a n d 3 f or t he 
3 sec o n dar y e n d p oi nts ( H 0 2, H 0 3, H 0 4). T h e n ull h y p ot hesis ass ociate d wit h eac h of t hes e 
e n d p oi nts is gi ve n bel o w: 
•  H 0 1: t he ti me - n or malize d n u m ber of HA E attac ks i n t he first 6 - m o nt h ti me peri o d of t he 
Acti ve Ar m a n d i n t he Place b o Ar m p eri o d are e q ual .  
•  H 0 2: t he perce nta ge re d u cti o n i n t he ti me- n or malize d n u m ber of H A E attac ks f or t he 
6- m o nt hs of t he Acti ve Ar m a n d t he 6- m o nt h Place b o Ar m p eri o d are e q u al . 
•  H 0 3 : t he n u m ber of s u bjects w h o d o n ot e x perien ce a H A E attac k i n t he first 3 m o nt hs of 
t he Acti ve Ar m a n d t h e 3- m o nt h Place b o Peri o d are e q ual. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  H 0 4: t he S G A R T at t he e n d of Treat me nt Peri o d ( Da y 1 8 2) of s u bjects tre ate d wit h 
C S L 3 1 2 a n d place b o ar e e q ual . 
T he ge neral pr ocess fl o w of t he h y p ot hesis testi n g is as f oll o ws: t he n ull h y p ot hesis 
ass ociate d wit h t he pri mar y e n d p oi nt H 0 1 will be teste d first. If a n d o nl y if t he res ulti n g 
2-si de d p- val ue is < 0. 0 5, testi n g of H 0 2 will be perf or me d. If a n d o nl y if H 0 2 ca n be reject e d 
( 2-si de d p- val u e < 0. 0 5), H 0 3 is teste d at 2-si de d al p ha of 5 %. If a n d o nl y if H 0 3 ca n be 
rejecte d ( 2-si de d p- v al ue < 0. 0 5), H 0 4 is teste d at 2-si de d al p ha of 5 %. T his hierarc hi cal 
testi n g pr oce d ure d o es n ot re q uire a dj ust me nt of t he al p ha le v el. 
All ot her tests will be perf or me d wit h 2 -si de d al p h a of 5 % i n a n e x pl orat or y ma n ner. 
1 0. 3. 3  S afet y A n al yses  
Safet y dat a will be s u m m arize d usi n g t he s afet y a n al ysis set .  
A d verse e ve nts wit h a start date a n d ti me occ urri n g after t he first a d mi nistrati o n of t he st u d y 
dr u g will be c o nsi dere d treat me nt- e mer g e nt A Es ( T E A Es). A d v erse e ve nts  wit h missi n g or 
partial start date or ti me will als o be c o nsi dere d T E A Es f oll o wi n g t he w o rst-case pri n ci ple 
u nless t he partial data clearl y i n dicates t hat t he A E starte d bef ore first a d mi nistrati o n date a n d 
ti me.  
Treat me nt -e mer ge nt A Es  occ urri n g u ntil t he F oll o w-u p Visit will be s u m marize d. O nl y 
T E A Es will be i ncl u de d i n a nal ysis, alt h o u g h al l A Es will be liste d.   
T he f oll o wi n g ta bles will be prese nt e d f or A Es occ urri n g at a n y d os e: 
•  S u m mar y of s u bjects wit h A Es ( n u m ber wit h a n y A E, wit h A Es occ urri n g wit hi n 
2 4 h o urs of i n vesti gati o nal pr o d uct i njecti o n, wit h S A E, wit h relate d A E, wit h A Es 
leadi n g t o st u d y disc o nti n uati o n, wit h eac h i nte nsit y, a n d wit h eac h o utc o me). 
•  S u m mar y of s u bjects wit h S A Es ( n u m ber wit h a n y S A E, wit h S A Es occ urri n g wit hi n 
2 4 h o urs of i n vesti gati o nal pr o d uct i njecti o n, wit h relate d S A E, wit h S A Es lea di n g t o 
st u d y disc o nti n uati o n, wit h eac h i nte nsit y, a n d wit h eac h o utc o m e). 
•  I nci de nce of s u bjects wit h A Es b y S O C  a n d P T . 
•  I nci de nce of s u bjects wit h S A Es b y S O C a n d P T . 
•  I nci de nce of s u bjects wit h A Es b y se verit y a n d S O C a n d P T .  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  I nci de nce of s u bjects wit h A Es b y rel ati o ns hi p t o i n vesti gati o nal pr o d uct a n d S O C 
a n d P T . 
•  I nci de nce of s u bjects wit h A Es lea di n g t o disc o nti n uati o n b y S O C a n d P T . 
•  I nci de nce of s u bjects wit h T E Es b y S O C a n d P T . 
•  I nci de nce of s u bjects wit h blee di n g e ve nts b y S O C a n d P T . 
•  I nci de nce of s u bjects wit h se vere h y p erse nsiti vit y / a na p h yla xis b y S O C a n d P T . 
•  T he n u m ber of s u bjects e x perie nci n g A Es w hic h o cc ur i n at least 1 treat me nt i n at 
least 1, 2, 3, 4, a n d 5 % of e ve nts will als o be pres e nte d. 
•  La b orat or y fi n di n gs re p orte d as A Es. 
S u m maries will i ncl u de t he n u m ber a n d p erce nta g e of s u bjects, t he n u m ber of A Es, a n d t h e 
n u m ber of A Es per i njecti o n a n d per s u bject y ear ( w here a p plica ble). 
A s u m mar y of n o n-seri o us A Es o nl y will be prese nte d b y treat me nt a n d als o b y S O C, P T , a n d 
treat me nt.  
S u m maries of I S Rs will be prese n t e d b y treat me nt a n d als o b y Me d D R A S O C  a n d P T , a n d 
treat me nt, wit h relati o ns hi p t o i n vesti gati o nal pr o d uct a n d wit h se verit y. 
A s u bject wit h m ore t ha n 1 occ urr e nce of t he sa m e A E will be c o u nte d o nl y o nce i n t he t otal 
of t h ose e x peri e nci n g t hat A E . Si milarl y, a s u bject wit h 1 or m ore A Es i n a partic ular S O C 
will be c o u nte d o nl y o nce i n t he t otal of t h ose e x p erie nci n g A Es i n t hat partic ular S O C.  
A d verse e ve nts, S A Es, A Es lea di n g t o st u d y disc o nti n uati o n a n d deat h will be liste d. 
1 0. 3. 4  P h ar m ac o ki netics  A n al yses  
T he P K a nal ysis will be perf or me d usi n g t he P K p o p ulati o n. 
Plas ma c o nce ntr ati o ns of C S L 3 1 2 will be liste d b y i n di vi d ual s u bjects a n d will be 
s u m marize d b y n o mi nal ti me p oi nts. I n di vi d ual a n d mea n C S L 3 1 2 plas ma c o nce ntrati o n 
vers us ti me will be pl otte d o n li near a n d se mi -l o garit h mic scales. Plas ma C S L 3 1 2 
c o nce ntr ati o ns will be s u m marize d wit h descri pti ve statistics : mea n, S D, perce nt  c o effi cie nt 
of variati o n, me dia n, mi ni m u m, ma xi m u m, a n d first a n d t hir d q uartiles f or c o nti n u o us 
varia bles, ge o m etric mea n a n d its res pecti ve 9 0 % CI . 
A d diti o nal i nf or mati o n o n P K a nal yses will be pr o vi de d i n t he S A P. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 0. 3. 5  P h ar m ac o d y n a mic A n al yses  
P har mac o d y na mic d ata will be s u m marize d usi n g t he P D p o p ulati o n. 
F XIIa - me diat e d kalli krei n acti vit y a n d F XII c o n ce ntrati o n will be assesse d f or t he 
p har mac o d y n a mics of C S L 3 1 2 as descri be d i n Ta ble  5 . 
F XIIa - me diat e d kalli krei n acti vit y a n d F XII c o n ce ntrati o n will be liste d b y i n di vi d ual s u bject 
a n d s u m marize d b y n o mi nal ti me p oi nt a n d treat me nt. 
A d diti o nal i nf or mati o n o n P D a nal yses will be pr o vi de d i n t he S A P. 
1 0. 3. 6  P h ar m ac o ki netic / P h ar m ac o d y n a mic Rel ati o ns hi ps  
P o p ulati o n P K a n d P K / P D m o delli n g will be e x pl ore d, as feasi b le, f or f urt her 
ti me-de pe n de nt c h aracterizati o n of P K vers us P D e n d p oi nts a n d / or safet y / efficac y 
e n d p oi nts a n d re p ort e d s e parat el y. A d diti o nal i nf or mati o n o n P K / P D a nal yses will be 
pr o vi de d se paratel y i n t he M o deli n g a n d Si m ulati o n A nal ysis Pla n. 
1 0. 3. 7  Ot her A n al yses  
A nal yses of e x pl or at or y e n d p oi nts will be descri b e d i n t he S A P. 
1 0. 3. 8  I nteri m A n al ysis 
N ot a p plica ble.  
1 1  Q u alit y Ass ur a nce  
T he st u d y ma y be s u bject t o a n a u dit b y C S L, a n a ut h orize d re prese nt ati ve(s) of C S L a n d / or 
i ns pecti o ns b y a n a ut h ori ze d healt h  a ut h orit y (e g, U S F o o d a n d D r u g A d mi nistrati o n [ F D A]). 
Healt h  a ut h orities ma y r e q uest access t o all st u d y d oc u me ntati o n, i ncl u di n g s o urce 
d oc u me nts f or i ns pecti o n a n d c o p yi n g, i n kee pi n g wit h l ocal re g ulati o ns. C S L will n otif y t he 
i n vesti gat or of a n y u pc o mi n g a u dit / i ns pecti o n. 
I n t he e ve nt of a n a u dit, all perti ne nt st u d y-relate d d oc u me ntati o n m ust be ma de a vaila ble t o 
t he a u dit or(s). If a n a u dit or i ns pecti o n occ urs, t h e i n vesti gat or at eac h st u d y site will per mit 
t he a u dit or / i ns pect or dir ect access t o all rel e va nt d oc u me nts a n d all ocat e t heir ti me as well 
as t he ti me of rele v a nt staff t o disc uss t he fi n di n gs a n d a n y rel e va nt iss ues. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 2  Re g ul at or y a n d Et hics C o nsi der ati o ns  
1 2. 1  Re g ul at or y C o nsi der ati o ns  
C S L or its a ge nts will s u b mit t he a p pr o priate d oc u me nts t o t he l ocal re g ul at or y a ge n cies a n d 
will a wait a p pr o val bef or e st u d y start. 
T his st u d y will be c o n d ucte d u n der a n F D A  Bi ol o gical Lice nse A p plicati o n  a n d d oc u me nte d 
i n acc or d a nce wit h t he a p plica ble re g ulat or y g ui deli nes a n d re q uire m e nts. 
T he pr oce d ures set o ut i n t his cli nical st u d y pr ot oc ol are desi g ne d t o e ns ure t hat C S L  a n d t he 
i n vesti gat or a bi de b y t he pri nci ples of t he c urre nt I C H G C P  g ui deli ne o n t he c o n d uct, 
e val uati o n a n d d oc u m e ntati o n of t his st u d y, as descri be d i n I C H To pic E 6 ( G ui deli ne f or 
G C P ). T he st u d y will als o be carrie d o ut acc or di n g t o all a p plica ble i nter nati o nal a n d nati o nal 
re g ulat or y r e q uire me nts. 
1 2. 2  Instit uti o n al Re vie w B o ar d / I n de pe n de nt Et hics C o m mittee  
T he i n vest i gat or m ust s u b mit t he cli nical st u d y  pr ot oc ol a n d I C Fs f or re vie w b y a n a ut h orize d 
a n d pr o perl y c o nstit ute d (acc or di n g t o l ocal g ui deli nes) I R B / I E C. Writte n a p pr o val m ust be 
recei v e d fr o m t he I R B / I E C bef ore c o m me nce m e nt of t he st u d y. 
F or Ja pa n sites o nl y, t he hea d of t he st u d y site s h o ul d s u b mit a writte n re p ort t o t he I R B 
pr o vi di n g t he details of all safet y-rel ate d i nf or mati o n re p orte d b y C S L. I n a d diti o n, t he 
cli nical st u d y pr ot oc ol is t o be rea p pr o ve d b y t he I R B a n n uall y. 
1 2. 3  S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
I nf or me d c o ns e nt of st u d y s u bjects acc or di n g t o t he sta n dar ds of G C P  a n d t he pri nci ples 
c o ntai ne d i n t he Declar ati o n of Helsi n ki m ust be i m ple me nte d i n t his cli nical st u d y bef ore 
pr ot oc ol-s pecifi e d pr oce d ures ar e carrie d o ut. I nf or mati o n s h o ul d be gi ve n i n b ot h oral a n d 
writte n f or m a n d s h o ul d be dee me d a p pr o pri ate b y t he I R B  / I E C. S u bjects, t heir relati ves ( or 
if necessar y, le gall y acce pta ble re pr ese ntati ves) m ust be gi ve n a m ple o p p ort u nit y t o i n q uire 
a b o ut details of t he st u d y. 
T he s u bject ( or if n ecessar y, le gall y acce pta ble re prese ntati ves) m ust be pr o vi de d wit h a c o p y 
of t he si g ne d i nf or me d c o nse nt f or m. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
S h o ul d t here be a n y a m e n d me nts t o t he cli nical st u d y pr ot oc ol t hat w o ul d directl y affect t he 
s u bject’s partici pati o n i n t he st u d y (e g, a c h a n ge i n a n y pr oce d ure), t h e I C F m ust be a me n de d 
t o i nc or p orate t his m o dificati o n. S u bject s m ust be i nf or me d of t he c h a n ge a n d t he y m ust si g n 
t he a me n de d I C F i n dicati n g t hat t he y re-c o nse nt t o partici pate i n t he st u d y. 
1 2. 4  S u bject C o nfi de nti alit y  
All s u bject na mes a n d c o ntact details will be ke pt c o nfi de ntial.  S u bjects will be i de ntifie d 
t hr o u g h o ut d oc u me ntati o n a n d e val uati o n b y t he n u m ber all otte d t o t he m d uri n g t he st u d y. 
Eac h s u bject  will be t ol d t hat all st u d y fi n di n gs will be ha n dle d i n t he strictest c o nfi de nce. 
T he i n vesti gat or at t he st u d y site will be res p o nsi ble f or ret ai ni n g s ufficie nt i nf or mati o n a b o ut 
eac h s u bject (e g, n a me, a d dress, p h o ne n u m ber a n d i de ntit y i n t he st u d y) s o t hat re g ulat or y 
a ge ncies or C S L ma y access t his i nf or mati o n s h o ul d t he nee d aris e. T hes e rec or ds s h o ul d be 
retai ne d i n a c o nfi de ntial ma n ner as l o n g as le gall y ma n date d acc or di n g t o l ocal 
re q uire me nts. 
S u bject me dical rec or ds pertai ni n g t o t he st u d y ma y be i ns pecte d / a u dite d at a n y ti me b y 
C S L e m pl o yees or t heir d ul y a ut h orize d re pres e ntati ves, a healt h  a ut h orit y or t he I R B / I E C. 
All rec or ds accesse d will be strictl y c o nfi de ntial.  C o nse nt t o partici pate i n t he st u d y i ncl u des 
c o nse nt t o t hese i ns pecti o ns / a u dits. 
1 2. 5   I n de m nit y a n d C o m pe ns ati o n 
C S L has ta ke n o ut i ns ura nce t o c o ver its o bli gati o ns u n der b ot h t he I n de m nit y a n d t he 
C o m pe nsati o n g ui deli nes f or i nj ur y t o s u bjects i n v ol ve d i n t he st u d y. 
Ot her details re g ar di n g c o m pe nsati o n a n d t he o bli gati o ns of t he i n vesti gat or / C S L are 
pr o vi de d i n t he Cli nical Trial Researc h A gree me nt f or t he st u d y ( see Secti o n 1 3. 1 ). 
1 3  A d mi nistr ati ve C o nsi der ati o ns  
1 3. 1  Cli nic al Tri al Rese arc h A gree me nt  
T his st u d y will be c o n d ucte d u n der a Cli nical Trial Researc h  A gree me nt bet wee n C S L 
(“ S p o ns or”) a n d t he i nstit uti o n(s) re pres e nti n g t he i n vesti gati o nal st u d y site(s) (“ A ut h orit y”). 
Fi na ncial s u p p ort t o t he i n vesti gati o nal site(s) will be detaile d i n t he Cli nical Trial 
A gree me nt.  T he Cli nical Trial Researc h A gree me nt m ust be si g ne d bef ore t he 
c o m me nce me nt of t h e st u d y a n d will clearl y deli n eate t he res p o nsi bilities a n d o bli gati o ns of 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 8  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
i n vesti gat or a n d C S L , a n d will f or m t he c o ntract u al basis u n der w hic h t he cli nical st u d y will 
be c o n d ucte d. Cli nical Trial A gree me nts ma y be e xec ute d b y el ectr o nic si g nat ure (c urre nt 
pr o vi der D oc u Si g n) i n c o m plia nce wit h 2 1 C F R Part 1 1 a n d si m ple or a d va nce d electr o nic 
si g nat ure acc or di n g t o E U Re g ulati o n N o 9 1 0/ 2 0 1 4 – eI D A S.  
1 3. 2  Cli nic al St u d y Re gistr ati o n a n d Res ults Discl os ure  
C S L will pr o vi de t he rele va nt cli nical st u d y pr ot oc ol i nf ormati o n i n p u blic data base (s) bef ore 
or at c o m me nce me nt of t he st u d y. C S L  ma y als o pr o vi de st u d y i nf or mati o n f or i ncl usi o n i n 
nati o nal re gistries acc or di n g t o l ocal re g ulat or y re q uire me nts. 
Res ults of t his st u d y will be discl ose d acc or di n g t o t he rele va nt r e g ulat or y re q uire me nts.  All 
p u blicati o ns i n peer- r e vie we d me dical j o ur n als res ulti n g fr o m t his st u d y will be liste d i n t he 
ori gi nal cli nical st u d y pr ot oc ol re gistrati o n rec or d. 
1 3. 3  I m ple me nt ati o n of t he Cli nic al St u d y Pr ot oc ol a n d A me n d me nt(s)  
Wit h t he e xce pti o n of me dical e mer g e ncies, n o c h a n ges or de vi ati o ns i n t he c o n d uct of t he 
si g ne d cli nical st u d y pr ot oc ol will be per mitte d wit h o ut d oc u me nte d a p pr o v al of t he C S L 
Me dical M o nit or or desi g nee a n d t he I R B / I E C. I n t he e ve nt of a m e dical e mer ge n c y, t he 
i n vesti gat or at t he st u d y site will i nstit ute a n y me dical pr oce d ures d ee me d a p pr o priate. 
H o we ver, all s uc h pr o ce d ures m ust be pr o m ptl y re p orte d t o t he C S L Me dical M o nit or a n d t he 
I R B / I E C.  
M o dificati o ns t o t he cli nical st u d y pr ot oc ol t hat ma y affect s u bject sa fet y or t he wa y t he 
st u d y is t o be c o n d ucte d will be d oc u me nte d i n a pr ot oc ol a me n d me nt, w hic h m ust be 
a p pr o ve d b y t he I R B / I E C.  
A d mi nis trati ve c ha n ges t o t he cli nical st u d y pr ot oc ol, defi ne d as mi n or c orrecti o ns a n d / or 
clarificati o ns t hat ha ve n o eff e ct o n t he w a y t he st u d y is t o be c o n d ucte d, will n ot re q uire 
I R B / I E C a p pr o val, b ut will be s u b mitte d t o t he I R B / I E C f or t heir i nf or mati o n. 
I n t he e ve nt of a state of e mer ge n c y or p u blic h ealt h t hreat res ulti n g i n tra v el restricti o ns t hat 
pre ve nt a s u bject fr o m r et ur ni n g t o t he st u d y site f or re q uire d st u d y assess me nts or 
pr oce d ur es, t hese assess me nts / pr oce d ures m a y be c o n d ucte d re m otel y wit h C S L a p pr o val. 
H o we ver, all s uc h assess me nts / pr oce d ures m ust be pr o m ptl y re p orte d t o C S L a n d t he I R B / 
I E C. T he f oll o wi n g o pti o ns ma y be i m ple me nte d “ o n- de ma n d” i n t he e ve nt of l ocal 
restricti o ns a n d at t he dis creti o n of C S L: 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 9 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  D irect t o s u bject s hi p me nt of i n vesti gati o nal pr o d uct f or s u bject 
self-a d mi nistrati o n . 
•  A ssess me nts a n d / or c oll ecti o n of bl o o d (e g, safet y, P K  / P D ) ma y be perf or me d 
re m otel y fr o m t he site vi a h o me healt h visits or via l ocal la b. 
•  Re m ote st u d y visits via p h o ne or vi de o t o: 
o  assess s u bject healt h stat us ( A Es, si de effects). 
o  c o nfir m s u p pl y of o n- de ma n d me dicati o n .  
o  c hec k o n c o nc o mita nt me dicati o ns .  
o  re vie w e Diar y e ntries t o assess H A E attac ks . 
o  re m ote c o m pleti o n of q u esti o n naires.  
o  s u per vise i n vesti gati o nal pr o d uct a d mi nistrati o n if nee de d. 
1 3. 4  Pr ot oc ol De vi ati o ns  
All i nsta nces w her e t he r e q uire me nts of t he cli nical st u d y pr ot oc ol were n ot c o m plie d wit h 
will be trac ke d.  C orres p o n di n g s u bjects ma y be wit h dra w n fr o m t he st u d y at t he discreti o n of 
t he i n vesti gat or a n d / or C S L.  Cli nical s t u d y pr ot oc ol de viati o ns arise w h e n eit her s u bjects 
w h o ha ve bee n e ntere d i n t he st u d y a n d / or t he st u d y sites de viate fr o m t he I E C / 
I R B-a p pr o ve d st u d y pr ot oc ol.  
If a maj or pr ot oc ol de viati o n (ie, a de viati o n t hat c o ul d ha ve a si g nifica nt effect o n t he 
s u bject’s safet y, ri g hts, or welfar e a n d / or o n t he i nte grit y of t he st u d y data) occ urs, t he 
i n vesti gat or m ust n otif y C S L a n d t he a p pr o priat e I R B / I E C as s o o n as p ossi ble or as per 
l ocal re q uir e me nts.  
1 3. 5  D oc u me nt ati o n a n d Rec or d Kee pi n g  
1 3. 5. 1  D at a C ollecti o n  
T he i n vesti gat or ( or d ele gate) will mai ntai n i n di vi d ual rec or ds f or eac h s u bject.  T hese r ec or ds 
s h o ul d i ncl u de dates w he n a s u bject visite d t he st u d y site, rec or ds of vital si g ns, me dical 
hist or y, or p h ysical e xa mi nati o ns, a d mi nistrati o n of i n vesti gati o nal pr o d uct or c o nc o mita nt 
t hera p y, a n y A Es e x perie nce d, a n d ot her n otes as a p pr o priate. T he se rec or ds (electr o nic or 
pa per) c o nstit ute s o urce data.   
E lectr o nic C R F e ntries will be c o nsi dere d s o urce d ata if t he e C R F is t he site of t he ori gi nal 
rec or di n gs (i e, t here is n o ot her writte n or el ectr o ni c rec or d of t he d ata).  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A n e C R F will be pr o vi de d b y C S L ( or dele gate) f or eac h s u bj ect e nr olle d i nt o t he st u d y. T he 
i n vesti gat or is res p o nsi ble f or e ns uri n g acc urate a n d pr o per c o m pleti o n of t he e C R F i n a 
ti mel y ma n ner s o t hat it al wa ys reflects t he latest o bser vati o ns o n t he s u bjects e nr olle d i n t he 
st u dy.  All e ntries o n t he e C R F m ust be bac ke d u p b y s o urce dat a u nless t he e C R F is 
c o nsi dere d  s o ur ce d ata. All s o urce data will be ke pt acc or di n g t o all a p plica ble re g ulat or y 
re q uire me nts. S o urce dat a m ust be c o m plete d le gi bl y f or eac h s u bject e nr olle d i nt o t he st u d y 
a n d si g ne d b y t he i n vesti gat or ( or del e gate). 
A n e C O A s ol uti o n will be use d b y t he s u bjects f or e ntr y a n d / or sites  f or re vie w.  
T he e C O A s ol uti o n is pr o vi de d as a mea ns t o ca pt ure electr o nic s o urce dat a i n a c o ntr olle d 
a n d c o nsiste nt wa y, a n d t o pr o vi de access f or i n vesti gat ors t o t hese s o urce data. T he  s yste m 
als o all o ws t he s u bject's healt h stat us t o be re m otel y m o nit ore d d uri n g t he st u d y. T he data 
resi di n g i n t he e C O A s yste m pr o vi der’s data base are c o nsi dere d t he s o urce, a n d are u n d er t he 
c ontr ol of t he i n vesti gat or at all ti mes.  
T he i n vesti gat or ( or d ele gate) will ha ve access t o all e C O A data e ntere d at site a n d  / or all 
data re p orte d wit hi n t he s u bject e Diar y vi a a sec ure, r ole - b ase d we b p ortal pr o vi de d b y a n 
e xter nal e C O A s yste m pr o vi der. T he e C O A s yste m pr o vi der will tra nsfer a c o p y of t he s o urce 
data acr oss t o C S L's cli nical data w are h o us e at a pre defi n e d fre q ue nc y vi a a sec ure d ata 
c ha n nel f or s yste matic re vie w b y t he C S L cli nical tea m.  
T he e C O A ve n d or e n ga g e d f or t his st u d y is res p o nsi ble f or pr o vi di n g a s ol uti o n t hat 
c o nf or ms t o all perti ne nt re g ulati o ns. T he s ol uti o n is n ot i n a n y wa y i nte n de d as a s u bstit ute 
f or n or mal me dical car e of t he s u bject. T he v e n d or pr o vi des t he ser vice of h osti n g of t he 
e C O A data o n be half of t he st u d y i n ves ti gat ors, u ntil s uc h a ti me as t he i n vesti gat or is i n 
recei pt of a certifie d arc hi ve c o p y of all diar y d ata relati n g t o s u bjects at t hat site a n d has 
c o nfir me d it is rea d a ble.  
1 3. 5. 2  D at a Q u alit y Ass ur a nce  
Data ge n erate d t hr o u g h o ut t he st u d y will be m o nit ore d a n d t he e C R Fs c hec ke d a g ai nst t he 
s u bject rec or ds f or c o m plete ness a n d acc urac y. T h e i n vesti gat or m ust pr o vi de direct access t o 
s o urce dat a d oc u me nts. C S L ’s st u d y m o nit or will perf or m t his f u ncti o n.  
F oll o wi n g c o m pleti o n of e C R F pa ges a n d e ntr y of t he data i n t o a data b ase, t he data will be 
c hec k e d electr o nicall y  f or c o nsiste nc y a n d pla usi bilit y. Q ueries will be ge nerate d f or 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
q uesti o na ble data a n d clarificati o n s o u g ht fr o m t he i n vesti gat or. T hese dat a q ueries m ust be 
res ol ve d i n a ti mel y ma n ner b y t he i n vesti gat or ( or dele gate). 
1 3. 5. 3  Rec or d Rete nti o n  
T he i n vesti gat or m ust f oll o w t he pri nci ples f or rec or d rete nti o n o utli ne d i n t he Cli nical Trial 
Researc h A gr ee me nt. A n i n vesti gat or st u d y file pre pare d b y C S L  ( or dele g ate), c o ntai ni n g all 
a p plica ble d oc u m e nts f or use at t he st u d y site, will be ma de a v aila ble t o t he i n vesti gat or 
bef ore t h e start of t he st u d y.  All st u d y d oc u me ntati o n a n d materials mai ntai ne d i n t he 
i n vesti gat or st u d y file m ust be ke pt i n c o nf or ma n ce wit h  a p plica ble nati o nal la ws a n d 
re g ulati o ns.  
All st u d y  d oc u me ntati o n a n d materials mai ntai ne d i n t he i n vesti gat or st u d y file at t he st u d y 
site m ust be a vaila ble f or i ns pecti o n b y C S L’s st u d y m o nit or ( or dele gate) t o deter mi ne t hat 
all re q uire d d o c u me ntati o n is prese nt a n d c orrect.  
T he st u d y ma y be a u dite d or i ns pecte d b y q ualifie d dele gates fr o m C S L or a c o m pete nt 
healt h  a ut h orit y. 
F oll o wi n g c o m pleti o n of t he st u d y, t he i n vesti gat or is res p o nsi ble f or arc hi vi n g t he 
i n vesti gat or’s st u d y file, t he s u bject’s rec or ds a n d t he s o urce d ata acc or di n g t o a p plica ble 
re g ulat or y r e q uire me nts.  
1 3. 6   St u d y a n d Site Cl os ure  
C S L reser ves t he ri g ht t o pre mat urel y disc o nti n ue or s us pe n d t he st u d y eit her at a p artic ular 
site or at all st u d y sites at a n y ti me a n d f or a n y reas o n. If s uc h acti o n is ta ke n, t he C S L St u d y 
M o nit or ( or dele gat e) will dis c uss t his wit h t he i n vesti gat or  at eac h st u d y site at t hat ti me a n d 
n otif y t he i n vesti gat ors (f or Ja pa n sites o nl y: t he h ea ds of t he me di cal i n stit utes) i n writi n g. If 
t he st u d y is s us pe n de d or ter mi nate d f or s afet y reas o ns, all i n vesti gat ors (f or Ja pa n sites o nl y: 
t he hea ds of t he m e dical i nstit utes) a n d t he rele va nt re g ulat or y a g e ncies will be i m me diatel y 
n otifie d of t he acti o n as well as t he r eas o n f or t he s us pe nsi o n / ter mi nati o n. T he i n vesti gat or 
(f or Ja p a n sites o nl y: t he hea ds of t he me di cal i nstit utes) at eac h st u d y site will a d vise t heir  
I R B / I E C o verseei n g t he st u d y of t he s us pe nsi o n / ter mi nati o n. 
1 3. 7   Cli nic al St u d y Re p ort  
A cli nical st u d y re p ort will be writte n after t h e c o m pleti o n of t he st u d y.  C S L or its a ge nt will 
write t he re p ort i n c o ns ultati o n wit h t he i n vesti gat or or, if a p plica bl e, a n o mi nate d  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
c o or di nati n g i n vesti gat or ( or dele g ate).  C S L re q uires t hat t he c o or di n ati n g i n vesti gat or will 
si g n t he cli nical st u d y re p ort.  
Pr o gress re p orts ma y b e pr o vi de d t o t he rele v a nt re g ulat or y b o dies i n acc or da nce wit h t heir 
re q uire me nts. 
1 3. 8   Use of D at a a n d P u blic ati o ns  
T he ri g hts a n d o bli gati o ns of i n vesti gat ors a n d C S L c o ncer ni n g a n y f or mal prese ntati o n or 
p u blicati o n of data c ollecte d as a direct or i n direct res ult of t his st u d y will be a d dress e d 
s pecificall y i n t he Cli nical Trial A gr ee me nt f or t he st u d y. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 4  Refere nces  
Ay g ö re n- P urs u n E, B y g u m A, Be usterie n K, et al. S oci oec o n o mic b ur de n of here ditar y 
a n gi oe de ma: r es ults fr o m t he here ditar y a n gi oe d e ma b ur de n of ill ness st u d y i n E ur o pe. 
Or p ha net J Rar e Dis. 2 0 1 4; 9: 9 9. 
Bj ör k q vist J, Jä msä A, a n d Re n né T. Plas ma kalli krei n: t he bra d y ki ni n- pr o d uci n g e nz y me. 
T hr o m b Hae m ost. 2 0 1 3; 1 1 0( 3): 3 9 9- 4 0 7. 
Bj ör k q vist J, Nic kel K F, Sta vr o u E, Re n né T. I n vi v o acti vati o n a n d f u ncti o ns of t he pr oteas e 
fact or XII. T hr o m b Hae m ost. 2 0 1 4; 1 1 2( 5): 8 6 8- 7 5. 
Bj ör k q vist J, de Maat S, Le wa n dr o ws ki U, Di Ge n nar o A, Osc hat z C, Sc h o ni g K, et al. 
Defecti ve gl yc os ylati o n of c oa g ulati o n fact or XII u n derlies here ditar y a n gi oe de ma t y pe III. 
J Cli n I n vest. 2 0 1 5; 1 2 5( 8): 3 1 3 2. 
B or k K, Bar nste dt S E, K oc h P, Tra u pe H. H ere dit ar y a n gi oe d e ma wit h n or mal C 1-i n hi bit or 
acti vit y i n w o me n. La ncet. 2 0 0 0; 3 5 6( 9 2 2 5): 2 1 3- 7.  
B or k K. Paste urize d C 1 i n hi bit or c o nce ntrat e i n here ditar y a n gi oe de ma: p h ar mac ol o g y, 
safet y, effi cac y a n d f ut ur e directi o ns. E x pert Re vie ws i n Cli nical I m m u n ol o g y. 
2 0 0 8; 4( 1): 1 3- 2 0. 
B or k K, W ulff K, Stei n m üller- Ma gi n L, Brae n ne I, Sta u bac h- Re nz P, Witz k e G, Har dt J. 
Here ditar y a n gi oe d e ma wit h a m utati o n i n t he plas mi n o ge n ge ne. Aller g y. 2 0 1 8 
Fe b; 7 3( 2): 4 4 2- 4 5 0. d oi: 1 0. 1 1 1 1 / all. 1 3 2 7 0. E p u b 2 0 1 7 Se p 7. 
Cicar di M, Le v y RJ, Mc Neil D L, Li H H, S heffer A L, Ca m pi o n M, et al. Ecalla nti de f or t he 
treat me nt of ac ute attac ks i n here ditar y a n gi o e de ma. N E n gl J Me d. 2 0 1 0; 3 6 3( 6): 5 2 3- 3 1. 
Cicar di M, A berer W, Ba nerji A, Bas M, Ber nstei n J A, B or k K, Ca baller o T, Far kas H, 
Gr u mac h A, Ka pl a n A P, Rie dl M A, Tri g gia ni M, Za nic helli A, Z ura w B; H A W K u n der t he 
patr o na ge of E A A CI ( E ur o pea n Aca de m y of Aller g y a n d Cli nical I m m u n ol o g y). 
Classificati o n, dia g n osis, a n d a p pr oac h t o treat me nt f or a n gi oe de m a: c o nse ns us re p ort fr o m 
t he Here ditar y A n gi o e de ma I nter nati o nal Wor ki n g Gr o u p. Aller g y. 2 0 1 4 Ma y; 6 9( 5): 6 0 2- 1 6. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Cs u ka D, Veszeli N, I mre h É, Z otter Z, S k o pál J, Pr o hász ka Z, Var ga L, Far kas H. 
C o m pre he nsi ve st u d y i nt o t he acti vati o n of t he plas ma e nz y me s yste ms d uri n g attac ks of 
here ditar y a n gi oe de ma d ue t o C 1-i n hi bit or deficie nc y. Or p ha net J o ur n al of Rare Diseas es. 
2 0 1 5; 1 0: 1 3 2. 
C u g n o M, Cicar di M, C o p p ola R, A g ost o ni A. Acti vati o n of fact or XII a n d clea va g e of hi g h 
m olec ular wei g ht ki ni n o ge n d uri n g ac ute attac ks i n here ditar y a n d ac q uire d C 1-i n hi bit or 
deficie nci es. I m m u n o p har mac ol o g y. 1 9 9 6; 3 3( 1- 3): 3 6 1- 4. 
Da vis A E, L u F, a n d M ejia P. C 1 i n hi b it or, a m ulti-f u ncti o nal seri n e pr oteas e i n hi bit or. 
T hr o m b Hae m ost. 2 0 1 0; 1 0 4( 5): 8 8 6- 8 9 3. 
De wal d G. A misse nse m utati o n i n t he plas mi n o ge n ge ne, wit hi n t he plas mi n o ge n kri n gle 3 
d o mai n, i n here ditar y a n gi oe de ma wit h n or mal C 1 i n hi bit or. Bi oc he m Bi o p h ys Res C o m m u n. 
2 0 1 8 Mar 2 5; 4 9 8( 1): 1 9 3- 1 9 8. 
E ur o Q ol Gr o u p 1 9 9 0 . Av aila ble fr o m: htt ps://e ur o q ol. or g/e q- 5 d- i nstr u me nts/e q- 5 d- 3l-a b o ut/ 
Kal mar L, H e ge d us T, Far kas H, et al. H A E d b: a n o vel i nter acti ve, l oc us -s p ecific m utati o n 
data base f or t he C 1 i n hi bit or ge ne. H u m M utat. 2 0 0 5; 2 5( 1): 1- 5. 
Ke n ne E, Nic kel K F, L o n g A T, F uc hs T A, Sta vr o u E X, Sta hl F R, Re n né T. Fact or XII: a 
n o vel tar get f or saf e pre v e nti o n of t hr o m b osis a n d i nfla m mati o n. J o ur nal of I nter nal 
Me dici ne. 2 0 1 5; 2 7 8( 6): 5 7 1- 8 5. 
Lä m mle B, W uille mi n W A, H u ber I, Kra us k o pf M, Z ürc her C, Pfl u gs ha u pt R, F urla n M. 
T hr o m b oe m b olis m a n d blee di n g te n de nc y i n c o n g e nital fact or XII d eficie n c y —a st u d y o n 7 4 
s u bjects fr o m 1 4 S wiss fa milies. T hr o m b Hae m ost. 1 9 9 1 Fe b 1 2; 6 5( 2): 1 1 7- 2 1. 
Larss o n M, Ra yz ma n V, N olte M W, Nic kel K F, Bj or k q vist J, Ja msa A, et al. A fact or XIIa  
i n hi bit or y a nti b o d y pr o vi des t hr o m b o pr otecti o n i n e xtrac or p oreal circ ulati o n wit h o ut 
i ncreasi n g blee di n g ris k. Sci Tra nsl Me d. 2 0 1 4; 6( 2 2 2): 2 2 2ra 2 1 7. 
L o n g h urst HJ, B or k K. H ere ditar y a n gi oe de ma: ca uses, ma nifestati o ns a n d treat me nt. Br J 
H os p Me d ( L o n d). 2 0 0 6 Dec; 6 7( 1 2): 6 5 4- 7. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Nasr I H, M a ns o n A L, Al Wa hs hi H A, L o n g h urst HJ. O pti mizi n g here ditar y a n gi oe de ma 
ma na ge me nt t hr o u g h tail ore d treat me nt a p pr oac hes. E x pert Re v Cli n I m m u n ol. 
2 0 1 6; 1 2( 1): 1 9- 3 1. 
N uss ber ger J, C u g n o M, A mst utz C, Cicar di M, Pellaca ni A, A g ost o ni A. Plas ma bra d y ki ni n 
i n a n gi o- oe de ma. L a ncet. 1 9 9 8; 3 5 1( 9 1 1 7): 1 6 9 3- 7. 
N uss ber ger J, C u g n o M, Cicar di M, A g ost o ni A. L ocal bra d y ki ni n ge n erati o n i n here ditar y 
a n gi oe de ma. J o ur n al of Aller g y a n d Cli nical I m m u n ol o g y. 1 9 9 9; 1 0 4( 6): 1 3 2 1- 2. 
Rat n off O D, C ol o p y J E. A fa milial he m orr ha gic trait ass ociate d wit h a d efi cie nc y of a cl ot-
pr o m oti n g fracti o n of plas ma. J Cli n I n vest. 1 9 5 5 A pr; 3 4( 4): 6 0 2- 1 3. 
Reill y M C, Z br oze k A S, D u kes E M. T he v ali dit y a n d re pr o d u ci bilit y of a w or k pr o d ucti vit y 
a n d acti vit y i m pair me nt i nstr u me nt. P har mac oec o n o mics. 1 9 9 3 N o v; 4( 5): 3 5 3- 6 5. 
Re n né T, Sc h maier A H, Nic kel K F, Bl o m bäc k M, a n d Maas C. I n vi v o r oles of fact or XII. 
Bl o o d. 2 0 1 2; 1 2 0( 2 2): 4 2 9 6- 4 3 0 3. 
R ose n F S, Pe ns k y J, D o nal ds o n V, C harac he P. Here ditar y A n gi o ne ur otic E de ma: T w o 
Ge netic Varia nts. Scie nce. 1 9 6 5; 1 4 8: 9 5 7- 8. 
Valerie v a A, Caccia S, Cicar di M. Rec o m bi na nt h u ma n C 1 esterase i n hi bit or (c o nestat alfa) 
f or pr o p h yla xis t o pre v e nt attac ks i n a d ult a n d a d olesce nt patie nts wit h here ditar y 
a n gi oe de ma. E x p ert Re v Cli n I m m u n ol. 2 0 1 8; 1 4( 9): 7 0 7- 7 1 8. 
D oi: 1 0. 1 0 8 0/ 1 7 4 4 6 6 6 X. 2 0 1 8. 1 5 0 3 0 5 5 
Ver p y E, C o ut ure- Tosi E, El deri n g E, L o pez- Trascasa M, S pät h P, Me o T, Tosi M. Cr ucial 
resi d ues i n t he car b o x y-t er mi nal e n d of C 1 i n hi bit or re veale d b y pat h o g e nic m uta nts i m paire d 
i n secreti o n or f u n cti o n. J Cli n I n vest. 1 9 9 5 Ja n; 9 5( 1): 3 5 0- 9. 
Wa ge n aar - B os I G, Hac k C E. Str uct ure a n d f u ncti o n of C 1-i n hi bit or. I m m u n ol Aller g y Cli n 
N ort h A m. 2 0 0 6 N o v; 2 6( 4): 6 1 5- 3 2. 
Weller K, Gr offi k A, Ma gerl M, To h me N, Mart us P, Kra use K, Metz M, Sta u bac h P, 
Ma urer  M. D e vel o p me nt a n d c o nstr uct vali dati o n of t he a n gi oe de m a q ualit y of life 
q uesti o n naire. Aller g y. 2 0 1 2 Oct; 6 7( 1 0): 1 2 8 9- 9 8. 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Z ura w B L, B usse PJ, W hite M, Jac o bs J, L u mr y W, Ba ker J, Crai g T, Gra nt J A, H ure witz D, 
Biel or y L, Cart wri g ht W E, K oleilat  M, R ya n W, Sc haefer O, M a n ni n g M, Patel P, Ber nstei n 
J A, Frie d ma n R A, Wil ki ns o n R, Ta n ner D, K o hl er G, G u nt her G, Le v y R, Mc Clella n J, 
Re d hea d J, G uss D, H e y ma n E, Bl u me nstei n B A, Kalf us I, Fra n k M M. N a n ofiltere d C 1 
i n hi bit or c o nce ntrate f or treat me nt of here ditar y a n gi oe de ma. N E n gl J Me d. 2 0 1 0 A u g 
5; 3 6 3( 6): 5 1 3- 2 2.  
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 5  A p pe n dices  
 




C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 0 9  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
Si g n at ure of Pri nci p al I n vesti g at or  
St u d y Title:  
A M ultice nter, D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, 
Parallel - Ar m St u d y t o I n vesti gate t he Efficac y a n d Safet y of 
S u bc uta ne o us A d mi nistrati o n of C S L 3 1 2 ( gara daci ma b ) i n t he 
Pr o p h ylactic Treat me nt of Here ditar y A n gi oe de ma  
Pr ot oc ol 
N u m ber:  
C S L 3 1 2 _ 3 0 0 1 
Site N u m ber:  < < > >  
I ha ve r ea d t he Cli nical St u d y Pr ot oc ol C S L 3 1 2 _ 3 0 0 1 title d “ A M ultice nter, D o u ble- Bli n d, 
Ra n d o mize d, Place b o -C o ntr olle d, Parallel - Ar m St u d y t o I n vesti gate t he Efficac y a n d Safet y 
of S u bc uta ne o us A d mi nistrati o n of C S L 3 1 2 ( gara daci ma b ) i n t he Pr o p h ylactic Treat me nt of 
Here ditar y A n gi oe d e ma . ” 
B y si g ni n g t his Cli nical St u d y Pr ot oc ol, I a gree t o c o n d uct t he cli nical st u d y, after a p pr o v al 
b y a n I nstit uti o nal Re vie w B oar d or I n d e pe n de nt Et hics C o m mittee (as a p pr o priate), i n 
acc or d a nce wit h t he Cli nical St u d y Pr ot oc ol, t he sta n dar ds of G o o d Cli nical Practice (as 
defi ne d b y t he I nt er nati o nal C o nfere n ce o n H ar m o nisati o n) a n d a p plica ble re g ulat or y 
re q uire me nts. 
C ha n ges t o t he Cli nical St u d y Pr ot oc ol will o nl y be i m ple me nte d after  writt e n a p pr o val is 
recei v e d fr o m C S L  a n d t he 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 (as 
a p pr o priate) wit h t he e xce pti o n of me dical e mer ge ncies. 
I will e ns ure t hat st u d y staff f ull y u n dersta n d a n d f oll o w t he Cli nical St u d y Pr ot oc ol. 
 
 
 
( Si g nat ure) 
 
 
Date ( D D M M M Y Y Y Y)  
( Pri nte d na me) 
 
 
 
( Title) 
 
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 0  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
A p pe n di x 2  
Here dit ar y A n gi oe de m a Att ac k 
Assess me nt  a n d  Re p orti n g I nstr ucti o ns 
f or St u d y  C S L 3 1 2 -3 0 0 1  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Versi o n: Versi o n 3 . 0 
 
 
 
 
Versi o n D ate: 2 8  J ul 2 0 2 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o m merci al i n C o nfi de nce . T his d oc u me nt a n d t he i nf or mati o n c o ntai ne d herei n are pr o prietar y a n d 
c o nfi de ntial. T his d oc u me nt a n d t he c o ntai ne d i nf or mati o n are i nte n de d f or discl os ure a n d use b y t h ose 
pers o n nel w h o are u n der a n o bli gati o n of c o nfi de ntialit y b y a si g ne d a gree me nt wit h S p o ns or (“ C S L 
Be hri n g”). Re pr o d ucti o n or discl os ure of t his d oc u me nt or its c o ntai ne d i nf or mati o n is f or bi d de n u nless at t he 
e x press re q uest or wit h t he writte n c o nse nt of C S L Be hri n g . 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 1  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
1 
P ur p ose  
T h e p ur p ose of t his d oc u me nt is t o pr o vi de i nstr ucti o ns o n t he re p orti n g of H A E s y m pt o ms 
b y t he s u bject a n d t he ass ess me nt of H A E attac ks a n d s u bse q ue nt f oll o w u p b y t he 
i n vesti gat or. T his d oc u me nt will als o prese nt a defi niti o n of a n H A E attac k a n d a set of 
sta n dar dize d re q uir e me nts t o ai d t he i n vesti gat or i n deter mi ni n g a n d rec or di n g a H A E attac k 
base d o n t he s u bject’s r e p orte d s y m pt o ms.  
2 
Here dit ar y A n gi oe de m a S y m pt o m Re p orti n g a n d H A E Att ac k 
Assess me nt  
All  s y m pt o ms p ote ntiall y relate d t o a n H A E attac k a n d i nf or mati o n o n t he use of o n- de ma n d 
me dicati o n t o treat t h ose s y m pt o ms d uri n g t he R u n-i n, Treat me nt a n d F oll o w- U p peri o ds, 
will be e ntere d b y t he s u bject i n a n e Diar y.  T he i n vesti gat or or dele g ate will re vie w t he dat a 
i n t he e Diar y a n d c ollect a d diti o nal i nf or mati o n t hat ma y be missi n g fr o m t he e Diar y a n d 
ot her rele v a nt i nf or mati o n nee de d f or t he ass ess me nt of t he s u bject re p orte d s y m pt o ms.  
2. 1  
S u bject Tr ai ni n g  
D uri n g scree ni n g, eli gi ble s u bjects f or e nteri n g t h e r u n-i n peri o d, will be trai ne d b y t he site’s 
pers o n nel o n i de ntif yi n g s y m pt o ms of a p ote ntial H A E attac k, t he us e of t h e e Diar y t o re p ort 
a s y m pt o m(s) a n d t he i nf or mati o n t he y will nee d t o re p ort a b o ut t heir s y m pt o ms. T he s u bject 
( wit h pare nt/le gal g u ar di a n if a p plica ble f or mi n ors) will c o nfir m his/ her u n dersta n di n g of 
w hat is re q uire d t o r e p ort s y m pt o ms p ote ntiall y relate d t o a n attac k. Sites will assess t he 
s u bject’s c o m plia nce wit h t he re p orti n g re q uire me nts d uri n g t he st u d y a n d ma y retrai n t he 
s u bject if necessar y. 
2. 2  
S u bject -re p orte d s y m pt o ms  
At t he o nset of a s y m pt o m(s) of a p ote ntial H A E attac k, s u bjects will be i nstr ucte d t o e nter 
i nf or mati o n a b o ut t he s y m pt o m(s) i n t he e Diar y. S u bjects ( wit h pare nt/ or l e gal g uar dia n if 
a p plica ble f or mi n ors) will als o be e nc o ura ge d t o n otif y a n d re p ort det ails t o t he st u d y site 
wit hi n 7 2 h o urs of t he start of t he first s y m pt o m(s) of a p ote ntial H A E attac k. W he n a s u bject 
i nitiates t he re p orti n g of s y m pt o ms of a p ote ntial H A E attac k i n t he e Diar y, he/s he will be 
re mi n de d t o c o ntact t he site wit hi n 7 2 h o urs of t he o nset of s y m pt o ms. I n ta n de m, t he site 
will recei ve a n e mail alert fr o m t he e Diar y p ortal i n dicati n g t hat a s u bject is e x perie n ci n g 
s y m pt o ms of a p ote ntial H A E at tac k.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 2  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
If o n de ma n d me di cati o n is nee de d, s u bjects d o n ot ha ve t o h ol d off/ dela y t he start of t he 
me dicati o n t o treat t he s y m pt o ms of t he p ote ntial H A E attac k till after c o nt acti n g t he site. 
N ote: if a d diti o nal s y m pt o ms are e x p erie nce d wit hi n 2 4 hrs, t he s y m pt o ms s h o ul d be e ntere d 
i n t he e Diar y as “ u p dates.” I n or der t o re p ort o nset (start) of a n e w s y m pt o m(s), t he ne w 
s y m pt o m(s) m ust occ ur at least 2 4 h o urs after res ol uti o n of t he pre vi o usl y re p orte d 
s y m pt o m(s). Here ditar y a n gi oe de ma  s y m pt o m res ol uti o n is defi ne d as t he s u bject n o l o n ger 
ha vi n g s y m pt o ms of t he p ote ntial attac k.  
T he f oll o wi n g i nf or mati o n nee ds t o be re p orte d i n t he e Diar y: 
•  Date a n d ti me of o ns et of first s y m pt o m of p ote ntial H A E attac k  
•  Date a n d ti me of H A E s y m pt o m(s) res ol uti o n  ( defi ne d as t he s u bject n o l o n ger ha vi n g 
s y m pt o ms of a n attac k)  
•  L ocati o n  (s) of H A E s y m pt o m(s) 
•  C o nfir mati o n of  de gree of i nterfere nce of H A E s y m pt o m(s) wit h t he s u bject’s dail y 
acti vities 
•  If o n de ma n d H A E me di cati o n  (s) was us e d t o treat H A E s y m pt o ms: 
o  Na me of me dicati o n  
o  Date a n d ti me of a d mi nistrati o n  
T he i n vesti gat or will c o nfir m a d diti o nal details wit h t he s u bject relate d t o t he H A E 
s y m pt o ms: 
•  L ocati o n of H A E s y m pt o m(s). 
•  Start/ E n d date  / ti me of s y m pt o m(s). 
•  D ose(s) of o n d e ma n d m e dicati o n(s) use d.  
•  R o ute(s) of A d mi nistrati o n of o n de ma n d me dicati o n(s) use d.  
•  Self -a d mi nistere d o n de ma n d me dicati o n(s)? ( yes / n o). 
•  A d mi nistrati o n of o n de ma n d me dicati o n(s) at a st u d y site, h o me or e mer ge nc y r o o m.  
•  Ty pe of me dical assista nce or i nter v e nti o n pr o vi de d b y a heal t hcare pr ofessi o nal 
d uri n g H A E s y m pt o ms, i ncl u di n g h os pitalizati o n or e mer g e nc y d e part me nt visits.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 3  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  Se verit y of t he attac k ( base d o n de gree of i nterfere nce i n dail y acti vities, a n d w het her 
or n ot  t he use of o n de m a n d me dicati o n a n d / or me dical assista nce was n ee de d)  
N ote: A ll o n de ma n d me dicati o ns use d bet wee n t he o nset a n d res ol uti o n of H A E 
s y m pt o ms nee d t o be rec or de d.  
2. 3  
Here dit ar y A n gi oe de m a S y m pt o ms I n dic ati ve of a n H A E Att ac k  
A n H A E attac k m ust be ass ociate d wit h at least 1 s y m pt o m/l ocati o n or a n y of c o m bi ne d 
m ulti ple s y m pt o ms /l ocati o ns, as liste d o n Ta ble 1  bel o w. T hese s y m pt o ms ma y de vel o p 
c o nc urr e ntl y or c o nsec uti vel y, t y picall y wit hi n 2 4 h o u rs. T he list of s y m pt o ms bel o w is n ot 
e x ha usti ve a n d it is mea nt t o assist t he i n vesti gat or/ dele gate i n i de ntif yi n g H A E attac k -relat e d 
s y m pt o ms a n d t heir i n dicati ve l ocati o ns.  
Ta ble 1. H A E S y m pt o m/ L oc ati o n ass oci ate d wit h a n H A E att ac k  
 
Peri p her al Att ac k 
S y m pt o ms (c ut a ne o us)  
A b d o mi n al Att ac k S y m pt o ms  
L ar y n ge al Att ac k 
S y m pt o ms  
L ocati o ns  
•  
hea d  
•  
face (e xter nal): li ps, 
n ose, c hee ks or e yes  
•  
nec k  
•  
ar ms/ ha n ds 
•  
c hest, s h o ul der or bac k  
•  
e xter nal a b d o mi nal area  
•  
e xter nal ge nit o uri nar y 
areas ( b utt oc ks) 
•  
le gs/ Feet 
•  
Ot hers  
•  
i nter nal a b d o me n (i ncl u di n g, 
b ut n ot li mite d t o, t he i ntesti ne, 
t he bla d der, a n d / or testicles or 
uter us)  
•  
 i nter nal ge nit o uri nar y 
(i ncl u di n g, b ut n ot li mite d t o, 
t he pe nis a n d/ or scr ot u m, or t he 
la bia a n d/ or v ul va) 
Face i nter nal or u p per 
air wa y/t hr oat  
•  
to n g ue  / palate/i nsi de 
m o ut h  
•  
nasal ca vit y  
•  
t hr oat / v oice b o x  
•  
u v ula  
•  
lar y n x 
 
S y m pt o ms  •  
pai n  / disc o mf ort  
•  
s ki n s welli n g 
•  
itc hi n g / irritati o n 
•  
ti g ht s ki n 
•  
b ur ni n g  
•  
re d ness / ras h 
 
•  
pai n  / cra m pi n g  / disc o mf ort  
•  
v o miti n g/ na usea  
•  
a b d o mi nal s welli n g  / bl oati n g  
/ti g ht ness / har d st o mac h  
•  
diarr hea  
•  
gass y  
•  
l o w bl o o d press ure 
•  
pass o ut/feel dizz y  
•  
diffic ult breat hi n g 
( d ys p nea), s pea ki n g, or 
s wall o wi n g 
•  
v oice c ha n ge  
•  
stri d or / w heezi n g  
•  
t hr oat ti g hte ni n g 
•  
t ur ni n g bl ue 
 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 4  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 4  
Att ac k Assess me nt  / C o nfir m ati o n b y t he I n v esti g at or 
T he I n vesti gat or or d ele g ate at eac h site will re vie w t he H A E s y m pt o ms re p orte d b y t he 
s u bject i n t he e Diar y, a n d c o nfir m a n H A E attac k(s) if a p plica ble. It is rec o m me n de d t hat t he 
sites li mit t he n u m ber of e x perie n ce d i n di vi d uals res p o nsi ble f or assessi n g s u bject re p orte d 
s y m pt o ms t o 1 or 2 i n di vi d uals, w here o n e of t he m s h o ul d be t he i n vesti gat or. T he assess ors 
m ust be e x perie n ce d wit h H A E a n d f a miliar wit h t he st u d y s u bject’s disease hist or y.  
Eac h ti me t he i n vesti gat or/ dele gate c o ntacts t he s u bject or a t a site visit, he/s he will re vie w 
t he s u bject’s e Diar y e ntri es. A d diti o nall y, t he s u bject will be re mi n de d t o h a ve his/ her eDiar y 
e ntries u p-t o- dat e a n d t o c hec k t hat s y m pt o ms i n dicati ve of a n H A E attac k are d oc u m e nte d as 
i nstr ucte d.  T he i n vesti gat or / dele gate ma y as k a d diti o nal pr o bi n g q uesti o ns a b o ut t he H A E 
s y m pt o ms e x perie nce d b y t he s u bject t o assist his/ her assess me nt of t h e s y m pt o ms a n d r ule 
o ut if t here ar e a n y p ossi ble alter nati ve eti ol o gies of t he s y m pt o ms. F or e xa m ple, w het her 
o nl y pr o dr o mal s y m pt o ms were e x perie n ce d a n d  / or if a n yt hi n g is differe nt fr o m pre vi o us 
e x perie n ces.  
Eac h i n di vi d ual H A E att ac k m ust be ass ociat e d wit h at least o ne s y m pt o m  or l ocati o n, b ut 
ma y be ass ociat e d wit h m ulti ple s y m pt o ms. T hese s y m pt o ms ma y de vel o p c o nc urre ntl y or 
c o nsec uti vel y wit hi n 2 4 h o urs. If t he i n vesti gat or c o nfir ms a n H A E attac k, t his s h o ul d be 
re p orte d i n t he e C R F as a si n gle H A E attac k i ncl u di n g t he s y m pt o m(s) ass ociate d wit h t he 
attac k. If t h ere h as bee n a c o m pletel y s y m pt o m- free 2 4- h o ur mi ni m u m se parati o n bet wee n 
t he res ol uti o n of t he pri or attac k a n d t he o ns et of n e xt attac k, t his ne w set of s y m pt o ms w o ul d 
c o nstit ute a ne w e v e nt a n d s h o ul d be re p orte d as a se parat e si n gle attac k if t he i n vesti gat or 
c o nfir ms t he H A E attac k.  
T he i n vesti gat or will deter mi ne if t he s y m pt o ms re p orte d b y t he s u bject di d n ot re prese nt a n 
H A E attac k. F or e xa m ple, if t he s y m pt o ms are n ot t y pical of a n attac k or if t here is a m ore 
li kel y alter nati ve ca use f or t he s y m pt o ms, or if t he s y m pt o ms di d n ot res ol ve f oll o wi n g t he 
a d mi nistrati o n of t he o n de ma n d me dicati o n. E xa m ples are t hr oat irritati o n d ue t o a n u p per 
res pirat or y ill ness or a b d o mi nal disc o mf ort d ue t o gastr oi ntesti nal u pset.  
I n a n eff ort t o mai ntai n c o nsiste nc y acr oss d ata c ollecti o n a n d a nal ysis wit hi n t his H A E 
pr o p h yla xis de vel o p me nt pr o gra m, t he f oll o wi n g rec o m me n dati o ns s h o ul d be f oll o we d:  
•  T he prese n ce of pr o dr o m al s y m pt o ms b y t he msel ves are n ot c o nsi dere d as H A E 
attac ks.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 5  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  S u bject re p orte d use of o n de ma n d me dicati o n t o treat t he pr o dr o mal s y m pt o ms b y 
itself will n ot be c o nfir mati o n t hat a n H A E attac k occ urre d.  
•  A n y use of o n de ma n d m e dicati o n ass ociat e d wit h pr o dr o mal s y m pt o ms o nl y, will be 
re p orte d as c o nc o mita nt me dicati o n i n t he e C R F a n d n ot as a n H A E o n de ma n d 
me dicati o n .  
H A E s y m pt o ms t hat are c o nfir me d as H A E attac ks b y t he I n vesti gat or or d ele gate will be  
rec or d e d i n t he e C R F ( See Secti o n 2. 4. 1) as s uc h a n d will be use d f or t he pri mar y effi cac y 
a nal ysis. All H A E s y m pt o ms re p orte d b y t he s u bj ect will be dis pla ye d i n a b y- s u bject listi n g.  
N ote: t hat t he assess me nt a n d o utc o me nee ds t o als o be rec or de d i n t he s u bject’s me dical 
rec or ds. 
S y m pt o ms re p orte d as A Es  
T he i n vesti gat or or desi g nee will  e val uate t h e s y m pt o m data e ntere d i n t he e Diar y b y t he 
s u bject usi n g t he sta n dar dize d set of re q uire me nts t o deter mi ne if t he s y m pt o ms re p orte d 
c o nstit ute a n H A E attac k or n ot. If t he i n vesti gat or c o nfir ms t he s y m pt o ms as a n H A E attac k, 
t he n t he H A E attac k will be re p ort e d i n t he e C R F. If t he assess me nt of t he s y m pt o ms are n ot 
c o nfir me d as a n H A E attac k, t he n t he eti ol o g y of t he s y m pt o ms m ust be re p orte d a n d 
rec or d e d as a n A E.  
2. 4. 1  D oc u me nti n g I n vesti g at or -C o nfir me d Att ac ks  
Acc ur ate a n d c o m plete d oc u me nti n g I n vesti gat or- c o nfir me d  H A E attac ks is i m p orta nt f or t he 
st u d y, as it will be use d f or t he st u d y pri mar y e n d p oi nt a nal ysis.  All H A E attac k i nf or mati o n 
s h o ul d be s u bsta ntiate d b y s u p p orti n g d oc u me ntati o n a n d me dical rec or ds. 
 T he site s h o ul d rec or d t he f oll o wi n g i nf or mati o n o n eac h attac k i n t he e C R F: 
•  Start date a n d ti me of a n attac k . 
•  E n d date a n d ti me of a n attac k . 
•  L ocati o n(s) of H A E s y m pt o ms. 
•  H A E s y m pt o m descri pti o n.   
•  H A E attac k s e verit y e v al uati o n (refer t o Secti o n 2. 4. 1. 3). 


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 6  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
•  Use of o n de ma n d treat m e nt (If yes, e nter t he f oll o wi n g i nf or mati o n i n H A E 
treat me nt f or m): 
o  Na me of o n d e ma n d me dicati o n . 
o  D ose(s) of o n d e ma n d m e dicati o n(s) use d.  
o  R o ute(s) of a d mi nistrati o n of o n de ma n d me dicati o n(s) use d. 
o  Start date a n d ti me of a d mi nistrati o n(s) of o n de ma n d me dicati o n(s) us e d.   
o  Se lect t he i de ntificati o n n u m ber of t he H A E attac k t he o n de ma n d treat me nt 
was gi ve n f or (t o be selecte d fr o m a list) i n t he e C R F. 
o  A d mi nistrati o n of o n- de ma n d me dicati o n(s) at a st u d y site, h o me, e mer ge nc y 
r o o m. 
2. 4. 1. 1  
Att ac k D ur ati o n  
T he d urati o n of a n H A E attac k will be re p orte d b y t he i n vesti gat or / dele gate c o nsi deri n g all 
a vaila ble me dical i nf or m ati o n i ncl u di n g t he o nset of first s y m pt o m a n d res ol uti o n of last of 
s y m pt o m of eac h attac k e ntere d i n t he eDi ar y. U nless t here has b ee n a c o m pletel y 
s y m pt o m-free 2 4- h o ur mi ni m u m se parati o n bet wee n t he o nset a n d res ol uti o n of all 
s y m pt o ms, a si n gle H A E attac k will be d oc u me nt e d o n t he basis of t he earliest start a n d t he 
latest e n d date of s y m pt o ms i n t he a nat o mic l ocati o ns liste d.  
2. 4. 1. 2  
Att ac k L oc ati o n  
Here ditar y a n gi oe d e ma attac ks ca n occ ur i n a n y a nat o mical l ocati o n  or m ulti ple l ocati o ns  of 
t he b o d y a n d t hese l ocati o ns are hi g hl y varia bl e. A n H A E attac k ma y ma nifest itself i n 
m ulti ple a nat o mic l ocati o ns. F or e xa m ple, s welli n g of t he ha n d a n d a b d o me n ma y occ ur a s 
s y m pt o ms of a si n gle attac k if t he y are te m p orall y ass ociate d (ie, o cc urri n g at t he sa me ti me 
or occ urri n g wit hi n o verl a p pi n g peri o ds wit hi n 2 4 h o urs ). U nless t here has bee n a c o m pletel y 
s y m pt o m-free 2 4- h o ur mi ni m u m se parati o n bet wee n t he o nset of ne w s y m pt o m a n d 
res ol uti o n of pri or s y m pt o ms i n a n y/all l ocati o n(s), a si n gle H A E attac k will be d oc u me nte d 
wit h all rele va nt l ocati o ns liste d i n t he e C R F.  


C S L Be hri n g, L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:  C S L 3 1 2 ( Fact or XIIa I n hi bit or 
M o n ocl o nal A nti b o d y)   
 
Pr ot oc ol versi o n: Ori gi nal  
 
Pa ge 1 1 7  of 1 1 7  
Date: 0 4 A u g ust  2 0 2 0  
C o nfi de ntial  
C S -S O P -0 4 -T 0 2 Versi o n 2 . 0 
 
 
Effecti ve Date: Wee k c o m me nci n g 2 5 -J u ne-2 0 1 8  
2. 4. 1. 3  
Att ac k Se verit y  
T he  se verit y of eac h H A E attac k (ie, mil d, m o derate, or se v ere) will be ass esse d b y t he 
i n vesti gat or or desi g nee base d o n t he s u bject’s descri pti o n of t he attac k. T he se verit y o ver t he 
ti me t hat t he attac k de vel o ps, pr o gresses, a n d res ol ves ca n ra n ge fr o m mil d t o se vere. T h e 
o verall attac k s e verit y will reflect t he ma xi m u m i nte nsit y of t he attac k, as assesse d b y t he  
i n vesti gat or. 
All attac ks re g ar dless of t he se verit y s h o ul d be ass ociate d wit h percei va ble s welli n g a n d/ or 
disc o mf ort. F urt her q ualifiers f or attac k se v erit y are descri be d bel o w. N ote t hat t hese ma y 
var y bet wee n s u bjects a n d attac ks.  
•  Mil d  
o  T he H A E attac k h as little t o n o effect o n dail y acti vities.  
o  T he use of H A E o n de ma n d me dicati o n t o treat t he attac k ma y n ot be n ecess ar y.  
o  Ot her c o nc o mita nt me dicati o n ( e g, a nal g esics) ma y be use d t o treat attac k s y m pt o ms.  
•  M o der ate  
o  T he H A E attac k ca uses d ail y acti vities t o be diffic ult. 
o  S o me assista nce ma y be nee de d t o c o m plet e dail y acti vities.  
o  T he use of H A E o n de ma n d me dicati o n t o treat t he attac k is pr o ba ble.  
•  Se vere  
o  T he H A E attac k ca uses mar ke d li mitati o n of dail y acti vities.  
o  Me dical assista nce  a n d i nter ve nti o n ma y be re q uire d , i ncl u di n g at cli nic e mer ge nc y 
r o o m visit or h os pitalizati o n. 
o  H A E o n - de ma n d m e dicati o n is use d t o treat t he attac k.  
 
 
 
 
 


V er si o n: 1. 0
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Si g n at ur e P a g e
C S L 3 1 2 _ 3 0 0 1 - Pr ot o c ol - 0 4 A u g 2 0 2 0
Si g n e d B y
D at e ( G M T)
A p pr o v e d- Cli ni c al S af et y P h y si ci a n A p pr o v al
0 5- A u g- 2 0 2 0 1 2: 5 8: 3 9
A p pr o v e d-
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0 5- A u g- 2 0 2 0 1 3: 3 8: 3 7
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SAP_001.pdf: 
S A P versi o n:  1. 0  
Pa ge 1 of 5 9  
Date: 2 1 A pr  2 0 2 1 
C o nfi de ntial  
S T A TI S TI C A L A N A L Y SI S P L A N ( S A P)  
A M ultice nter, D o u ble -Bli n d, R a n d o mize d, Pl ace b o - C o ntr olle d, P ar all el-Ar m St u d y  
t o I n vesti g ate t he Effic a c y a n d S afet y of S u bc ut a ne o us A d mi nistr ati o n of C S L 3 1 2 
(g ar a d aci m a b) i n t he Pr o p h yl actic Tre at me nt of Here dit ar y A n gi oe de m a  
C S L 3 1 2 _ 3 0 0 1 
C S L 3 1 2 ( Fact or XIIa I n hi bit or M o n ocl o nal A nti b o d y) 
P hase 3  
C S L Be hri n g, L L C 
1 0 2 0 First A ve n ue 
Ki n g of Pr ussia, Pe n ns yl va nia 
1 9 4 0 6 
U nite d States of A merica  
1. 0 - F I N A L 
2 1 A pr  2 0 2 1
N C T 0 4 6 5 6 4 1 8
2 0 2 0- 0 0 0 5 7 0- 2 5
St u d y  Nu m ber:  
St u d y  Pr o d uct:  
De vel o p me nt  Ph ase:  
S p o ns or:  
V ersi o n: 
V ersi o n Date:
N C T N u m ber:
E u dr a C T N u m ber: 
C o m pli a nce: 
T his st u d y 
will be c o n d ucte d i n acc or da nce 
wit h sta n dar ds of 
G o o d Cli nical Practice (as defi ne d b y t he I nter nati o nal C o u ncil f or 
Har m o nisati o n)  
a n d  
all  
a p plica ble  
nati o nal  
a n d  
l ocal 
re g ulati o ns.  
C O M M E R CI A L  I N C O N FI D E N C E 
T his d oc u me nt a n d t he i nf or mati o n c o ntai ne d herei n are pr o prietar y a n d c o nfi de ntial. T his d oc u me nt 
a n d t he c o ntai ne d i nf or mati o n are i nte n de d f or discl os ure t o a n d use b y t h ose pers o n nel w h o are u n der 
a n o bli gati o n of c o nfi de ntialit y b y a si g ne d a gree me nt wit h t he S p o ns or C S L Be hri n g L L C . T his 
d oc u me nt a n d t he c o ntai ne d i nf or mati o n ma y be discl ose d a n d use d o nl y t o t he e xte nt necessar y t o 
c o n d uct t he cli nical st u d y. Re pr o d ucti o n or discl os ure of t his d oc u me nt or its c o ntai ne d i nf or mati o n is 
f or bi d de n u nless at t he e x press re q uest or wit h t he writte n c o nse nt of C S L Be hri n g L L C.  


C S L Be hri n g  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 of 5 9  
Date: 2 1 A pr  2 0 2 1 
C o nfi de ntial  
 
 
Ta ble of C o nte nts  
List of Ta bles  .............................................................................................................................. 5 
List of Fi g ures ............................................................................................................................ 5 
1  
M o dificati o n Hist or y  .......................................................................................................... 6 
2  
List of A b bre viati o ns  .......................................................................................................... 7 
3  
P ur p ose ............................................................................................................................... 9 
4  
St u d y Desi g n ....................................................................................................................... 9 
4. 1  
O bjecti ves a n d E n d p oi nts ............................................................................................ 1 1  
4. 2  
St u d y H y p ot heses......................................................................................................... 1 3  
4. 3  
St u d y Treat me nts  ......................................................................................................... 1 4 
4. 4  
Ra n d o mizati o n Pr oce d ur es a n d Bli n di n g..................................................................... 1 4  
4. 5  
Deter mi nati o n  of t he Sa m ple Size  ............................................................................... 1 5 
4. 6  
Pla n ne d I nteri m A n al yses a n d Re vie ws ....................................................................... 1 7  
4. 6. 1  
I nteri m A nal ys es Ot her T ha n Sa m ple Size Re-esti mati o n ...................................... 1 7 
4. 6. 2  
I nteri m Sa m ple Size Re-esti mati o n ......................................................................... 1 7 
4. 6. 3  
I n de pe n de nt Data M o nit ori n g C o m mittee .............................................................. 1 7 
5  
C ha n ges fr o m t he Pr ot oc ol Pla n ne d A nal yses .................................................................. 1 8  
6  
St u d y A nal ysis Sets ........................................................................................................... 1 8  
6. 1  
Scree ne d  A n al ysis Set  .................................................................................................. 1 8 
6. 2  
I nte nti o n-t o-Treat A nal ysis Set  .................................................................................... 1 8 
6. 3  
Safet y A n al ysis Set  ...................................................................................................... 1 8 
6. 4  
Per Pr ot oc ol A nal ysis Set  ............................................................................................. 1 8 
6. 5  
P har mac o ki netic A nal ysis Set  ...................................................................................... 1 9 
6. 6  
P har mac o d y na mic A nal ysis Set  ................................................................................... 1 9 
7  
Ge neral C o nsi derati o ns ..................................................................................................... 1 9  
7. 1  
C or o na vir us Disease 2 0 1 9 ( C O VI D- 1 9) I m pact  .......................................................... 2 0 
7. 2  
M ultice nter St u dies  ...................................................................................................... 2 3 
7. 3  
Treat me nt Descri pt ors  .................................................................................................. 2 3 
8  
Data Ha n dli n g C o n ve nti o ns .............................................................................................. 2 3  
8. 1  
Missi n g Data  ................................................................................................................ 2 3 
8. 1. 1  
I m p utati o n of N o n-Date Missi n g Data  .................................................................... 2 4 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
8. 1. 2  
I m p utati o n of Partial Dat es ..................................................................................... 2 4 
8. 2  
Ge ner al Deri v e d Varia bles  ........................................................................................... 2 5 
8. 2. 1  
Refere n ce D ates a n d St u d y Da ys  ............................................................................ 2 5 
8. 2. 2  
D urati o ns a n d Ti me t o E ve nt Data .......................................................................... 2 5  
8. 2. 3  
Baseli ne Defi niti o n .................................................................................................. 2 5  
8. 2. 4  
C ha n ge fr o m Baseli ne ............................................................................................. 2 6  
8. 2. 5  
M ulti ple Assess me nts  .............................................................................................. 2 6 
8. 2. 6  
Act ual Treat me nt  ..................................................................................................... 2 6 
 
 
 
 
 
8. 2. 1 2  
B MI  ......................................................................................................................... 3 0 
8. 3  
St u d y Peri o ds relati ve t o Treat me nt ............................................................................. 3 0  
9  
St u d y P o p ulati o n ............................................................................................................... 3 1  
9. 1  
S u bject Di s p ositi o n ...................................................................................................... 3 1 
9. 2  
Pr ot oc ol De viati o ns ...................................................................................................... 3 3  
9. 3  
De m o gra p hic a n d Baseli ne C haracteristics  ................................................................. 3 4 
9. 4  
Pri or/ C o nc o mita nt Me dicati o ns  ................................................................................... 3 5 
1 0  Efficac y A nal yses  ............................................................................................................. 3 6 
1 0. 1  
A nal ysis of Pri mar y E n d p oi nt ...................................................................................... 3 6  
1 0. 1. 1  
Pri mar y Esti ma n d  .................................................................................................... 3 8 
1 0. 1. 2  
Pri mar y Efficac y A nal ysis  ....................................................................................... 3 9 
1 0. 1. 3  
S u p ple me ntar y A n al yses of Pri mar y Esti ma n d ....................................................... 4 1  
1 0. 2  
S u b gr o u p A nal yses ....................................................................................................... 4 2  
1 0. 3  
A nal ysis of Sec o n dar y E n d p oi nts ................................................................................ 4 3  
1 0. 3. 1  
Sec o n dar y Esti ma n d ................................................................................................ 4 3  
1 0. 3. 2  
S ec o n dar y Efficac y A nal ysis  ................................................................................... 4 3 
1 0. 3. 3  
S u p ple me ntar y A n al yses of Sec o n dar y E n d p oi nts  .................................................. 4 7 
 
1 0. 5  
M ulti ple C o m paris o ns a n d M ulti plicit y  ....................................................................... 5 1 
1 0. 6  
Treat me nt C o m plia nce  ................................................................................................. 5 1 
1 1  Safet y A n al yses  ................................................................................................................. 5 2 
C CI
C CI
C CI
C CI
C CI
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
11. 1  
E xte nt of E x p os ure ....................................................................................................... 5 2  
11. 2  
A d ver se E v e nts ............................................................................................................ 5 2 
11. 3  
Cli nical La b orat or y E val uati o ns .................................................................................. 5 5  
11. 4  
Ot her Safet y M eas ur es  ................................................................................................. 5 5 
1 1. 4. 1  
Vital Si g ns  ............................................................................................................... 5 5 
1 1. 4. 2  
E C G  ......................................................................................................................... 5 6 
1 1. 4. 3  
P h ysical E xa mi nati o n  .............................................................................................. 5 6 
1 2  P ha r mac o ki netic A nal yses ................................................................................................ 5 6 
1 2. 1  
Dr u g C o nce ntr ati o n Meas ures ..................................................................................... 5 6  
1 3  P har mac o d y na mic a n d Bi o mar kers A nal yses  ................................................................... 5 7 
1 3. 1  
P har mac o d y na mic A nal yses  ........................................................................................ 5 7 
1 3. 2  
Bi o mar ker A n al yses  ..................................................................................................... 5 7 
1 4  P har mac o ki netic/ P har mac o d y na mic A n al yses  ................................................................. 5 8 
1 5  Refere n ces  ......................................................................................................................... 5 9 
 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
List of Ta bles  
Ta ble 1 Pri mar y St u d y O bjecti ve a n d E n d p oi nt ...................................................................... 1 1  
Ta ble 2 Sec o n dar y St u d y O bjecti ves a n d E n d p oi nts ............................................................... 1 1  
 
Ta ble 4 Sa m ple Size J ustificati o n f or Ja p a nese S u bjects - Met h o d 1 ...................................... 1 6 
Ta ble 5 Sa m ple Size J ustificati o n f or Ja p a nese S u bjects - Met h o d 2 ...................................... 1 7 
 
 
Ta ble 8 O ver vie w St u d y Peri o ds .............................................................................................. 3 0  
Ta ble 9 P ote ntial Pr ot oc ol De viati o ns ...................................................................................... 3 3  
 
List of Fi g ures  
Fi g ure 1 St u d y O ver vie w ........................................................................................................... 9 
 
C CI
C CI
C CI




C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 7 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
2  
List of A b bre vi ati o ns  
A b bre vi ati o n  
Ter m  
A Da M  
A nal ysis Data M o del  
A E  
A d verse e ve nt  
A E SI  
A d verse e ve nt of s pecial i nterest  
 
 
a P T T 
Acti vate d partial t hr o m b o plasti n ti me 
A T C  
A nat o mical t hera p e utic c he mical  
A T S  
All treate d s u bjects a n al ysis set  
B L Q  
Bel o w Li mit of Q ua ntificati o n  
C DI S C  
Cli nical Data I nterc ha n g e Sta n dar ds C o ns orti u m  
CI  
C o nfi de nce i nter v al  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C S L  
C S L Be hri n g  
C S P  
Cli nical St u d y Pr ot oc ol  
C S R  
Cli nical st u d y re p ort  
C T M S  
Cli nical Trial Ma na ge me nt S yste m  
D B L  
Data base l o c k  
B D R M  
Bli n d  Data re vie w meeti n g  
B MI  
B o d y Mass I n de x  
E C G  
Electr ocar di o gra m  
e C O A  
Electr o nic cli nical o utc o mes assess me nt  
e C R F 
Electr o nic case re p ort f or m  
e Diar y  
Electr o nic diar y  
E O S  
E n d of st u d y  
 
 
F A S  
F ull a nal ysis set  
H A E  
Here ditar y a n gi oe d e ma  
I C F 
I nf or me d c o ns e nt f or m 
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
 
 
I P 
I n vesti gati o nal pr o d uct 
I R T 
I nteracti ve res p o nse t ec h n ol o g y 
I S R 
I njecti o n site reacti o n 
I T T 
I nte nti o n-t o-Treat  
I V 
I ntra ve n o us 
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y A cti vities  
M S A P  
M o deli n g a n d si m ulati o n a nal ysis pla n  
C CI
C CI
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 8 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
A b bre vi ati o n  
Ter m  
P D  
P har mac o d y na mic  
P K  
P har mac o ki netic  
P P  
Per pr ot oc ol  
P T  
Preferre d ter m  
Q o L  
Q ualit y of Life  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S D T M  
St u d y Data Ta b ulati o n M o del  
S C  
S u bc uta ne o us  
 
 
S O C  
S yste m or ga n class  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nts  
T F Ls  
Ta bles, Listi n gs, Fi g ures  
 
 
 
 
C CI
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 9 of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
3  
P ur p ose  
T his S A P pr o vi des a d et aile d a n d c o m plete des cri pti o n of t he pla n ne d st atistical a nal yses of 
t he st u d y C S L 3 1 2 _ 3 0 0 1 t o s u p p ort t he Cli nical St u d y Re p ort ( C S R). T his S A P c o m plies wit h 
t he I nter n ati o nal C o u ncil f or Har m o nisati o n (I C H) E 9 ‘ Statistical Pri nci ples f or Cli nical Trials’ 
a n d E 9( R 1) ‘ Statistical Pri nci ples f or Cli nical Trials: A d de n d u m o n Esti ma n ds a n d Se nsiti vit y 
A nal ysis i n Cli nical Trials’, a n d is base d u p o n t he f oll o wi n g st u d y d oc u me nts: 
•  Cli nical St u d y Pr ot oc ol ( C S P) Ori gi nal ( date d 0 4 A u g 2 0 2 0), 
•  electr o nic Cas e Re p ort F or m (e C R F), Versi o n 1. 0 ( date d 1 6 Dec  2 0 2 0). 
P o p ulati o n p har mac o ki netic ( P K) a nal yses are d escri be d wit hi n t he m o deli n g a n d si m ulati o n 
a nal ysis pla n ( M S A P) a n d re p orte d se p aratel y.  
M oc k ta bles, listi n gs, a n d fi g ures s hells are pr o vi de d i n a se parate s u p p orti n g d oc u me nt. 
All decisi o ns r e gar di n g t he fi nal a nal ysis of t he st u d y res ults, as defi ne d i n t his S A P, ha ve b ee n 
ma de  bef ore  data b ase  l oc k  ( D B L)  a n d  u n bli n di n g  of  t he  st u d y  d ata.  D e viati o ns  fr o m  t he 
a nal yses i n t his S A P will be detaile d i n t he C S R.  
4  
St u d y Desi g n  
T his is a m ultice nter, d o u ble- bli n d, ra n d o mize d, pl ace b o-c o ntr olle d, parallel- ar m, p hase 3  
st u d y t o i n vesti gate t he efficac y a n d safet y of a si n gle d ose of 2 0 0 m g C S L 3 1 2 a d mi nistere d 
b y s u bc uta ne o us (S C ) i njecti o n o nce m o nt hl y as pr o p h yla xis t o pre ve nt h ere ditar y a n gi oe de ma 
(H A E ) attac ks i n a d olesce nt ( 1 2 t o 1 7 years, i ncl usi ve) a n d  a d ult s u bjects wit h H A E. T his st u d y 
will be c o n d ucte d gl o ball y. As s h o w n i n  Fi g ure 1 , t he st u d y c o nsists of a Scree ni n g Peri o d ( u p 
t o 1 m o nt h), a R u n-i n Peri o d ( u p t o 2 m o nt hs), a Treat me nt Peri o d ( 6 m o nt hs), a n d eit her a 2 -
m o nt h F oll o w -u p Peri o d (ie, 3 m o nt hs after  last i n vesti gati o nal pr o d uct a d mi nistrati o n) or e ntr y 
i nt o t he o pe n-la bel P hase 3 b St u d y C S L 3 1 2 _ 3 0 0 2.  
Fi g ure 1 St u d y O ver vie w  
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 0  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Scree ne d s u bj ects w h o m eet all t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria will 
e nter t he R u n -i n Peri o d. S u bjects w h o d o n ot meet t he scree ni ng criteria f or e nteri n g t he R u n -
i n Peri o d wit hi n 3 0 da ys ma y be res cree ne d wit h c o nfir mati o n fr o m t he s p o ns or. Rescree ni n g 
is all o we d o nce. S u bjects w h o d o n ot meet t he mi ni m u m H A E attac k rat e d uri n g t he R u n-i n 
Peri o d a n d / or all ot her criteria f or e nteri n g t he Treat me nt Peri o d will be c o nsi dere d R u n-i n 
fail ures a n d ca n n ot be res cree n e d. 
 
S u bjects meeti n g t he eli gi bilit y criteria will e nter t he Treat me nt Peri o d after t he R u n -i n 
Peri o d. If a s u bject is u na ble t o e nter t he Treat me nt Peri o d b y Da y 6 0, C S L Be hri n g ( C S L) 
a p pr o val is re q uir e d f or t he s u bject t o e nter t h e Treat me nt Peri o d. 
 
Eli gi ble s u bjects will be ra n d o mize d 3: 2 t o eit her t he C S L 3 1 2 Acti ve Ar m ( C S L 3 1 2 S C o nce 
a m o nt h) or t h e Place b o Ar m  ( Place b o S C o nce  a m o nt h). All s u bjects  will be ra n d o mize d 
base d o n  a ge ( ≤ 1 7 years, > 1 7 years) a n d  baseli ne attac k rate o bser ve d d uri n g t he R u n -i n 
Peri o d ( 1 t o < 3 attac ks / m o nt h, a n d ≥ 3 attac ks / m o nt h) f or a d ults o nl y. 
 
S u bjects w h o ter mi nate earl y fr o m t he st u d y (i e, b ef ore Da y 1 8 2) will u n der g o t he assess me nts 
s pecifie d f or t he E n d of Treat me nt Visit ( Da y 1 8 2), if p ossi ble. 
 
S u bjects w h o disc o nti n ue treat me nt wit h C S L 3 1 2 will be e nc o ura g e d t o re mai n i n t he st u d y 
u ntil Da y 1 8 2 i n or der t o c ollect st u d y assess me nts.  S u bjects ma y wit h dra w fr o m t he st u d y at 
a n y  ti me  at  t heir  o w n  r e q uest,  or  at  t he  dis creti o n  of  t he  i n vesti gat or  or  C S L  f or  safet y, 
be ha vi oral, or a d mi nistrati ve reas o ns. If t he s u bject wit h dra ws fr o m t he st u d y, a n d als o 
wit h dra ws c o nse nt f or discl os ure of f ut ure i nf or m ati o n, C S L ma y retai n a n d c o nti n ue t o use 
a n y data a n d s a m ples c ollecte d bef ore wit h dra wal of c o nse nt.  
 
S u bjects w h o s uccessf ull y c o m plete t he c urre nt st u d y ( C S L 3 1 2 _ 3 0 0 1) ma y ha ve t he o pti o n t o 
r oll o ver i nt o a n o pe n-la b el p hase 3 b St u d y C S L 3 1 2 _ 3 0 0 2. T he Da y 1 8 2 E n d of Treat me nt 
Peri o d Visit c orres p o n ds t o t he first da y of t he o pe n-la bel p hase 3 b st u d y f or s u bjects r olli n g-
o ver i nt o St u d y C S L 3 1 2 _ 3 0 0 2. S u bjects will e nter St u d y C S L 3 1 2 _ 3 0 0 2 after c o m pleti n g t he 
Da y 1 8 2 assess me nts a n d si g ni n g t he I C F f or St u d y C S L 3 1 2 _ 3 0 0 2. S u bjects w h o c h o ose n ot 
t o partici pate i n St u d y C S L 3 1 2 _ 3 0 0 2 are re q uire d t o c o m plete t he F oll o w- u p Visit ( Da y 2 4 2, 
w hic h is a p pr o xi matel y 3  m o nt hs after t he last d os e of i n vesti gati o nal pr o d uct).  
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 1  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
4. 1  
O bjecti ves a n d E n d p oi nts  
T he pri mar y o bjecti ve of t his st u d y is t o e val uate t he efficac y of S C a d mi nistrati o n of C S L 3 1 2 
as pr o p h yla xis t o pre ve nt H A E attac ks i n s u bjects wit h H A E. 
Ta ble 1 Pri m ar y St u d y O bjecti ve a n d E n d p oi nt  
O bjecti ve  
E n d p oi nt  
S u m m ar y Me as ure(s)  
Pri m ar y   
Ti me -n or malize d n u m ber of 
here ditar y a n gi oe de ma ( H A E) 
attac ks d uri n g treat me nt fr o m 
Da y 1 t hr o u g h Da y 1 8 2 a 
T he ti me -n or malize d n u m ber of H A E attac ks 
( per m o nt h a n d a n n ualize d) i n s u bjects treate d 
o nce a m o nt h wit h eit her C S L 3 1 2 ( Acti ve Ar m) 
or place b o ( Place b o Ar m) d uri n g t he peri o d fr o m 
Da y 1 t hr o u g h Da y 1 8 2 ( 6 m o nt hs). 
aO nl y  i n vesti gat or-c o nfir me d H A E attac ks base d o n t he i n vesti gat or’s assess me nt of s u bject -re p orte d s y m pt o ms 
will be i ncl u de d i n t he a nal ysis of pri mar y efficac y e n d p oi nt. Descri pti o ns of c o nfir me d H A E attac k are pr o vi de d 
i n C S P Secti o n 8. 1. 3 a n d C S P A p pe n di x 2. 
T he sec o n d ar y o bjecti ves of t he st u d y are: 
1.  T o c har acteri ze t he cli nical efficac y of S C C S L 3 1 2 i n t he pr o p h ylactic treat me nt of  
H A E.  
2.  To e val uate t he s afet y of S C C S L 3 1 2 i n t he pr o p h ylactic treat me nt of H A E. 
Ta ble 2 Sec o n d ar y St u d y O bjecti ves a n d E n d p oi nts  
O bjecti ve  
E n d p oi nt  
S u m m ar y Me as ure(s)  
Efficac y E n d p oi nts  
1.  
T he re d ucti o n i n t he attac k 
rate d uri n g t he Treat me nt 
Peri o d c o m pare d t o t he R u n -
i n Peri o d 
T he perce nta ge re d ucti o n (at least ≥ 5 0 %, ≥ 7 0 %, ≥ 
9 0 or e q ual t o 1 0 0 % [attac k free]) i n t he ti me-
n or malize d n u m ber of H A E attac ks i n s u bjects 
treate d o nce a m o nt h wit h eit her C S L 3 1 2 ( Acti ve 
Ar m) or place b o ( Place b o Ar m) d uri n g t he peri o d 
fr o m Da y 1 t hr o u g h Da y 1 8 2 ( 6 m o nt hs) c o m pare d t o 
t he R u n-i n Peri o d, as well as f or t he first 3- m o nt h 
ti me peri o d a n d f or t he sec o n d 3-m o nt h ti me peri o d 
of t he Acti ve a n d Place b o Ar ms c o m pare d t o t he 
R u n -i n Peri o d. 
1.  
T he ti me -n or malize d n u m ber 
of H A E attac ks re q uiri n g o n-
de ma n d treat me nt 
T he ti me -n or malize d n u m ber ( per m o nt h a n d 
a n n ualize d) of H A E attac ks re q uiri n g o n- de ma n d 
treat me nt i n s u bjects treate d o nce a m o nt h wit h eit her 
C S L 3 1 2 ( Acti ve Ar m) or place b o ( Place b o Ar m) 
d uri n g t he peri o d fr o m Da y 1 t hr o u g h Da y 1 8 2 ( 6 
m o nt hs), as well as f or t he first 3 -m o nt h ti me peri o d 
a n d f or t he sec o n d 3- m o nt h ti me peri o d of t he Acti ve 
a n d Place b o Ar ms. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 2  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
O bjecti ve  
E n d p oi nt  
S u m m ar y Me as ure(s)  
Efficac y E n d p oi nts  
1.  
T he ti me -n or malize d n u m ber 
of m o derate a n d / or se vere 
H A E attac ks  
T he ti me -n or malize d n u m ber ( per m o nt h a n d 
a n n ualize d) of m o derate a n d / or se vere H A E attac ks 
i n s u bjects treate d o nce a m o nt h wit h eit her C S L 3 1 2 
( Acti ve Ar m) or place b o ( Place b o Ar m) d uri n g t he 
peri o d fr o m Da y 1 t hr o u g h Da y 1 8 2 ( 6 m o nt hs), as 
well as f or t he first 3 -m o nt h ti me peri o d a n d f or t he 
sec o n d 3- m o nt h ti me peri o d of t he Acti ve a n d 
Place b o  ar m. 
1.  
Ti me -n or malize d n u m ber of 
H A E attac ks at vari o us ti me 
p oi nts d uri n g t he treat me nt 
peri o d 
T he ti me -n or malize d n u m ber of H A E attac ks ( per 
m o nt h a n d a n n ualize d) i n s u bjects treate d o nce 
m o nt hl y wit h eit her C S L 3 1 2 ( Acti ve Ar m) or 
place b o ( Place b o Ar m) d uri n g t he first 3- m o nt h ti me 
peri o d a n d t he sec o n d 3- m o nt h ti me  
peri o d of C S L 3 1 2 ( Acti ve Ar m) a n d place b o 
( Place b o Ar m).  
 
T he perce nta ge re d ucti o n will be calc ulate d f or t he 
ti me- n or malize d n u m ber 
of H A E attac ks bet wee n t he Acti ve Ar m a n d t he 
Place b o Ar m f or t he 6- m o nt h treat me nt peri o d, as 
well as f or t he first 3 m o nt hs a n d t he sec o n d 3 
m o nt hs of t he treat me nt peri o d. 
1.  
 
 
 
C o m paris o n of t he distri b uti o n of res p o nses t o 
t hera p y bet wee n C S L 3 1 2 a n d place b o at t he e n d of 
t he Treat me nt Peri o d at Da y 1 8 2 base d o n t he 
pr o p orti o ns of s u bjects wit h a "e xcelle nt, 
g o o d, fair, p o or or n o ne" res p o nse t o t hera p y. 
Safet y E n d p oi nts  
2.  
•  
A Es  
•  
A E SIs  
•  
S A Es  
•  
C S L 3 1 2 i n d uce d a nti -
C S L 3 1 2 a nti b o dies 
•  
Cli nicall y si g nifica nt 
a b n or malities i n 
la b orat or y assess me nts 
(ie, la b orat or y 
a b n or malities re p orte d as 
A Es).  
T he n u m ber a n d perce nta ge of s u bjects  
e x perie nci n g t he s pecifie d safet y e ve nts  
o n treat me nt wit h C S L 3 1 2 or place b o 
d uri n g t he e ntire Treat me nt Peri o d u ntil 
F oll o w- u p or Fi nal Visit.  
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 3  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
4. 2  
St u d y H y p ot heses  
F o ur t ests, o ne f or t he pri mar y e n d p oi nt ( H 0 1) a n d 3 f or t he  s ec o n dar y e n d p oi nts ( H 0 2, H 0 3, 
H 0 4), will be perf or me d  i n a hierar c hical or d er wit h a n 2-si de d al p ha of 5 % eac h. 
 
F o ur n ull h y p ot heses are defi ne d: 
•  H 0 1: t he ti me -n or malize d n u m ber of H A E attac ks i n t he first 6-m o nt h ti me peri o d of 
t he Acti ve Ar m a n d i n t h e Place b o Ar m p eri o d are e q ual. 
•  H 0 2: t he per ce nta g e r e d ucti o n i n t he  mea ns of t he  ti me-n or malize d n u m ber of H A E 
attac ks  f or  t he  6 -m o nt hs  of  t he  Acti ve  Ar m c o m pare d  t o  t he  6-m o nt h  Place b o  Ar m 
peri o d ar e e q ual t o zer o. 
•  H 0 3: t he n u m ber of s u bjects w h o d o n ot e x perie n ce a H A E attac k i n t he first 3 m o nt hs 
of t he Acti ve Ar m a n d t h e first 3- m o nt h Place b o P eri o d are e q ual.  
•  H 0 4: t he perce nt of s u bjects wit h g o o d or e xcelle nt res p o nses t o t he 
 at t he e n d 
of T reat me nt Peri o d ( Da y 1 8 2) are e q ual  f or s u bjects treate d wit h C S L 3 1 2 a n d place b o. 
Met h o ds t o c o ntr ol f or m ulti plicit y are descri be d i n Secti o n 1 0. 5 . 
 
 
 
C CI
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 4  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
4. 3  
St u d y Tre at me nts  
T he i n vesti gati o nal pr o d ucts i n t his st u d y are 2 0 0 m g C S L 3 1 2 a n d place b o.  
 
S u bjects ra n d o mize d t o t he Acti ve Ar m will recei ve C S L 3 1 2 S C o nce a m o nt h f or 6 m o nt hs. 
T he first d ose of C S L 3 1 2 will be a 4 0 0 m g l oa di n g d ose a d mi nistere d s u bc uta ne o usl y o n t he 
sa me da y as 2 s e par ate i njecti o ns at t he st u d y site (ie, M o nt h 1). S u bse q ue nt d oses of C S L 3 1 2 
will be 2 0 0 m g a d mi nistere d S C o nce m o nt hl y f or 5 c o nsec uti ve m o nt hs (ie, M o nt hs 2 t hr o u g h 
6).  
 
S u bjects ra n d o mize d t o t he Place b o Ar m will rec ei ve v ol u me- matc he d place b o o nce m o nt hl y 
f or 6 m o nt hs. T he first d ose of place b o i n t he Place b o Ar m will be v ol u me-matc he d  ( 4 0 0 m g 
l oa di n g d ose) place b o  a d mi nistere d S C as 2 se p arate i njecti o ns (ie, M o nt h 1). S u bjects will 
t he n recei v e v ol u me-mat c he d place b o S C o nce a m o nt h f or 5 c o nsec uti ve m o nt hs (ie, M o nt hs 
2 t hr o u g h 6). 
4. 4  
R a n d o miz ati o n Pr oce d ures a n d Bli n di n g  
S u bjects will be ra n d o mize d usi n g a bl oc k ra n d o mizati o n b y mea ns of ce ntralize d  I nteracti ve 
Res p o nse Tec h n ol o g y  (I R T) t o 1 of 2 treat me nt ar ms i n a 3: 2 rati o t o eit her t he Acti ve Ar m or 
t o t he Place b o Ar m. Stratif yi n g varia bles will be a ge ( ≤ 1 7 years, > 1 7 years) a n d, f or a d ults, 
t he s u bject’s baseli ne attac k rat e ( 1 t o < 3 attac ks/ m o nt h, a n d ≥ 3 attac ks/ m o nt h). 
 
Ra n d o mizati o n will be d o ne ce ntrall y. T he ra n d o mizati o n list will be ge nerate d acc or di n g t o 
t he a p pr o ve d ra n d o mizati o n s pecificati o ns, w hic h i ncl u des f urt her ra n d o mi zati o n details. T he 
I R T  ser vi ce  pr o vi der  will  kee p  t he  ra n d o mizati o n  c o de  o n  file. I n v esti gati o nal  site  staf f, 
i ncl u di n g t he i n vesti gat ors, will be bli n de d t o treat me nt all ocati o n. Su bjects a n d C S L staff / 
desi g nates partici p ati n g i n t he c o n d uct of t he st u d y will als o be  bli n de d t o treat me nt all ocati o n 
( d o u ble- bli n d).  
 
T he I R T will assi g n t he i n vesti gati o nal pr o d uct (I P) t o eac h s u bject. T he I P will be pac ka ge d 
a n d  la belle d  t o  e ns ure  bli n di n g  is  mai ntai ne d  a n d  C S L 3 1 2  Prefille d  S yri n g e is  n ot 
disti n g uis ha ble fr o m t he place b o.  
 
St u d y  u n bli n di n g  will  ta ke  place  f oll o wi n g  l oc ki n g  of  t he  st u d y dat a b ase  e xce pt  i n  t he 
sit uati o ns  as  brea ki n g  t he  bli n d  f or  a n  e mer ge nc y or  a n  a d-h oc  safet y  u n bli n di n g.  O ut p uts 
i ncl u di n g u n bli n de d i nf or mati o n mi g ht als o be g e nerat e d  f or meeti n gs wit h  t he i n de pe n de nt 
data m o nit ori n g c o m mittee (I D M C , see Secti o n 4. 6. 3 ). A de q u ate pr o ce d ures are i n place t o 
e ns ure t he i nte grit y of t h e bli n de d data wit hi n C S L. 
 
All bl o o d sa m ples c ollecte d f or P K / P D a nal yze d b y t he ce ntral la b orat or y will re mai n  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 5  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
bli n de d u ntil data base l oc k. I n a d diti o n, res ults fr o m assess me nt of a P T T will n ot be a vaila ble 
t o s u bjects, st u d y site pers o n nel, or C S L a n d t heir dele gates w h o are bli n de d t o treat me nt 
assi g n me nt. 
 
T he bi oa nal yst a n d p har mac o ki neticist res p o nsi ble f or t he sa m ple a nal ysis a n d P K / P D, 
i m m u n o ge nicit y, a n d c oa g ulati o n e val uati o ns will be u n bli n de d. H o we ver, t he y will a gree n ot 
t o discl ose t he ra n d o mizati o n sc he d ule or a n y d ata pri or fi nal data b ase l oc k a n d u n bli n di n g. 
 
F or f ur t her det ails please see t he C S P . 
 
4. 5  
Deter mi n ati o n  of t he S a m ple Size  
I n t otal, 6 0 s u bjects are pla n ne d t o be ra n d o mize d. 
F ort y s u bjects wit h C 1-I N H H A E t y pe 1 a n d t y pe 2 c o m pleti n g t he 6- m o nt h Treat me nt  
Peri o d are n ee de d t o ac hi e ve a p o w er of a p pr o xi m atel y 9 0 % f or a t w o- si de d Wilc o x o n Test 
(al p ha of 5 %). S u bjects will be ra n d o mize d t o t he Acti ve Ar m or t he Place b o Ar m wit h a rati o 
of 3: 2. A n attac k rate p er m o nt h of 0. 3 1 2 5 f or C S L 3 1 2-treate d s u bjects a n d of 1. 3 f or s u bjects 
recei vi n g place b o are ass u me d. T he m o nt hl y attac k rates of place b o a n d of C S L 3 1 2 are 
ass u me d t o be P oiss o n distri b ute d. 
T he sa m ple size calc ulati o n is perf or me d wit h S A S 9. 4 usi n g pr oc p o wer pr oce d ure wit h 
t w osa m ple wilc o x o n test = W M W w hic h perf or ms p o wer a n al yses f or t h e Wilc ox o n- Test f or 
t w o i n de pe n de nt gr o u ps, i.e. t he C S L 3 1 2 a n d t he Place b o treat me nt i n St u d y C S L 3 1 2 _ 3 0 0 1. 
T he Wilc o x o n Ra n k S u m test is testi n g fr o m de part ure fr o m t he n ull h y p ot hesis a n d is 
assessi n g if t here is a l ocati o n s hift bet wee n t he distri b uti o ns of t h e H A E attac k rates of t he 
C S L 3 1 2 a n d t he Place b o treat me nt. S A S Pr oc P o wer pr oce d ure us es t he O’ Brie n- Castell oe 
a p pr oac h t o c o m p ute a p pr o xi mate p o wer. Al p ha is set t o 5 % [ O’ Brie n & Castell oe, 2 0 0 6 ]. 
T he ass u me d m o nt hl y attac k rat es of place b o a n d of C S L 3 1 2 (i.e. 1. 3 a n d 0. 3 1 2 5 
attac ks/ m o nt h, res pecti vel y) are use d as t he t w o m ea ns of t he t w o P oiss o n distri b uti o ns. T he 
ra n d o mizati o n rati o of 3: 2 was i m ple me nte d b y G R O U P N S = ( 2 4 1 6) res ulti n g i n a t otal 
sa m ple size of 4 0 w hic h is t he l o west o ne reac hi n g 9 0 % p o wer.  
It is tar gete d t o r a n d o mize a p pr o xi matel y 5 a d ol es ce nts i nt o t he treat me nt p eri o d wit h a 
ra n d o mizati o n rati o of 3: 2 (acti ve: place b o).  
To all o w f or s ufficie nt safet y data, t o i ncrease t h e li keli h o o d of a d olesce nts e nteri n g t he st u d y 
a n d, t o ha ve at least 4 0 s u bjects reac hi n g t he e n d of t he st u d y, a n a d diti o nal 2 0 s u bjects are 
pla n ne d t o be ra n d o mize d. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 6  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
I n case it is n ot feasi ble t o ra n d o mize t he tar gete d n u m ber of a d oles ce nts, t he tar get e d t otal 
sa m ple size will be ac hie ve d by ra n d o mizi n g t he n ee de d n u m ber wit h a d ult s u bjects. 
I n a d diti o n, it is tar gete d t o i ncl u de 5 Ja pa nes e s u bjects  i nt o t he t otal 6 0 s u bjects ra n d o mize d. 
Base d o n Met h o d 1 a n d Met h o d 2 i n t he [ Basic pri nci ples o n Gl o bal Cli nical Trials ] t he 
sa m ple size of t he J a pa nese s u bjects are pla nne d as bel o w. T he p oi nt esti mate of t he e n d p oi nt 
i n eac h ar m f or Ja p a nese p o p ulati o n a n d ot her re gi o ns (f or Met h o d 2) are ass u me d as t he 
sa me as t hat f or t h e gl o bal p o p ulati o n. 
Met h o d  1 
Wit h setti n g t he n otati o ns of treat me nt differe nces bet wee n C S L 3 1 2 a n d pl ace b o ar m as 
D, t he treat me nt differ e n ce i n t he gl o bal p o p ulati o n as D all, a n d t he treat me nt differe n ce 
i n t he Ja pa nese s u b p o p ul ati o n as DJa pa n, t he pr o ba bilities of DJa pa n/ Dall > 0. 5 were 
calc ulate d f or t he setti n gs t hat t he gl o bal sa m ple size is 6 0 patie nts ( C S L 3 1 2 ar m = 3 6 
patie nts, a n d place b o ar m = 2 4 patie nts) i ncl u di n g t he Ja pa nes e sa m ple size of 5 – 8. 
T he Ja pa n ese sa m ple sizes of eac h ar m w ere r o u n de d base d o n t he 3: 2 ra n d o miz ati o n 
rati o. 
Ta ble 4 S a m ple Size J ustific ati o n f or J a p a nese S u bjects - Met h o d 1  
J a p a nese s a m ple size  
Pr o b a bilit y ( %) of D J a p a n/ Dall > 0. 5  
T otal  
C S L 3 1 2  
Plac eb o  
Wit h me dia n  
Wit h mea n  
5  
3  
2  
6 4  
7 0  
6  
4  
2  
6 3  
7 1  
7  
4  
3  
6 5  
7 6  
8  
5  
3  
7 3  
7 6  
 
Met h o d  2 
Wit h setti n g t he n otati o ns of treat me nt differe nces bet wee n C S L 3 1 2 a n d pl ace b o ar m as 
D, t he treat me nt differ e n ce i n t he gl o bal p o p ulati o n as D all, t he treat me nt differe nce i n 
t he Ja pa nes e s u b p o p ulati o n as DJa pa n a n d t he treat me nt differe nce i n ot her re gi o ns x as 
D ot h er - x, t he pr o ba bilities of t hat all of t he gl o bal, J a pa n a n d ot her re gi o ns of D > 0 were 
calc ulate d f or t he setti n gs t hat t he gl o bal sa m ple size is 6 0 patie nts ( C S L 3 1 2 ar m = 3 6 
patie nts, a n d place b o ar m = 2 4 patie nts) , t he Ja p a nese sa m ple size is 5 – 8, t he sa m ple 
size of N ort h A merica a n d E ur o pe are ass u me d t o be t he sa me. T h e sa m ple sizes of 
eac h ar m f or J a pa n a n d ot her re gi o ns w ere r o u n de d u p base d o n 3: 2 ra n d o mizati o n 
rati o. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 7  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Ta ble 5 S a m ple Size J ustific ati o n f or J a p a nese S u bjects - Met h o d 2 
S a m ple  size f or e ac h re gi o n 
Pr o b a bilit y ( %) of all of D  > 0  
Ja pa n 
N o rt h A merica * 
E ur o pe *  
Wit h me dia n  
Wit h mea n  
5  
2 7  
2 8  
7 5  
8 6  
6  
2 7  
2 7  
7 3  
8 5  
7  
2 6  
2 7  
7 0  
9 1  
8  
2 6  
2 6  
6 7  
9 2  
* E x pect e d t hat t he sa m ple sizes f or N ort h A merica a n d E ur o pe w o ul d be t he sa me. If 
n ot di visi ble, t he sa m ple size of E ur o pe i ncl u des o ne m ore patie nts t ha n t hat of N ort h 
A merica.  
 
As t he res ults, if t he Ja pa nese sa m ple size is 8, t he pr o ba bilities t o ac hie ve 
c o nsiste nc y  bet wee n t he Ja pa nese s u bs et a n d t he gl o bal p o p ulati o n are 6 7 %－9 2 % 
usi n g mea n a n d me dia n wit h 3: 2 ra n d o mizati o n rati o base d o n Met h o d 1 a n d 2. 
Ei g ht y perce nt pr o b a bilit y w o ul d be ac hie v e d wit h 5 Ja pa nese p atie nts alrea d y w he n 
usi n g t he mea n a n d Met h o d 2.  
 
4. 6  
Pl a n ne d I nteri m A n al yses a n d Re vie ws  
4. 6. 1  
I nteri m A n al yses Ot her T h a n S a m ple Size Re-esti m ati o n 
N o f or mal i nteri m a nal ys es are pl a n ne d f or t his st u d y.  
4. 6. 2  
I nteri m S a m ple Size Re-esti m ati o n 
I nteri m sa m ple size r e-esti mati o n is n ot a p plica ble f or t his st u d y.  
4. 6. 3  
I n de pen de nt D at a M o nit ori n g C o m mittee  
A n i n de pe n de nt d ata m o nit ori n g c o m mittee (I D M C) will be esta blis he d t o m o nit or t he safet y 
a n d  efficac y  dat a  ge ner ate d  d uri n g  t he  st u d y.  T he  I D M C  will  c o nsist  of  a n  i n de pe n de nt 
statisticia n a n d cli nical s pecialists i n t he fiel ds of H A E ma na ge me nt, w h o als o ha ve e x perie n ce 
i n cli nical trials. T he I D M C will re vie w acc u m ul ati n g data fr o m t he o n g oi n g st u d y. Base d o n 
t hese re vie ws, t he I D M C will a d vise o n t he f urt her c o n d uct of t he st u d y. N o s uccess or f utilit y 
t hres h ol ds will be set f or t he I D M C re vie ws; C S L will n ot st o p t he st u d y  u nless a maj or safet y 
iss ue has bee n i de ntifie d. T he c o m p ositi o n, acti vities, a n d res p o nsi bilities of t he I D M C will be 
descri be d s e par atel y i n t he I D M C c harter.  A se p arate I D M C S A P a n d I D M C T F L S hells wi ll 
be create d.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 8  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
5  
C h a n ges fr o m t he Pr ot oc ol Pl a n ne d A n al yses  
Esti ma n d defi niti o n has bee n u p date d t o reflect t he p ote ntial i m pact of t he o n g oi n g c or o na vir us 
disease 2 0 1 9 ( C O VI D - 1 9) pa n de mic, see Secti o n 7. 1  a n d Secti o n 1 0. 1. 1 . 
 
C o m paris o n of t he distri b uti o n of res p o nses t o t hera p y bet wee n C S L 3 1 2 a n d place b o at t he e n d 
of t he Treat me nt Peri o d will use t he  
 at Visit Da y 1 8 2 o nl y . If s u bject’s St u d y Visit Da y 
1 8 2  
 val ue is missi n g t he s u bject will n ot be i ncl u de d i n t he 
, see 
Secti o n 1 0. 4 .  
 
Als o , h y p ot hesis H 0 2 a n d h y p ot hesis H 0 4  hav e  b ee n defi ne d m ore cl earl y  b y m o dif yi n g t he 
w or di n g , see Secti o n 4. 2 . 
 
T here  ar e  n o f urt her c h a n ges  t o  t he  a nal yses  pla n ne d  c o m pare d  t o  t he  C S P. A n y  c ha n ges 
c o n d ucte d after fi n alizati o n of t he S A P will be n ote d i n t he Cli nical  St u d y Re p ort.   
6  
St u d y A n al ysis Sets  
6. 1  
Scree ne d A n al ysis Set  
T he scree ne d a nal ysis set c o m prises all s u bjects w h o pr o vi de writte n i nf or me d c o nse nt a n d 
w h o u n der g o st u d y scr ee ni n g pr oce d ures.  
Tec h nical N ot e: C o nsi der all s u bjects wit h a n i nf or me d c o nse nt date c ollect e d. 
6. 2  
I nte nti o n-t o-Tre at A n al ysis Set  
T he i nte nt i o n-t o-treat (I T T) a nal ysis set c o m prises all s u bjects i n t he scree n e d a nal ysis set w h o 
were ra n d o mize d. T h e I T T a nal y sis set will be a nal yze d usi n g t he treat me nt t o w hic h t he 
s u bject was ra n d o mize d, re gar dl ess of t he treat me nt act uall y recei ve d. 
 
A n y s u bject w h o recei ves a treat me nt ra n d o mizati o n n u m ber will be c o nsi d ere d t o ha v e bee n 
ra n d o mize d.  
6. 3  
S afet y A n al ysis Set  
T he  saf et y ( S A F) a n al ysis set c o m prises all s u bjects i n t he I T T a nal ysis set w h o recei ve d at 
least 1 d ose of i n vesti gati o nal pr o d uct a n d will be a nal yze d usi n g t he act ual treat me nt recei v e d .  
6. 4  
Per Pr ot oc ol A n al ysis Set  
T he per - pr ot oc ol ( P P) a n al ysis set c o m prises all s u bjects i n t he I T T a n al ysis set w h o recei ve 
at least 1 d ose of i n vesti g ati o nal pr o d uct a n d w h o c o m pl y wit h t he pr ot oc ol. Decisi o ns 
re gar di n g e xcl usi o n fr o m t he P P a nal ysis will be ma de a n d d oc u m e nte d bef ore t he st u d y data 
C CI
C CI
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 1 9  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
are u n bli n de d.  
6. 5  
P h ar m ac o ki netic A n al ysis Set  
T he P K a n al ysis set c o m prises all s u bjects i n t h e s afet y a nal ysis set wit h at least 1 meas ura ble 
c o nce ntr ati o n of C S L 3 1 2.  P K a nal ysis set  will be a nal yze d usi n g t he act ual treat me nt recei v e d . 
6. 6  
P h ar m ac o d y n a mic A n a l ysis Set 
T he  P D  a nal ysis  set c o m prise s u bjects  i n  t he  safet y  a nal ysis  set  f or  w h o m  at least  1  P D 
meas ure me nt  was  o btai ne d.  P D  a n al ysis  set  will  be  a nal yze d  usi n g  t h e  act u al  treat me nt 
recei v e d. 
7  
Ge ner al C o nsi der ati o ns  
Datasets  will  be  create d  acc or di n g  t o  C li nical  Data  I nterc h a n ge  Sta n dar ds  C o ns orti u m 
( C DI S C)  sta n dar ds.  St u d y  data  will  be  pr o vi de d  i n  St u d y  Data  Ta b ul ati o n  M o del  ( S D T M) 
f or mat. A n al ysis data will be pr o vi de d i n A n al ysis Data M o del ( A Da M) f or mat. 
S A S versi o n 9. 4 or hi g her will be use d t o perf or m all data a nal yses a n d t o ge nerate Ta bles, 
Fi g ures a n d Listi n gs ( T F Ls ). 
All I C H re q uire d d ata i n t he data base will be pres e nte d i n data listi n gs.  
De pe n di n g o n t he a nal ysis sets, all data fr o m a s u bject or a s u bset of dat a ma y be e xcl u de d 
fr o m cert ai n a nalyses as defi ne d i n Secti o n  9. 2  (e. g., a nal yses bas e d o n t he P P A nal ysis set). 
S u m maries of c o nti n u o us varia bles will be i n ter ms of t he n u m ber of missi n g a n d n o n- missi n g 
o bser vati o ns,  mea n (wit h  res pecti ve  9 5 %  c o nfi de nce  i n ter v al  ( CI),  if  a p plica ble),  sta n dar d 
de viati o n, me dia n, first q uartile ( Q 1), t hir d q u artile ( Q 3), mi ni m u m a n d ma xi m u m.  
Cate g orical varia bles will be s u m marize d usi n g c o u nts a n d perce nta ges.  
A nal yses t hat use ot her descri pti ve statistics will be defi ne d a n d descri be d  i n t he a p plica ble 
S A P secti o n.  
S u m mar y statistics of l ocati o n para meters ( e. g., mea n, me dia n, q uartiles) will be re p orte d t o 
o ne m ore deci mal place t ha n t he c ollecte d data. S u m mar y statistics of varia bilit y ( e. g., S D) will 
be re p orte d t o o ne m ore deci mal place t ha n t he c o m me ns urate l ocati o n para m eter. F or e xa m ple, 
t he mea n a n d me di a n f or a ge will be re p orte d t o o ne deci mal place beca use it is c ollect e d i n 
f ull years. T he S D of a g e will t he n be re p orte d t o 2 deci mal places. Descri pti ve perce ntag es 
a n d  pr o p orti o ns  will  be  dis pla ye d  t o  o ne  deci mal  place.  Perce nt a ges  a n d  pr o p orti o ns  t o  be 
teste d will be calc ulat e d t o 4 deci mal places. D urati o ns will be dis pla y t o 1 deci mal place. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 0  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
T he b y- s u bject listi n gs will be s orte d b y t he treat me nt ar m, s u bject n u m ber, a n d t he n b y visit / 
date a n d ti me, or ite m n u m ber (if a p plica ble).  
F or matti n g f or dat es a n d ti mes will be:  
•  Dates o nl y – d d m m m y y y y;  
•  Ti mes o nl y – h h: m m or h h: m m:ss (as a p pr o priate);  
•  Dates a n d ti mes – d d m m m y y y y h h: m m or d d m m m y y y y h h: m m:ss (as a p pr o priate).  
 
Ge ner all y,  o nl y  data  of  pre -s pecifie d  pla n n e d visits will  be  use d  i n  statistical s u m mar y 
a nal yses,  a n d  calc ulati o ns  of  a n y  deri v e d  para meters; data  of u ns c he d ule d visits will  be 
i ncl u de d i n t he listi n gs o nl y . 
Act ual,  rat her  t ha n pla n ne d,  sa m pli n g  ti me   p oi nts  will  be  use d  i n  t he  deri vati o n  of  P K 
para meters a n d i n t he i n di vi d ual c o nce ntrati o n -ti me pl ots a n d listi n g of P K c o nce ntrati o n data. 
Pla n ne d  sa m pli n g ti me  p oi nts will  be  use d  i n  t he  descri pti ve  s u m maries  a n d  i n  mea n  a n d 
me dia n  pl ots. C o nce ntrati o n -ti me data will be liste d acc or di n g t o act ual sa m pli n g ti me p oi nts 
relati ve t o d osi n g ti me.  
 
Assess me nt  wi n d o ws  will  n ot  be  defi ne d  f or  classif yi n g  meas ure m e nts  o btai ne d  o utsi de 
sc he d ule d ass ess me nt ti mes. 
7. 1  
C or o n a vir us D ise ase 2 0 1 9 (C O VI D -1 9 ) I m p act  
As it is e x pecte d t hat t he C O VI D - 1 9 pa n d e mic will be  o n g oi n g d uri n g t he c o n d uct of t he st u d y, 
t he i m pact of C O VI D -1 9 will be assesse d a n d re p orte d.  
 
P ri mar y Esti ma n d 
T he pri mar y esti ma n d is defi ne d i n Secti o n 1 0. 1. 1  a n d is ta ki n g i nt o acc o u nt i nterc urre nt e v e nt s 
s uc h as:  
•  misse d d oses  w hic h mi g ht be ca us e d b y iss ues i n t he dr u g deli ver y t o t he p atie nt d ue t o 
C O VI D - 1 9, t h e  C O VI D-1 9  disease  itself  or  C O VI D -1 9  v acci nati o n  sc h e d uli n g/si de 
eff ects (i nter c urr e nt e ve nt of n o n- c o m plia nce t o treat me nt ); 
•  earl y treat me nt  or  st u d y disc o nti n uati o n  w hic h  mi g ht  be  ca use d  b y  C O VI D - 1 9 
(i nterc urre nt e v e nts of earl y treat me nt or st u d y disc o nti n uati o n).  
F urt her e ve nts i ntr o d uce d b y C O VI D - 1 9 (f or e x a m ple c o nc o mita nt me dicati o ns use d t o treat 
C O VI D -1 9 or vacci nati o ns) will be assesse d i n t he Bli n d Data R e vie w Meeti n g ( B D R M ) a n d 
mi g ht lea d t o a n e xcl usi o n of a s u bject or s u bject’s data  fr o m t he P P A nal ysis S et w hic h is t he 
st u d y a nal ysis set  defi ne d f or t he s u p ple me ntar y a n al ysis of t he pri mar y esti ma n d. H A E attac ks 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 1  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
will be als o assesse d d uri n g B D R M if t h ose c o ul d be tri g gere d b y C O VI D -1 9 a n d d eci si o n will 
be ma de t o e x cl u de t h ose s u bjects or s u bject’s data fr o m t he P P A nal ysis  S et. 
S u bject Dis p ositi o n: St u d y Treat me nt Disc o nti n uati o n or St u d y Disc o nti n uati o n 
S u bjects w h o e x perie nce eit her st u d y treat me nt disc o nti n uati o n or st u d y disc o nti n uati o n d ue 
t o C O VI D-1 9 will ha ve t he reas o n ca pt ure d i n t he e C R F. O n t he a p pr o pri ate e C R F f or m f or 
st u d y disc o nti n uati o n (“ C o ncl usi o n of S u bject Partici pati o n” f or m) or e C R F f or m f or treat me nt 
disc o nti n uati o n (“ E n d of Treat me nt” f or m) as  reas o n ‘ Pa n de mic Relate d’ ca n be selecte d. Cases 
of st u d y treat me nt disc o nti n uati o n or st u d y disc o nti n uati o n d ue t o pa n de mic will be i ncl u de d 
i n t he s u m mar y of s u bject dis p ositi o n. 
A d verse E v e n ts 
A d verse  e ve nts  ass oci ate d  wit h  C O VI D -1 9,  w hic h  ca n  i ncl u de a cli nicall y  si g nifica nt 
la b orat or y fi n di n g li ke a p ositi ve test res ult f or C O VI D-1 9, will be re p ort e d b y i n vesti gat ors. 
C O VI D -1 9  ass oci ate d  a d verse  e v e nts  are  i de ntifie d  via  Me d D R A  c o di n g.  Rele va nt  a d verse 
e ve nts will be i de ntifie d f or re p orti n g b y t he f oll o wi n g Sta n dar dise d M e d D R A Q uer y ( S M Q): 
C O VI D -1 9 ( S M Q). All C O VI D -1 9 ass ociat e d a d verse e ve nts will be i ncl u de d i n sta n dar d A E 
ta bles. 
A n o ver vie w s u m mar y ta ble of C O VI D- 1 9 ass ociate d treat me nt -e m er ge nt a d verse e v e nts 
( T E A Es), i ncl u di n g n u m ber a n d perce nta ges of s u bjects as well as t he n u m ber of e v e nts, will 
be pr o vi de d f or t he S afet y A nal ysis Set i ncl u di n g f or t he f oll o wi n g: 
•  A n y T E A E (re late d/ n ot r elate d), 
•  Seri o us T E A E (r elate d / n ot relate d), 
•  T E A E res ulti n g i n deat h (relate d/ n ot relate d) , 
•  T E A E lea di n g t o disc o nti n uati o n of st u d y treat me nt (relate d/ n ot rel ate d), 
•  T E A E lea di n g t o st u d y wit h dra wal (relate d/ n ot rel ate d), 
•  T E A E b y ma xi m u m se verit y ( mil d, m o derate, se v ere, missi n g). 
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d: 
•  T E A Es  occ urri n g wit hi n 7 da ys of C O VI D -1 9 vacci ne a d mi nistrati o n  b y P T, A m o n g 
S u bjects Recei vi n g C O VI D -1 9 Vacci n ati o n  
•  T E A Es  e xcl u di n g t h ose occ urri n g wit hi n 7 da ys of C O VI D -1 9 vacci ne a d mi nistrati o n  
b y P T. 
 
T he f oll o wi n g listi n gs of C O VI D -1 9 ass o ciate d a d verse e v e nts will be pr o vi de d :  
•  A n y A E , 
•  A Es wit hi n 7 da ys of C O VI D- 1 9 vacci ne a d mi nistrati o n. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 2  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
C o nc o mita nt Me dicati o ns 
C o nc o mita nt me dicati o ns use d t o treat C O VI D - 1 9 ass ociate d  a d verse e ve nts  will be fla g ge d i n 
t he listi n g of pri or a n d c o nc o mita nt me dicati o ns. 
F or c o nc o mita nt me dicati o ns w hic h are li n ke d t o s pecific a d verse e v e nts, t he e C R F c ollects 
i nf or mati o n t o i de ntif y t he s pecific a d verse e ve nt (e. g., A d verse E ve nt I D) . As descri be d i n t he 
A d verse  E ve nts  secti o n,  rele v a nt  a d verse  e ve nts  will  be  i de ntifie d  b y  t he  f oll o wi n g 
Sta n dar dize d  Me d D R A Q uer y ( S M Q): C O VI D -1 9 ( S M Q).  
F or i de ntificati o n of C O VI D -1 9 v acci n es t he W H O Dr u g Sta n dar dise d Dr u g Gr o u pi n g ( S D G) 
‘V acci nes f or C O VI D - 1 9’ will be utilize d, bas e d o n t he W H O Dr u g-Gl o bal dicti o nar y versi o n 
use d f or c o di n g of pri or a n d c o nc o mita nt me dicati o ns. 
C O VI D - 1 9 vacci nati o ns will be liste d b y s u bject s h o wi n g start a n d e n d date:ti me, d ose, r o ute, 
fre q ue n c y,  pri mar y  i n di cati o n  f or  t he  me dicati o n,  a n d  c o n c o mita nt  me dicati o n  fla g  ( Pri or, 
Pri or/ C o nc o mita nt, C o nc o mita nt) . If t he v acci nati o n ma n ufact urer na me is pr o vi de d, it will be 
liste d as well. 
F urt her, a listi n g will be pre pare d i ncl u di n g t he d ate o f C O VI D-1 9 vacci nati o ns, al o n g wit h 
date  a n d  ti me  of  pre vi o us  a n d  s u bse q ue nt  st u d y  treat me nt ,  date  of  first  H A E  attac k  after 
vacci nati o n wit h c orr es p o n di n g H A E I D a n d date of first A E wit h A E I D after vacci nati o n f or 
all s u bjects i n t he Saf et y A nal ysis Set . If t he v acci nati o n ma n ufact urer na m e is pr o vi de d, it will 
be a d de d. 
Visit M o dalit y  a n d Misse d Visits  
C ha n ges t o s u bjects’ visits ca use d b y t h e C O VI D -1 9 pa n de mic will be ca pt ure d f or eac h s u bject 
i n  t he  e C R F  o n  t he  “ Visit”  f or m.  It  ca n  be  d eter mi ne d  if  a  visit  was  n ot  d o ne  d ue  t o 
“ E pi de mic/ Pa n de mic Rel ate d ( S pecif y)” or if a n visit c o ntact m o de/ m o dalit y c ha n ge d d u e t o 
E pi de mic/ Pa n de mic reas o n ( Yes, N o). T he n u m b er of s u bjects wit h misse d visits or alter nate 
visit m o dalit y  (e. g., r e m ote visit) d ue t o C O VI D- 1 9 will be s u m marize d b y visit a n d o verall 
a n d will be liste d.  
Pr ot oc ol De viati o ns ( P Ds) 
Pr ot oc ol  de viati o ns  d ue  t o  t he  C O VI D -1 9  pa n d e mic  will  be  c ollecte d  i n  t he  Cli nical  Trial 
Ma na ge me nt S yste m ( C T M S) per t he st u d y s pecific Pr ot oc ol De viati o n pl a n.  
Pa n de mic relate d pr ot oc ol de viati o ns are i de ntifie d wit hi n C T M S b y usi n g t he ter m “ C O VI D -
1 9” as t he first ter m wit hi n t he de viati o n descri pti o n. I n a d diti o n, t he s u b -cate g or y of ‘ ot h er’ 
will be c h ose n .  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 3  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
C O VI D - 1 9-relate d pr ot o c ol de viati o ns will be s u m marize d as s u b-cate g ories u n der e xisti n g 
cate g ories of pr ot o c ol de viati o ns. All C O VI D -1 9 relate d pr ot oc ol d e viati o ns will a p pear i n t he 
listi n g of pr ot oc ol de viati o ns a n d will be fla g ge d. All P Ds will be re vie w e d d uri n g Bli n de d 
Data Re vie w M eeti n g ( B D R M, see Secti o n 9. 2 ). 
O ver vie w of C O VI D -1 9 I m pact  
N u m ber a n d per ce nta g es of s u bjects wit h at least o ne of t h e f oll o wi n g d u e t o C O VI D -1 9 will 
be s u m marize d i n a n o v er vie w ta ble:  
•  S u bjects wit h A n y C O VI D- 1 9 I m pact, 
•  Pr ot oc ol De viati o ns, 
•  Missi n g Visit , 
•  Alter nate Visit M o dalit y , 
•  St u d y Treat me nt Disc o nti n uati o n, 
•  St u d y Disc o nti n uati o n, 
•  A n y A Es/ T E A Es , 
•  A n y Seri o us A Es/ T E A Es , 
•  S u bjects recei v e d C O VI D - 1 9 vacci ne. 
7. 2  M ultice nter St u dies  
Data  fr o m  all  partici pati n g  sites  will  be  p o ole d  pri or  t o  a nal ysis.  Listi n gs  will  i ncl u de  site 
i nf or mati o n as part of t he s u bject I D. T he sites will n ot be c o nsi dere d i n a n y a nal ysis. T here is 
n o ra n d o mizati o n stratifi cati o n per site.  
7. 3  Tre at me nt Descri pt ors  
F or ta ble s u m maries d is pla ye d c ol u m ns will be la belle d a n d or dere d: 
•  C S L 3 1 2, 
•  Place b o,  
•  Total  ( n ot a p plica ble f or efficac y). 
8  
D at a H a n dli n g C o n ve nti o ns  
8. 1  
Missi n g D at a  
Missi n g data occ urs w he n a n y re q ueste d data are n ot pr o vi de d, lea di n g t o bla n k fiel ds o n t he 
c ollecti o n i nstr u me nt. T hese data will be i n dicate d b y t he use of a “ bla n k” i n s u bject listi n g 
dis pla ys. A ns wers  s uc h  as  “ N ot  a p plica ble”  a n d  “ N ot  e val ua ble”  are  n ot  c o nsi dere d  t o  be 
missi n g data a n d s h o ul d be dis pla ye d as c ollecte d. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 4  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
O nl y missi n g val ues f or t he pri mar y effi cac y e n d p oi nt (i.e., ti me -n or malize d n u m ber of H A E  
attac ks) d uri n g  Tr eat me nt  Peri o d will  ha ve  a n  i m pact  o n  t he pri mar y a nal yses  of  t he  
c o m paris o n bet wee n C S L 3 1 2 vers us place b o. T h e  ti me -n or malize d  n u m b er  of  H A E  attac ks  
will be c o nsi dere d as missi n g f or s u bjects w h o disc o nti n ue d wit hi n 3 0 da ys after t he first st u d y 
dr u g a d mi nistrati o n. 
T he pri mar y efficac y e n d p oi nt will be har dl y missi n g d ue t o t he r o b ust deri vati o n r ule  (i.e., t he 
n or malizati o n of t he n u m ber of H A E attac ks b y  ti me ) a n d treat me nt p olic y strate g y f or t he 
esti ma n d.  It  is  ass u me d  t hat  t he  o utc o me s f or  disc o nti n ue d s u bjects  are  c o m para ble  t o  t he 
o utc o mes f or t h ose w h o d o n ot disc o nti n ue.  
I n t he pre vi o us p has e II st u d y C S L 3 1 2 _ 2 0 0 1 t here was n o patter n i n t he attac ks u n der P lace b o 
a n d C S L 3 1 2  o bser ve d. It ca n be ass u me d fr o m st u d y C S L 3 1 2 _ 2 0 0 1 t hat t he attac k rate f or a n 
o bser vati o n peri o d of  > 3 0  da ys a n d < 6 m o nt hs is c o m para ble t o t he attac k rate of ca. 6 m o nt hs.  
F or sec o n dar y e n d p oi nts w hic h are als o bas e d o n t he H A E attac k rate t he ass u m pti o n a b o ve is 
s u bse q ue ntl y als o a p plica ble.  
T he details of ha n dli n g missi n g data are prese nt e d i n t he c orres p o n di n g secti o ns of t his S A P 
f or res p ecti ve a n al yses (e. g., pri mar y a n d sec o n dar y efficac y a nal yses, safet y a nal yses).  
8. 1. 1  
I m p ut ati o n of N o n-D ate Missi n g D at a  
S u bjects wit h t he assess me nt of treat me nt relati o ns hi p f or A Es a n d S A Es missi n g will ha ve t he 
w orst case ass u me d t o i m p ute t he relati o ns hi p: if relati o ns hi p t o st u d y treat me nt is missi n g a n d 
t he e ve nt start e d o n or aft er t he first a d mi nistrati o n of st u d y treat me nt it will be ass u me d t o be 
“relate d ”. If t he A E or S A E wit h missi n g relati o ns hi p starte d bef ore t he first i njecti o n  of st u d y 
treat me nt (e. g., d uri n g Scree ni n g Peri o d or R u n -i n Peri o d), it will be c o nsi dere d as “ n ot relate d ” 
(realistic case). I n listi n gs t hese i m p ute d relati o ns hi ps will be fla g ge d. 
F or varia bles w hic h d eter mi ne t he pr o p orti o n of e ve nts  e. g., A d verse E ve nts , all s u bjects wit h 
a n o n-missi n g  val ue i n t he res pecti ve a n al ysis set will be i ncl u de d i n t he de n o mi nat or w he n 
calc ulati n g t he perce nt a g es, u nless ot her wise state d.  
8. 1. 2  I m p ut ati o n of P arti al D ates 
T here will be  n o i m p utati o n of partial or c o m plet e missi n g dates.  
To  deter mi ne if a n A E is treat me nt-e mer ge nt , see r ules i n Secti o n  1 1. 2 . 
To  deter mi n e t he cate g or y f or me dicati o ns, see r ul es i n Secti o n 9. 4 . 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 5  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
8. 2  
Ge ner al Deri ve d  Vari a bles  
8. 2. 1  
Refere nce D ates a n d St u d y D a ys  
Refere n ce d ates ar e use d t o assi g n st u d y peri o ds relati ve t o treat me nt ( Secti o n  8. 3 ). 
•  T he safet y ref ere n ce dat e is t he treat me nt start dat e a n d will be use d t o cal c ulate st u d y da y 
f or  saf et y  meas ur es. T h e res pecti ve  st u d y  da y  will  be  calc ulate d  as  ( d ate  of  i nterest - 
refere nce date) + 1 if t he date of i nterest occ urs o n or after t he refere nce dat e. If t he date of 
i nterest occ urs bef or e t he refere n ce dat e, t he n t he st u d y da y will be calc ulate d as ( date of 
i nterest – ref ere n ce d ate). T here will be n o st u d y da y zer o. 
•  T he efficac y ref ere n ce date will be t he sa me as t he safet y refere n ce d ate  a n d is t he start d ate 
of t he efficac y e val u ati o n peri o d . 
8. 2. 2  
D ur ati o ns a n d Ti me t o E ve nt D at a  
D urati o ns of a n e ve nt (e. g., d urati o n of a n A E) will be calc ulate d i n da ys as: 
•  (e ve nt e n d d ate – e v e nt start date) + 1 . 
T h us, t here will be n o d urati o n of 0. If start a n d e n d ti me are a v aila ble, t he y will als o be use d 
t o calc ulate t h e d urati o n i n h o urs or mi n utes. If start or e n d d ate are p artiall y or c o m pletel y 
missi n g d urati o n will n ot be calc ul ate d. 
F or ela pse d ti me (e . g., o nset of A Es) us e 
•  (e ve nt date – ref er e nce d ate) or 
•  e ve nt date:ti me – refer e n ce date:ti me if a p pr o priat e. 
To tra nsf or m d ur ati o ns  or ela pse d ti mes, w hic h are calc ul ate d i n da ys i nt o wee ks, di vi de t he 
n u m ber of da ys b y 7; t o re p ort i n m o nt hs, di vi de t he n u m ber of da ys b y 3 0. 4 3 7 5; t o re p ort i n 
yea rs,  di vi de  t h e  n u m ber  of  da ys  b y  3 6 5. 2 5. T h ese  al g orit h ms  ret ur n  deci mal  n u m bers  a n d 
i g n ore t he act ual n u m bers of da ys i n t he m o nt hs or years (t he cale n dar da ys) bet wee n start date 
a n d st o p date. T he " y ear" use d i n t hese al g orit h ms is 3 6 5. 2 5 da ys l o n g, a n d  t he " m o nt h" is o ne 
t welft h of t hat year. 
8. 2. 3  
B aseli ne Defi niti o n  
Baseli ne  is  defi ne d  as  t he  m ost  rece nt,  n o n -missi n g  val ue  pri or  t o  first  st u d y  dr u g 
a d mi nistrati o n. Deter mi nati o n of t he baseli ne val ue als o c o nsi ders u nsc he d ule d visits d uri n g 
t he R u n-i n Peri o d or Scree ni n g Peri o d.  
All baseli ne meas ure me nts m ust ha ve bee n c ollect e d pri or t o t he first a d mi nistrati o n of st u d y 
dr u g.  Meas ure m e nts  t hat  are  o btai ne d  after  t he  first  st u d y  dr u g  a d mi nistrati o n  will  be 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 6  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
c o nsi dere d p ost -b aseli ne val ues. If t he m eas ure me nt of a varia bl e is n ot ma de o n a gi ve n s u bject 
pri or t o first st u d y dr u g a d mi nistrati o n, t he baseli ne val ue f or t hat s u bject will be set t o missi n g 
f or t hat varia bl e.  
8. 2. 4  
C h a n ge fr o m B aseli ne  
C ha n ge fr o m b aseli ne will o nl y be calc ulat e d f or meas ures t hat ha v e n o n- missi n g a n d vali d 
baseli ne a n d p ost- bas eli ne rec or ds.   
C ha n ge fr o m bas eli ne is calc ulate d as:  
•  visit val ue – baseli ne val ue.  
Perce nta g e c ha n g e fr o m baseli ne will be cal c ulate d as:  
•  (c ha n ge fr o m bas eli ne / baseli ne val ue) * 1 0 0.  
 
8. 2. 5  
M ulti ple Assess me nts  
All data will be re p orte d acc or di n g t o t he n o mi nal visit date f or w hic h it was re p orte d (t hat is, 
n o visit wi n d o ws will be a p plie d d uri n g dat a set creati o n t o re -assi g n ass ess me nts t o ot her visits 
or ti me p oi nts base d o n s uc h wi n d o ws). 
If  a  l a borat or y  sa m ple  was  re p eate d  d ue  t o  tec h nical  pr o ble ms  t he  res ults  fr o m  t he  vali d 
sa m ple(s) f or t his visit will be use d i n t he a nal ysis. If a la b orat or y sa m ple w as re peate d as safet y 
f oll o w-u p t o m o nit or a b n or mal val ues of t he i nitial sa m ple, t he i nitial sa m ple (re veali n g t he 
a b n or mal val ues) of t his visit will be use d i n t he a nal ysis.  
Data fr o m all assess me nts (sc he d ule d a n d u nsc h e d ule d), i ncl u di n g m ulti ple assess me nts, will 
be i ncl u de d i n listi n gs. 
8. 2. 6  
Act u al Tre at me nt  
B ot h, pla n ne d vial n u m bers i nte grate d fr om I R T a n d t he act ual a d mi nistere d vial  n u m bers 
will be c ollecte d via e C R F. After ge n eral u n bli n di n g t he s u bjects’ act ual treat me nt will be 
deri ve d fr o m u n bli n de d vial  re p orts w hic h i ncl u de all vials wit h t he vial n u m ber a n d act ual 
treat me nt i n t h ose vials. If a s u bject’s act u al treat m e nt is t he sa me as t he assi g ne d treat me nt, 
t he n act ual treat me nt is t he assi g ne d treat me nt.  
If a s u bject recei ves a tr eat me nt differe nt fr o m t he pla n ne d it will be deci de d d uri n g t he 
Bli n de d Data Re vie w Meeti n g o n a n i n di vi d ual base w hat will be c o nsi dere d t he act ual 
treat me nt.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 7  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 8  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 2 9  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 0  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
8. 2. 1 2  B MI  
B o d y Mass I n de x ( B MI) will be pr o vi de d via  t he e C R F a n d calc ulate d usi n g t he f oll o wi n g 
f or m ula: 
B MI ( k g/ m²) = Wei g ht ( k g) / [ Hei g ht ( m)]² 
If o nl y o ne or n eit her is a vaila ble, t he n B MI is missi n g. 
8. 3  
St u d y Peri o ds rel ati ve t o Tre at me nt  
T he f oll o wi n g defi niti o ns f or t he peri o ds of efficac y a n d safet y will be use d t o defi ne t he 
d urati o ns use d i n t he de n o mi nat or of t he ti me- n or malize d  e n d p oi nts a n d safet y e n d p oi nts 
s uc h as e x p os ur e a n d s u bject-years.  
Ta ble 8 O ver vie w St u d y Peri o ds  
St u d y Peri o d  
St art D at e  
E n d D ate  
D ur ati o n  
Scree ni n g 
Peri o d  
date of I nf or me d 
C o nse nt 
date/ da y o n w hic h 
eli gi bilit y f or R u n -i n 
Peri o d was c o nfir me d  
Da y 1 Visit date of R u n -i n 
Peri o d – date of I nf or me d 
C o nse nt  
R u n -in Peri o d  
date/ da y o n w hic h 
eli gi bilit y f or R u n -
i n Peri o d was 
c o nfir me d 
date of t he Da y 1 Visit of 
Treat me nt Peri o d  
Da y 1 Visit date of t he 
Treat me nt Peri o d or Date of 
R u n- i n C o m pleti o n/ N o n -
c o m pleti o n [ w hic he ver is first] 
– Da y 1 Visit date of R u n- i n 
Peri o d  
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 1  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
St u d y Peri o d  
St art D at e  
E n d D ate  
D ur ati o n  
Treat me nt 
Peri o d/  
Efficac y 
E val uati o n 
Peri o d  
date of t he Da y 1 
Visit of Treat me nt 
Peri o d  
date of t he Da y 1 8 2 Visit 
of t he Treat me nt Peri o d 
or t he E n d of St u d y date 
f or s u bjects w h o 
pre mat urel y disc o nti n ue d 
[ w hic he ver occ urs 
earlier ] 
Da y 1 8 2 Visit date of t he 
Treat me nt Peri o d or E n d of 
St u d y date [ w hic he ver is first] – 
Da y 1 Visit date of t he 
Treat me nt Peri o d + 1 
F oll o w -u p 
Peri o d  
date of t he Da y 
1 8 2 Visit of t he 
Treat me nt Peri o d  
date of t he F oll o w -u p/  
Fi nal Visit ( Da y 2 4 2 
Visit)  
date of t he F oll o w -u p/ Fi nal 
Visit ( Da y 2 4 2 Visit) – date  of 
t he Da y 1 8 2 Visit of Treat me nt 
Peri o d  
Safet y Peri o d  
date  a n d ti me of 
t he first 
a d mi nistrati o n of 
i n vesti gati o nal 
pr o d uct  
Date of E n d of St u d y  
Date of E n d of St u d y - date of 
t he first a d mi nistrati o n of 
i n vesti gati o nal pr o d uct 
Tec h ni cal N ot es:  
•  Scree ni n g Peri o d: T he first da y of t he R u n-i n Peri o d ma y occ ur o n t he sa me da y as t he 
Scree ni n g Visit f or s u bjects meeti n g t he eli gi bilit y criteria f or t he R u n -i n Peri o d. T h ose 
s u bjects will t he n ha ve n o Scree ni n g Peri o d. 
•  R u n-i n Peri o d: T he e C R F ‘ St u d y C o m pleti o n’ f or m will o nl y be c o m plete d f or s u bjects 
i n t he T reat me nt Peri o d. T h us, if a s u bject is n ot eli gi ble f or treat me nt t he R u n -i n N o n-
C o m pleti o n is ca pt ure d o n t he ‘ Treat me nt Peri o d I ncl usi o n Criteria’ f or m. 
•  F oll o w- u p Peri o d: A F oll o w- u p P eri o d will be o nl y a vaila ble f or s u bject s w h o di d n ot 
r oll o ver t o C S L 3 1 2 _ 3 0 0 2. 
 
9  
St u d y P o p ul ati o n  
9. 1  
S u bject Dis p ositi o n  
T he  f oll o wi n g  s u m mar y  will  be  pr o vi d e d b y treat me nt  ar m a n d  t otal  usi n g  t he  Scree ne d 
A nal ysis Set:  
•  T he n u m ber a n d p erce nta ge of s u bjects w h o pr o vi de d I nf or me d C o ns e nt, 
•  T he n u m ber a n d p erce nta ge of s u bjects scree n e d , 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o e ntere d t he R u n-i n Peri o d, 
o  T he n u m ber a n d per ce nta ge of s u bjects w h o disc o nti n ue d fr o m t he st u d y d uri n g t he 
R u n- i n Peri o d wit h reas o n f or disc o nti n uati o n ( perce nt a ges base d o n t he n u m ber 
w h o disc o nti n ue d), 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o w ere n ot assi g ne d t o st u d y treat me nt, 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o w ere ra n d o mize d, 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 2  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
•  T he n u m ber a n d perce nta ge of s u bjects w h o e ntere d t he Treat me nt Peri o d  (ra n d o mize d a n d 
recei v e d l oa di n g d ose), 
o  T he  n u m ber  a n d  perce nta ge  of  s u bjects  w h o  disc o nti n ue d  t he  st u d y  d uri n g  t he 
Treat me nt Peri o d wit h reas o n f or st u d y disc o nti n uati o n ( perce nt a ges base d o n t he 
n u m ber w h o disc o nti n ue d), 
o  T he  n u m ber  a n d  p erce nta ge  of  s u bjects  w h o  pre mat urel y  disc o nti n ue  treat me nt 
d uri n g  Trea t me nt  Peri o d wit h  reas o n  f or  treat me nt  disc o nti n uati o n  ( perce nta ges 
base d o n t he n u m ber w h o disc o nti n ue d), 
o  T he  n u m ber  a n d  per ce nt a ge  of  s u bjects  w h o  c o m plete d  t he  treat me nt  ( 6 - m o nt h 
peri o d wit h st u d y dr u g a d mi nistrati o n o nce m o nt hl y), 
•  T he n u m ber a n d p erce nta ge of s u bjects w h o c o m plete d t he st u d y, 
•  T he n u m ber a n d perce nta ge of s u bjects r olli n g o ver t o t he C S L 3 1 2 _ 3 0 0 2 (o pe n -la bel p h ase 
III b st u d y), 
•  T he n u m ber a n d p erce nta ge of s u bjects i n Scree ne d A nal ysis Set,  
•  T he n u m ber a n d p erce nta ge of s u bjects i n S A F A n al ysis S et, 
•  T he n u m ber a n d p erce nta ge of s u bjects i n I T T A nal ysis Set, 
•  T he n u m ber a n d p erce nta ge of s u bjects i n P P A nal ysis S et, 
•  T he n u m ber a n d p erce nta ge of s u bjects i n P K A n al ysis S et, 
•  T he n u m ber a n d p erce nta ge of s u bjects i n P D A n al ysi s S et. 
 
Tec h nical N ote: S u bjects will be fla g g e d as c o m plete d t he st u d y if “ Di d t h e s u bject c o m plet e 
t he st u d y?” a ns w ere d wit h “ Yes” o n t he E O S f or m.  
Reas o ns  f or st u d y wit h dra wal  a n d  st u d y  treat me nt  disc o nti n uati o n  will  be  prese nte d  i n  t he 
or der t he y are dis pla y e d i n t he e C R F.   
T he f oll o wi n g listi n gs will be pr o vi de d: 
•  Dis p ositi o n  ( date  of  i nf or me d  c o nse nt,  date  of  eli gi bilit y  f or  R u n -i n,  date  of 
ra n d o mizati o n, date of first a n d last st u d y dr u g a d mi nistrati o n, E n d of Treat me nt ( E o T) 
date, E n d  of  St u d y  ( E O S)  date,  reas o n  f or  treat me nt  disc o nti n uati o n  a n d/ or  st u d y 
disc o nti n uati o n). 
•  A nal ysis Sets (i ncl u de d i n A nal ysis Set: Scree n e d A nal ysis Set ( yes, n o), I T T A nal ysis 
Set ( yes, n o), P P A nal ysis Set ( yes, n o), P K A nal ysis S et ( yes, n o), P D A nal ysis Set 
( yes, n o), r eas o n e x cl u de d fr o m a n y a n al ysis set). 
 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 3  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
9. 2  
Pr ot oc ol De vi ati o ns  
All i de ntifie d pr ot oc ol d e viati o ns t hr o u g h o ut t he st u d y will be liste d pri or t o data bas e l oc k  a n d 
will be  classifie d i nt o mi n or /maj or  b y C S L. Maj or  pr ot oc ol de viati o ns are defi ne d as d e viati o ns 
t hat  c o ul d  ha ve  a  si g nifica nt  eff ect  o n  t he  s u bject’s  safet y, ri g hts,  or  welfare  a n d/ or  o n  t he 
i nte grit y of t he st u d y data.  
T he pr ot oc ol de viati o ns’ classificati o n  i nt o mi n or a n d maj or will be reassesse d u n der statistical 
c o nsi derati o ns. D uri n g t he bli n de d data re vi e w  meeti n g ( B D R M), t he  classificati o n  a n d t h e 
s u bject’s assi g n me nt t o a n y a nal ysis set will be dis c usse d i n d etail. T h e decisi o ns ma de d uri n g 
t he B D R M will be d oc u me nte d i n t he B D R M mi n utes a n d a gree d u p o n pri or t o data bas e l oc k 
f or fi nal a n al ysis. 
Ta ble 9 P ote nti al Pr ot oc ol De vi ati o ns 
P ote nti al Pr ot oc ol De vi ati o ns  
P ote nti al  E xcl usi o n 
Fr o m A n al ysis Set  
S u bject di d n ot pr o vi d e i nf or me d c o nse nt  a n d/ or i nf or me d c o ns e nt 
date missi n g  
Scree ni n g, S A F , I T T, 
P P, P K,  P D  
S u bject ra n d o mize d b ut n ot treate d wit h st u d y  treat me nt 
S A F , P P, P K, P D  
S u bjects treate d wit h i nc orrect st u d y treat me nt  
P P, P K, P D  
S u bject  ra n d o mize d  a n d  treat e d  b ut  d o es  n ot  h a ve  at  least  o ne 
meas ura ble P K c o nce ntr ati o n  
P K  
S u bject ra n d o mize d a n d treate d b ut d o es n ot ha v e at least o ne P D 
meas ure me nt  
P D  
S u bject ra n d o mize d  a n d  treate d  b ut  wit h o ut  pri mar y  efficac y 
assess me nt  
P P  
S u bject  ra n d o mize d  a n d  treate d  b ut  vi olate d  i ncl usi o n  a n d/ or 
e xcl usi o n criteria  
P P,  ( S A F , I T T, P K, 
P D)  
S u bject ra n d o mize d a n d treate d b ut c o m plia n ce o utsi de 8 0 -1 2 0 %  
P P, ( P K, P D)  
S u bject r a n d o mize d a n d treate d b ut recei v e d pr o hi bite d c o nc o mita nt 
me dicati o n  
P P, ( P K, P D)  
S u bject wit h  C O VI D -1 9 dia g n os is 
P P  (S A F , P K, P D)  
 
Pr ot oc ol de viati o ns ca us e d b y t he C O VI D -1 9 pa n de mic will be d oc u m e nte d t hr o u g h o ut t he 
e ntire st u d y. T he y will be assi g ne d as a se parate pr ot oc ol de viati o n cate g or y “ ot her” wit h free -
te xt “ C O VI D- 1 9” a n d dis c usse d d uri n g t he Bli n de d Data Re vie w M eeti n g. C O VI D - 1 9 relate d 
pr ot oc ol de viati o ns  will be s u m marize d  a n d liste d s e parat el y fr o m all ot her pr ot oc ol de viati o ns 
a n d will als o be disc usse d i n t he C S R. 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 4  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Pri or t o t he Bli n de d Data Re vie w Meeti n g, a list of c o nc o mita nt me dicati o ns use d i n t he st u d y 
will be pr o vi de d t o C S L as a n E xcel file i n t he sa me f or mat as t he c orres p o n di n g listi n g of 
c o nc o mita nt  me dicati o ns  i n  t he  T F L s hells.  T his  E xcel  file  will  be  re vie we d  b y  C S L  a n d 
c o nc o mita nt me dicati o n p ote ntiall y i nterferi n g wit h t he P K/ P D a nal ysis or wit h t he efficac y  
a nal ysis will be fla g ge d.  S u bjects wit h s uc h a c o nc o mita nt me dicati o n fla g ge d will be e xcl u de d 
fr o m t he res p ecti ve a n al ysis set. 
 
T he f oll o wi n g b y- s u bject listi n gs will be pr o vi de d usi n g t he Scree ne d A nal ysis  Set  : 
•  Ra n d o mize d a n d act ual treat me nt,   
•  all pr ot oc ol de viati o ns relate d t o i ncl usi o n a n d e xcl usi o n criteria, 
•  all pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m a n y a nal ysis set, 
•  C O VI D - 1 9 r elate d pr ot o c ol de viati o ns, 
•  all ot her pr ot oc ol de viati o ns. 
 
9. 3  
De m o gr a p hic a n d B aseli ne C h ar acteristics  
T he  f oll o wi n g  s u m maries  will  be  pr o vi de d  b y treat me nt  ar m a n d  t otal  usi n g  I T T  a n d  P P 
A nal ysis Set:  
•  De m o gra p hic c haracteristics: se x, race, et h nicit y, a ge, hei g ht a n d b o d y wei g ht at Scree ni n g, 
a n d b o d y mass i n de x at Scree ni n g. 
•  H A E hist or y: hist or y of lar y n geal attac k ( yes, n o), fa mil y hist or y of H A E ( yes, n o), H A E 
t y pe ( C 1-I N H t y pe 1, C 1-I N H t y pe 2), pr o p h ylactic H A E t hera p y wit hi n 3 m o nt hs bef ore 
Scree ni n g  ( y es,  n o),  n u m ber  of  H A E  attac ks  b ef ore  t he  start  of  pr o p h ylactic  t hera p y , 
n u m ber  of  H A E  attac ks  wit hi n  3  m o nt hs bef ore  Scree ni n g ,  pri mar y  l ocati o ns  of  H A E 
attac ks i n t he last 3 m o nt hs pri or Scree ni n g. 
•  Me dical hist or y b y s yste m or ga n class ( S O C) a n d preferre d ter m ( P T) – i ncl u de me dical 
hist or y wit h a n e n d date pri or t o i nf or me d c o nse nt date. 
•  C o nc o mita nt  diseases  b y  S O C  a n d  P T – i ncl u de  me dical  hist or y  wit h  a n  e n d  date  after 
i nf or me d c o nse nt or fla g ge d as o n g oi n g. 
•  Stratificati o n fact ors: a g e ( ≤1 7 year, > 1 7), bas eli ne H A E attac k rate o bser ve d d uri n g t he 
R u n-i n Peri o d ( 1 t o < 3 attac ks / m o nt h, a n d ≥ 3 attac ks/ m o nt h). 
 
Tec h nical N ot e: T he bas eli ne H A E attac k rate as use d f or ra n d o mizati o n will n ot be ca pt ure d 
i n e C R F a n d ca n b e o nl y o btai ne d fr o m t he u n bli n de d ra n d o mizati o n file at t he e n d of t h e st u d y 
a n d/ or bli n de d ra n d o mizati o n files, if a vaila b le.  
Me dical hist or y a n d c o nc o mita nt diseases will be c o de d b y Me dical Dicti o nar y f or Re g ulat or y 
Acti vities  ( Me d D R A).  T here  will  be  p eri o dic  u p dates  of  t he  M e d D R A  versi o n.  T he  l atest 
lice nse d versi o n will be use d, a n d versi o n u p d ates will be i m ple me nte d u po n a vaila bilit y.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 5  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
B y -s u bject listi n gs f or all a vaila ble d ata usi n g t he Scree ne d  A nal ysis Set  will be pr o vi de d f or 
eac h cate g or y m e nti o ne d a b o ve a n d f urt her f or: 
•  Re pr o d ucti ve  s yste m  fi n di n gs  (c hil d beari n g  p ote ntial,  met h o d  of  birt h  c o ntr ol,  date  a n d 
ti me of pre g na n c y test, s peci me n t y pe, a n d pre g n a nc y test res ult).  
T h ose listi n gs will f urt her c o ntai n a n I T T a n d P P fla g. 
9. 4  
Pri or/ C o nc o mit a nt Me dic ati o ns  
Re p orte d  me dicati o ns  will  be  c o de d  usi n g  Worl d  Healt h  Or g a nizati o n  Dr u g  Dicti o nar y 
E n ha nce d ( W H O -D D E , versi o n use d will be i n dicate d i n t he c orres p o n di n g T L F S hells ). T he 
s u m mar y of me dicati o ns will s h o w t he n u m ber a n d perce nta ge of s u bjects ta ki n g me dicati o n 
dis pla ye d f or A n at o mical T hera pe utic C he mical ( A T C) class le vel 4 a n d Preferre d Ter m. If t he 
le vel 4 A T C na me is n ot a vaila ble, t he n t he le vel 3 A T C na me will be use d a n d if t he le vel 3 
A T C na me is n ot a vaila bl e t he n t he le vel 2 A T C na me will be use d.  
T he f oll o wi n g classificati o n of c o nc o mita nt me dicati o n relate d t o start dat e of st u d y 
treat me nt peri o d will be a p plie d: 
•  Assi g n t o ‘ Pri or O nl y’ if t he c o nc o mita nt me dicati o n start date a n d e n d date is pri or t o  first 
st u d y  treat me nt  start  d ate;  if  t he  s u bject  has  n ot  ta ke n a n y  st u d y  treat me nt;  or  t he 
c o nc o mita nt me dicati o n start date is missi n g a n d t he  c o nc o mita nt me dicati o n e n d date is 
bef ore t h e st u d y treat me nt start date;  
•  Assi g n t o ‘ Pri or a n d C o nc o mita nt’ if t he c o nc o mita nt me dicati o n start date is pri or t o  first 
st u d y  treat me nt  start  dat e  a n d  t he  c o nc o mita nt me dicati o n  e n d  date  is  o n  or  after  st u d y 
treat me nt start date or o n g oi n g treat me nt; 
•  Assi g n t o ‘ C o nc o mita nt O nl y’ if t he c o nc o mita nt me dicati o n start date is o n or after t h e  
first st u d y treat me nt start date.  
If me dicati o n start a n d/ or st o p dat es are partiall y or c o m pletel y missi n g, me dicati o ns will be 
ass u me d  t o  be  ‘ C o nc o mita nt  O nl y’,  u nless  t here  is  clear  e vi de nce  (t hr o u g h  c o m paris o n  of 
partial  dates)  t o  s u g gest  t hat  t he  me dicati o n  start e d  pri or  t o  t he  dat e  of  t he  first  st u d y  dr u g 
a d mi nistrati o n. If t here is clear e vi de nce t o s u g g es t t hat t he me dicati o n start e d pri or t o t he date 
of first st u d y dr u g a d mi nistrati o n (t he a vaila ble parts of t he d ate are pri or t o t he c orres p o n di n g 
parts of t he date of first st u d y dr u g a d mi nistrati o n), t he me dicati o n will be ass u me d t o be ‘ Pri or 
a n d C o nc o mita nt’, u nless t here is clear e vi de n ce t o s u g gest t hat t he me dicati o n st o p pe d pri or 
t o t he date of t he first st u d y dr u g a d mi nistrati o n (t he a vaila ble parts of t he me dicati o n e n d date 
are pri or t o t he c orres p o n di n g parts of t he date of first st u d y dr u g a d mi nistrati o n of st u d y). If 
t his is t he case, t he me dicati o n will be c o nsi dere d ‘ Pri or O nl y’. 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 6  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
I n t he s u m mar y of pri or a n d c o nc o mita nt me dicati o ns, eac h s u bject will be c o u nte d o nce wit hi n 
eac h u ni q ue ter m. F or e xa m ple, if a s u bject  ta kes A m o x ycilli n o n 2 se pa rate  occasi o ns,  t he 
s u bject is c o u nte d o nl y o nce u n der t h e c orres p o n di n g A T C class. 
O n -de ma n d H A E me dicati o n will be s u m marize d as se parate bl oc k wit hi n t he s u m maries of 
pri or a n d c o nc o mita nt me dicati o n (as a “ virt ual” A T C class ” O n -de ma n d H A E Me dicati o n”) . 
T he o n- de ma n d H A E me dicati o n will als o be re p orte d i n t heir ori gi nal A T C class .  
Tec h nical N ote: O n -de m a n d H A E me dicati o ns pri or t o R u n -in Peri o d are c ollecte d i n t he C R F 
f or m ‘C o nc o mita nt a n d Pri or Me dicati o ns’ wit h Pri mar y I n dicati o n as ‘ St u d y I n dicati o n Ac ut e 
H A E  Treat me nt’. O n- d e ma n d  H A E  me dicati o n s o n/after start  of  t he R u n-i n  Peri o d  are 
c ollecte d i n a se p arat e C R F f or m  ‘O n -de ma n d Treat me nt ’.  
S u m maries a n d b y-s u bject listi n gs will be gi ve n f or Safet y A n al ysis Set . Listi n gs will i ncl u de 
me dicati o n/t h era p y start a n d e n d date:ti me  or o n g oi n g stat us, d ose, r o ute, fre q ue nc y, pri mar y 
i n dicati o n f or t he me dicati o n, A E ter m if a p plica ble, me dical hist or y ter m if a p plica ble a n d 
c o nc o mita nt me dicati o n fla g ( Pri or, Pri or/ C o nc o mita nt, C o nc o mita nt).  
Se parate s u m m ari es a n d listi n gs are pla n ne d f or C O VI D -1 9 v acci n es, see S ecti o n 7. 1 . 
1 0  
Effic ac y A n al yses  
1 0. 1  
A n al ysis of Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt is t he ti me-n or malize d n u m ber of H A E attac ks  per m o nt h  duri n g t he 
Treat me nt P eri o d fr o m D a y 1 (first st u d y dr u g a d mi nistrati o n) t hr o u g h Da y 1 8 2 (i ncl usi ve).  
 
S u bjects  will  e nter  H A E  s y m pt o ms  i nt o  t heir  e Diar y , t he  start  a n d  e n d  date  a n d  ti me,  t he 
i nterfer e nce of H A E s y m pt o m(s) wit h dail y acti vities, a n d l ocati o n(s) of t he H A E s y m pt o m(s). 
I n vesti gat or-r e p orte d  H A E  attac ks  will  be  base d  u p o n  re vie w  of  s u bject  diaries,  rele v a nt 
i nter val me dical hist or y, a n d p h ysicia n j u d g me nt. T he i n vesti gat or ma y as k clarif yi n g q uesti o ns 
t o assist i n his/ her assess me nt of w het her or n ot a n H A E attac k occ urre d. If a n attac k occ urre d, 
t he n t he i n vesti gat or will rec or d a n attac k i n t he e C R F f or m, t he start/e n d date a n d ti me, t he 
attac k l ocati o n(s), a n d t he se verit y of t he attac k base d o n t he m ost se vere s y m pt o ms. F or e ver y 
visit, t he in vesti gat or will re p ort all H A E attac ks t hat ha ve occ urre d i n t he i nteri m si nce t he last 
visit t he s u bject atte n de d.  
F or all a nal yses  c o nsi deri n g H A E a ttac ks, o nl y t h e H A E attac ks c o nfir me d a n d re p ort e d b y t he 
i n vesti gat or usi n g t he eC R F ‘ H A E A ttac ks’ f or m will be use d .  
H A E attac ks wit h a start date  o n or after t he first d a y of t he R u n -i n Peri o d b ut pri or t o t he date 
a n d ti me of t he first st u d y dr u g a d mi nistrati o n will be c o u nte d f or t h e R u n-i n Peri o d.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 7  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
H A E attac ks wit h a start date a n d ti me after t he first st u d y dr u g a d mi nistrati o n t hr o u g h Visit 
Da y 1 8 2 (i ncl usi ve)  or E n d of St u d y  visit  ( w hate ver is first) will be c o u nte d f or t he Treat me nt 
Peri o d  a n d will be i ncl u de d i n t he a nal yses of efficac y . 
T he pri mar y e n d p oi nt will be a nal yze d usi n g t he I T T a n d P P A nal ysis Set. T he I T T A nal ysis 
Set  will  be  use d  as  t he  pri mar y  a nal ysis  a n d  t he  P P A nal ysis Set  will  be  use d  as  t he 
s u p ple me ntar y a n al ysis  (see Sec ti o n 1 0. 1. 3 ). 
T he pri mar y e n d p oi nt , ti me-n or malize d n u m ber of H A E attac ks per m o nt h, is calc ulate d per 
s u bject as: 
[t he n u m ber of H A E attac ks / le n gt h of s u bject treat me nt i n da ys] * 3 0. 4 3 7 5 
 
w here t he l e n gt h of s u bject treat me nt is calc ul ate d as:  
[t he date of St u d y Visit Da y 1 8 2 or t he E n d of St u d y date [ w h ate ver is first] – 
t he date of St u d y Visit Da y 1 of t he Treat me nt Peri o d  + 1].  
 
T o tra nsf or m t h e le n gt h of s u bject tr eat me nt w hic h are cal c ulate d i n d a ys i n years t he n u m ber 
of  da ys  is  di vi de d  b y  3 6 5. 2 5.  T h us,  ti me -n or malize d  n u m ber  of  H A E  attac ks  per  y ear  is 
calc ulate d p er s u bject as:  
[t he n u m ber of H A E attac ks / le n gt h of s u bject treat me nt i n da ys] * 3 6 5. 2 5. 
 
T he ti me -n or malize d n u m ber of H A E attac ks will n ot be calc ulate d if t he  s u bject’s o bser v ati o n 
ti me f or t he T reat me nt P eri o d is less t ha n 3 0 da ys, i.e. s u bject disc o nti n ue d wit hi n 3 0 da ys after 
first st u d y dr u g a d mi nistrati o n.  
 
T he ra n d o mizati o n is stratifie d b y t he varia bles a ge ( ≤ 1 7 years, > 1 7 years) a n d, f or a d ults, t he 
s u bject’s baseli ne attac k rate ( 1 t o < 3 attac ks/ m o nt h, a n d ≥ 3 attac ks/ m o nt h) d uri n g t he R u n -
i n peri o d. A ge a n d bas eli ne attac k rate are n o t re g ar de d as c o nf o u n d er or effect m o difier. T he 
stratificati o n  b y  a ge  is  i m ple me nte d  t o  miti gate  t he ris k  t h at  a d oles ce nt  s u bjects  c o ul d  be 
ra n d o mize d all  t o  t he  sa me  treat me nt, wit h  w orst  case  sce nari o  t hat  all  a d olesce nts  are  o n 
place b o tr eat me nt. T here is n o si g nifica nt p h ysi ol o gical basis t o s u g gest differe nt efficac y or 
safet y pr ofiles i n a d ults a n d a d olesce nts a n d t he distri b uti o n of attac k l ocati o ns i n a d olesce nt 
s u bjects ty picall y mirr ors t hat of a d ults [ Mac Gi n nitie, 2 0 1 4 ].   
 
It is e x pecte d t hat ar o u n d 5 0 % of s u bjects will ha v e 1 t o < 3 attac ks/ m o nt h a n d ar o u n d 5 0 % of 
s u bjects will ha ve ≥ 3 attac ks/ m o nt h as bas eli ne  attac k rate [Ba n erji, 2 0 1 8 ]. Beca us e of t he 
stratifie d  ra n d o mizati o n  t hese  t w o  s u b gr o u ps  of  s u bjects  will  be  e q uall y  distri b ute d  t o  t he 
Acti ve a n d t o t he Place b o ar m. It is ass u me d  t hat t he treat me nt effect, i.e. t he ti me-n or malize d 
n u m ber of H A E attac ks  o bser ve d u n der C S L 3 1 2 treat me nt , is n ot i m pacte d by  t he  baseli ne 
attac k r ate.  Ne vert heless, t he ti me -n or malize d n u m ber of H A E attac ks will be c o m pare d f or 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 8  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
t he 6 m o nt hs of t he Acti v e Ar m a n d t h e 6 m o nt hs of Place b o Ar m usi n g a P oiss o n Re gressi o n 
m o del i ncl u di n g baseli ne attac k rate as fi xe d effect i n a  se nsiti vit y a nal ysis, see Secti o n 1 0. 1. 2 .  
 
1 0. 1. 1  
Pri m ar y Esti m a n d  
T he pri mar y i nterest is t o assess t he treat me nt effect of C S L 3 1 2 d uri n g treat me nt fr o m Da y 1 
t hr o u g h Da y 1 8 2 w hile s u bjects are all o we d t o treat H A E attac ks wit h o n- de ma n d me dicati o ns.  
 
T he pri mar y esti ma n d i n li ne wit h t he pri mar y i nterest of t he st u d y f oll o ws t he treat me nt  
p olic y strate g y a n d is des cri be d as f oll o ws: 
•  Treat me nt C o n diti o n: m o nt hl y treat me nt of C S L 3 1 2 or place b o  
•  P o p ulati o n: t he tar get patie nt p o p ulati o n defi ne d b y eli gi bilit y criteria a n d w h o were 
ra n d o mize d (I T T).  
•  Varia ble: ti me -n or malize d n u m ber of H A E attac ks per m o nt h d uri n g treat me nt fr o m Da y 
1 t hr o u g h Da y 1 8 2. 
I nterc urre nt  e ve nts: T he  occ urre n ce  of a n  i nterc urre nt  e ve nt  is irrele va nt.  All  o bser ve d 
val ues will be use d re g ar dless of occ urre nce of a n y of t he f oll o wi n g i nterc urre nt e v e nts: 
o  a d mi nistrati o n of o n -de ma n d me dicati o n i n a d diti o n t o pr o p h ylactic treat me nt wit h 
C S L 3 1 2, 
o  Pr o hi bite d c o nc o mita nt  me dicati o ns d ue or n ot  d ue t o  C O VI D -1 9 or C O VI D - 1 9 
vacci nati o n,  
o  n o n- c o m plia nce  t o  treat me nt  d ue  or  n ot  d ue  t o  C O VI D -1 9  or  C O VI D - 1 9 
vacci nati o n,  
o  earl y st u d y disc o nti n uati o n d ue or n ot d ue t o C O VI D- 1 9. 
•  P o p ulati o n- le vel  s u m mar y:  me dia n  ti me-n or malize d  n u m ber  of  H A E  attac ks  per m o nt h 
d uri n g treat me nt fr o m D a y 1 t hr o u g h Da y 1 8 2 b y treat me nt. 
 
If  a  s u bject  disc o nti n ue d  t he  st u d y  earl y after  bei n g  c o nti n u o usl y  t he  first  3 0  da ys  i n  t he 
treat me nt peri o d, t he o bs er vati o n is ter mi nat e d b y t he Earl y Ter mi nati o n Visit . It is ass u m e d 
t hat t he attac k rate f or s u bjects, w h o disc o nti n ue d t he st u d y after t he 3 0t h st u d y da y a n d bef ore 
t he e n d of t he 6t h m o nt h, is c o m para ble t o t he attac k rate fr o m s u bjects w h o ha ve t he e ntire 6 
m o nt hs  treat me nt  peri o d   o bser ve d. T his  ass u m pti o n  is  base d  o n  C S L 3 1 2 _ 2 0 0 1  data  w hic h 
s h o we d t hat t he C S L 3 1 2 treat me nt effect was mai ntai ne d o ver ti me. T heref ore, t he pri mar y 
e n d p oi nt will be c o nsi dere d meas ur a ble a n d n ot missi n g, ie, t he ti me -n or malize d n u m ber of 
H A E attac ks will be calc u late d base d o n t he H A E attac ks re p orte d u ntil t he Earl y Ter mi nati o n 
Visit . 
 
I n  case a  s u bject  disc o nti n ues  st u d y  treat me nt  d ue  or  n ot  d ue  t o  C O VI D -1 9  b ut c o nti n ues 
partici pati o n i n t he st u d y f or m ore t ha n 3 0 d a ys be y o n d t he last st u d y dr u g a d mi nistrati o n,  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 3 9  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
t he H A E attac ks u ntil t he last st u d y dr u g a d mi nistrati o n pl us 3 0 d a ys will be i ncl u de d  i n t he 
H A E attac k a nal ysis a n d le n gt h of s u bject treat me nt i n da ys will be deri ve d as:  
 
[ date of last st u d y dr u g a d mi nistrati o n – t he d ate of St u d y Visit D a y 1 of t he 
T reat me nt Peri o d + 31].  
 
Missi n g data is o nl y gi ve n if s u bjects disc o nti n ue t he st u d y wit hi n  3 0 da ys after t he first st u d y 
dr u g  a d mi nistrati o n  i n  t he  treat me nt  peri o d.  A n  a p pr oac h  t o  ha n dle  t hese  missi n g  data  b y 
se nsiti vit y a nal ysis is descri be d i n Secti o n  1 0. 1. 2 . 
 
D uri n g  t he  B D R M,  it  will  be  assesse d  if  s u bjects  ha ve  misse d  s u bse q ue nt  st u d y  dr u g 
a d mi nistrati o ns a n d if t his mi g ht lea d t o t he e xcl usi o n of s u bject’s data fr o m t he a nal yses. All 
decisi o ns will be d oc u me nte d i n t he B D R M mi n utes. 
 
A  C O VI D -1 9  dia g n osis  a n d  res ulti n g  i nterc urre nt  e ve nts  are  irrel e va nt  f or  t he  pri mar y 
esti ma n d. All o bser ve d  v al ues will be use d re gar dless of occ urre nce of a n y of t he f oll o wi n g 
C O V I D-1 9  relate d i nterc urre nt e ve nts: me dicati o ns gi ve n t o treat C O VI D - 1 9 or C O VI D - 1 9 
vacci nati o ns . No n- c o m plia nce t o treat me nt  a n d earl y disc o nti n uati o n will b e ha n dle d t he s a me 
i n de pe n de nt if it is relate d t o C O VI D- 1 9 or n ot.  
 
1 0. 1. 2  
Pri m ar y Effic ac y A n al ysis  
F ol l o wi n g t he esti ma n d  descri be d i n Secti o n  1 0. 1. 1 , t he pri mar y efficac y e n d p oi nt bet wee n 
C S L 3 1 2 a n d place b o  is t este d f or a differe n ce b y c o m pari n g t he ti me-n or malize d n u m ber of 
H A E attac ks i n t he 6 m o nt hs of t he Acti ve  Ar m a n d i n t he 6 - m o nt h Place b o Ar m peri o d b y 
usi n g a t w o -si de d Wilc o x o n Test  ( Hierarc hical Testi n g H 0 1). T he m o nt hl y C S L 3 1 2 d ose will 
be e val uat e d a gai nst m o nt hl y place b o at al p ha = 5 %:  
H 0 1: a1 = 0   vers us   H1 1: a1 ≠ 0 
I n  t h e  a b o ve  h y p ot hesis,  t he  ter m  “a1”  is  t he  s hift bet wee n  t h e  2  distri b uti o ns  of  m o nt hl y 
C S L 3 1 2 a n d m o nt hl y place b o. 
 
T he ti me -n or malize d n u m ber of H A E attac ks per m o nt h a n d per year will be s u m marize d  
descri pti vel y f or t he 6 m o nt hs of t he Acti ve Ar m a n d t he 6- m o nt h Place b o Ar m peri o d b y 
me dia n a n d mea n w it h c orres p o n di n g 9 5 % CIs.  
 
 
 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 0  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Se nsiti vit y A n al ysis c o nsi deri n g b aseli ne att ac k r ate  
 
As a se nsiti vit y a nal ysis,  t he ti me-n or malize d n u m ber of H A E attac ks will b e c o m pare d f or t he 
6 m o nt hs of t he Acti ve Ar m a n d t he 6 m o nt hs of  t he Place b o Ar m usi n g a ge ne ralize d li near 
m o del  ( G L M)  f or  c o u nt  data ass u mi n g  a  P oiss o n  distri b uti o n  wit h  t he  l o garit h m  as  li n k 
f u ncti o n  a n d  Pears o n  c hi-s q uare  scali n g  of  sta n dar d  err ors  t o  acc o u nt  f or  p ote ntial  o ver 
dis persi o n. T he m o del i ncl u des treat me nt (cate g orical) a n d t he ti m e-n or malize d baseli ne attac k 
rate d uri n g  R u n -i n  Peri o d (c o nti n u o us)  as  c o vari ates.  T o  acc o u nt  f or  t he  le n gt h  of  s u bject 
treat me nt, t he l o g arit h m of t he le n gt h of s u bject  treat me nt is use d as a n offset vari a ble i n t he 
m o del: 
l o g λ i =l o g (ti) + β ′ xi   
w here  λi  is t he e x pecte d n u m ber of H A E attac ks of s u bject i (i = 1, …, n wit h n t he n u m ber of 
s u bjects i n  I T T A nal ysis Set ),  l o g(ti) is  t he  offs et wit h   ti as  t he le n gt h  of t he  i-t h s u bj ect 
treat me nt i n  da ys a n d  x i is  t he c o variate  of  s u bject  i  w hic h  i ncl u des  t he  ti me-n or malize d 
baseli ne attac k rate of s u bject i  a n d t he treat me nt i nf or mati o n of s u bject i. 
 
Fr o m  t his  m o del,  t he  least  s q uares  mea n  ti me -n or malize d  n u m b er  of  H A E  attac ks  a n d  t he 
sta n dar d err ors are esti mate d f or C S L 3 1 2 a n d place b o. T h e mea n ti me-n or malize d n u m ber of 
H A E attac ks rati o f or C S L 3 1 2 relati ve t o t he place b o a n d t he c orres p o n di n g 9 5 % c o nfi de nce 
i nter val ar e als o esti mate d. To re p ort as m ea n attac k rate p er m o nt h, t he recei ve d esti mates are 
tra nsf or me d b y t he e x p o ne ntial f u ncti o n a n d scale d b y ti me.  
 
T he mea n ti me -n or malize d n u m ber of H A E attac ks rati o f or C S L 3 1 2 relati ve t o place b o a n d 
t he c orr es p o n di n g 9 5 % c o nfi de nce i nter v al esti mate d b y t he m o del d es cri be d a b o v e will be 
use d  t o  calc ulate  t he  perce nta g e  differe nce  i n  t he  mea n ti me-n or malize d  n u m ber  of  H A E 
attac ks f or C S L 3 1 2 fr o m place b o as:  
1 0 0 % * ( mea n ti me-n or malize d n u m ber of H A E attac ks rati o - 1).  
 
T he 9 5 % CI f or t he p erce nta ge diff ere n ce will be calc ulate d wit h t h e esti mat e d u p per a n d l o wer 
c o nfi de nce li mits f or t he mea n ti me -n or malize d n u m ber of H A E attac ks rati o, tra nsf or m b y 
s u btracti n g 1 a n d m ulti pl yi n g b y 1 0 0 %. 
 
T he se nsiti vit y anal ysis  c o nsi deri n g  bas eli ne  attac k  rat e  will  be carrie d  o ut  usi n g  t he  I T T 
A nal ysis Set.  
 
Tec h nical N ote: t he ti me -n or malize d bas eli ne attac k rate d uri n g R u n -i n Peri o d (c o nti n u o us) 
will be deri ve d as d efi ne d i n Secti o n 1 0. 3. 2. 1 . 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 1  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Se nsiti vit y A n al ysis f or missi n g v al ues 
 
Missi n g val ues occ ur  if t he o bser vati o n ti me f or t he treat me nt peri o d is less t ha n 3 0 da ys, i.e., 
a s u bject disc o nti n ue d wit hi n 3 0 da ys after first st u d y dr u g a d mi nistrati o n . T heref ore, o nl y a 
ver y l o w n u m ber of s u bjects wit h a missi n g pri mar y e n d p oi nt are t o b e e x p ecte d. 
 
T o assess t he i m pact of missi n g data f or t he pri mar y efficac y esti ma n d a s yste matic a p pr oac h 
will be a p plie d . F or eac h treat me nt  ar m, a ra n g e of val ues f or t he n u m ber of ti me-n or malize d 
H A E attac ks per m o nt h fr o m 0 t o 6 s u b di vi de d i nt o 9 i ncre me nts bet w ee n  t w o c o ns ec uti ve 
i nte ger val ues will be ge n erate d. All  p ossi ble c o m bi nati o ns fr o m t he  s u b di vi de d ra n g es will be 
i m p ute d t o re place t he missi n g val ues. F or t he c o m paris o n of acti ve treat me nt vers us place b o , 
o bser ve d  a n d i m p ute d d ata  will  be  a nal y ze d  usi n g  t he Wilc o x o n  Test  a n d  res ults  will  be 
classifie d  i nt o  ne gati ve  (i.e.,  place b o  si g nifica ntl y  better),  ne utral  (i.e.,  n o  si g nifica nt 
differe n ce) a n d p ositi ve (i.e., acti ve treat me nt si g nifica ntl y better) .  
 
A gra p h  w here  t he  x -a xis  prese nts  t he  s u b di vi de d  ra n g e  f or  place b o  a n d  t he  y -a xis  t he 
s u b di vi de d  ra n ge  f or  t he  acti ve  treat me nt will  vis ualize  all  s ce nari os  a n d  disti n g uis he d  t he  
differe nt o utc o mes b y differe nt c ol ors a n d s y m b ols. T he t otal n u m ber of s u bjects wit h missi n g 
o utc o me  i n  place b o  a n d  acti ve treatme nt  ar m  will  be  a d de d  t o  t he  gra p h. T his se nsiti vit y 
a nal ysis will o nl y be a p plie d t o t he I T T A nal ysis S et. 
1 0. 1. 3  
S u p ple me nt ar y A n al yses of Pri m ar y Esti m a n d  
T he  pri mar y  esti ma n d  descri be d  a b o v e  is  c o m ple me nte d  b y  a n  a d diti o nal  s u p ple me ntar y  
esti ma n d a n d a nal ysis. 
 
O nl y s u bjects i n t he P P A nal ysis S et will be i ncl u de d. T he i nterest is t o assess t he treat me nt  
effect of C S L 3 1 2 d uri n g treat me nt fr o m D a y 1 t hr o u g h Da y 1 8 2 w hile s u bj ec ts are all o we d t o 
treat H A E attac ks wit h o n-de ma n d me di cati o ns b ut e xcl u di n g s u bjects w h o d o n ot c o m pl y wit h 
t he pr ot oc ol. 
 
T he  a d diti o nal  esti ma n d  i n  li ne  wit h  t he  i nterest  of  t he  st u d y  f oll o ws  t h e  treat me nt  p olic y 
strate g y a n d is descri be d as f oll o ws: 
•  Treat me nt C o n diti o n: m o nt hl y treat me nt of C S L 3 1 2 or place b o.  
•  P o p ulati o n:  t he  tar get  s u bject  p o p ulati o n  defi ne d  b y  eli gi bilit y  criteria,  w h o  were 
ra nd o mize d, r ecei ve d at l east 1 d ose of C S L 3 1 2 a n d w h o c o m pl y wit h t he pr ot oc ol ( P P). 
•  Varia ble: ti me -n or malize d n u m ber of H A E attac ks per m o nt h d uri n g treat me nt fr o m Da y 
1 t hr o u g h Da y 1 8 2. 
•  I nterc urre nt  e ve nts:  T he  occ urre n ce  of  a n  i nterc urre nt  e ve nt  is  irreleva nt.  All  o bser ve d 
val ues will be use d re g ar dless of occ urre nce of a n y of t he f oll o wi n g i nterc urre nt e v e nts: 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 2  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
o  a d mi nistrati o n of o n -de ma n d me dicati o n i n a d diti o n t o pr o p h ylactic treat me nt wit h 
C S L 3 1 2, 
o  earl y st u d y disc o nti n uati o n d ue or n ot d ue t o C O VI D- 1 9. 
•  P o p ulati o n- le vel s u m mar y: descri pti ve statistics of t he ti me-n or malize d n u m ber of H A E 
attac ks d uri n g treat me nt fr o m Da y 1 t hr o u g h D a y 1 8 2 b y treat me nt. 
W he n  a  s u bject  w h o  w as  at  least  3 0  da ys  i n  t he  treat me nt  peri o d  aft er  t he  f irst  st u d y  dr u g 
a d mi nistrati o n disc o nti n ues st u d y treat me nt d u e or n ot d ue t o C O VI D -1 9 b ut sta ys be y o n d t he 
last st u d y dr u g a d mi nistrati o n i n t he st u d y f or m ore t ha n 3 0 da ys, t he H A E attac ks u ntil t he last 
st u d y  dr u g  a d mi nistrati o n  pl us  3 0  da ys  t hereaft er  will  be  i ncl u de d  i n  t he  s u p ple me ntar y 
a nal ysis of t he pri mar y esti ma n d.  
If a s u bject h as a C O VI D- 1 9 i nfecti o n w hile  partici pati n g i n t he st u d y, his/ her attac ks will be 
assesse d d uri n g t he B D R M t o deter mi ne if t he y mi g ht be ca use d/ tri g gere d b y ot her fact ors, 
e. g.C O VI D -1 9. If t her e is clear e vi de nce t hat t he y are d ue t o t he C O VI D - 1 9 i nfecti o n or 
ot her, t he y mi g ht be e xcl u de d fr o m t he a n al yses. Misse d st u d y dr u g a d mi nistrati o ns n ot d ue 
or d ue t o C O VI D- 1 9 or C O VI D - 1 9 vacci nati o n mi g ht als o lea d t o t he e x cl usi on of a s u bject 
or s u bject’s data fr o m t he s u p ple me ntar y a n al ysis as well as pr o hi bite d c o n c o mita nt 
me dicati o ns d ue or n ot d ue t o C O VI D- 1 9 or C O VI D- 1 9 vacci nati o n. 
1 0. 2  
S u b gr o u p A n al yses  
If  ≥ 5 Ja pa nese s u bjects  are  e nr olle d  t o  t he  st u d y,  t he  f oll o wi n g s u b gr o u p a nal ysis  will  be 
carri e d o ut f or Ja p a nese  a n d all s u bjects: 
•  D escri pti ve a nal ysis  of t he pri mar y e n d p oi nt: ti me-n or malize d n u m ber of H A E attac ks 
per m o nt h d uri n g t he Treat me nt Peri o d , see Secti o n 1 0. 1 ; 
•  Descri pti ve  a nal ysis of t he re d u cti o n i n attac k rate  d uri n g t he Treat me nt  Peri o d, see 
Secti o n 1 0. 3. 2. 1 ; 
•  Descri pti ve a n al ysis of ti me -n or malize d n u m b er of H A E attac ks re q uiri n g o n -de ma n d 
treat me nt, see Secti o n 1 0. 3. 2. 2 ; 
•  O ver vie w s u m mar y of T E A Es , see Secti o n 1 1. 2 ; 
 
If    ≥  5  Ja pa nese  s u bjects  are  e nr olle d  t o  t he  st u d y,  t he f oll o wi n g  s u b gr o u p  a nal ysis  will  be 
carri e d o ut f or Ja p a nese/ n o n -Ja pa nes e s u bjects: 
•  S u m mar y f or C S L 3 1 2 c o nce ntrati o ns , see Secti o n 1 2. 1 . 
 
S u m maries f or C S L 3 1 2 c o nce nt rati o ns will f urt her be stratifie d b y  A ge gr o u p (a d oles ce nt [ 1 2 
t o ≤ 1 7 years] a n d a d ult [ > 1 7 years] s u bjects), s ee Secti o n 1 2. 1 . 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 3  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
1 0. 3  
A n al ysis of Sec o n d ar y E n d p oi nts  
Efficac y sec o n dar y e n d p oi nts are: 
•  T he re d ucti o n i n t he attac k rate d uri n g t he Treat me nt Peri o d c o m pare d t o t he R u n -i n Peri o d, 
•  T he ti me - n or malize d n u m ber of H A E attac ks re q uiri n g o n-de ma n d treat me nt , 
•  T he ti me - n or malize d n u m ber of m o derate a n d / or se vere H A E attac ks, 
•  Ti me -n or malize d  n u m ber  of  H A E  attac ks  at  vari o us  ti me  p oi nts  d uri n g  t he  treat me nt 
peri o d, 
•  
. 
 
Safet y sec o n d ar y e n d p oi nts are: 
•  A Es , 
•  A E SIs , 
•  S A Es , 
•  C S L 3 1 2 i n d uce d a nti- C S L 3 1 2 a nti b o dies, 
•  Cli nicall y si g nifica nt a b n or malities i n la b orat or y assess me nts (ie, la b orat or y a b n or malities 
re p orte d as A Es). 
1 0. 3. 1  
Sec o n d ar y Esti m a n d  
N o sec o n dar y esti ma n d is defi ne d. 
1 0. 3. 2  
Sec o n d ar y Effic ac y A n al ysis  
 Sec o n dar y efficac y e n d p oi nts will be a nal yze d f or I T T A n al ysis S et.  
1 0. 3. 2. 1  
T he Re d ucti o n i n t he Att ac k R ate d uri n g t he Tre at me nt Peri o d 
c o m p are d t o t he R u n -i n Peri o d 
T he sec o n d ar y efficac y e n d p oi nt of t he perce nta ge re d ucti o n i n t he ti me- n or malize d n u m ber 
of H A E attac ks is calc ulate d wit hi n a s u bject as:  
1 0 0  *  [ 1 – (ti me-n or malize d  n u m ber  of  H A E  attac ks  per  m o nt h  d uri n g T reat me nt 
Peri o d / ti me- n or malize d n u m ber of H A E attac ks p er m o nt h d uri n g R u n-i n Peri o d )] 
 
wit h ti me -n or malize d n u m ber of H A E attac ks p er m o nt h d uri n g Treat me nt Peri o d  as defi n e d 
i n Secti o n 1 0. 1  a n d wit h ti me -n or malize d n u m ber of H A E attac ks per m o nt h d uri n g R u n -i n 
Peri o d defi ne d as:  
[t he n u m ber of H A E attac ks d uri n g R u n-i n Peri o d / le n gt h R u n-i n Peri o d i n   
da ys] * 3 0. 4 3 7 5 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 4  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
w here t he l e n gt h of s u bject ’s R u n-i n Peri o d is calc ulate d as: 
[Da y 1 Visit date of t he Treat me nt Peri o d or Dat e of R u n -i n C o m pleti o n/ N o n-
c o m pleti o n [ w hic he ver is first] – Da y 1 Visit date of R u n-i n Peri o d] 
 
f or t he e ntir e 6- m o nt hs Treat me nt Peri o d  a n d will be s u m marize d a n d teste d via a t w o-si de d 
Wilc o x o n Test wit h al p h a = 5 %.  
 
T he n u m ber a n d p erce nta ge of res p o n d ers a n d n o n-res p o n ders will be pres e nte d wit h 
c orres p o n di n g 9 5 % CIs. A s u bject is classifie d as a res p o n der if t he perce nt a ge re d u cti o n i n 
ti me-n or malize d H A E attac ks is ≥ 5 0 %. I n a d diti o n, t he n u m ber a n d perce nta ge of s u bjects 
wit h perce nt a ge re d ucti o ns of ≥ 7 0 %, a n d ≥ 9 0 % will be pres e nte d wit h c orres p o n di n g 9 5 % 
CIs.  
 
T he n u m ber a n d p erce nta ge of s u bjects wit h a perce nta ge re d ucti o n of 1 0 0 %, ie, w h o d o n ot 
e x perie n ce a H A E attac k a n d s o are attac k -free, will be prese nte d a n d s u m marize d wit h 
c orres p o n di n g 9 5 % CI f or t he 6 - m o nt h Treat me nt Peri o d, a Fis her -Test will be perf or me d t o 
assess  f or diff er e nces b et wee n treat me nt  ar ms. 
 
T he  n u m ber  a n d  per ce nt a ge  of  s u bjects  w h o  d o  n ot  e x perien ce  a  H A E  attac k  i n  t he  first  3 
m o nt hs  after  first  st u d y  dr u g  a d mi nistrati o n  a n d  s o  are  attac k -free  will  be  prese nte d  a n d 
s u m marize d  wit h c orres p o n di n g  9 5 %  CIs.  A  Fis her -Test  will  be  p erf or me d  t o assess f or 
differe n ces b et wee n tr eat me nt  ar ms ( Hierarc hi cal Testi n g H 0 3) . 
 
T he  sa me  a n al ysis  will  be  re peate d  f or  t he  sec o n d  3  m o nt hs  after  first  st u d y  dr u g 
a d mi nistrati o n.  
 
1 0. 3. 2. 2  
T he ti me -n or m alize d n u m ber of H A E att ac ks re q uiri n g o n -
de m a n d tre at me nt  
T he sec o n d ar y efficac y e n d p oi nt of ti me- n or malize d n u m ber of H A E attac ks per m o nt h 
re q uiri n g o n-de ma n d treat me nt is calc ulate d as:  
1 0 0 * [ 1 – ( n u m ber of H A E attac ks re q uiri n g o n-de ma n d treat me nt d uri n g T reat me nt 
Peri o d / le n gt h of s u bject treat me nt i n da ys)] * 3 0. 4 3 7 5 
 
a n d  a n n ualize d  ti me -n or malize d  n u m ber  of  H A E  attac ks  re q uiri n g  o n -d e ma n d  treat me nt  is 
calc ulate d as:  
1 0 0 * [ 1 – ( n u m be r of H A E attac ks re q uiri n g o n-de ma n d treat me nt d uri n g Treat me nt 
Peri o d  / le n gt h of s u bject treat me nt i n da ys)] * 3 6 5. 2 5. 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 5  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
B ot h will be s u m marize d descri pti vel y f or t he 6 - m o nt h Treat me nt Peri o d . Differe n ces bet wee n 
t he treat me nt ar ms will be teste d i n a n e xpl orat or y ma n ner via a t w o -si de d Wilc o x o n Test wit h 
al p ha = 5 %.  
 
A n H A E attac k re q uiri n g o n- de ma n d treat me nt is defi ne d as a n attac k f or w hic h t he date of  
a d mi nistrati o n of a n o n- d e ma n d treat me nt is bet w ee n t he start (i n cl u di n g) a n d e n d date 
(i ncl u di n g) of a H A E attac k.  
 
Tec h nical N ot e: Use a ns wer f or “ O n de ma n d treat me nt ta ke n?” fr o m C R F f or m “ H A E attac k” 
t o fla g H A Es re q uiri n g o n-de ma n d treat me nt. 
 
1 0. 3. 2. 3  
T he ti me -n or m alize d n u m ber of m o der ate or se vere H A E 
att ac ks  
F or  t he  a nal ysis  of  t he  ti me - n ormalize d  n u m ber  of  m o derate  or  se vere  H A E  attac ks,  a n  
a nal o g ue calc ulati o n a n d  a nal yses as descri be d i n Secti o n  1 0. 3. 2. 2  will be d o ne c o nsi deri n g all 
H A E attac ks classifie d as m o derate or s e vere.  
 
1 0. 3. 2. 4  
Ti me -n or m alize d n u m ber of H A E att ac ks at v ari o us ti me p oi nts 
d uri n g t he T re at me nt P eri o d 
T he ti me - n or malize d n u m ber of H A E attac ks ( p er m o nt h a n d a n n ualize d) d uri n g, t he first 3-
m o nt hs Treat me nt Peri o d a n d t he sec o n d 3- m o nt hs Treat me nt Peri o d will be s u m marize d 
descri pti vel y  a n d c o m p ar e d bet wee n t he treat me nt ar ms usi n g a t w o-si de d Wilc o x o n Test 
wit h al p ha = 5 %. 
T he ti m e-n or malize d n u m ber of H A E attac ks  ( p er m o nt h) f or t he differe nt Treat me nt Peri o d s 
is calc ulate d f or a s u bject as:  
[ n u m ber of H A E attac ks wit hi n  first 3- m o nt hs or sec o n d 3- m o nt hs Treat me nt Peri o d/ 
le n gt h of s u bject treat me nt i n da ys] * 3 0. 4 3 7 5  
a n d the ti me-n or malize d n u m ber of H A E attac ks (a n n ualize d) as:  
[ n u m ber of H A E attac ks wit hi n first 3- m o nt hs or sec o n d 3-m o nt hs Treat me nt Peri o d/ 
le n gt h of s u bject treat me nt i n da ys] * 3 0. 4 3 7 5  
wit h le n gt h of s u bjects treat me nt i n da ys deri v e d as: 
•  First  3 -m o nt hs  Tr eat me nt  Peri o d: [t he  date  of  St u d y  Visit  Da y 9 1  or t he  E n d  of 
St u d y date  [ w hate v er is first] – t he date of St u d y Visit Da y 1 of t he Treat me nt Peri o d 
+ 1 ]; 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 6  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
•  Sec o n d 3 -m o nt hs Treat me nt Peri o d: [ t he date of St u d y Visit Da y 1 8 2 or t he E n d of 
St u d y date  [ w h ate ver is first] – t he date of St u d y Visit Da y 9 1 of t he Treat me nt 
Peri o d ]. 
Tec h ni cal N ot e: A s u bject  w h o  disc o nti n ue d i n t he first t hree m o nt hs of Treat me nt Peri o d will 
ha ve a ti me-n or malize d n u m ber of H A E attac ks  f or t he first 3- m o nt hs b ut n ot f or t he sec o n d 
3- m o n t hs Treat me nt Peri o d. 
T he perce nta ge re d u cti o n i n t he ti me -n or malize d n u m ber of H A E attac ks f or  t he Acti ve Ar m 
c o m pare d  t o  t he  ti me-n or malize d  n u m ber  of  H A E  attac ks f or t h e  Place b o  Ar m  ( bet w ee n 
s u bjects) will be calc ul ate d as: 
 
1 0 0 * [( mea n ti me- n or malize d n u m ber of H A E attac ks f or C S L 3 1 2 - mea n ti me -
n or malize d n u m ber of H A E attac ks f or Place b o) / m ea n ti me- n or malize d n u m ber of 
H A E attac ks f or Place b o]  
a n d 
1 0 0 * [( me dia n ti me- n or malize d n u m ber of H A E attac ks f or C S L 3 1 2 - me dia n ti me -
n or malize d n u m ber of H A E attac ks f or Place b o) / me dia n ti me - n or malize d n u m ber of 
H A E attac ks f or Place b o].   
 
T he 9 5 % t w o -si de d C o nfi de nce I nter v als f or t he relati ve differe n ce i n mea ns a n d me dia ns will 
be calc ulate d b y usi n g t he esti mate d u p per a n d l o wer c o nfi d e nce li mits f or t he c orres p o n di n g 
ti me-n or malize d n u m ber of H A E attac ks rati o, tra nsf or m b y s u btracti n g 1 a n d m ulti pl yi n g b y 
1 0 0 % [ Be ye n e & M oi ne d di n g, 2 0 0 5 , Price & B o nett, 2 0 1 0 ]. 
T he per ce nta g e re d u cti o n will be  calc ulate d f or t he ti me - n or malize d n u m ber of H A E attac ks 
bet wee n t he Acti ve Ar m  a n d t he Place b o Ar m f or t he 6 - m o nt h Treat me nt P eri o d ( Hierarc hical 
Testi n g H 0 2) , as well as f or t he first 3 m o nt hs a n d t he sec o n d 3 m o nt hs of t he Treat me nt 
Peri o d. 
 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 7  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
1 0. 3. 3  
S u p ple me nt ar y A n al yses of Sec o n d ar y E n d p oi nts  
T he sec o n d ar y e n d p oi nts:  
- 
perce nt a ge r e d ucti o n i n t he ti me- n or malize d n u m ber of H A E attac ks,  
- 
n u m ber a n d per ce nta g e of s u bjects wit h perce nta g e re d ucti o ns of ≥ 5 0 %, ≥  7 0 %, a n d 
≥ 9 0 %, 
- 
ti me- n or malize d n u m ber of H A E attac ks per m o nt h re q uiri n g o n-de ma n d treat me nt , 
- 
t he ti me-n or malize d n u m ber of m o derate or s e vere H A E attac ks , 
(see Secti o n 1 0. 3. 2. 1 , Secti o n 1 0. 3. 2. 2 , Secti o n 1 0. 3. 2. 3 ) will be  f urt her s u m marize d s e paratel y 
f or t he first 3 m o nt hs Treat m e nt Peri o d ( St u d y Da y 1 t o Da y 9 1), as well as t he sec o n d 3 m o nt hs 
Treat me nt Peri o d ( St u d y Da y 9 2 t o Da y 1 8 2).  
 
S u p ple me ntar y A nal ysis of Sec o n dar y  E n d p oi nts will be c o n d ucte d f or I T T A nal ysis Set.  
 
H A E att ac ks  
T he n u m ber a n d p erce nta ge of mil d, m o derate, a n d se vere H A E attac ks will be prese nte d as 
well as t he ti me - n or malize d n u m ber of mil d, m o derate, a n d s e vere H A E attac ks d uri n g R u n-
i n Peri o d a n d Treat me nt Peri o d. 
 
A b y -s u bject listi n g will s h o w all details per H A E attac k s orte d b y treat me nt ar m, s u bject-I D 
a n d H A E Attac k I D i ncl u di n g: n o mi nal visit, start a n d e n d date:ti me, a n at o mical l ocati o n, 
se verit y, o n de ma n d treat me nt ta ke n, p ote ntial tri g ger f or t his H A E attac k. 
 
A n a d diti o nal listi n g will prese nt a bs ol ute n u m ber a n d ti me- n or malize d n u m be r of all, mil d, 
m o derate, a n d s e ver e H A E attac ks per R u n -i n Peri o d a n d Treat me nt Peri o d, d urati o n of R u n-
i n Peri o d a n d Treat me nt Peri o d as use d f or ti me-n or malizati o n f or eac h s u bject. 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 8  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 4 9  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 0  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
Ti me t o first H A E att ac k after D a y 1 a n d after D a y 1 5 d uri n g Tre at me nt Peri o d  
Ti me  t o first H A E attac k after St u d y Da y 1 a n d aft er St u d y Da y 1 5 d uri n g Treat me nt Peri o d 
will be a nal yze d usi n g t h e Ka pla n -M eier met h o d.  Ti me t o first H A E attac k after D a y 1 will 
be deri ve d as:  
 
Date of first H A E attac k after St u d y Da y 1  – D ate of St u d y Da y 1, 
 
a n d Ti me t o first H A E att ac k aft er D a y 1 5 will be deri ve d as:  
Date of first H A E attac k after St u d y Da y 1 5 – [ Date of St u d y Da y 1 + 1 4]. 
 
S u bjects wit h n o H A E attac k will be ce ns ore d at Visit Da y 1 8 2 or at E n d of St u d y Visit 
( w hate ver is first). K a pla n -Meier  ( K M) c ur ves wit h 9 5 % CI will be pl otte d b y treat me nt ar m 
s h o wi n g t he perce nta ge of s u bjects ha vi n g n o attac k (s u bjects u n der ris k) o v er  st u d y da ys. 
T he c orr es p o n di n g life ta ble will be prese nte d. T h e me dia n ti me, t he 2 5 % a n d 7 5 % perce ntile 
ti mes u ntil t he first H A E attac k will be cal c ulate d f or eac h treat me nt  ar m b ase d o n t he K M 
a p pr oac h . T he me dia n ti me rati o will be calc ul ate d f or C S L 3 1 2 a gai nst place b o. S u m mar y 
ta ble will f urt her i ncl u de mi ni m u m a n d ma xi m u m ti mes t o t he first attac ks.  
 
 
 
 
 
 
  
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 1  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
1 0. 5  
M ulti ple C o m p aris o ns a n d M ulti plicit y  
F o ur test o ne f or t he pri mar y e n d p oi nt ( H 0 1) a n d 3 f or t he 3 sec o n d ar y e n d p oi nts ( H 0 2, H 0 3, 
H 0 4) will be perf or me d  i n a hierar c hical or d er wit h a n 2-si de d al p ha of 5 % eac h, see Secti o n 
4. 2 . F o ur n ull h y p ot heses are defi ne d: 
 
•  H 0 1: t he ti me -n or malize d n u m ber of H A E attac ks i n t he first 6 -m o nt h ti me peri o d of 
t he Acti ve Ar m a n d i n t h e Place b o Ar m p eri o d are e q ual. 
•  H 0 2: t he per ce nta g e r e d u cti o n i n mea ns of t he ti me-n or malize d n u m b er of H A E attac ks 
f or t he 6-m o nt hs of t he Acti ve Ar m c o m pare d t o  t he 6-m o nt h Place b o Ar m peri o d are 
e q ual.  
•  H 0 3: t he n u m ber of s u bjects w h o d o n ot e x perie n ce a H A E attac k i n t he first 3 m o nt hs 
of t he Acti ve Ar m a n d t h e first 3- m o nt hs of t he P lace b o Peri o d are e q ual.  
•  H 0 4: t he perce nt of s u bjects wit h g o o d or e xcelle nt res p o nses t o t he  
 at t he e n d 
of Treat me nt Peri o d ( Da y 1 8 2) are e q ual f or s u bjects treate d wit h C S L 3 1 2 a n d place b o.  
 
T he ge neral pr ocess fl o w of t he h y p ot hesis testi n g is as f oll o ws:  
t he n ull h y p ot hesis ass ociate d wit h t he pri mar y e n d p oi nt H 0 1 will be teste d first. If a n d o nl y if 
t he res ulti n g 2-si de d p-val ue is < 0. 0 5, testi n g of H 0 2 will be perf or me d. If a n d o nl y if H 0 2 ca n 
be r ejecte d ( 2 -si de d p-v al ue < 0. 0 5), H 0 3 is teste d at 2 -si de d al p h a of 5 %. If a n d o nl y if H 0 3 
ca n be r eject e d ( 2 -si de d p- val ue < 0. 0 5), H 0 4 is teste d at 2-si de d al p h a of 5 %.  
 
T his hierarc hi cal testi n g pr oce d ur e c o ntr ols f or t he o verall al p h a le vel  of 5 %.  All ot her tests 
will be perf or me d wit h 2 -si de d al p ha of 5 % i n a n e x pl orat or y ma n n er. 
1 0. 6  
Tre at me nt C o m pli a nce  
C o m plia nce  will  be  s u m marize d  f or  t he Safet y A nal ysis  S et f or all  i njecti o ns  a d mi nistere d 
d uri n g t he Treat me nt Peri o d.  
T he 1. 2 m L prefille d s yri n ges c o ntai n 2 0 0 m g gara daci ma b  ( C S L 3 1 2) at a c o nce ntrati o n of 1 7 0 
m g per 1 m L.  A l oa di n g d oes will be a d mi nistere d b y t he use of t w o pre-filled s yri n ges a n d 
e ver y s u bse q u e nt d ose will be a d mi nistere d b y use of o ne pre-fille d s yri n g e. I n e C R F o nl y t he 
inf or mati o n i s c ollecte d if o ne or t w o s yri n ges ha ve bee n a d mi nistere d a n d if t he f ull v ol u me 
of t he st u d y dr u g f or t hat i njecti o n was a d mi nistere d ( Yes, N o). T he act ual a d mi nistere d m L is 
n ot d oc u me nte d. 
Tec h nical N ote: T h e l oa di n g d ose will be treate d as o ne i njecti o n f or all calc ulati o n s defi ne d i n 
t his S A P e ve n t h o u g h t he a d mi nistrati o n will re q uire t he use of t w o s yri n ges a n d wi ll ha ve t w o 
kit n u m bers rec or d e d i n t he C R F . 
C CI


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 2  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
T h us, treat me nt c o m plia n ce will be base d o n n u m b er i njecti o n wit h ‘ was t he f ull v ol u me of t he 
st u d y dr u g a d mi nistere d’ a ns wer e d wit h ‘Yes ’ i n relati o n t o t he pla n ne d n u m ber of i njecti o ns. 
Treat me nt c o m plia nce f or eac h s u bj ect will be deri ve d f or t he Treat me nt Peri o d as: 
Treat me nt c o m plia nce ( %) = 1 0 0 × ( N u m ber of i njecti o ns wit h f ull v ol u me   
                                               a d mi nistere d  / T otal pla n ne d n u m ber of i njecti o ns), 
wit h T otal pla n ne d n u m ber of i njecti o n is 6 per C S P ( o nce per m o nt h wit hi n 6-m o nt h Treat me nt 
Peri o d).  
Treat me nt  C o m plia nce  as  well  as  details  f or  de vice  malf u ncti o ns  or  ot her  err ors  will  be 
s u m marize d usi n g descri pti ve statistics al o n g wit h f urt her e x p os ure d ata (see Secti o n 1 1. 1 ). 
1 1  
S afet y A n al yses  
Safet y data will be s u m m arize d usi n g t he Safet y A nal ysis Set.   
1 1. 1  
E xte nt of E x p os ure  
E x p os ure a n d Tr eat me nt C o m plia nce (see Secti o n 1 0. 6 ) will be descri pti vel y s u m marize d b y 
treat me nt ar m: 
•  N u m ber of S C i njecti o ns recei v e d, 
•  Treat me nt C o m plia nce  ( %), 
•  Treat me nt C o m plia nce cate g ories ( < 8 0 %, 8 0 - 1 0 0 %), 
•  N u m ber of i njecti o ns wit h n ot t he f ull v ol u me a d mi nistere d , 
•  N u m ber of use err ors , 
•  N u m ber of de vi ce malf u ncti o ns b y cate g or y of m alf u ncti o n, 
•  N u m ber of ot her iss ues. 
 
Listi n gs of i n di vi d ual s u bject data will pres e nt all i njecti o n  rec or ds f or Safet y A nal ysis Set . 
1 1. 2  
A d verse E ve nts  
A Es will be c o de d usi n g t he Me d D R A dicti o nar y.  Treat me nt -e mer ge nt A Es ( T E A Es), defi ne d 
as A Es starti n g o n or after t he date ( a n d ti me if a vaila ble) of t he first st u d y dr u g a d mi nistrati o n, 
will be s u m marize d. All A Es re gar dless of w het h er t he y were treat me nt -e mer ge nt or n ot will 
be liste d.  
A Es wit h c o m pletel y or partiall y missi n g date or ti me will be c o nsi dere d treat me nt -e mer g e nt 
f oll o wi n g t he w orst-case pri nci ple, u nless t he  partial date cl earl y i n dicates t hat t he A E start e d 
bef ore t he first a d mi nistr ati o n of st u d y dr u g. A Es wit h c o m pletel y missi n g start dates will be 
c o nsi dere d tr eat me nt -e m er ge nt. If o nl y t he da y is missi n g, a n d t he start m o nt h a n d year of t he 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 3  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
A E is bef ore t he st art m o nt h a n d year of t h e first a d mi nistrati o n of st u d y dr u g, t he A E will be 
c o nsi dere d n o n- tr eat me nt-e mer g e nt. If da y a n d m o nt h are missi n g a n d t he start year of t he A E 
is  bef ore  t he  y ear  of  t he  first  a d mi nistrati o n  of  st u d y  dr u g,  t he A E  will  be  c o nsi dere d  n o n-
treat me nt-e mer ge nt.  
S u m maries  of  T E A Es  will  c o u nt  t he  n u m ber  of  s u bjects,  t hat  is,  s u bjects  wit h  m ulti ple 
occ urr e nces of t he sa me T E A E will be c o u nte d o nce i n t he t otal of t h ose e x perie nci n g t his P T.  
Si milarl y, a s u bject wit h 1 or m ore P T i n a S O C will be c o u nte d o nce i n t he t otal  of t h ose 
e x perie n ci n g P Ts i n t hat S O C.  
I njecti o n site  reacti o ns  (I S Rs) will  be  s u m marize d  b y  S O C  a n d  P T  f or mi n g  a  virt ual  S O C 
“I njecti o n Site Reacti o ns”.  To d eci de w hic h P Ts will be c o nsi dere d I S Rs , C S L will be pr o vi de d 
a list i n E xcel f or mat of  all P Ts f o u n d i n t he data base. C S L will re vie w t his list a n d mar k t he 
P Ts c o nsi dere d I S Rs i n  a c ol u m n of t his E xcel s h eet. T he P Ts s u m mari ze d as I S Rs will als o be 
re p orte d i n t heir ori gi nal Me d D R A S O C. F or t he “ A n y T E A E” e ntr y,  t he I S R will be re p orte d 
o nce; t he y will  n ot be c o u nte d i n b ot h t heir ori gi nal a n d virt ual S O C. I S Rs will be prese nte d as 
first “ S O C” f oll o wi n g t he “ A n y T E A E ” e ntr y. T h e Me d D R A S O Cs a n d P Ts will be prese nte d 
i n desce n di n g fr e q ue nc y of t he o verall C S L 3 1 2 cate g or y. Wit hi n t he sa m e fre q ue n c y, S O Cs 
a n d P Ts will be or dere d al p ha beticall y.  
O ver vie w s u m mar ies of T E A Es will be pr o vi de d b y treat me nt ar m a n d t otal s u m marizi n g:  
•  A n y T E A Es;  
o  T E A Es relate d t o st u d y dr u g; 
o  T E A Es lea di n g t o st u d y disc o nti n uati o n; 
o  T E A E te m p orall y rel ate d ( o nset wit hi n 2 4 h after start  of st u d y dr u g 
a d mi nistrati o n ); 
o  T E A Es b y se verit y ( Mil d, M o derate, Se v ere); 
o  T E A Es b y o utc o me ( D eat h, N ot Rec o vere d or  N ot Res ol ve d, Rec o vere d or 
Res ol ve d, Re c o ver e d or Res ol ve d wit h Se q uelae, Rec o veri n g or Res ol vi n g, 
U n k n o w n); 
o  T E A E i de ntifie d as I nj ecti o n Site Reacti o n (I S R);  
 I S Rs relate d t o st u d y dr u g; 
 I S Rs b y se verit y; 
•  A n y Seri o us T E A Es ( S A Es);  
o  S A Es relate d t o st u d y dr u g; 
o  S A Es lea di n g t o st u d y disc o nti n uati o n; 
o  S A E te m p orall y relate d;  
o  S A Es b y se verit y ( Mil d, M o derate, Se v ere); 
o  S A Es b y o utc o me ( Deat h, N ot Rec o vere d or N ot Res ol ve d, Rec o vere d or 
Res ol ve d, Rec o ver e d or Res ol ve d wit h Se q uelae, Rec o veri n g or Res ol vi n g, 
U n k n o w n). 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 4  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
T he f oll o wi n g s u m mar y ta bles will be pr o vi de d: 
•  All T E A Es b y S O C a n d P T, 
•  All T E A Es lea di n g t o st u d y disc o nti n uati o n b y S O C a n d P T, 
•  All T E A Es b y se verit y a n d b y S O C a n d P T, 
•  All T E A Es relate d t o st u d y dr u g b y S O C a n d P T, 
•  All A E SI b y S O C a n d P T, 
•  All I S Rs b y S O C a n d P T, 
•  All S A Es b y S O C a n d P T, 
•  All N o n -seri o us T E A Es b y S O C a n d P T, 
•  La b orat or y Fi n di n gs re p orte d as A Es, 
•  All A Es ca us e d b y C O VI D - 1 9 (see Secti o n 7. 1 ), 
•  T E A Es occ urri n g  7 da ys of C O VI D-1 9 v acci n e a d mi nistrat i o n (see Secti o n 7. 1 ), 
•  All  T E A E S  e xcl u di n g  T E A Es  occ urri n g  wit hi n  7  da ys  of  C O VI D -1 9  vacci ne 
a d mi nistrati o n . 
 
S u m maries will i ncl u de t he n u m ber a n d p erce nta g e of s u bjects, t he n u m ber of T E A Es, a n d 
t he n u m ber of T E A Es p er i njecti o n a n d per s u bject year ( w h ere a p plica ble) deri ve d as:  
 
T E A E rate p er S C I njecti o n  ( A E RI) = 
N u m b e r  of  E v e nt s  f o r p a rti c ul a r  S O C
P T
⁄
 
N u m b e r  of  S C  I nj e cti o n s
; 
a n d T E A E r ate per  S u bject S C Year ( A E R S) = 
N u m b e r  of  E v e nt s  f o r p a rti c ul a r  S O C
P T
⁄
 
S u bj e ct  S C  y e a r s
. 
w here s u bject S C years will be t he s u m of t he ti me i n years t hat s u bjects were e x p ose d t o 
st u d y dr u g a d mi nistere d b y S C i njecti o ns deri ve d as:  
[ date of St u d y C o m pleti o n  or date of st u d y disc o nti n uati o n [ w hate ver is first] – t he date of 
St u d y Visits Da y 1 wit hi n Treat me nt Peri o d + 1] / 3 6 5. 2 5. 
All A Es (treat me nt -e mer ge nt a n d n o n treat me nt -e mer ge nt) will be liste d i ncl u di n g Me d D R A 
S O C, P T a n d ver bati m, A E start a n d e n d date:ti me, d urati o n of A Es i n da ys, i nte nsit y, seri o us 
stat us, relati o ns hi p t o st u d y dr u g, o utc o me, acti o n ta ke n, a n d A E fla gs ( TE A E S, S A E, A E SI, 
cli nicall y si g nifica nt la b orat or y fi n di n g, te m p oral relati o ns hi p).  
T he f oll o wi n g listi n gs will be pr o vi de d:  
•  All N o n -T E A Es,  
•  All T E A Es,  
•  All T E A Es lea di n g t o st u d y disc o nti n uati o n, 
•  All T E A Es relate d t o la b orat or y fi n di n gs, 
•  All T E A Es ca use d b y C O VI D - 1 9, 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 5  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
•  All S A Es , 
•  All S A Es wit h fatal o utc o me , 
•  All T E A Es occ urri n g wit hi n 7 da ys of C O VI D- 1 9 vacci ne a d mi nistrati o n . 
1 1. 3  
Cli nic al L a b or at or y E v al u ati o ns  
La b orat or y tests will be s u m marize d des cri pti vel y b y sc he d ule d visit a n d treat me nt ar m. F or 
la borat or y tests wit h c o nti n u o us val ues, descri pti v e statistics f or t he meas ure d val ues a n d f or 
c ha n ge fr o m baseli ne will be prese nte d. Defi niti o n of t he baseli ne assess me nt ca n be f o u n d i n 
Secti o n 8. 2. 3 . La b orat or y tests wit h cate g orical v al ues will be s u m marize d b y n u m ber a n d 
perce nt a ge of s u bjects i n t he res pecti ve cate g ories ( base d o n s u bjects of t he Safet y A n al ysis 
Set wit h n o n- missi n g val ues at t his St u d y Visit ). S u m mar y ta bles will be pr o vi de d f or 
he mat ol o g y, bi oc he mistr y, c oa g ulati o n, a n d i m m u n o ge nicit y ( bi n di n g a nti b o dies: i n hi bit or y 
a n d n o n-i n hi bit or y; s pecific t o F XIIa i n hi bit or m o n ocl o nal a nti b o d y, a nti- C S L 3 1 2) a n d 
uri nal ysis. All la b orat or y test  res ults (sc he d ule d a n d u nsc he d ule d) will be liste d. 
T he listi n gs will i ncl u de test na me a n d u nit al o n g wit h n or mal ra n ge, t he s a m pli n g date a n d 
ti me, t he test res ult, a n assess me nt w het her t he res ult is hi g h (a b o ve n ormal ra n ge) or l o w 
( bel o w n or mal r a n ge). A n y c o m me nts t o t he la b orat or y test will be pr o vi de d i n a se parate 
listi n g, if a p plica ble. 
A b y -s u bject listi n g f or la b orat or y a b n or malities will be pr o vi de d i n t he sa me f or mat as t he 
la b orat or y listi n gs descri be d a b o ve b ut o nl y c o ntai ni n g i nf or mati o n a b o ut a b n or mal 
la b orat or y r es ults. 
T he la b orat or y t ests will be prese nt e d i n t he f oll o wi n g gr o u pi n g a n d se q ue nce as s pecifie d i n 
Ta ble 4 of t he C S P. T he test na mes use d i n t he T F L o ut p uts ma y differ d e p e n di n g o n t he 
ter mi n ol o g y use d b y t he ce ntral la b orat or y. T he test na mes a n d u nits as pr o vi de d i n t he 
la b orat or y dat a tra nsf er will be use d. 
T he n u m ber a n d perce nta ge of s u bjects wit h cli ni call y si g nifica nt la b orat or y fi n di n gs relat e d 
t o a n T E A E will be s u m marize d b y l a b orat or y test. T h ose will be i de ntifie d t hr o u g h t he e C R F 
f or m ‘Cli nical Si g nifica nt Safet y La b Data .’ Perce nta ges will be base d o n s u bjects i n t he Safet y 
A nal ysis Set wit h n o n- missi n g val ues at eac h St u d y Visit .  
 
1 1. 4  
Ot her S afet y Me as ures  
1 1. 4. 1  
Vit al Si g ns  
S yst olic a n d  diast olic bl o o d press ure, res pirat or y rate, p ulse rate, te m perat ure, hei g ht, a n d b o d y 
wei g ht will be c ollecte d as vital si g ns.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 6  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Vital Si g ns will be prese nte d i n sta n dar d u nits a n d i n al p ha betical or d er. S u m maries t o be 
pr o d uce d will be:  
•  descri pti ve statistics f or vital si g ns at eac h sc he d ule d visit a n d c ha n ge fr o m baseli ne 
( visit val ue – baseli ne val ue) . 
 
Listi n gs t o be pr o d uce d are: 
•  vital si g ns res ults a n d c ha n ge fr o m b aseli ne b y n o mi nal visit, visit date a n d ti me. 
1 1. 4. 2  
E C G  
All E C G fi n di n gs w ill be s u m marize d b y treat me nt ar m a n d liste d b y s u bject i ncl u di n g 
n o mi nal visits, assess me nt date a n d ti me, cli nicall y si g nifica nt a n d a b n or m al stat us ( Yes, N o) 
a n d relate d A E  I D. 
1 1. 4. 3  
P h ysic al E x a mi n ati o n  
Date a n d ti me of p erf or me d p h ysical e xa mi nati o ns will be liste d o nl y.  
1 2  
P h ar m ac o ki netic A n al yses  
Plas ma sa m ples f or C S L 3 1 2 c o nce ntrati o ns will be c ollecte d d uri n g Treat me nt Peri o d at t he 
f oll o wi n g st u d y visits: Da y 1, Da y 3 1, D a y 6 1, Da y 9 1, Da y 1 2 1, Da y 1 5 1, Da y 1 8 2 a n d D a y 
2 4 2 (if a p plica ble ).  
All a nal yses i n t his secti o n will be base d o n t he P K A nal ysis Set  a n d will b e o nl y c o n d ucte d 
f or s u bjects treate d wit h C S L 3 1 2. 
1 2. 1  
Dr u g C o nce ntr ati o n Me as ures  
T he s u m maries will be gi ve n b y n o mi nal ti me p oi nts ( pla n ne d ti me p oi nts) wit h descri pti ve 
statistics: mea n, S D, perce nt c oefficie nt of v ariati o n, me dia n, mi ni m u m, ma xi m u m, a n d first 
a n d t hir d q uartiles f or c o nti n u o us varia bles, ge o m etric mea n a n d its res pecti ve 9 0 % CI. 
 
T he ge o metric c oefficie nt of variati o n will be e x presse d as a perce nta ge a n d will be calc ulate d 
as  1 0 0 *s qrt(e x p( S D l o g2)- 1). T he  ge o metric  mea n  a n d  its  9 0 %  CI  will  b e  calc ul ate d  b y  l o g -
tra nsf or mi n g t he data, cal c ulati n g t he mea n a n d t he l o wer a n d u p per li mits of t he 9 0 % Wal d CI 
of t he l o g -tr a nsf or me d d ata, a n d s u bse q ue ntl y b ac k tra nsf or mi n g t he mea n a n d t he l o wer a n d 
u p per li mits.  
T he s u m maries f or C S L 3 1 2 c o nce ntrati o ns will be als o stratifie d acc or di n g t o t he f oll o wi n g: 
•  A ge (a d oles ce nt [ 1 2 t o ≤ 1 7 years] a n d a d ult [ > 1 7 years] s u bjects), 
•  Re gi o n (Ja pa n es e a n d n o n-Ja pa nes e s u bjects). 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 7  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Bel o w l o wer Li mit of Q ua ntificati o n ( B L Q)  of C S L 3 1 2 plas ma c o nce ntrati o ns  will be ha n dle d 
as f oll o ws: 
•  pre - d ose B L Q res ults ( pri or first st u d y dr u g a d mi nistrati o n) will be treate d as zer o;  
•  all ot her p ost-d ose B L Q r es ults will be set t o missi n g.  
If i n  t otal m ore  t ha n  5 0 %  of  t he  val ues  at a  n o mi nal ti me  p oi nt  are  i m p ute d  (i.e.,  B L Q) or 
missi n g, t he n t he s u m mar y statistics will n ot be dis pla ye d.   
Mea n ( ± S D)  C S L 3 1 2 c o nce ntrati o ns vers us n o mi nal ti me p oi nt will be pl otte d o n li near a n d 
se mi-l o garit hmic scales.  
All  c o nce ntrati o ns r es ults will be liste d b y s u bject , i ncl u di n g act ual sa m pli n g date a n d ti me, 
n o mi nal ti me p oi nt a n d  act ual ti me fr o m e n d of pre vi o us i njecti o n. B L Q res ults will be liste d 
as “ B L Q”.  
1 3  
P h ar m ac o d y n a mic a n d Bi o m ar kers A n al yses  
All a nal yses i n t his secti o n will be base d o n P D A n al ysis  Set.  
1 3. 1  
P h ar m ac o d y n a mic A n al yses  
Sa m ples f or F XII c o n ce ntrati o ns a n d F XIIa -me diate d kalli krei n acti vit y will be c ollecte d 
d uri n g Treat me nt Peri o d at t he f oll o wi n g st u d y visits: Da y 1, Da y 3 1, Da y 6 1, Da y 9 1, Da y 
1 2 1, Da y 1 5 1, Da y 1 8 2 a n d Da y 2 4 2 (if a p plica ble).  
T he s u m maries will be gi ve n b y n o mi nal ti me p oi nts ( pla n ne d ti me p oi nts) a n d b y treat me nt 
ar m wit h descri pti ve statistics: mea n, S D, perce nt c oefficie nt o f variati o n, me dia n, mi ni m u m, 
ma xi m u m,  a n d  first  a n d  t hir d  q uartiles  f or  c o nti n u o us  varia bles,  ge o metric  mea n  a n d  its 
res pecti ve  9 0 %  CI. All  P D  c o nce ntrati o n  res ults  will  be  liste d  b y  s u bject,  i ncl u di n g  act ual 
sa m pli n g date a n d ti me, n o mi nal ti me p oi nt a n d  act ual ti me fr o m e n d of pre vi o us i njecti o n. 
Mea n ( ± S D) c o n ce ntr ati o n/acti vit y -ti me pr ofiles will be pl otte d usi n g n o mi nal ( pla n ne d) 
ti me. F XIIa-me diate d k alli krei n acti vit y % of Baseli ne val ues will als o be pr o vi de d i n t he 
listi n gs, s u m maries, a n d fi g ures.  
B L Q res ults will n ot be c o nsi dere d f or s u m maries a n d will be liste d o nl y.  
1 3. 2  
Bi o m ar ker A n al yses  
Sa m ples c ollecte d d uri n g Treat me nt Peri o d at t he f oll o wi n g st u d y visits: Da y 1, Da y 3 1, Da y 
6 1, Da y 9 1, Da y 1 2 1, D a y 1 5 1, Da y 1 8 2 a n d D a y 2 4 2 (if a p plica ble) will be st ore d f or 
p ote ntial testi n g of H A E bi o mar kers a n d will be destr o ye d wit hi n 5 years after c o m pleti o n of 
t he st u d y.  


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 8  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
Bi o mar ker a nal ys es will be descri b e d wit hi n a Bi o mar ker A nal ysis Pla n a n d re p orte d 
se parat el y. 
1 4  
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses  
P K / P D m o delli n g will be e x pl ore d, as feasi ble, f or f urt her ti me -d e pe n d e nt c haracteri zati o n 
of P K vers us P D e n d p oi nts a n d / or safet y / efficac y e n d p oi nts a n d re p orte d se parat el y.  
A d diti o nal i nf or mati o n o n P K / P D a nal yses will be pr o vi de d se p aratel y i n t he M o deli n g a n d 
Si m ulati o n A nal ysis Pla n.  
 
 


C S L Be hri n g L L C  
St u d y N u m ber:  C S L 3 1 2 _ 3 0 0 1  
 
St u d y Pr o d uct:   C S L 3 1 2  
 
S A P versi o n:  1. 0  
 
Pa ge 5 9  of 5 9  
Date:  2 1 A P R  2 0 2 1 
C o nfi de ntial  
  
 
 
 
  
 
 
1 5  
Refere nces  
Mi nistr y of Healt h, La b o ur, a n d Welfare. Basic pri nci ples o n Gl o bal Cli nical Trials. 
htt ps:// w w w. p m da. g o.j p/files/ 0 0 0 1 5 7 0 0 0. p df  ( T he ori gi nal d oc u me nt i n Ja p a nese) 
htt ps:// w w w. p m da. g o.j p/files/ 0 0 0 1 5 3 2 6 5. p df  ( T he E n glis h tra nslati o n b y P M D A) 
[ P u blis he d o nli ne Se pte m ber 2 8, 2 0 0 7]. 
Ba nerji A, Rie dl M A, Ber nstei n J A, et al. Effect of La na d el u ma b C o m pare d Wit h Place b o o n 
Pre ve nti o n of Here ditar y A n gi oe de ma Attac ks : A Ra n d o mize d Cli nical  Trial . 
J A M A.2 0 1 8; 3 2 0( 2 0): 2 1 0 8 – 2 1 2 1. d oi: 1 0. 1 0 0 1/ja ma. 2 0 1 8. 1 6 7 7 3. 
Be ye ne, J., M oi ne d di n, R. Met h o ds f or c o nfi d e nce i nter val esti mati o n of a rati o para meter 
wit h a p plicati o n t o l ocati o n q u otie nts. B M C Me d Res Met h o d ol 5, 3 2 ( 2 0 0 5). 
htt ps:// d oi. or g/ 1 0. 1 1 8 6/ 1 4 7 1- 2 2 8 8- 5- 3 2. 
Mac Gi n nitie AJ. Pe diatri c her e ditar y a n gi oe de ma. Pe diatric Aller g y a n d I m m u n ol o g y 2 0 1 4: 
2 5: 4 2 0 – 4 2 7. 
Ge offre y  R  N or ma n,  J eff  A  Sl oa n  &  Kat hlee n  W  Wyr wic h  ( 2 0 0 4)  T he  tr ul y  re mar ka ble 
u ni versalit y of half a sta n dar d de vi ati o n: c o nfir mati o n t hr o u g h a n ot her l o o k, E x pert Re vie w of 
P har mac oec o n o mics & O utc o mes Researc h, 4: 5, 5 8 1- 5 8 5, D OI: 1 0. 1 5 8 6/ 1 4 7 3 7 1 6 7. 4. 5. 5 8 1 
O’ Brie n, R. G. a n d Castell oe, J. M. ( 2 0 0 6), Pr o cee di n gs of t he T hirt y -first A n n ual S A S Users 
Gr o u p I nter nati o nal C o nf ere nce, Pa p er 2 0 9 - 3 1. Car y, N C: S A S I nstit ute I nc;. E x pl oiti n g t he 
Li n k  bet wee n  t he Wilc o x o n – Ma n n – W hit ne y Test  a n d  a  Si m ple  O d ds  Statistic.  3 1st A n n ual 
S A S Users Gr o u p I nter nati o nal C o nfere nce. Lect ure c o n d ucte d fr o m, Car y, N C. Availa ble. 
Price, R o bert & B o nett, D o u glas. ( 2 0 0 2). Price R M, B o nett D G.. Distri b uti o n- free c o nfi de nce 
i nter vals  f or  diff ere n ce  a n d  rati o  of  me dia ns.  J  Stat  C o m p ut  Si m ul  7 2:  1 1 9-1 2 4.  J o ur nal  of 
Statistical C o m p utati o n a n d Si m ulati o n. 7 2. 1 1 9 - 1 2 4. 1 0. 1 0 8 0/ 0 0 9 4 9 6 5 0 2 1 2 1 4 0. 
Reill y  M C,  Z br oze k  A S,  D u kes  E M  ( 1 9 9 3).  T he  vali dit y  a n d  re pr o d u ci bilit y  of  a  w or k 
pr o d ucti vit y a n d acti vit y i m pair me nt i nstr u me nt. P h ar m ac oec o n o mics 4: 3 5 3- 3 6 5. 
va n H o ut B, Ja nsse n M F, Fe n g Y S, K o hl ma n n T, B ussc h bac h J, G olic ki D, Ll o y d A, Scal o ne 
L, Ki n d P, Pic kar d A S. I nteri m sc ori n g f or t he E Q- 5 D- 5 L: ma p pi n g t he E Q- 5 D- 5 L t o E Q- 5 D -
3 L val ue sets. Val ue Healt h. 2 0 1 2 J ul- A u g; 1 5( 5): 7 0 8- 1 5. d oi: 1 0. 1 0 1 6/j.j val. 2 0 1 2. 0 2. 0 0 8. 
E p u b 2 0 1 2 Ma y 2 4. P MI D: 2 2 8 6 7 7 8 0.  
Weller K, Ma gerl M, Pe veli n g - O ber h a g A, Mart us P, Sta u bac h P, Ma urer M. T he A n gi oe de ma 
Q ualit y of Life Q u esti o n naire ( A E -Q o L) - ass ess me nt of se nsiti vit y t o c ha n ge a n d mi ni mal 
cli nicall y i m p orta nt differe nce. Aller g y. 2 0 1 6 A u g; 7 1( 8): 1 2 0 3- 9. d oi: 1 0. 1 1 1 1/all. 1 2 9 0 0. E p u b 
2 0 1 6 J u n 1 3. P MI D: 2 7 0 3 8 1 0 9. 


V er si o n: 1. 0
Si g n at ur e P a g e 1  of 1
--- D o N ot D et a c h T hi s Si g n at ur e P a g e ---
gl b d ct m p
Pri nt D at e: 2 8- J ul- 2 0 2 2 1 2: 1 3: 3 6 G M T- 0 4: 0 0
Si g n at ur e P a g e
C S L 3 1 2 _ 3 0 0 1 - St ati sti c al A n al y si s Pl a n - V 1. 0 - 2 1 A pr 2 0 2 1
Si g n e d B y
D at e ( G M T)
A p pr o v e d-
 A p pr o v al
2 2- A pr- 2 0 2 1 0 8: 2 0: 4 1
A p pr o v e d- Cli ni c al D e v el o p m e nt P h y si ci a n A p pr o v al
2 2- A pr- 2 0 2 1 1 0: 5 7: 2 8
P P D
P P D
P P D