A Multicenter, RandomiZed, Active-ControLled Study to Evaluate the Safety and Tolerability of Two Blinded Doses of Abelacimab (MAA868) Compared With Open-Label Rivaroxaban in Patients With Atrial Fibrillation (AZALEA)
Phase: PHASE2
Conditions: Atrial Fibrillation (AF), Stroke
Sponsor: Anthos Therapeutics, Inc.

D oc u me nt T y pe:   
Fi nal Pr ot oc ol  
D oc u me nt Date:    
1 8 A pril 2 0 2 3 
St u d y Title:    
A M ultice nter, Ra n d o mi Ze d, Acti ve- C o ntr o Lle d St u d y t o E val uate t he 
Safet y a n d T olera bilit y of T w o Bli n de d D oses of A belaci ma b 
( M A A 8 6 8) C o m pare d wit h O pe n- La bel Ri var o xa ba n i n Patie nts wit h 
Atrial Fi brillati o n ( A Z A L E A)  
Pr ot oc ol Refere nce N u m ber: A N T - 0 0 6 
N C T N u m ber:   
N C T 0 4 7 5 5 2 8 3  
 
 

A nt h os  T hera pe utics  
Pa ge 1  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
 
A N T H O S  T H E R A P E U TI C S,  I N C. 
 
A belaci ma b  ( M A A 8 6 8) 
 
Cli ni cal  Tri al  Pr ot oc ol  A N T -0 0 6  
 
A  M ultice nte r, R a n d o mi Z e d, A cti ve-C o ntr o L le d St u d y t o 
E v al u ate t he S afet y a n d T oler a bilit y of T w o Bli n de d D oses of 
A bel aci m a b  ( M A A 8 6 8) C o m p are d  wit h  O pe n -L a bel  Ri v ar o x a b a n 
i n P atie nts wit h Atri al Fi brill ati o n ( A Z A L E A) 
 
 
 
 
D oc u me nt  t y pe: 
Pr ot oc ol  
I N D n u m ber  
 
E U D R A C T  n u m ber:  
2 0 2 0 -0 0 4 5 0 7 -1 3  
Versi o n  n u m ber:  
 
Cli nic al  Trial  P hase:  
II b 
Release  date:  
1 8 -A pr -2 0 2 3  
S p o ns or:  
A nt h os  T hera pe utics  
5 5  Ca m bri d ge  P k w y,  Ste.  1 0 3  
Ca m bri d ge,  M A  0 2 1 4 2  
 
 
 
 
 
 
 
 
Pr o pert y of A nt h os T hera pe utics  
C o nfi de ntial  
M a y n ot be us e d, di v ul ge d, p u blis he d or ot her wis e discl os e d  
wit h o ut t he c o ns e nt of A nt h os T hera pe utics  

Pa ge 2  
A nt h os  T hera pe utics 
P hase  2 Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
P RI N CI P A L  I N V E S TI G A T O R SI G N A T U R E  P A G E  
Pr ot oc ol N u m ber:  
A N T -0 0 6  
Pr ot oc ol Title:  A M ultice nter,  Ra n d o mize d, A cti ve - C o ntr olle d St u d y t o E val uate  t he 
Safet y a n d T oler a bilit y of T w o Bli n de d D oses of A belaci ma b ( M A A 8 6 8) C o m pare d 
wit h O pe n -La b el Ri var o xa ba n i n Patie nts wit h Atrial Fi brillati o n  
Pri nci p al  I n vesti g at or’s St a te m e nt a n d Si g n at ure:  
I, t he u n d ersi g ne d, h a ve r ea d pr ot oc ol A N T- 0 0 6 (i ncl u di n g all a p pe n dices). I a gree t o 
c o n d uct t he cli nical st u d y as descri be d  a n d i n c o m plia nce wit h  I nt er nati o nal C o nfere nce  o n 
Har m o nisati o n (I C H) G ui deli nes f or G o o d Cli nical Practice ( G C P) a n d a p plica ble 
re g ulat or y r e q uire me nts. I a gree t o i nf or m all w h o assist me i n t he c o n d uct of t his st u d y of  
t heir res p o nsi bilities a n d o bli gati o ns.  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g n at ure of Pri nci p al I n vesti g at or  
D ate  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
N a me of Pri nci p al I n vesti g at or ( pri nte d)  
I n vesti g ati ve Site N a me, A d dress a n d Tele p h o ne N u mber:  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
D o c u Si g n E n v el o p e I D: 5 A 4 A 2 0 F 2- 8 C 4 D- 4 C 1 5- 8 3 9 8- 1 2 5 7 C A F D 5 7 4 B

A nt h os  T hera pe utics  
Pa ge 3  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
N otific ati o n  of  se ri o us a d vers e  e ve nts 
Dear  I n vesti gat or, 
Y o u  m ust  re p ort a seri o us a d verse e v e nt ( S A E) (i nitial or  f oll o w-u p)  t o
 as  s u m m ariz e d 
bel o w. Refer t o Se cti o n 8. 4  of t he pr ot oc ol f or S A E crit eria a n d a d diti o nal re q uire me nts. 
F urt her d etails o n t he met h o d of re p orti n g a S A E will be pr o vi de d t o sites.  
• C o m plet e  S A E  re p ort 
• S u b mit S A E re p ort t o 
) wit hi n 2 4 h o urs 
after a ware n ess of t he S A E  
 
 

A nt h os  T hera pe utics  
Pa ge 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
T a ble of C o nte nts  
 
N otificati o n  of  seri o us a d v erse e ve nts ................................................................................... 3  
Ta ble of C o nte nts ........................................................................................................................ 4  
List of a b bre viati o ns  .............................................................................................................. 8  
P har mac o ki n eti c defi niti o ns a n d s y m b ols  ........................................................................... 1 1  
Gl ossar y  of  ter ms ................................................................................................................. 1 2  
: ................................................................................................................. 1 3  
Pr ot oc ol  s y n o psis ................................................................................................................. 1 4  
1  I ntr o d ucti o n .......................................................................................................................... 1 7  
1. 1  
Bac k gr o u n d  ....................................................................................................... 1 7  
1. 2  
A belaci ma b ( M A A 8 6 8)  .................................................................................... 1 9  
1. 3  
St u d y p ur p ose  ................................................................................................... 2 3  
2  St u d y o bjecti ves a n d e n d p oi nts  ........................................................................................... 2 3  
2. 1  
Pri mar y  o bjecti ve  .............................................................................................. 2 3  
2. 2  
Sec o n dar y o bje cti v e(s)  ...................................................................................... 2 3  
2. 3  
E x pl orat or y o bjecti ve(s)  ................................................................................... 2 3  
3  I n vesti gati o nal Pl a n ............................................................................................................. 2 4  
3. 1  
St u d y desi g n  ...................................................................................................... 2 4  
3. 2  
Rati o nale f or st u d y desi g n  ................................................................................ 2 8  
3. 3  
Rati o nale f or d os e/r e gi me n  ............................................................................... 2 8  
3. 4  
Rati o nale  f or c h oic e of  c o m parat or ................................................................... 2 9  
3. 5  
Rati o nale f or E xte nsi o n Peri o d  ......................................................................... 2 9  
4  P o p ulati o n  ............................................................................................................................ 3 0  
4. 1  
I ncl usi o n criteri a ............................................................................................... 3 0  
4. 2  
E xcl usi o n criteria  .............................................................................................. 3 0  
4. 3  
E xte nsi o n peri o d i ncl usi o n criteria  ................................................................... 3 1  
4. 4  
E xte nsi o n peri o d e xcl usi o n criteria  ................................................................... 3 1  

A nt h os  T hera pe utics  
Pa ge 5  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
5  Pr oce d ures a n d assess me nts  ................................................................................................ 3 2  
5. 1  
I nf or me d c o nse nt pr o ce d ures ............................................................................ 3 2  
5. 2  
Patie nt scr ee ni n g  ............................................................................................... 3 3  
5. 3  
Baseli ne Saf et y  ................................................................................................. 3 4  
5. 4  
Cli nic al E n d p oi nts ............................................................................................. 3 5  
5. 5  
Ot her assess me nts  ............................................................................................. 3 6  
5. 6  
 ................................................................... 3 8  
6  Treat me nt  ............................................................................................................................. 3 8  
6. 1  
St u d y treat me nt  ................................................................................................. 3 8  
6. 2  
Treat me nt assi g n me nt a n d ra n d o mi zati o n  ........................................................ 3 8  
6. 3  
Treat me nt bli n di n g  ............................................................................................ 3 9  
6. 4  
Treati n g t he p ati e nt  ........................................................................................... 3 9  
6. 5  
St u d y treat me nt i nterr u pti o ns ............................................................................ 4 1  

A nt h os  T hera pe utics  
Pa ge 6  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
6. 6  
Per ma ne nt st u d y dr u g disc o nti n u ati o n  .............................................................. 4 2  
6. 7  
C o nc o mit a nt tr eat me nt  ...................................................................................... 4 3  
6. 8  
Ris ks a n d be nefits  ............................................................................................. 4 4  
7  St u d y C o m pleti o n a n d Disc o nti n uati o n  ............................................................................... 4 7  
7. 1  
St u d y c o m pleti o n a n d p ost -st u d y treat me nt...................................................... 4 7  
7. 2  
Disc o nti n uati o n of st u d y tre at m e nt  ................................................................... 4 8  
7. 3  
Wit h dra wal of i nf or m e d c o nse nt  ...................................................................... 4 8  
7. 4  
L ost t o f oll o w -u p  .............................................................................................. 4 9  
7. 5  
Earl y st u d y t er mi n ati o n b y t he S p o ns or  ............................................................ 4 9  
8  Safet y m o nit ori n g  ................................................................................................................ 4 9  
8. 1  
A d verse e ve nts  .................................................................................................. 4 9  
8. 2  
Rec o m m e n de d tr eat me nt of bl ee di n g a d verse e v e nts  ....................................... 5 0  
8. 3  
Rec o m m e n de d tr eat me nt of ot h er a d verse e ve nts  ............................................ 5 0  
8. 4  
Seri o us a d verse e ve nt re p orti n g  ........................................................................ 5 1  
8. 5  
Re p orti n g Me di cati o n err ors i ncl u di n g mis use/a b use  ...................................... 5 3  
8. 6  
Pre g na nc y re p orti n g  .......................................................................................... 5 3  
9  Data re vi e w a n d data b ase ma n a ge m e nt  ............................................................................... 5 4  
9. 1  
Site m o nit ori n g  ................................................................................................. 5 4  
9. 2  
Data c ollecti o n  .................................................................................................. 5 5  
9. 3  
Data base m a na ge m e nt a n d q u alit y c o ntr ol  ....................................................... 5 5  
1 0  Data a nal ysis  ........................................................................................................................ 5 5  
1 0. 1  
A nal ysis sets  ..................................................................................................... 5 6  
1 0. 2  
Patie nt d e m o gra p hics a n d ot h er baseli n e c har act eristi cs  .................................. 5 6  
1 0. 3  
Treat me nts  ........................................................................................................ 5 6  
1 0. 4  
A nal ysis of t he pri m ar y vari a ble(s)  .................................................................. 5 6  
1 0. 5  
A nal ysis of sec o n dar y varia bles ....................................................................... 5 6  

A nt h os  T hera pe utics  
Pa ge 7  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
1 0. 6  
A nal ysis of ot her e x pl or at or y vari a bles  ............................................................ 5 7  
1 0. 7  
Sa m ple siz e calc ulati o n  ..................................................................................... 5 8  
1 0. 8  
A d h oc data re vie ws  .......................................................................................... 5 9  
1 1  Et hic al c o nsi d erati o ns  .......................................................................................................... 5 9  
1 1. 1  
Re g ulat or y a n d et hical c o m plia nc e  ................................................................... 5 9  
1 1. 2  
Res p o nsi bilities of t he i n vesti g at or a n d et hi cs c o m mittee  ................................ 5 9  
1 1. 3  
P u blicati o n of st u d y pr ot oc ol a n d res ults  .......................................................... 5 9  
1 2  Pr ot oc ol a d her e nce  ............................................................................................................... 6 0  
1 2. 1  
Pr ot oc ol A me n d m e nts ....................................................................................... 6 0  
1 3  Refere nc es  ............................................................................................................................ 6 1  
1 4  A p pe n di x 1 –  C o m p o ne nts of t h e C H A 2 D S 2 -V A Sc Sc ore  ................................................ 6 4  
1 5  A p pe n di x 2 –  Ma na ge m e nt of Bl ee di n g  .............................................................................. 6 5  
1 5. 1  
A belaci ma b  ....................................................................................................... 6 5  
1 5. 2  
Ri var o xa ba n  ...................................................................................................... 6 6  
1 6  A p pe n di x 3 –  Assess me nt Sc he d ules  .................................................................................. 6 7  
 
 
 

A nt h os  T hera pe utics  
Pa ge 8  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
List of a b bre vi ati o ns  
A D A  
a nti-dr u g  a nti b o dies 
A D C C  
a nti b o d y-de p e n de nt  cell-me di ate d  c yt ot o xicit y 
A E  
a d verse e ve nt  
A F  
Atrial  Fi brillati o n  
A L T  
ala ni n e a mi n otra nsferase 
A L P  
al kali ne p h os p hatase  
a P T T 
acti v ate d  partial  t hr o m b o plasti n ti me 
A S T  
as partat e a mi n otra nsferase 
A U C  
area u n der  c o nc e ntrati o n  ti m e c ur ve 
B MI  
b o d y mass  i n de x 
B U N  
bl o o d urea nitr o ge n  
C D C  
c o m ple me nt de p e n de nt  c yt ot o xicit y 
C E C  
Cli nic al  E n d p oi nt  C o m mittee  
C F R  
C o de  of  Fe deral Re g ulati o n  
C R N M  
cli ni call y  rele va nt n o n -maj or  
C R O  
C o ntr act Resear c h  Or ga nizati o n  
C S R  
cli ni cal  st u d y re p ort 
C V  
c oefficie nt  of  variati o n  
D M C  
Data  M o nit ori n g  C o m mittee  
D O A C  
direct  oral  a ntic oa g ula nt(s) 
D V T  
dee p vei n  t hr o m b osis 
E C  
Et hics  C o m mittee  
e C R F 
electr o nic case re p ort/r ec or d f or m 
E C G  
electr ocar di o gra m 
E D C  
electr o nic dat a  ca pt ure 
E o E  
E n d of E xte nsi o n Treat me nt  
E o S  
E n d  of  St u d y  
E o T  
E n d  of  Treat me nt  
Fcγ Rs  
Fc  ga m ma  rece pt ors 
FI H  
first-i n-h u ma n  
F F P  
fres h fr oze n plas ma  
F XI  
fact or XI  
F XIa  
acti v ate d  f act or XI  
F XI -A S O  
F XI -a ntise nse oli g o n ucle oti de 
F XI: C  
F XI c oa g ul ati o n acti vit y  

A nt h os  T hera pe utics  
Pa ge 9  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
F XI f 
free fact or XI  
F S H  
f ollicle sti m ul ati n g h or m o ne  
G C P  
G o o d  Cli ni cal  Practice  
G L P  
G o o d  La b orat or y  Practice  
γ-G T  
ga m ma -gl uta m yl  tra nsferase 
HI V  
h u ma n  i m m u n o defici e nc y vir us  
H R  
hazar d  rati o 
I B 
i n vesti gat or’s b r oc h ure 
I C H 
I nter nati o nal C o nf ere nce o n Har m o niz ati o n of Tec h nical R e q uire me nts f or 
Re gistrati o n of P har ma ce uticals f or H u ma n Use  
I C F 
i nf or me d c o nse nt f or m 
I G 
i m m u n o ge nicit y 
I N 
i n vesti gat or n otificati o n  
I R B 
I nstit uti o n al R e vie w  B oar d  
I S R 
i njecti o n site reacti o n 
I S T H 
I nter nati o nal S ociet y  o n  T hr o m b osis  a n d Hae m ostasis  
i. v. 
i ntra ve n o us 
I x R S 
I nteracti ve We b  or  V oice  Res p o nse  S yste m  
K d  
e q uili bri u m diss ociati o n  c o nsta nt 
k g  
kil o gra m(s)  
L L O Q  
l o wer li mit of  q ua ntificati o n  
L M W H  
l o w m olec ul ar  wei g ht  he pari n  
m A bs  
m o n ocl o nal  a nti b o dies 
M C V  
mea n  c or p usc ul ar  v ol u me  
M C H  
mea n  c or p usc ul ar  he m o gl o bi n  
M C H C  
 mea n  c or p usc ular he m o gl o bi n c o nc e ntrati o n 
Me d D R A  
Me dical  Dicti o nar y  f or R e g ulat or y  Acti vities 
m g  
milli gra m(s)  
MI  
m y ocar di al  i nfarcti o ns 
m L  
milliliter(s)  
N O A E L  
n o  o bser ve d  a d verse effect  l e vel 
O T C  
o ver t he c o u nter  
P C C  
pr ot hr o m bi n  c o m ple x  c o nce ntrate 
P D  
p har mac o d y na mic(s)  
P K  
p har mac o ki netic(s)  
p. o.  
b y m o ut h;  orall y  
P T  
pr ot hr o m bi n  ti me 

A nt h os  T hera pe utics  
Pa ge 1 0  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
P R O  
patie nt -re p ort e d o utc o me(s)  
P S D D  
per ma ne nt  st u d y dr u g disc o nti n uati o n  
 
 
Q o L  
Q ualit y  of  Life  
R B C  
re d bl o o d cell(s) 
R D W  
re d cell distri b uti o n  wi dt h  
r F VIIa 
rec o m bi n a nt acti vat e d  fact or VII  
S A E  
seri o us a d verse e ve nt 
s.c. 
s u bc uta ne o us 
s Cr 
ser u m creati ni ne 
S o C  
sta n dar d of  care 
S S C  
St u d y  Steeri n g  C o m mittee  
S U S A R  
 s us pecte d u ne x pe cte d  seri o us a d verse  rea cti o ns 
T A FI  
t hr o m bi n a cti v a ble fi bri n ol ysis i n hi bit or 
T B L  
t otal bilir u bi n  
TI A  
tra nsie nt isc he mic attac k  
TI MI  
T he  T hr o m b osis  I n M y ocar dial  I nfar cti o n ( TI MI) St u d y  Gr o u p 
T G A  
t hr o m bi n ge nerati o n assa y  
T K A  
t otal k ne e art hr o plast y 
T X A  
tra ne xa mic aci d 
U L N  
u p per  li mit of  n or mal  
V K A  
vita mi n  K  a nta g o nists 
V T E  
ve n o us t hr o m b oe m b olis m 
W B C  
w hite  bl o o d  cell(s) 
W O C B P  
w o me n  of  c hil d-beari n g  p ote ntial  
 

A nt h os  T hera pe utics  
Pa ge 1 1  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  v
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
P h ar m ac o ki netic  defi niti o ns  a n d  s y m b ols 
A U C 0 -t 
T he are a u n der t he plas ma c o nce ntrati o n -ti me c ur v e fr o m ti m e zer o t o ti me 
‘t’ w here  t is a defi n e d  ti me p oi nt  after  a d mi nistr ati o n  [ mass x  ti me / v ol u me]  
A U C i nf 
T he  area u n der  t he pl as ma  c o n ce ntr ati o n -ti m e c ur ve fr o m ti me zer o t o i nfi nit y 
[ mass x ti me / v ol u m e]  
A U C last 
T he are a u n der t he plas ma c o nce ntrati o n -ti me c ur v e fr o m ti m e zer o t o t he 
ti me of t he l ast q ua ntifia ble c o nc e ntrati o n [ m ass x ti me / v ol u me] 
C 0  
T he  i nitial c o nc e ntrati o n  at  t he e n d of  a n i ntra v e n o us i nf usi o n 
C L  
T he s yste mi c cl eara nc e f oll o wi n g i ntra v e n o us a d mi nistrati o n  
C ma x  
T he o bser ve d m a xi m u m plas m a c o nce ntrati o n f oll o wi n g s u bc uta ne o us dr u g 
a d mi nistr ati o n [ mass / v ol u m e]  
F  
Bi oa vaila bilit y  
T 1/ 2  
T he  ter mi nal eli mi nati o n  half -lif e [ti me] 
T ma x  
T he  ti me t o r eac h t he ma xi m u m  c o nce ntrati o n  aft er  dr u g  a d mi nistrati o n 
[ti me] 
Vss  
T he  ste a d y stat e v ol u m e  of  distri b uti o n  f oll o wi n g i ntr a ve n o us a d mi nistrati o n 
 

A nt h os  T hera pe utics  
Pa ge 1 2  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
Gl oss ar y  of  ter ms 
 
Assess me nt  
A  pr oce d ure  use d t o  ge nerate  d ata  re q uire d b y  t h e st u d y 
D osa ge  
D ose  of  t he st u d y treat me nt gi ve n  t o t he patie nt  i n a ti me u nit  
E nr oll me nt  
P oi nt/ti me of pati e nt e ntr y i nt o t he st u d y at w hic h i nf or me d 
c o nse nt m ust be o btai ne d (i.e ., pri or t o starti n g a n y of t he 
pr oce d ures descri be d i n t he pr ot oc ol)  
I n vesti gati o nal dr u g  
T he  st u d y dr u g  w h ose  pr o perties  ar e bei n g  test e d i n t he st u d y; 
t his defi niti o n  is c o nsiste nt wit h  U S  C F R  2 1  Secti o n  3 1 2. 3  a n d 
Directi v e 
2 0 0 1/ 2 0/ E C 
a n d 
is 
s y n o n y m o us 
wit h 
“i n vesti g ati o n al ne w dr u g” or “test s u bsta nc e”  
Scree n  Fail ure  
A  patie nt  w h o  is scree ne d b ut is n ot  tre ate d or  ra n d o mize d 
Patie nt  or  s u bject 
A  trial partici pa nt  
Patie nt  or  S u bject  n u m ber  
A u ni q ue n u m b er assi g ne d t o eac h patie nt u p o n si g ni n g t he 
i nf or me d c o nse nt. T his n u m ber is t he defi niti v e, u ni q ue 
i de ntifier f or t he patie nt a n d s h o ul d be use d t o i de ntif y t he 
patie nt t hr o u g h o ut t he st u d y f or all data c olle cte d, sa m ple 
la bels, etc. 
Ra n d o miz ati o n  n u m ber  
A  u ni q ue  i de ntifier assi g ne d  t o ea c h  ra n d o mize d p atie nt, 
c orres p o n di n g t o a s pe cific treat me nt ar m assi g n me nt  
St u d y  treat me nt 
A n y dr u g a d mi nister e d  t o t he st u d y partici pa nts  as p art of t he 
re q uire d st u d y pr oce d ur es; i n cl u des i n vesti g ati o n al dr u g (s), 
c o ntr ol(s), or n o n -i n vesti gati o nal me dici nal pr o d u ct(s) 
St u d y  treat me nt 
disc o nti n uati o n  
W he n  t he patie nt  per ma ne ntl y  st o ps ta ki n g t he assi g n e d  st u d y 
treat me nt pri or  t o t h e defi ne d  st u d y tre at m e nt c o m pleti o n  date  
St u d y  treat me nt peri o d  
I nter val of  ti me i n t he pla n ne d  c o n d uct of  a st u d y. A  treat m e nt 
peri o d is ass oci ate d 
wit h a p ur p ose (e. g ., s cree ni n g, 
ra n d o miz ati o n, tre at m e nt, f oll o w-u p),  w hic h  a p plies  acr oss  all 
ar ms of a st u d y  
Varia ble  
A meas ure d val ue or assesse d res p o nse t hat is deter mi ne d i n 
s pecific assess me nts a n d use d i n data a n al ysis t o e val uate t he 
dr u g bei n g test e d i n t h e st u d y  
Wit h dra wal  of  c o nse nt 
Wit h dra wal of c o nse nt fr o m t he st u d y is defi ne d as w he n a 
patie nt d oes n ot wa nt t o partici p ate i n t he st u d y a n y l o n ger, 
a n d d oes n ot wa nt a n y f urt her visits or assess me nts, a n d d oes 
n ot  wa nt  a n y  f urt her st u d y r elate d c o nt act,  a n d d oes  n ot  all o w 
a nal ysis of alre a d y o btai n e d bi ol o gic materi al w hic h has n ot 
alrea d y bee n a nal yze d, a n d d o es n ot all o w f urt her use of 
alrea d y o btai n e d bi ol o gic materi al f or f ut ur e resear c h.  
 
 

A nt h os  T hera pe utics  
Pa ge 1 3  
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Pr ot oc ol  N o.  A N T -0 0 6  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A nt h os  T hera pe utics  
Pa ge 1 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
Pr ot oc ol  s y n o psis 
 
Pr ot oc ol  N u m ber  
A N T -0 0 6  
F ull  Title  
A  M ultice nter,  Ra n d o miz e d,  Acti ve -C o ntr oll e d  St u d y  t o E val uate  t he 
Safet y a n d T olera bilit y of T w o Bli n de d D oses of A belaci ma b 
( M A A 8 6 8) C o m pare d  wit h  O pe n -La bel  Ri var o x a ba n  i n Patie nts  wit h 
Atrial Fi brillati o n  
Brief  Title  
Ra n d o miz e d, Acti v e -C o ntr olle d St u d y t o E val uate T w o Bli n de d 
D oses  of  A belaci ma b  ( M A A 8 6 8) C o m pare d  wit h  Ri var o xa ba n  i n 
Patie nts wit h Atrial Fi brill ati o n  
S p o ns or  a n d  Cli nic al 
Tri al P h ase  
A nt h os  T hera pe utics,  I nc. 
P hase  2 b  
I nter ve nti o n T y pe  
Bi ol o gic  
St u d y  T y pe  
I nter ve nti o nal 
P u r p ose  a n d 
R ati o n ale  
T he  p ur p ose  of  t he A N T -0 0 6  st u d y is t o e val uat e t h e blee di n g  pr ofile 
of a bela ci m a b relati ve t o ri var o x a ba n i n p ati e nts wit h Atrial 
Fi brillati o n ( A F) at m o d erat e -t o-hi g h ris k of str o ke  
Pri m ar y  O bjecti ve  
• T o  e val u ate t he effect  of  a belaci ma b  rel ati ve t o ri v ar o xa ba n o n  t h e 
rate of m aj or or cli nic all y r ele v a nt n o n-m aj or ( C R N M) blee di n g 
e ve nts 
Sec o n d ar y 
O bjecti ve(s)  
• T o  e val u ate t he effect  of  a belaci ma b  rel ati ve t o ri v ar o xa ba n o n  t h e 
rate of m aj or bl ee di n g e v e nts 
• T o  e val u ate t he effect  of  a belaci ma b  rel ati ve t o ri v ar o xa ba n o n  t h e 
rate of m aj or or mi n or blee di n g e ve nts 
St u d y  Desi g n  
T his is a n e ve nt -dri ve n, r a n d o miz e d, acti ve -c o ntr olle d, bli n de d 
e n d p oi nt, par all el -gr o u p st u d y t o e val uate t h e effe cts of t w o bli n de d 
d oses  of  a bela ci m a b  rel ati v e t o o p e n -la b el ri var o xa ba n o n  t he r ate of 
maj or or C R N M blee di n g e ve nts i n patie nts wit h A F w h o are at 
m o derat e -t o-hi g h ris k of str o ke.  
Patie nts wit h A F w h o are at m o der ate -t o-hi g h ris k of isc he mi c str o ke 
will be e nr olle d. R a n d o mi zati o n i nt o treat me nt gr o u ps w ill be 
stratifi e d b y t he use of c o nc o mita nt a nti plat elet use at baseli n e 
( yes/ n o) a n d re nal f u ncti o n ( Cr Cl ≤5 0 ml/ mi n or Cr Cl > 5 0 ml/ mi n). 
T he st u d y is c o m prise d of u p t o 4 peri o ds: 1) scree ni n g ( u p t o 4 
wee ks), 2) st u d y  dr u g  treat me nt peri o d  t hr o u g h t h e e n d  of  treat me nt 
peri o d  ( E o T) visit, 3) a n o pti o nal e xt e nsi o n peri o d  b e gi n ni n g at t he 
E o T visit  f or q u alif yi n g patie nts o n t h eir ra n d o mize d st u d y treat me nt 
at t he E o T visit w h o als o me et t h e i ncl usi o n/e xcl usi o n  criteria f or t h e 
e xte nsi o n peri o d a n d pr o vi d e writte n i nf or me d c o nse nt  t o rec ei ve 
o pe n -la bel a belaci ma b tr eat me nt, a n d 4 ) a tr a nsiti o n peri o d t o 
a p pr o priat e sta n dar d of c are ( S o C) a ntit hr o m b otic t h era p y per t h e 
discreti o n of t he i n v esti gat or t hr o u g h t he E n d of St u d y ( E o S) visit.  
P o p ul ati o n  
A p pr o xi matel y  1, 2 0 0  m ale  a n d fe mal e patie nts  wit h  A F  at m o derat e - 
t o-hi g h ris k of str o ke i n w h o m a nti c oa g ul ati o n t hera p y is i n dicate d 
a n d pla n ne d f or t he d urati o n of t he st u d y.  
 

A nt h os  T hera pe utics  
Pa ge 1 5  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
Ke y  I n cl usi o n 
crite ri a 
1.  A ble  t o pr o vi de  writte n  i nf or m e d c o nse nt b ef ore  a n y st u d y 
assess me nt is perf or me d  
2.  Male  a n d fe male patie nts ≥ 5 5  years  ol d  
3.  Hist or y of A F or atri al fl utter wit h pla n ne d i n defi nite 
a ntic o a g ulati o n.  Patie nts  wit h  ne wl y  di a g n ose d  A F  ar e eli gi ble.  
4.  A  C H A 2D S 2-V A Sc  of  ≥4  O R  
a C H A 2D S 2-V A Sc  of  ≥3 wit h  at least 1  of  t he f oll o wi n g: 
• Pla n ne d c o nc o mit a nt use of a nti platel et m e dic ati o n (i.e., 
as piri n a n d/ or  P 2 Y 1 2  i n hi bit or) f or t h e d urati o n  of  t h e trial 
• Cr Cl  ≤5 0  ml/ mi n  b y  t he C o c kcr oft -Ga ult  e q uati o n 
Ke y  E xcl usi o n 
crite ri a 
1.  Use of  ot her i n vesti gati o nal dr u gs wit hi n 5 half-li ves pri or t o 
e nr oll m e nt or  u ntil  t he e x pe cte d  p h ar ma c o d y na mic  effect has 
ret ur ne d t o b aseli n e, w hic he ver is l o n ger 
2.  Hist or y of h y perse nsiti vit y t o a n y of t he st u d y dr u gs (i ncl u di n g 
ri var o xa ba n) or  its e xci pie nts,  t o dr u gs  of  si milar c h e mical cl asses, 
or a n y c o ntrai n dic ati o n liste d i n t he l a bel f or ri var o x a ba n  
3.  Patie nts  wit h  a n i ntracr a nial or  i ntra oc ular blee d  wit hi n  t he 3 
m o nt hs pri or t o scre e ni n g  
4.  Cli nic all y  si g nifica nt mitral  ste n osis ( val ve area  < 1. 5  c m 2) 
5.  Mec ha nic al  heart  val v e  or  ot her  i n di cati o n f or a ntic o a g ulati o n 
t hera p y ot h er t ha n atrial fi brillati o n (e. g., v e n o us 
t hr o m b oe m b olis m) 
6.  K n o w n  prese nce  of  a n atrial m y x o ma or  left ve ntri c ular  t hr o m b us 
7.  Hist or y  of  left atrial a p pe n da ge cl os ure or  re m o val 
8.  Acti ve  e n d ocar ditis 
9.  S yst olic  B P  > 1 8 0  m m  H g  or  diast olic  B P  > 1 0 0  m m  H g  o n 
re peat e d meas ure me nts at scree ni n g 
1 0.  Pla n ne d  i n vasi ve pr oce d ur e  wit h  p ote ntial  f or u nc o ntr olle d 
blee di n g ( e. g ., maj or s ur ger y)  
1 1.  A n y  str o ke wit hi n  1 4  d a ys  bef ore  ra n d o miz ati o n or  TI A  wit hi n  3 
da ys bef ore ra n d o mizati o n  
1 2.  A  Cr Cl  < 1 5  m L/ mi n  or  o n  dial ysis  at t he ti me of Scree ni n g  
1 3.  Platel et  c o u nt ≤7 0, 0 0 0/ m m 3 at t he Scr ee ni n g  Visit  
1 4.  He m o gl o bi n  < 8  g/ d L  at  t he Scre e ni n g  Visit  
1 5.  a P T T or  P T  > 1. 5 x  t h e u p per  li mit of  n or mal  ( U L N) at t he 
Scree ni n g Visit, if t he p ati e nt is n ot o n a n a nti c oa g ul a nt  
 
St u d y  tre at me nt 
All ocati o n  1: 1: 1  
• A belaci ma b  ( M A A 8 6 8) 9 0  m g  s u bc uta ne o usl y (s.c.) m o nt hl y  
• A belaci ma b  ( M A A 8 6 8) 1 5 0  m g  s.c. m o nt hl y  
• Ri var o xa ba n  2 0  m g  b y  m o ut h  ( p. o.) o n ce  p er  da y  wit h  e ve ni n g 
meal  
[ N ote: Pati e nts  wit h  a Cr Cl  ≤5 0  ml/ mi n  b y  t he C oc kcr oft -Ga ult 
e q uati o n will re cei ve t he 1 5 m g p. o. d ail y d ose of ri v ar o xa ba n]  

A nt h os  T hera pe utics  
Pa ge 1 6  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
St atistic al 
c o nsi der ati o ns 
Ass u mi n g a hazar d rati o ( H R) of 0. 6 0 f or eac h d ose of a bela ci m a b 
c o m pare d wit h ri var o xa b a n, at least 1 6 6 pri mar y o ut c o me e v e nts will 
pr o vi de at least 8 0 % p o wer f or e ac h a b ela ci m a b ar m vs. ri var o xa ba n 
wit h a 2 -si de d al p ha of 0. 0 5. A p pr o xi m atel y 1, 2 0 0 p atie nts s h o ul d 
pr o vi de  t he r e q uisit e n u m b er  of  e ve nts  o ver  a n esti m ate d  trial d urati o n 
of 2 7 m o nt hs.  
T he pri mar y a nal ysis will c o m pare e ac h a bel aci ma b re gi me n wit h 
ri var o xa ba n f or t he ti me t o first occ urre n ce  of  maj or  or  C R N M  blee di n g 
i n t he O n-Treat me nt A nal ysis Set. F or ea c h treat me nt re gi me n, t he 
e ve nt r ate will be esti mat e d wit h 9 5 % c o nfi de n ce i nter vals ( CIs). T he 
ti me t o first e ve nt will  be  a nal yz e d  usi n g  t he C o x  pr o p orti o nal  haz ar ds 
m o del i ncl u di n g treat me nt a n d t he f oll o wi n g t w o stratifi cati o n fact ors 
as c o variates:  
1.  Pla n ne d  use  of  c o nc o mita nt a nti plat elet me di cati o n  use  (i.e., as piri n 
a n d/ or P 2 Y 1 2 i n hi bit or) f or t he d urati o n of t he trial  
2.  Cr Cl  ( C oc kcr oft-Ga ult)  ≤ 5 0  ml/ mi n  
Ke y  w or ds  
Ra n d o miz e d,  pr os pecti ve,  bli n d e d  e n d p oi nt e val u ati o n,  a bel aci ma b, 
M A A 8 6 8, ri var o xa ba n, atrial fi brillati o n  
 
 

A nt h os  T hera pe utics  
Pa ge 1 7  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
1  
I ntr o d ucti o n 
1. 1  
B ac k gr o u n d  
Atrial fi brill ati o n ( A F) is t he m ost c o m m o n a b n or mal he art r h yt h m e nc o u nt ere d i n cli nical 
practi ce, a cc o u nti n g f or a p pr o xi m atel y o ne t hir d of h os pitali zati o ns f or car diac d ysr h yt h mi as. 
T his  c o m m o n car diac arr h yt h mi a is esti m ate d  t o affe ct a p pr o xi m atel y  2. 3  milli o n  i n t he U nit e d 
States  ( U S) a n d m ore  t ha n 6  milli o n  i n di vi d u als i n E ur o pe.  T hese  fi g ur es are pr ojecte d  t o gr o w 
ra pi dl y be ca use of t he a gi n g p o p ulati o n a n d t he ass ociate d i ncr ease i n a ge-r elate d c o- 
m or bi dities t hat pre dis p ose i n di vi d uals t o A F ( Ra h m a n et al 2 0 1 4 ). 
A F  is ass ociate d  wit h  a 4 - t o 5 -f ol d i ncrease i n e m b olic str o ke, wit h  t he a bs ol ute ris k de pe n de nt 
o n  a ge as  well  as ot her  ris k fact ors (Ja n uar y et al 2 0 1 4 ). T he  ris k of  str o ke ass ociate d  wit h  A F 
rises wit h a g e t o 2 3. 5 % f or patie nts a ge d 8 0 t o 8 9 y ears; t h us, m ost p ati e nts wit h A F r e q uire 
life-l o n g t hera p y wit h  a ntic o a g ulati o n  to  pre v e nt  str o ke a n d ot her  s yste mic e m b olic e ve nts. T he 
C H A 2D S 2-V A Sc ris k sc ore is a vali date d a n d wi del y use d stratific ati o n t o ol t o pre di ct 
t hr o m b oe m b olic ris k i n A F patie nts a n d t o i d e ntif y patie nts w h o s h o ul d be nefit fr o m 
a ntic o a g ulati o n  t hera p y (Li p  et  al  2 0 1 0;  Ja n uar y et al 2 0 1 4 ; Hi n dric ks  et  al  2 0 2 0 ). It is esti mate d 
t hat 8 5 t o 9 0 % of A F patie nts re q uire a ntic oa g ulati on t hera p y.  
A ntic oa g ul ati o n  wit h  eit her direct  oral  a ntic o a g ula nt  dr u gs  ( D O A Cs) or  vita mi n  K  a nta g o nists 
( V K A), s uc h as  warfari n,  ha ve  bee n  de m o nstrate d  t o be  effecti ve i n re d uci n g t he ris k of  str o ke 
a n d s yste mi c e m b olis m ( Ja n uar y et al 2 0 1 4; Hi n dric ks et al 2 0 2 0 ). I n a m eta-a nal ysis t hat 
i ncl u de d data fr o m f o ur pi v otal p hase 3 cli nical trials of DO A Cs f or str o ke pre ve nti o n i n 
patie nts wit h A F, treat me nt wit h D O A Cs was ass ociat e d wit h a re d uce d ris k of str o ke a n d 
s yste mic e m b olic e ve nts a n d were safer wit h res pect t o seri o us or life -t hreat e ni n g blee di n g, 
partic ularl y i ntra cra ni al h e m orr ha g e, alt h o u g h t h ere was a n i n crease i n g astr oi ntesti nal 
blee di n g o bser ve d wit h se ver al D O A Cs ( R uff et al 2 0 1 4 ). T h o u g h D O A Cs are safer t ha n 
warfari n, t her e re mai ns a si g nifi ca nt ris k of bl ee di n g wit h e x isti n g a g e nts w hic h c o nti n u es t o 
li mit t h e use of a ntic o a g ula nts i n p ati e nts wit h A F. Re gistr y st u di es i n dicat e s u bsta ntial rates 
of  u n dertreat m e nt,  partic ularl y  i n hi g h -ris k patie nt  p o p ulati o ns  w h o  are at i ncrease d ris k of  b ot h 
t hr o m b oe m b olic a n d maj or blee di n g e ve nts (H uis ma n et al 2 0 1 7 ). T h us, t here re mai ns a n u n met 
me dic al n ee d f or a he m ost asis -s pari n g a ntic o a g ula nt t hera p y effe cti v e i n re d uci n g t he ris k of 
t hr o mb oe m b olic e ve nts, b ut wit h a l o wer ris k of bl ee di n g e ve nts.  
Fact or  XI  ( F XI) ser ves as  a cr ucial li n k bet wee n  t he i ntri nsic (c o ntact-acti vati o n)  pat h wa y  a n d 
t he c o m m o n pat h wa y of t he c o a g ulati o n c asca de (Fi g ure 1 -1 ). I n t he classic vi e w of t he 
c oa g ulati o n  c asca de,  acti vati o n  of  t he i ntri nsic pat h w a y  lea ds Fa ct or  XII  t o acti vate F XI,  w hic h 
ulti m atel y le a ds t o acti vati o n of t he c o m m o n p at h wa y a n d t he ge ner ati o n of fi bri n — a n 
e nz y matic c asca de t h at is refle cte d i n t he acti vate d partial t hr o m b o plasti n ti me (a P T T), a 
c o m m o nl y  perf or m e d  la b orat or y test. B ut  it is n o w  esta blis he d  t hat d uri n g  i n vi v o  he m ostasis, 
t he i nitial t hr o m bi n t hat is ge ner ate d b y tiss ue fact or acti vati o n of t he e xtri nsi c pat h wa y ca n 
als o acti v ate  F XI, le a di n g t o a m plifi cati o n  i n t he ge n erati o n  of  t hr o m bi n (Fi g ure 1 -1 ) (Gaila ni  
a n d Re n né 2 0 0 7 ; C h e n g et al 2 0 1 0 ). 
Se veral li nes of e vi de nc e, h o we ver, s u g gest t hat F XI -me di ate d a m plifi cati o n of t hr o m bi n 
ge nerati o n 
ma y be dis pe nsa ble f or p h ysi ol o gic he m ostasis. I n fact, t hr o m bi n -me diat e d 
acti v ati o n  of  F XI  m a y  act uall y  pla y  a delet eri o us  r ole b y  pr o m oti n g  t he f or mati o n of  pat h ol o gic 
t hr o m bi t hat le a d t o isc he mic str o kes a n d  s yste mi c e m b oli.  T his  is ill ustrate d b y  rare i n di vi d uals 
b or n  wit h  a n i n herite d deficie nc y  of  F XI.  C haracterizati o n  of  t hese i n di vi d uals i n di cat e t hat 
t he y are at l o wer ris k of  isc he mic str o ke a n d ve n o us  t hr o m b oe m b olis m ( V T E) c o m p are d  t o t he 
ge neral p o p ulati o n ( Sal o m o n et al 2 0 1 1; Preis et al 2 0 1 7 ). At t he sa m e ti me, s p o nta n e o us 

A nt h os  T hera pe utics  
Pa ge 1 8  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
blee di n g i n t hese i n di vi d uals is rare, a n d blee di n g e v e nts t hat t h e y d o e x perie n ce ar e t y pic all y 
mil d a n d oc c ur i n tiss ues a ss ociat e d wit h hi g h fi bri n ol ytic acti vit y s uc h as t h e oral m u c osa, 
nasal m u c osa, a n d uri nar y tr act ( D u ga a n d Sal o m o n 2 0 1 3 ). A si mil ar p he n ot y pe has b ee n 
reca pit ulate d i n n o n -h u ma n  pri m ate  stu dies  w her e  F XI  i n hi biti o n has  b ee n  s h o w n t o lea d t o a 
re d ucti o n i n t hr o m b us f or mati o n wit h o ut a n i ncre ase d ris k of blee di n g (Cr os b y et al 2 0 1 3 ). 
C o n versel y, p o p ulati o n st u dies s u g gest t hat i ncre ase d circ ulati n g le vels of F XI are ass ociate d 
wit h a n i ncr ease d ris k of str o ke a n d V T E e ve nts ( Meijers et al 2 0 0 0; S uri et al 2 0 1 0 ). 
Fi g ure 1 -1  
C o a g ul ati o n c asc a de wit h acti v ati o n of F act or XI b y t hr o m bi n  
 
A cli nical tri al of a ntise nse oli g o n ucle oti de 
me diate d s u p pressi o n of F XI ( F XI -A S O) 
de m o nstrat e d a ntit hr o m b otic effi cac y i n patie nts u n der g oi n g el ecti ve u nilateral t ot al k n ee 
art hr o plast y ( T K A) ( B üller et al 2 0 1 5 ). I n t his st u d y, patie nts ra n d o mize d t o t he F XI-A S O 
gr o u ps  were  starte d o n  treat m e nt 3 6  da ys  bef ore  s ur ger y a nd  ac hie ve d  a p pr o xi m atel y  6 0 %  a n d 
8 0 % le vels of F XI i n hi biti o n i n t he 2 0 0 m g a n d 3 0 0 m g d ose gr o u ps, res pecti v el y, o n t he d a y 
of  t he s ur ger y. Patie nts  i n t he F XI -A S O  2 0 0  m g  d ose  gr o u p  ha d  si milar a ntit hr o m b otic effi cac y 
t o sta n dar d of care pr o p h yla xis wit h s.c. e n o xa pari n, w hile patie nts i n t he F XI -A S O 3 0 0 m g 
d ose  gr o u p  ha d  a statisti call y si g nifi ca nt r e d ucti o n i n t he rate of  t otal V T E  e ve nts  c o m pare d  t o 
sta n dar d of  care  pr o p h yla xis  wit h  s.c. e n o xa pari n  ( 4 % vs.  3 0 %,  P < 0. 0 0 1).  Stri ki n gl y,  i n hi biti o n 
of  F XI  i n pati e nts  u n der g oi n g  T K A  di d  n ot  res ult i n a n i ncrease d ris k of  blee di n g  c o m par e d  t o 
e n o xa pari n. Pati e nts i n b ot h F XI -A S O d ose gr o u ps ha d fe wer p ost o perati ve maj or a n d 
cli ni call y rele va nt n o n -m aj or ( C R N M) bl ee di n g e ve nts s u g gesti n g t hat F XI i n hi biti o n i n 
patie nts  u n der g oi n g  ort h o p e dic  s ur ger y has  a ntit hr o m b otic  effi cac y  wit h  n o  i ncr ease i n 
blee di n g c o m p are d t o e n o x a pari n. Si milar res ults were o bser ve d i n a cli ni cal st u d y of a 
m o n ocl o nal  a nti b o d y  i n hi bit or of  acti vate d  F XI,  os oci ma b,  als o i n patie nts  u n d er g oi n g  ele cti v e 
T K A ( Weitz et al 2 0 2 0 ). 
O verall,  t hese res ults s u g gest t hat i n hi biti n g F XI  ma y  lea d t o effecti ve a ntic o a g ulati o n  wit h  a n 
i m pr o ve d safet y pr ofil e o ver e xisti n g a ntit hr o m b otic dr u gs i n ter ms of ble e di n g.  

A nt h os  T hera pe utics  
Pa ge 1 9  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
1. 2  
A bel aci m a b ( M A A 8 6 8)  
A belaci ma b  ( M A A 8 6 8) is a f ull y h u ma n  m o n ocl o nal  a nti b o d y t hat bi n ds  t he catal yti c d o m ai n 
of  F XI  i n b ot h  t h e z y m o ge n  a n d acti vat e d  fa ct or XI  ( F XIa) f or ms wit h  hi g h  affi nit y  a n d p ot e nc y 
(K oc h et al 2 0 1 9 ). I n pre cli nical st u di es, a d mi nistrati o n of a belaci ma b d ose-d e pe n de ntl y 
pr ol o n ge d t he acti vat e d partial t hr o m b o pl asti n ti me (a P T T) i n vitr o. I n vi v o, a si n gle 
s u bc uta ne o us (s.c.) d ose of a bela ci m a b at a 3 m g/ k g d ose i n c y n o m ol g us m o n ke ys le d t o a 
s ustai ne d pr ol o n gati o n  of  a P T T t hat l asts m ore  t h a n a m o nt h.  F urt h er m ore,  i n a n e x p eri me ntal 
m o del of car oti d arter y t hr o m b osis i n d uce d b y Fe Cl 3  i n F XI-/- mice r ec o nstit ute d wit h h u m a n 
F XI, d ose -de pe n d e nt pr ol o n gati o n of t h e a P T T was ass ociate d wit h t he pre v e nti o n of c ar oti d 
arter y t hr o m b osis.  
F urt her  details  ca n be  f o u n d i n t he a b ela ci m a b  I n vesti gat or’s Br oc h ure  (I B). 
 
A d diti o n al pre -cli nic al st u dies  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H u m a n  St u dies  wit h  a bel aci m a b  
Cli nic al e x p erie n ce wit h a belaci ma b, i ncl u di n g res ults fr o m c o m plete d st u di es a n d o n g oi n g 
st u dies i n patie nts, is s u m m ariz e d bel o w.  
P h as e 1 st u di es  
I n t he first-i n-h u m a n ( FI H) st u d y ( C M A A 8 6 8 X 2 1 0 1), si n gle S C a d mi nistrati o n of a belaci ma b 
u p t o 2 4 0  m g was safe a n d well -t olerat e d i n healt h y s u bjects (K oc h 2 0 1 9 ). T he i nci d e nce of 
a d verse e v e nts ( A Es) was c o m p ara bl e a cr oss a bela ci ma b d ose gr o u ps a n d t h e p o ole d pla ce b o 
gr o u p. N o blee di n g e ve nts, h y perse nsiti vit y rea cti o ns ( H S Rs), or i njecti o n site reacti o ns (I S Rs) 
were re p orte d. I ncreasi n g d oses of a belaci ma b were ass ociate d wit h > 9 0 % re d ucti o ns i n free 
F XI c o nc e ntrati o ns. T h e re d u cti o n i n free F XI le vels was ass ociat e d wit h a d ose a n d ti me -
de pe n de nt pr ol o n g ati o n of t he a P T T. T he o nset of r o b ust re d ucti o ns i n free F XI a n d F XI 
c oa g ulati o n acti vit y ( F XI: C), as well as a P T T pr ol o n gati o n, were o bser ve d a p pr o xi m atel y 1 2 -

A nt h os  T hera pe utics  
Pa ge 2 0  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
2 4 h o urs  after  S C  a d mi nistrati o n of d oses  i n t h e e x pecte d  thera p e uti c  ra n g e of a bel aci ma b. 
S u bc uta ne o us  d oses  u p t o  1 5 0 m g  res ult e d i n a m ea n  a P T T pr ol o n g ati o n  of > 2 -f ol d fr o m 
basel i ne t hr o u g h Da y 2 9, w hile d oses > 1 5 0 m g u p t o t he t o p d ose test e d, 2 4 0 m g, e xte n d e d t h e 
d urati o n  of a P T T  pr ol o n gati o n  u p t o  an d  t hr o u g h Da y  4 3, wit h o ut  a n y f urther  a P T T 
pr ol o n gati o n. A nal ysis of p har ma c o ki netic ( P K) data fr o m a hi g h b o d y m ass i n de x ( B MI ≥3 5 
k g/ m 2)  c o h ort a d mi nist ere d 2 4 0 m g  d e m o nstrate d  t hat hi g h er  B MI  was  ass ociate d wit h  a 
m o dest  re d u cti o n i n a bel aci ma b e x p os ure  a n d a  m o deratel y  s h orter d ur ati o n  of a P T T 
pr ol o n gati o n.  L o w  titer le v els of a nti- dr u g a nti b o di es  ( A D A) were  detecte d  i n s o me s u bje cts 
e x p ose d t o a bel aci ma b at 1 or m ore sa m pli n g ti me p oi nts. A D A f or mati o n was n ot ass ociate d 
wit h A Es or a n y dete cta ble effe cts o n P K or p har mac o d y na mics ( P D). 
I n t he C M A A 8 6 8 A 1 1 0 1  st u d y, a si n gle S C  a d mi nistrati o n of  a belaci ma b u p t o  1 5 0 m g  w as  
safe a n d well  t ol erat e d i n he alt h y  Ja pa nese s u bj ects. T he re were  n o seri o us  ad verse  e ve nts 
(S A E s) or st u d y disc o nti n uati o ns d ue t o A Es. All A Es were mil d i n se verit y, a n d t he i nci d e nce 
of A Es  was  si milar bet wee n  t he ab ela ci m a b  d ose  gr o u ps  a n d pl ace b o. N o  ble e di n g e ve nts , 
H S Rs, or I S Rs were re p orte d. T he P K/ P D pr ofile of a bela ci m a b i n h ealt h y Ja pa nese s u bj ects 
was  ge nerall y  c o m par a ble t o t he P K/ P D  pr ofi le o bser ve d  i n the  FI H  st u d y. Alt h o u g h A D A s 
were dete cte d i n s u bje cts at vari o us ti m e p oi nts, t her e was n o i n di cati o n t hat P K/ P D or safet y 
was affecte d. 
I n t he A N T- 0 0 3 st u d y, si n gle i ntra ve n o us (I V) a d mi nistrati o n of a belaci ma b u p t o 1 5 0 m g 
was safe a n d well-t olerate d i n healt h y s u bjects ( Yi 2 0 2 2 ). At 1 h o ur after t he start of t he I V 
i nf usi o n (t he first ti me p oi nt assesse d), a belaci ma b pr o d uce d > 9 9 % re d ucti o n i n free F XI 
c o nce ntrati o ns a n d i ncreases i n a P T T c o nsiste nt wit h t he e x pecte d P D effects of a belaci ma b. 
At hi g her d oses, t he P D effects of a belaci ma b were s ustai ne d f or at least 4 wee ks a n d 
ret ur ne d t o baseli ne b y Da y 1 0 6 (e n d of st u d y). C o nsiste nt wit h t he res ults fr o m t he FI H 
st u d y, t he P K e x p os ure of a belaci ma b a n d d urati o n of F XI i n hi biti o n was m o deratel y l o wer 
i n patie nts wit h a hi g h B MI, p ossi bl y d ue t o t he o bser ve d lar ger v ol u me of distri b uti o n 
a n d sli g htl y faster cleara nce of a belaci ma b. Asi de fr o m c ha n ges i n a P T T, n o cli nicall y 
rele va nt c ha n ges i n t he cli nical la b orat or y tests a n d electr ocar di o gra m ( E C G) para meters 
were o bser ve d. N o blee di n g e ve nts occ urre d, a n d n o H S Rs or I S Rs were re p orte d. 
P h as e 2 st u di es 
Ve n o us thr o m b oe m b olis m pr eve nti o n st u d y 
T he  A N T- 0 0 5  st u d y was  a m ultice nt er,  ran d o mi ze d,  acti ve- c o ntr olle d, d ose-ra n gi n g  st u d y t o 
co m pare t h e effic ac y a n d s afet y of 3 bli n de d d oses of I V a belaci m a b c o m par e d t o o pe n-la b el 
t hr o m b o pr o p h yla xis wit h  S C  e n o xa p ari n i n pa tie nts u n der g oi n g  electi ve u nilateral  T K A 
(Ver ha m me 2 0 2 1 ). Patie nts were ra n d o miz e d t o rec ei ve o ne of 3 d oses of a bela ci ma b I V o nc e 
a p pr o xi matel y 4- 8  h o urs  after s ur ger y or sta n dar d of care  ( S o C) t hr o m b o pr o p h yla xis wit h 
e n o xa pari n u p t o t he pr ot o c ol ma n d ate d asce n di n g v e n o gra p h y o n Da y 1 0, t hat was a dj u di cat e d 
b y a bli n de d i n de p e n de nt a dj u dic ati o n c o m mitte e. Res ults de m o nstrate d t h at I V a d mi nistrati o n 
of a belaci ma b  aft er T K A  s ur ger y was as s ociate d wit h  a d ose- de pe n de nt  re d ucti o n i n t he rate 
of V T E  e v e nts  ( Fi g ure 1 - 2). T he rate of V T E  i n t he e n o xa pari n gr o u p  was  2 2 %. B y  c o m p aris o n, 
t he rat e of V T E i n t he a bel aci ma b 3 0 m g gr o u p ( 1 3 %) was n o n-i nferi or t o  e n o xa pari n, w hile 
t he rat e of V T E  in  t h e a belaci ma b  7 5 m g  ( 5 %; p < 0. 0 0 1)  a n d 1 5 0 m g  d ose  gr o u ps  ( 4 %; p < 0. 0 0 1) 
were s u peri or t o e n o xa pari n d e m o nstrati n g t hat a bel a ci ma b has r o b ust a ntit hr o m b otic effi ca c y. 
T here were n o d eat hs or H S Rs, a n d t he p erce nt of patie nts w h o e x peri e nce d a n A E was si milar 
i n t he a bel aci ma b a n d en o xa p ari n  gr o u ps.  Bl ee di n g  occ urre d  i n 2 %, 2 %, a n d  n o ne  of t he 
pa tie nts i n t he 3 0, 7 5, a n d 1 5 0 m g a belaci m a b gr o u ps, res pecti vel y, a n d i n n o ne of t he patie nts 
i n t he e n o xa pari n gr o u p ( Fi g ur e  1- 2 ). All  maj or  or C R N M  blee di n g  e ve nts  i n a bel aci ma b 

A nt h os  T hera pe utics  
Pa ge 2 1  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol
 
Pr ot oc ol  N o.  A N T -0 0 6  
patie nts were ass ociat e d wit h t he s ur gical site. A t otal of 6 S A Es were re p ort e d i n 5 a b ela ci m a b 
patie nts. T hree S A Es of ‘ peri pr ost hetic j oi nt i nfecti o n’ re p orte d i n a bela ci m a b pati e nts were 
j u d ge d as ‘ p ossi bl y rel ate d’ t o treat me nt b y t he I n v esti gat or. 
Fi g ure 1- 2  
S u m m ar y of t he A N T -0 0 5 St u d y  
Atri al fi brill ati o n st u di es  
A N T -0 0 4 was a r a n d o mize d, patie nt -a n d-In vesti gat or -bli n d e d, pla ce b o-c o ntr oll e d st u d y  t hat 
e val uate d t he safet y, t olera bilit y, P K, a n d P D effects of m o nt hl y S C a d mi nistrati o n of 
a bela ci m a b i n A F patie nts wit h a C H A 2 D S 2 -V A Sc sc ore of 0 -1 i n me n or 1 -2 i n w o me n ( Yi 
2 0 2 2 ). A t otal of 1 8  patie nts  were ra n d o mi ze d, 8 i n C o h ort  1 ( 1 2 0  m g S C  a belaci ma b or 
matc hi n g pla ce b o) a n d 1 0 i n C o h ort 2 ( 1 8 0  m g S C  a bela ci m a b or matc hi n g plac e b o) . Re p eat 
S C a d mi nistrati o n of a b ela ci m a b u p t o 1 8 0  m g f or 3 m o nt hs was  safe a n d well t olerate d. T h ere 
were n o de at hs or S A Es, a n d n o maj or or C R N M  e v e nts were r e p orte d. I n a d diti o n , n o H S Rs  
or I S Rs were  re p orte d. 
A N T -0 0 6  is a n o n g oi n g, e v e nt-dri v e n, ra n d o miz e d, a cti ve -c o ntr olle d, p arallel -gr o u p  P hase 2 b  
st u d y t o e v al uate t he safet y a n d t oler a bilit y of 2 bli n d e d d oses of a b ela ci m a b c o m pare d t o o pe n -
la bel ri var o xa b a n o n t h e rat e of maj or or C R N M blee di n g e ve nts i n patie nts  wit h A F  at 
m o derat e -t o-hi g h ris k of str o ke.  Patie nts were ra n d o ml y assi g ne d 1: 1: 1 t o a b ela ci m a b 9 0  m g  
S C m o nt hl y, a belaci ma b 1 5 0  m g S C m o nt hl y, or ri v ar o xa ba n oral ( P O) dail y. Ra n d o miz ati o n 
was  stratifie d b y c o nc o mita nt a nti pl atelet use at baseli ne a n d re nal f u nc ti o n at scre e ni n g. T he 
9 0 a n d 1 5 0  m g a belaci ma b d oses wer e sel ect e d b as e d o n a P K/ P D m o del t hat p r e dicte d t hat 
t hese d oses w o ul d ac hie ve l e vels of F XI i n hi biti o n t h at brac ket t he cli nic all y effica ci o us ra n ge. 
At near ste a d y -stat e, t h e 9 0 m g d ose is pre dict e d t o pr o vi de a p pr o xi mat el y 8 0 % F XI i n hi biti o n 
at tr o u g h w hile t he 1 5 0  m g d ose is pre dicte d t o pr o vi de a p pr o xi matel y 9 7 % F XI i n hi biti o n at 
tr o u g h. T he pri mar y safet y e n d p oi nt is t h e c o m p osite of maj or a n d C R N M ble e di n g e v e nts  
ce ntrall y a dj u dicate d b y a n i n de pe n de nt Cli ni cal E v e nts C o m mitt ee ( C E C) bli n d e d t o treat me nt 
assi g n me nt. A n i n de pe n de nt  pr o gra m -wi de  Data M o nit ori n g C o m mitt ee ( D M C ) is pr o vi di n g 
o versi g ht of t he  saf et y of st u d y partici p a nts. 
E nr oll m e nt was c o m plete i n Dec e m ber 2 0 2 1. A t otal of 1, 2 8 7 s u bjects were ra n d o mize d wit h 
3 3 5 s u bjects i n N ort h A merica ( U S a n d Ca na da), 8 9 6 s u bjects i n E U c o u ntries ( Czec h 
Re p u blic, H u n gar y, a n d P ol a n d), a n d 5 6 s u bjects i n Asia ( K orea a n d Tai wa n). T h e mea n a ge 
of s u bjects is 7 3. 9 years (ra n ge 5 5 -9 3 years), 4 4 % are f e mal e, t he mea n C H A 2 D S 2 -V A Sc sc ore 
is 4. 7, a p pr o xi mat el y 2 0 % ha ve a creati ni ne cl eara n ce ≤5 0 m L/ mi n ( C oc k cr oft-Ga ult e q u ati o n), 

A nt h os  T hera pe utics  
Pa ge 2 2  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
a n d a p pr o xi m atel y 2 4 % were o n c o nc o mit a nt a nti platelet t her a p y at baseli ne.  As of Se pt e m ber  
2 0 2 2, t he m ea n ti me of a patie nt o n tr eat m e nt i n t he A N T-0 0 6 st u d y is greater t ha n 1 2  m o nt hs 
a n d t here are patie nts w h o ha ve b ee n f oll o we d f or 1. 5 years.  
P h as e 3 st u di es of a b el a ci m a b i n p ati e nts wit h c a n c er -ass o ci at e d t hr o m b osis ( o n g oi n g)  
U n der I N D  
a belaci m a b is bei n g d e vel o p e d t o r e d uce t he ris k of rec urr e nt V T E i n 
patie nts wit h ca ncer -ass ociat e d t hr o m b osis ( C A T). T he A N T -0 0 7 a n d A N T -0 0 8 P hase 3 
st u dies are s u m m ariz e d bel o w. 
A N T -0 0 7  
T he A N T -0 0 7 st u d y is a  gl o bal P hase 3 pr os pecti ve, ra n d o miz e d, o pe n -l a bel, bli n d e d e n d p oi nt 
e val uati o n ( P R O B E), acti v e c o ntr olle d st u d y t o e v al uat e w het her a bel aci ma b a d mi nister e d 
o nce m o nt hl y is n o n -i nferi or t o t wice dail y (BI D ) oral a pi xa ba n i n t er ms of V T E rec urre nc e i n 
pati e nts wit h ca ncer a n d rece ntl y dia g n ose d V T E. A N T -0 0 7 is pla n ne d t o e nr oll a p pr o xi matel y 
1 6 5 5  s u bjects wit h c a ncer a n d s y m pt o matic/ i nci de ntal pr o xi m al l o wer l e g dee p v ei n 
t hr o m b osis (D V T ) a n d/ or eit her s y m pt o m ati c p ul m o nar y e m b olis m ( P E) or i nci d e ntal P E.  T he 
st u d y pri mar y e n d p oi nt is t o de m o nstrat e n o ni nferi orit y of a b elaci ma b f or pre ve nti n g V T E 
rec urre nce r elati ve t o a pi xa ba n. 
 
. A n  i n de pe n de nt C E C  
bli n de d t o treat me nt assi g n me nt will re vi e w a n d a dj u dicat e ke y e n d p oi nt e v e nts i ncl u di n g ca use 
of deat h, s us pect e d  D V T, s us pecte d P E, a n d bl ee di n g e ve nts.  
A N T -0 0 8  
T he A N T -0 0 8 st u d y is a  gl o bal P hase 3 P R O B E, a cti ve c o ntr olle d st u d y t o asse ss w het her 
a bela ci m a b a d mi nist ere d o nce m o nt hl y is n o n -i nferi or t o o nce dail y ( Q D) S C i njecti o n of 
dalte p ari n i n pre v e nti n g V T E rec urr e nce i n p ati e nts wit h gastr oi ntesti n al/ g e nit o uri nar y 
(GI/ G U ) ca nc ers a n d rec e ntl y dia g n ose d V T E. A N T -0 0 8 is pla n ne d t o e nr oll a p pr o xi matel y 
1 0 2 0  s u bjects wit h GI/ G U ca n cer a n d a ne wl y dia g n ose d, o bjecti v el y c o nfir me d s y m pt o m ati c 
or i nci de ntall y det ect e d pr o xi m al l o wer -li m b D V T, s y m pt o matic P E, or i nci d e ntall y detecte d 
P E.  T he st u d y pri mar y e n d p oi nt is t o de m o nstrate n o ni nferi orit y of a belaci ma b f or pre ve nti n g 
V T E rec urre n ce  r elati ve t o d alt e pari n. 
 
 A n i n de pe n d e nt C E C 
bli n de d t o treat me nt assi g n me nt w ill re vi e w a n d a dj u dicat e ke y e n d p oi nt e v e nts i ncl u di n g ca use 
of deat h, s us pect e d D V T, s us pecte d P E, a n d bl ee di n g e ve nts.  
T he P hase 3 A N T -0 0 7 a n d A N T -0 0 8 st u dies wer e i nitiate d i n t h e first half of 2 0 2 2, a n d t he 
first patie nt was e nr olle d i n A N T-0 0 7 i n Ma y  2 0 2 2 . A n i n de pe n de nt pr o gra m -wi de  D M C  will 
pr o vi de o versi g ht of t he  safet y of st u d y parti ci pa nts. 
 
S u m m ar y of cli nic al e x peri e nce of A bel aci m a b  
I n s u m mar y, i n hi biti n g F XI wit h a bel aci ma b has t he p ote nti al t o be a n o vel a ntic o a g ula nt wit h 
a n i m pr o ve d ble e di n g pr ofile o v er e xisti n g a ntit hr o m b otic dr u gs t hat ha ve b ee n a p pr o v e d f or 
patie nts wit h A F . T he cli nic al dat a wit h a belaci ma b t o date s u g gest t hat i n hi biti o n of F XI wit h 
a bela ci m a b is safe a n d well -t oler ate d i n he alt h y s u bjects as well as p ati e nts wit h A F a n d 
patie nts w h o ha ve u n der g o ne T K A. A bela ci m a b lea ds t o r o b ust re d ucti o ns i n F XI acti vit y a n d 
a pr ol o n gati o n of a P T T. C o nsiste nt wit h cli nic al res ults wit h ot h er F XI a g e nts, e m er gi n g data 
wit h a bela ci m a b i n t h e A N T -0 0 5 st u d y s u g gest t hat t hese P D effects tra nslat e t o cli nic al 
effica c y i n t er ms of a re d ucti o n i n V T E i n patie nts w h o ha ve u n der g o ne electi ve T K A.  

A nt h os  T hera pe utics  
Pa ge 2 3  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
1. 3  
St u d y p ur p ose  
T he  p ur p ose  of  t h e A N T -0 0 6  st u d y is t o e v al uate t h e ble e di n g  pr ofil e  of  a bel aci ma b  r elati ve t o 
ri var o xa ba n i n patie nts wit h A F at m o derat e -t o-hi g h ris k of str o ke.  
2  
St u d y o bjecti ves a n d e n d p oi nts  
2. 1  
Pri m ar y  o bjecti ve  
O bjecti ve  
E n d p oi nt(s)  
•  T o  e val uate t he effect of a belaci ma b relati ve t o 
ri var o xa ba n o n t he rate of maj or or cli nicall y 
rele va nt n o n-maj or ( C R N M) blee di n g e ve nts  
•  Ti me t o first  e ve nt of c o m p osite of I nter nati o nal 
S ociet y o n T hr o m b osis a n d Hae m ostasis (I S T H)-
defi ne d maj or blee di n g or C R N M blee di n g e ve nts  
2. 2  
Sec o n d ar y o bjecti ve(s)  
2. 3  
E x pl or at or y  o bjecti ve(s)  
O bjecti ve  
E n d p oi nt(s)  
•  
 
 
 
 
 
 
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O bjecti ve  
E n d p oi nt(s)  
•  T o e val uate t he effect of  a belaci ma b relati ve t o 
ri var o xa ba n o n t he rate of maj or blee di n g e ve nts  
•  Ti me t o first e ve nt I S T H -defi ne d maj or blee di n g 
e ve nts 
•  T o e val uate t he effect of a belaci ma b relati ve t o 
ri var o xa ba n o n t he rate of 
maj or or 
mi n or 
blee di n g e ve nts  
•  Ti me t o first e ve nt I S T H -defi ne d maj or or mi n or 
blee di n g e ve nts  

A nt h os  T hera pe utics  
Pa ge 2 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol
 
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O bjecti ve  
E n d p oi nt(s)  
•  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
  
  
  
 
 
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
3  
I n vesti g ati o n al Pl a n 
3. 1  
St u d y desi g n  
T his  is a n e ve nt-dri ve n,  ra n d o miz e d, acti ve-c o ntr oll e d,  bli n de d  e n d p oi nt,  par all el -gr o u p  st u d y 
t o e val uat e t he effect of  t w o bli n de d  d oses  of  a belaci ma b  relati ve t o o pe n -la b el ri var o xa b a n o n 
t he rat e of maj or or C R N M blee di n g e ve nts i n patie nts wit h A F w h o are at m o d erate -t o-hi g h 
ris k of str o ke. 
Ra n d o miz ati o n i nt o treat me nt gr o u ps will be stratifi e d b y t he use of c o nc o mita nt a nti pl atelet 
use at baseli ne ( yes/ n o) a n d r e nal f u n cti o n ( Cr Cl ≤5 0 ml/ mi n or Cr Cl > 5 0 ml/ mi n).  
T he st u d y is c o m prise d of u p t o 4  peri o ds: 1) scree ni n g ( u p t o 4 wee ks), 2) st u d y dr u g tr eat me nt 
peri o d t hr o u g h t he e n d of tr eat me nt peri o d ( E o T) visit , 3) a n o pti o n al e xte nsi o n peri o d 
be gi n ni n g at t h e E o T visit f or q ualif yi n g pati e nts t o recei v e o pe n -la bel a bel aci ma b treat me nt, 
a n d 4 ) tra nsiti o n p eri o d t o a p pr o priate st a n dar d of car e a ntit hr o m b otic t hera p y p er t h e discreti o n 
of t he i n vesti gat or t hr o u g h t he E n d of St u d y ( E o S) visit.   
 
 

A nt h os  T hera pe utics  
Pa ge 2 5  
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Fi g ure 3 -1  
St u d y desi g n  
Scree ni n g peri o d 
D uri n g t he Scree ni n g Peri o d ( Da y - 3 0 t o Da y - 1), all scree ni n g assess me nts will b e  c o m plete d, 
a n d t he i n vesti gat or will deter mi ne w het her t he patie nt is eli gi ble f or t he st u d y. 
Patie nts e nteri n g t he e xte nsi o n peri o d s h o ul d ha ve eli gi bilit y c o nfir me d per Secti o n 4. 3 a n d 
4. 4 at a n y ti me bet wee n t he m o nt hl y visit pri or t o E o T a n d t he act ual E o T/ E xte nsi o n Da y 1 
visit.  
See Secti o n 5. 2 f or f urt her details o n scree ni n g a n d re-scree ni n g. 
R a n d o miz ati o n a n d tre at me nt 
I n vesti gat ors s h o ul d ta ke meas ures t o mi ni mize t he d urati o n of ti me fr o m w he n t he patie nt is 
scree ne d u ntil deter mi ne d t o be eli gi ble f or ra n d o mizati o n i nt o t he st u d y. Eli gi ble patie nts w h o 
are n ot o n oral a ntic oa g ulati o n at scree ni n g s h o ul d be ra n d o mize d as s o o n as p ossi ble i nt o t he 
st u d y a n d be gi n t heir assi g ne d st u d y dr u g o n Da y 1 .
Patie nts w h o meet all st u d y e ntr y criteria b ut are o n oral a ntic oa g ulati o n t hera p y at scree ni n g 
will be tra nsiti o ne d fr o m t heir baseli ne a ntic oa g ula nt t hera p y pri or t o bei n g ra n d o mize d a n d 
recei ve t he first a d mi nistrati o n of st u d y dr u g o n Da y 1 acc or di n g t o t he g ui deli nes i n Ta ble  3- 1 . 
Si milarl y, patie nts recei vi n g ri var o xa ba n i n t he Ra n d o mize d Treat me nt Peri o d a n d e nteri n g 
t he 

A nt h os  T hera pe utics  
Pa ge 2 6  
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Pr ot oc ol  N o.  A N T -0 0 6  
E xte nsi o n Peri o d s h o ul d tra nsiti o n acc or di n g t o t he g ui deli nes i n  Ta ble 3- 1 .  
T a ble 3- 1  
Tr a nsiti o n G ui deli nes 
B as eli ne  a ntic o a g ul a nt 
t her a p y 
I nstr ucti o ns 
Direct oral 
a ntic oa g ula nt  ( D O A C) 
T he  patie nt’s  last d ose  of  D O A C  s h o ul d be  a p pr o xi matel y  1 2 -2 4  h o urs  pri or 
t o recei vi n g st u d y me dicati o n o n Da y 1. 
Vita mi n  K  a nta g o nist 
( V K A) 
After e nr olle d a n d f o u n d t o be eli gi ble, patie nts s h o ul d ha ve t heir V K A 
dis c o nti n ue d , a n d I N Rs s h o ul d t he n be  perf or me d  e ver y  1  t o 2  da ys  base d  o n 
i nitial I N R. T he patie nt s h o ul d be ra n d o mize d as s o o n as p ossi ble (i deall y 
wit hi n  3 6  h o urs)  o nce  t he I N R is < 2. 5.  Sites  ma y  c ollect re peat I N R s a m ples 
usi n g p oi nt of care de vices or s e n d f or l ocal a nal ysis, i n w hic h cas e res ults 
will re mai n as part of s o urce d oc u me ntati o n o nl y.  
Eli gi ble  patie nts  will  be  ra n d o mi ze d i nt o o ne  of  t he f oll o wi n g tr eat me nt gr o u ps:  
•
Treat me nt  gr o u p  1:  a bel aci ma b  9 0  m g  s.c. m o nt hl y
•
Treat me nt  gr o u p  2:  a belaci ma b  1 5 0  m g  s.c. m o nt hl y
•
Treat me nt  gr o u p  3:  ri v ar o xa ba n 2 0  m g  p. o. o nc e  per  da y  wit h  t he e ve ni n g  meal
[ N ote: Pati e nts  wit h  a Cr Cl  ≤5 0  ml/ mi n  b y  t he C o c k cr oft -Ga ult  e q uati o n  will  recei ve
t he 1 5 m g p. o. dail y d ose of ri v ar o xa ba n]
Patie nts  will  be  ra n d o mi ze d o n  Da y  1,  w hic h  will  be  t he date  of  t h e first a d mi nistrati o n  of  st u d y 
dr u g. Patie nts will be c o nt act e d b y p h o ne o n Da y 8 f or a ge ner al he alt h a n d safet y c he c k. 
Patie nts will be assesse d f or A Es a n d c ha n ges i n c o n c o mit a nt m e dicati o n e v er y m o nt h d uri n g 
t he st u d y treat me nt peri o d;  patie nts  assi g ne d  t o a b ela ci ma b  will  rec ei ve t h eir s.c. i njecti o n a n d 
patie nts  assi g ne d  t o ri var o xa ba n will  ha v e  st u d y me dicati o n  c o m pli a nce assesse d  d uri n g  t hese 
m o nt hl y visits. E ver y t hir d m o nt h, t hese visits will i ncl u de a d diti o n al saf et y assess me nts a n d 
c olle cti o n of b l o o d sa m pl es f or la b orat or y a nal ysis. 
W here per mitte d, visits as i n dicate d i n t he Assess me nt Sc he d ule ( A p pe n di x 3 ), ma y be 
c o n d ucte d at h o me b y st aff q ualifie d t o a d mi nist er s.c. i nje cti o ns or b y tele p h o ne/ vi de o-call, 
de pe n di n g o n treat me nt ar m. I n t he case of visits c o n d ucte d i n t he pati e nt’s h o me, wit h t he 
patie nt’s c o nse nt, t he I n vesti gat or a n d/ or del e gat e d staff will arra n ge f or t he ser vic e a n d will 
pr o vi de t he patie nt’s na me a n d a d dr ess t o t he pers o n nel c o n d ucti n g t he i n -h o me visit, w hic h 
will be eit her site staff or l ocall y c o ntr act e d a ge n c y staff.  
Si nce  t his is a n e v e nt-dri ve n  st u d y, t he d ur ati o n  of  tr e at me nt f or a gi v e n  partici pa nt  i n t he st u d y 
will de pe n d o n t h e rat e of acc r u al of m aj or a n d C R N M blee di n g e ve nts. As a res ult, t he ti me 
o n  st u d y dr u g  will  var y  fr o m patie nt  t o patie nt,  de pe n di n g  o n  w he n  t h e patie nt  e nr olls  i n relati o n 
t o t he E o T visit f or eac h patie nt. Base d o n e ve nt rat es i n si milar tri als, t he esti m ate d d uratio n 
of t he st u d y is e x pe cte d t o be a p pr o xi m atel y  2 7  m o nt hs,  b ut  t his ma y  ta ke l o n ger de p e n di n g  o n  
t he rat e of  patie nt  re cr uit me nt a n d cli nic al e n d p oi nt e ve nt rat es (Patel et al 2 0 1 1 ). 
If a patie nt has w hat is e x pecte d t o be a per ma ne nt disc o nti n uati o n of st u d y dr u g, t he patie nt 
s h o ul d c o m plet e t he visit  pr oc e d ures  as  i n dicate d i n t he Per ma ne nt  St u d y  Dr u g  Disc o nti n uati o n 
( P S D D) visit. Refer t o Secti o n 6. 6  f or m ore details. 
O pti o n al E xte nsi o n Peri o d  
I n or der t o pr o vi de l o n g er-ter m data, a n o pti o n al o p e n-la bel e xt e nsi o n peri o d ma y be o p e ne d 
b y t he S p o ns or if t he D M C st o ps t he st u d y pre mat ur el y d ue t o a n i m bala nc e of blee di n g 

A nt h os  T hera pe utics  
Pa ge 2 7  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
s u bsta ntiall y fa v ori n g a belaci ma b o ver ri v ar o xa ba n, a n d be nefit :ris k clearl y fa v ors a bela ci m a b. 
T he i n vesti g ati ve sit e has t he o pti o n of partici pati n g or n ot partici pati n g i n t he e xt e nsi o n peri o d. 
Patie nts w h o c o m plet e t he E o T visit o n st u d y tr eat m e nt a n d m eet t he eli gi bilit y  criteri a f or t he 
e xte nsi o n peri o d ma y p artici pat e  (see Secti o n 4. 3  a n d 4. 4 ). 
T he E o T visit will ser ve as Da y 1 of t he e xte nsi o n p eri o d.  
 
 
 
 
.    
 
E n d  of  Tre at me nt  ( E o T), E n d of E xte nsi o n tre at me nt ( E o E) a n d  E n d  of  St u d y  ( E o S) 
W he n  t he pres pecifie d  n u m b er  of  a dj u dic ate d  cli ni cal  e n d p oi nt e ve nts  ha v e  bee n  rea c he d or t he 
st u d y is st op pe d  earl y  o n t h e basis of a re c o m m e n dati o n fr o m t he D M C , sites will be n otifie d 
b y t he S p o ns or’s Cli nical St u d y Te a m t o sc h e d ule ea c h pati e nt f or t h eir E o T visit.   
If t he e xte nsi o n peri o d h as bee n o pe ne d a n d a patie nt is eli gi ble t o partici p ate, t he E o T visit 
will  ser ve as Da y 1 of t he e xt e nsi o n peri o d ( Secti o n 3. 1. 4 ).  Patie nts c o m pleti n g t he e xte nsi o n 
peri o d will ha ve a n  e n d of e xte nsi o n treat me nt ( E o E) visit (Fi g ure 3 -1 ). 
As part of t he E o T / E o E, t he I n vesti g at or will ma ke arra n ge m e nts t o i nitiate tra nsiti o ni n g t h e 
patie nt t o a p pr o priate sta n dar d -of -c are a ntic oa g ulati o n t hera p y f oll o wi n g t h e g ui deli nes i n 
Secti o n  7. 1 . T he patie nt ma y be as ke d t o c o m plet e a n o pti o nal patie nt e x perie nc e s ur ve y as part 
of t he E o T visit. A  mi ni m u m  of  4 -wee ks  after t he E o T / E o E visit  or  after t he pati e nt  has  starte d 
t heir S o C a ntic o a g ulati o n  t her a p y ( w hic he ver is l o n ger), a f oll o w-u p  visit  eit her b y  
tele p h o n e/ vi d e o-call or i n-pers o n will be c o nsi d ere d t he  E o S visit.   
 
St u d y  Steeri n g  C o m mittee  
A  St u d y  Steeri n g  C o m mittee  ( S S C), le d b y  t he T hr o m b ol ysis  i n M y ocar dial  I nfarcti o n ( TI MI) 
St u d y  Gr o u p,  a n Aca de mic  Researc h  Or ga ni zati o n  at Bri g ha m  a n d W o m e n’s  H os pital  a n d 
Har var d Me dical Sc h o ol, al o n g wit h t h e S p o ns or, will ha ve o v erall res p o nsi bilit y f or t h e 
c o n d uct a n d s u per visi o n of t he st u d y. T h e S S C will ma ke all fi nal re c o m m e n dati o ns t o t h e 
S p o ns or re g ar di n g trial stat us (e. g., m o dific ati o n or st o p pi n g).  
T he S S C, al o n g wit h t he S p o ns or, will be pri maril y res p o nsi ble f or t he creati o n, re vie w, a n d 
s u b missi o n of  p u blicati o ns  a n d prese ntati o ns  relate d t o t he st u d y a n d a n y a p pr o ve d  s u b-st u dies 
or a ncillar y a nal yses after c o m pleti o n of t h e st u d y. A n y materials or p u blic ati o ns m ust be 
s u b mitte d t o t he S p o ns or  f or re vie w a n d c o m me nt pri or  t o p u blicati o n  or  p u blic  disse mi nati o n.  
F urt her det ails of t h e c o m p ositi o n, r ol es, res p o nsi biliti es, a n d pr ocesses of t he S S C will be 
d oc u me nt e d i n t h e S S C C harter.  
 
Cli nic al  E v e nts  C o m mittee  
A  Cli nical  E ve nts  C o m mitt ee  ( C E C) will  re vi e w a n d a dj u dic ate ke y  e n d p oi nt e ve nts  i ncl u di n g 
deat hs, s us pec te d str o k es/tra nsi e nt isc he mic att ac ks ( TI As), s us pecte d s yste mic e m b olic e ve nts, 
s us pecte d m y ocar dial i nfar cti o ns ( MI), s us pecte d ve n o us t hr o m b oe m b olis m ( V T E) e v e nts a n d 
o vert ble e di n g e v e nts.  
C E C  me m b ers  will  be  bli n de d  t o all tr eat me nt assi g n me nts.  T he  C E C -a dj u di cat e d  data  will  b e 
use d i n t he fi n al safet y a n d effi cac y a nal yses.  

A nt h os  T hera pe utics  
Pa ge 2 8  
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Pr ot oc ol  N o.  A N T -0 0 6  
  
D uri n g t he e xte nsi o n peri o d, blee di n g , cere br o v asc ul ar , a n d s yste mic e m b oli c e n d p oi nt e ve nts 
will be c e ntrall y re vie we d a n d classifie d  b y t he C E C . 
F urt her d etails  of t he c o m p ositi o n, r oles, res p o nsi bilities, a n d pr ocesses of t he C E C d uri n g t he 
ra n d o miz e d a n d e xte nsi o n peri o ds will be d oc u me nt e d i n t he C E C C hart er.  
 
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 D M C will m o nit or t he pr o gress of t he st u d y a n d e n s ure t hat t he safet y of 
patie nts  i n t he st u d y is n ot  c o m pr o mise d.  T he  D M C  will  re vie w acc u m ulati n g  dat a  o n  a re g ular 
basis a n d will ha v e ac cess t o u n bli n de d data. Base d o n re vie w of safet y e ve nts a n d, i n partic ul ar, 
blee di n g e v e nts, t he D M C will ma ke re c o m m e n dati o ns t o t he S S C o n t he c o nti n uati o n of t he 
st u d y. I n parti c ular, t he D M C m a y a d vise t he S S C o n a n i m b ala n ce of blee di n g s u bsta ntiall y 
fa v ori n g a belaci ma b o v er ri var o xa b a n a n d a be n efit:ris k cle arl y fa v ori n g a belaci ma b as 
descri be d i n Secti o n 3. 1. 3 . T he D M C ma y als o rec o m me n d c ha n ges t o t he pr ot oc ol t o e ns ure 
t he safet y of trial p ati e nts or m a y re c o m m e n d earl y t er mi nati o n of t he st u d y t o t h e S S C. D M C 
o versi g ht will c o nti n u e d uri n g t h e e xt e nsi o n peri o d.  
F urt her details of t he c o m p ositi o n, r oles, res p o nsi biliti es, a n d pr ocesses o f t he D M C will be 
d oc u me nt e d i n t h e D M C C harter.  
3. 2  
R ati o n ale f or st u d y desi g n  
T he  pri mar y  o bjecti ve  of  t his st u d y is t o e val uate t he blee di n g  pr ofile  of  a bela ci m a b  relati ve t o 
ri var o xa ba n i n patie nts wit h A F at m o derat e-t o-hi g h ris k of str o ke.  
Rati o nale  a n d j ustificati o n f or t he ke y  el e me nts  of  t he st u d y desi g n  are as  f oll o ws: 
• R a n d o miz ati o n : T his decreases t h e c ha nc e of a n i m bala n ce i n patie nt c hara cteristics 
bet wee n tr eat me nt gr o u ps.  
• Str atific ati o n : Ra n d o mize d pati e nts will be stratifie d i nt o treat me nt gr o u ps ac c or di n g 
t o t heir c o n c o mita nt use  of  a nti pl atelet me dicati o ns  at baseli ne  a n d re nal f u ncti o n si n ce 
t hese fact ors ma y i nfl ue nce t he u n derl yi n g bl ee di n g ris k i n pati e nts. 
• Bli n di n g : T he st u d y will be o pe n-la bel wit h res pe ct t o a b ela ci m a b vs. ri var o xa ba n; 
h o we ver, i n vesti gat ors a n d patie nts r a n d o mi ze d t o a bela ci m a b will be bli n de d t o t he 
a bela ci m a b d ose. T his desi g n all o ws m or e si m plicit y i n t he c o n d u ct of t he tri al a n d 
decreases t he p ati e nt’s b ur de n b y eli mi nati n g t he  n ee d t o recei v e plac e b o i nj ecti o ns of  
t he st u d y dr u g  i n patie nts  ra n d o mize d t o ri var o xa ba n or  t he nee d  t o ta ke a  dail y  pla c e b o i n 
patie nts ra n d o mize d t o a belaci ma b.  
Bias will be a v oi de d b y f oll o wi n g strict ra n d o mi zati o n pr oce d ures a n d ha vi n g st u d y 
e n d p oi nts a dj u dic ate d  b y  a n i n de pe n d e nt C E C  c o m prise d  of  q ualifie d  e x perts  w h o  will 
a dj u dic ate e ve nts i n a cc or da n ce wit h e n d p oi nt e val u ati o n g ui d eli n es.  
• Acti ve c o ntr ol: Pr o vi des a c o m paris o n gr o u p f or safet y, t olera bilit y, a n d effi cac y 
e n d p oi nts. 
T he  pati e nt  p o p ulati o n  will  be  descri be d  i n m ore  d et ail  i n Secti o n  4  bel o w.  
3. 3  
R ati o n ale f or d ose/re gi m e n  
T he a b ela c i m a b 9 0 m g a n d 1 5 0 m g d oses were selecte d f or t his st u d y be ca use t he y are li kel y 
t o brac k et t he effic aci o us d ose ra n ge base d o n t he a vaila ble pr ecli nic al, g e netic, a n d cli ni cal 
st u dies. Precli ni cal st u di es s u g gest t hat F XI i n hi biti o n of 5 0 % or m ore ma y res ult i n a l o wer 
i nci de n ce of V T E (Cr os b y et al 2 0 1 3 ). H u ma n ge netic e pi de mi ol o g y data mea n w hile s u g gest 
t hat re d uci n g F XI  le vels b y  8 0 %  or  m ore  are ass ociate d  wit h  a re d uce d i nci d e nce of  str o ke a n d 

A nt h os  T hera pe utics  
Pa ge 2 9  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
V T E ( Sal o m o n et al 2 0 0 8,  Sal o m o n et al 2 0 1 1 , Preis et al 2 0 1 7 ). I n cli nical st u dies of a ge nts 
t hat t ar get F XI,  F XI  re d ucti o n b y  a p pr o xi mat el y  5 0 %  wit h  eit her a F XI -A S O  or  a m o n ocl o nal 
a nti b o d y dire cte d a gai nst F XIa were ass ociate d wit h si milar a ntit hr o m b oti c effica c y t o 
e n o xa pari n, w hil e i n hi biti o n of F XI b y a p pr o xi matel y 8 0 % or m ore was ass ociat e d wit h 
s u peri or a ntit hr o m b otic effica c y  c o m p are d  t o e n o x a p ari n  i n patie nts  u n der g oi n g  el ecti v e T K A 
(B üller et al 2 0 1 5 ; Weitz et al 2 0 2 0 ). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he D M C will o nl y re c o m me n d pr oce e di n g t o t he e xte nsi o n if t he saf et y a n d be nefit:ris k of 
t he 1 5 0 m g d ose of a b ela ci m a b is fa v ora bl e as c o m p ar e d t o ri var o xa b a n. T his d ose r eca pit ul ates 
w hat is see n i n pati e nts wit h se vere Fact or XI defici e nc y a n d is t he d ose bei n g i n v esti gate d i n 
se veral o n g oi n g P hase 3 pi v otal trials. Pati e nts w h o were ra n d o miz e d t o t he 1 5 0 m g d ose will 
re mai n o n t hat d ose. 
 
 
3. 4  
R ati o n ale  f or c h oice  of  c o m p ar at or 
Ri var o xa ba n, a direct fact or Xa i n hi bit or, will be t h e c o m par at or a ntic oa g ula nt a ge nt i n t his 
st u d y. Hist oricall y, warfari n has be e n t he sta n dar d of care a nti c oa g ul a nt f or p ati e nts wit h A F. 
Warfari n, h o we ver, h as a narr o w t h era pe utic ra n ge, re q uires fre q ue nt l a b orat or y m o nit ori n g, 
a n d is c o m m o nl y n ot use d i n hi g h er ris k A F pati e nts d ue t o t he ris k of blee di n g. B y c o ntr ast, 
ri var o xa ba n is o ne of t he m ost wi d el y use d D O A Cs a n d d oes n ot re q uire re g ular l a b orat or y 
m o nit ori n g.  
Ri var o xa ba n has be e n a p pr o ve d f or t h e re d u cti o n of str o ke a n d s yste mi c e m b olis m i n A F. 
Ri var o xa ba n  was  de m o nstr ate d  t o be  n o n -i nf eri or t o warfari n  i n re d uci n g t he ris k of  str o ke a n d 
s yste mic e m b olis m a n d was  n ot  si g nifica ntl y differe nt  fr o m warfari n  i n t he i nci de nc e of  maj or 
or cli ni call y r ele va nt n o n -maj or bl ee di n g e ve nts i n t he R O C K E T -A F st u d y ( Patel et al 2 0 1 1 ). 
C o m pare d t o warfari n, patie nts rec ei vi n g ri var o x a ba n ha d si g nifi ca ntl y l o wer rat es of 
i ntracr a nial he m orr ha g e a n d fatal blee di n g e ve nts. 
3. 5  
R ati o n ale f or E xte nsi o n Peri o d  
T he e xt e nsi o n peri o d will pr o vi de t he o p p ort u nit y t o c olle ct l o n g-ter m data o n a b ela ci m a b use 
a n d all o w patie nts access t o a b ela ci m a b pri or t o its mar keti n g a ut h orizati o n.  
 
 

A nt h os  T hera pe utics  
Pa ge 3 0  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
4  
P o p ul ati o n  
A p pr o xi matel y 1 2 0 0 patie nts 
wit h 
A F at 
m o d erate -t o-hi g h ris k of str o ke i n 
w h o m 
a ntic o a g ulati o n t h era p y is i n di cat e d a n d pla n ne d f or t he d ur ati o n of t he st u d y will be 
ra n d o mize d. 
4. 1  
I ncl usi o n criteri a 
Patie nts  eli gi ble f or i ncl usi o n i n t his st u d y m ust  f ulfill all  t he f oll o wi n g criteria: 
1.  A ble  t o pr o vi de  writte n  i nf or me d c o nse nt bef ore  a n y st u d y assess me nt  is perf or me d  
2.  Male  a n d fe male patie nts ≥ 5 5  years  ol d  
3.  Hist or y  of  A F  or  atrial fl utter wit h  pl a n ne d  i n defi nit e a ntic oa g ulati o n.  Patie nts  wit h  ne wl y 
dia g n ose d A F ar e eli gi bl e.  
4.  A  C H A 2D S 2-V A S c  of  ≥4  O R  
A  C H A 2D S 2-V A Sc  of  ≥3  wit h  at least 1 of  t he f oll o wi n g: 
a. Pla n ne d c o nc o mit a nt use of a nti platel et m e dic ati o n use (i.e., as piri n a n d/ or P 2 Y 1 2 
i n hi bit or) f or t he d urati o n of t h e trial 
b.  Cr Cl  ≤5 0  ml/ mi n  b y  t he C oc kcr oft -Ga ult  e q u ati o n  (s ee Secti o n  5. 3. 3 ) 
4. 2  
E xcl usi o n criteri a  
Patie nts  f ulfilli n g a n y of  t he f oll o wi n g criteria are n ot  eli gi ble f or i ncl usi o n i n t his st u d y: 
1.  Use of ot her i n vesti g ati o n al dr u gs wit hi n 5 half -li v es pri or t o e nr oll me nt or u ntil t h e 
e x pect e d p har ma c o d y na mic eff ect h as ret ur ne d t o baseli ne, w hic h e ver is l o n g er  
2.  Hist or y of h y perse nsiti vit y t o a n y of t he st u d y dr u gs (i ncl u di n g ri var o xa b a n) or its 
e xci pi e nts, t o dr u gs of si milar c he mi cal cl asses, or a n y c o ntrai n di cati o n liste d i n t he l a bel 
f or ri var o xa ba n ( See Se cti o n 6. 7. 1  f or e xa m ples) 
3.  Patie nts  wit h  a n i ntracr a nial or  i ntra oc ular ble e d  wit hi n  t he 3  m o nt hs  pri or  t o scree ni n g 
4.  Cli nic all y  si g nifica nt mitral  ste n osis ( val ve area  < 1. 5  c m 2) 
5.  Mec ha nic al  heart  v al ve  or  ot her  i n di cati o n f or a nti c oa g ulati o n  t her a p y ot her  t ha n 
atrial fi brillati o n (e. g., ve n o us t hr o m b oe m b olis m)  
6.  K n o w n  prese nce  of  a n atrial m y x o ma or  left ve ntri c ular  t hr o m b us 
7.  Hist or y  of  left atrial a p pe n da g e cl os ure or  re m o val 
8.  Acti ve  e n d ocar ditis 
9.  S yst olic  B P  > 1 8 0  m m  H g  or  diast olic  B P  > 1 0 0  m m  H g  o n  re peate d m eas ure me nts  
at scree ni n g 
1 0.  Pla n ne d  i n vasi v e pr oce d ure  wit h  p ote ntial  f or u nc o ntr olle d  blee di n g  (e. g., maj or  s ur ger y) 
1 1.  A n y  str o ke wit hi n  1 4  da ys  bef ore  ra n d o mizati o n or  TI A  wit hi n  3  da ys  bef ore  ra n d o mizati o n 
1 2.  A  Cr Cl  < 1 5  m L/ mi n  or  o n  dial ysis  at t he ti me of Scree ni n g  
1 3.  Platel et  c o u nt ≤7 0, 0 0 0/ m m 3 at t he Scr ee ni n g  Visit  
1 4.  He m o gl o bi n  < 8  g/ d L  at  t he Scre e ni n g  Visit  
1 5.  a P T T or P T > 1. 5 x t he u p per li mit of n or m al ( U L N) at t he Scre e ni n g Visit, if t he patie nt 
is n ot o n a n a ntic oa g ula nt 
1 6.  W o me n of c hil d -b eari n g p ot e nti al ( W O C B P), defi ne d as all w o me n p h ysi ol o gic all y 
ca pa bl e of bec o mi n g pr e g na nt, u nl ess t he y a gree t o use hi g hl y effecti ve met h o ds of 
c o ntrac e pti o n d uri n g t h eir partici pati o n i n t h e trial a n d f or at least 1 0 wee ks after t he last 
d ose of a belaci ma b f or w o me n ra n d o mize d t o a belaci ma b. Hi g hl y effe cti v e c o ntrac e pti o n 
met h o ds i ncl u de:  
• T otal  a bsti ne nc e  ( w he n t his is i n li ne wit h  t he pref err e d  a n d us ual  lifest yl e of  t he patie nt). 
Peri o dic a bsti ne nc e (e. g., cale n dar, o v ulati o n, s y m pt ot her m al, p ost -o v ulati o n met h o ds) 
a n d wit h dra wal are n ot a cce pta bl e met h o ds of c o ntra ce pti o n  

A nt h os  T hera pe utics  
Pa ge 3 1  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
• Fe m ale sterili zati o n ( ha ve ha d s ur gic al bil ater al o o p h orect o m y 
wit h or 
wit h o ut 
h ysterect o m y) t o t al h yst erect o m y or t u bal li gati o n at l east si x we e ks bef ore ta ki n g 
i n vesti gati o nal dr u g. I n c ase of o o p h orect o m y al o ne, o nl y w he n t he re pr o d ucti ve stat us 
of t he w o ma n has be e n c o nfir m e d b y f oll o w u p h or m o ne le vel assess me nt  
• Male sterilizati o n of se x ual pa rt n er (at least 6 m o nt hs pri or t o scree ni n g). F or fe m al e 
patie nts i n t he st u d y, t he v asect o miz e d male p art ner s h o ul d be t h e s ole part n er f or t h at 
patie nt  
• Use of oral (estr o ge n a n d pr o gester o ne), i njecte d or i m pl a nte d h or m o n al met h o ds of 
c o ntrac e pti o n or pla ce m e nt of a n i ntra uteri n e de vi ce (I U D) or i ntra uteri ne s yste m (I U S) 
or ot her f or ms of h or m o nal c o ntrace pti o n t hat h a ve c o m para ble efficac y (fail ur e rat e < 
1 %),  f or e xa m ple h or m o ne  v a gi nal  ri n g or  tra ns der mal h or m o ne  c o ntra ce pti o n.  H or m o nal 
c o ntrac e pti v e 
met h o ds s h o ul d n ot be use d or e nc o ura ge d if c o nsi dere d t o b e 
c o ntrai n dicate d. I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble o n 
t he sa me pill f or a mi ni m u m of 3 m o nt hs bef ore t a ki n g i n vesti gati o nal dr u g. 
W o me n  are c o nsi dere d  p ost -m e n o pa usal  a n d n ot  of  c hil d-beari n g  p ote nti al  if t h e y ha ve  ha d 
1 2 m o nt hs of nat ural (s p o nta ne o us) a me n orr he a wit h a n a p pr o priate cli nic al pr ofil e (e. g., 
a ge a p pr o priate, hist or y of v as o m ot or s y m pt o ms) or ha ve ha d s ur gical bilateral 
o o p h orec t o m y ( wit h or  wit h o ut  h yster ect o m y),  t ot al h ysterect o m y  or  t u b al li gati o n at le ast 
si x wee ks  a g o. I n t he case of  re p orte d me n o pa usal  stat us or  o o p h orect o m y  al o ne,  o nl y  w he n 
t he re pr o d ucti ve st at us of t he w o m a n has bee n c o nfir me d b y f oll o w u p h or m o ne l e vel 
assess me nt wit h  f ollicl e sti m ul ati n g h or m o n e  ( F S H) is s he c o nsi dere d  n ot  of  c hil d-beari n g 
p ote ntial.  
1 7.  Se x uall y a cti v e males wit h f e male part ners w h o are W O C B P m ust a gree t o use a c o n d o m 
or use ot her relia ble birt h c o ntr ol m et h o ds d uri n g t heir ti me i n t he st u d y a n d s h o ul d n ot 
fat her a c hil d or d o nate s per m d uri n g t he st u d y p eri o d 
1 8.  Hist or y  of  dr u g  a d dicti o n  or  alc o h ol a b use i n t h e past  2  years,  as  j u d ge d b y  t he I n vesti gat or 
1 9.  Si g nifica nt ill ness w hic h has n ot res ol v e d wit hi n t w o ( 2) wee ks pri or t o t he start of t he 
st u d y dr u g 
2 0.  A n y me dical or ps yc hiatric c o n diti o n w hic h i n t h e j u d g me nt of t he I n vesti gat or ma y 
precl u de p ati e nts of c o m pl yi n g wit h st u d y re q uire m e nts f or t he d urati o n of t he st u d y  
4. 3  
E xte nsi o n peri o d i ncl usi o n crite ri a  
Patie nts  eli gi ble f or i ncl usi o n i n t he e xte nsi o n peri o d m ust  f ulfill all t he f oll o wi n g criteria: 
1.  O n g oi n g  st u d y treat me nt f or t he ra n d o mize d p art of t he trial at t he E o T visit  
2.  A ble t o pr o vi de writte n i nf or me d c o nse nt t o e nter t h e exte nsi o n p eri o d  
4. 4  
E xte nsi o n peri o d e xcl usi o n criteri a  
Patie nts  f ulfilli n g a n y of  t he f oll o wi n g criteri a are n ot  eli gi ble  f or i ncl usi o n i n t he e xte nsi o n 
peri o d : 
1.  Hist or y of h y perse nsiti vit y t o a b ela ci ma b  
2.  Patie nts wit h a n i ntr acra nial or i ntra oc ular bl ee d wit hi n t he 3 m o nt hs pri or t o E o T  
3.  Cli nic all y si g n ific a nt mitral ste n osis ( val v e area < 1. 5 c m 2) 
4.  Mec ha nic al heart val ve or ot her i n di cati o n f or a nti c oa g ulati o n t hera p y ot her t ha n atri al 
fi brill ati o n ( e. g., ve n o us t hr o m b o e m b olis m) 
5.  K n o w n prese nce of a n atri al m y x o ma or l eft ve ntric ular t hr o m b us  
6.  Hist or y of left atrial a p pe n da g e cl os ure or r e m o val  
7.  Acti ve e n d o car ditis  
8.  S yst olic B P > 1 8 0 m m H g or diast olic B P > 1 0 0 m m H g o n re peate d me as ure me nts   
9.  Pla n ne d i n v asi ve pr oc e d ure wit h p ot e nti al f or u n c o ntr olle d blee di n g (e. g. maj or s ur ger y)  

A nt h os  T hera pe utics  
Pa ge 3 2  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
1 0.  A n y str o ke wit hi n 1 4 da ys bef ore E o T  or TI A wit hi n 3 da ys bef ore E o T  
1 1.  Platel et c o u nt ≤7 0, 0 0 0/ m m 3  
1 2.  He m o gl o bi n < 8 g/ d L  
1 3.  W o me n of c hil d -be ari n g p ote ntial ( W O C B P)  as descri be d i n Secti o n 4. 2.  
1 4.  Se x uall y a cti v e m ales wit h f e male part ners w h o are W O C B P m ust a gree t o use a c o n d o m 
or u se ot her relia bl e birt h c o ntr ol met h o ds d uri n g t h eir ti me i n t he st u d y a n d s h o ul d n ot 
fat her a c hil d or d o nate s per m d uri n g t he st u d y p eri o d 
1 5.  Hist or y of dr u g a d dicti o n or alc o h ol a b use i n t h e past 2 years, as j u d ge d b y t h e 
I n vesti gat or 
1 6.  Si g nifica nt ill ness w hic h has n ot res ol v e d wit hi n t w o ( 2) wee ks pri or t o t he E o T  
1 7.  A n y me dical or ps yc hiatri c c o n diti o n w hic h i n t he j u d g me nt of t he I n vesti gat or ma y 
precl u de p ati e nts of c o m pl yi n g wit h st u d y re q uire m e nts f or t he d urati o n of t he st u d y  
 
5  
Pr oce d ures a n d assess me nts  
Patie nts s h o ul d be se e n f or all visits/ assess me nts as o utli ne d i n t he Assess me nt Sc he d ule 
(A p pe n di x  3 ) wit hi n  t he per mitt e d  visit  wi n d o ws.  All  ra n d o mi ze d p ati e nts  will  be  f oll o we d 
u ntil t h e E o S visit, e ve n if t he y pre mat urel y disc o nti n ue d st u d y dr u g (see Secti o n 6. 5 ). 
5. 1  
I nf or m e d c o nse nt pr oce d ures 
Eli gi ble patie nts ma y o nl y b e i ncl u de d i n t he st u d y after pr o vi di n g writt e n ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n) I nstit uti o nal Re vie w B oar d (I R B) or Et hics C o m mittee ( E C)- 
a p pr o ve d i nf or m e d c o nse nt.  
A nt h os T hera pe uti cs or a dele gate o n t heir be h alf will pr o vi de t o i n vesti gat ors a pr o p ose d 
i nf or me d c o nse nt f or m (I C F) t hat c o m plies wit h t h e I C H E 6 G o o d Cli nical Practice ( G C P) 
g ui deli n e a n d re g ulat or y r e q uire me nts a n d is c o nsi d ere d a p pr o pri ate f or t his st u d y. T he I C F 
als o i ncl u des a  secti o n rel ate d t o o pti o nal  f ut ur e resear c h w hic h  will  r e q uire a se parate  si g nat ur e 
if t he patie nt a grees t o f ut ure researc h. A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d 
b y  t he I n vesti gat or m ust  be  a gree d  t o b y  A nt h os  T hera pe uti cs  bef ore  s u b missi o n t o t he I R B or 
E C.  
I nf or mati o n a b o ut c o m m o n si de effe cts alre a d y k n o w n a b o ut t he i n vesti gati o nal dr u g ca n b e 
f o u n d i n t he I B. I nf or mati o n a b o ut c o m m o n  si de eff e cts  alre a d y  k n o w n  a b o ut ri var o x a ba n c a n 
be f o u n d i n t he S u m mar y of Pr o d uct C harac teristi cs [ Xarelt o®  (ri var o xa b a n) S m P C ] a n d 
Prescri bi n g I nf or mati o n [ Xarelt o ®  (ri var o x a ba n) –  Pac ka ge I nsert ]. T his i nf or mati o n is 
i ncl u de d i n t he patie nt i nf or me d c o nse nt a n d s h o ul d be disc usse d wit h t he pati e nt d uri n g t h e 
st u d y as nee de d. A n y ne w i nf or m ati o n r e gar di n g t he safet y pr ofile of t he i n vesti g ati o nal dr u g 
t hat is i de ntifie d bet wee n  I B u p dat es  will  be  c o m m u nicat e d  as  a p pr o priate,  f or e xa m ple,  via  a n 
I n vesti gat or N otific ati o n  or  a n A g gre gate  Saf et y  Fi n di n g.  Ne w  i nf or mati o n w hi c h  res ults i n a n 
u p date t o t he i nf or me d c o nse nt m ust be disc usse d wit h t he patie nt.  
E ns ure  patie nts  are i nf or me d of  t he c o ntra ce pti o n  r e q uire m e nts o utli ne d  i n t h e Secti o n  4. 2  
( E xcl usi o n criteria). 
A se parate o pti o nal c o nse nt f or m f or t h e c ollecti o n of 
 will als o be 
offere d t o patie nts.  
A  c o p y of  t he a p pr o ve d  versi o n  of  all c o nse nt f or ms m ust be  pr o vi de d  t o t he 
 
after I R B/ E C a p pr o val.  

A nt h os  T hera pe utics  
Pa ge 3 3  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
5. 2  
P atie nt scree ni n g  
D uri n g  t he scree ni n g peri o d,  patie nts  will  u n der g o  a me dic al  hist or y  a n d p h ysical  e xa mi nati o n 
i ncl u di n g c olle cti o n of vit al si g ns a n d a 1 2-lea d E C G. Bl o o d a n d uri ne sa m ples will be ta k e n 
f or cli nical la b orat or y testi n g a n d ot her  scree ni n g assess me nts.  If a scre e ni n g la b orat or y res ult 
is o utsi de  eli gi bilit y  re q uire m e nts, t h ose la b orat or y t ests w hic h  di d  n ot  meet  eli gi bilit y  crit eria 
ma y be re -t este d. All res ults m ust be a vaila bl e pri or t o ra n d o miz ati o n f or t h e pati e nt t o be 
e nr olle d i n t he st u d y.  
I n ge neral, it is per missi ble t o re-scre e n a pati e nt if s/ he fails t he i niti al Scree ni n g or falls o ut 
of  t he scree ni n g wi n d o w  ti meli nes. A  ne w  scree ni n g n u m ber  will  be  assi g ne d  t o a patie nt  w h o 
is re-scree ne d, t h us n o scree ni n g n u m ber will be use d t wice. Re -testi n g of la b orat or y tests, 
w hic h di d n ot meet eli gi bilit y crit eria, wit hi n t he s cree ni n g wi n d o w d oes n ot c o nstit ut e re - 
scree ni n g as it is per mitt e d wit hi n a scree ni n g wi n d o w. 
Reas o ns  f or screen  fail ur e will  b e  d oc u m e nte d  i n t he site l o g. A d diti o n all y,  d e m o gra p hic  data, 
reas o n f or scree n fail ure (i ncl usi o n/ e xcl usi o n) a n d seri o us a d verse e ve nt ( S A E) data - as 
a p plic a ble - will  be  c ollect e d  i n t he cli nical data base  fr o m patie nts  w h o  are c o nsi dere d  scree n 
fail ures. A d verse e ve nts fr o m scree n fail ures, w hic h are n ot c o nsi der e d t o b e S A Es, will be 
f oll o we d b y t he i n vesti g at or a n d c olle cte d o nl y i n t h e s o urce dat a. 
F or a n y q uesti o ns a b o ut patie nt eli gi bilit y or scree ni n g pr o ce d ures, t he i n vesti gat or is  
e nc o ura ge d t o c o ntact 
 
 
 
 
 
P atie nt  de m o gr a p hics/ ot her  b aseli ne  c h ar acteristics 
De m o gra p hic a n d baseli ne c haracteristic dat a will be c olle cte d o n all ra n d o mize d patie nts. 
Rele va nt me di cal hist or y/c urre nt m e dic al c o n diti o ns a n d c o nc o mita nt me dic ati o ns prese nt 
bef ore si g ni n g of t h e i nf or m e d c o nse nt will als o be r ec or de d.  
I n vesti gat ors ha v e t he discr eti o n t o rec or d a b n or mal t est fi n di n gs o n t he me di cal hist or y 
electr o nic case re p ort f or m (e C R F), if i n t heir j u d g m e nt, t he test a b n or malit y  was  prese nt  pri or 
t o t he i nf or me d c o nse nt si g nat ure. 
Baseli ne  C H A₂ D S ₂-V A Sc  sc ore c o m p o ne nts  a n d a ntic oa g ula nt-naï ve  stat us will  be  c ollecte d i n 
t he cli nic al data base. F or t h e p ur p oses of t his st u d y, a patie nt will b e c o nsi der e d a ntic oa g ula nt-
naï ve if, i n t h eir me di cal hist or y, t he y ha ve n ot bee n treate d wit h a nti c oa g ul a nt t hera p y, e. g., 
V K A, D O A C, or pare nteral a ntic o a g ula nt t her a p y, f or m ore t ha n 6 0 c o nti n u o us da ys at a n y 
ti me. 
 
Hei g ht  a n d  wei g ht  
Hei g ht  i n ce nti meters  (c m) a n d b o d y  wei g ht  [t o t he n e arest  0. 1  kil o gra m  ( k g) i n i n d o or cl ot hi n g, 
b ut wit h o ut  s h oes] will be meas ure d  as part of  t he p h ysical e x a mi n ati o n at t h e scree ni n g visit. 
 
B MI  will  be  calc ul ate d  b y  t he E D C  s yste m usi n g  t he f oll o wi n g f or m ula: 
B MI = B o d y wei g ht ( k g) / [ Hei g ht ( m)] 2  
B MI  res ults will  be  d oc u m e nte d  i n t h e e C R F t o 2  deci mal  places.  
 

A nt h os  T hera pe utics  
Pa ge 3 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
 
He p atitis scre e n, HI V scree n  
All patie nts will be scree ne d f or HI V, He patitis B  a n d C. I n t he e ve nt a pati e nt is re -scree n e d, 
t hese tests d o n ot h a ve t o b e re peate d. 
5. 3  
B aseli ne S afet y  
 
P h ysic al  e x a mi n ati o n  
A p h ysical e xa mi n ati o n will i ncl u d e t he e xa mi nati o n of ge neral a p p eara nc e, s ki n, nec k 
(i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l y m p h n o des, 
e xtre miti es, m usc ul os kel etal, vasc ular, a n d ne ur ol o gi cal.  
I nf or mati o n fr o m all p h ysical  e xa mi nati o ns  m ust  be  r ec or de d as  a part  of  s o urce d oc u me nt ati o n 
at t he st u d y site. Si g nific a nt  fi n di n gs t hat were  pr ese nt  pri or  t o t he p ati e nt  si g ni n g t he i nf or me d 
c o nse nt will  be  d o c u me nte d  i n t he Me di cal  Hist or y  p art  of  t he e C R F. Si g nifica nt  fi n di n gs m a de 
after starti n g t he st u d y dr u g, w hic h meet t he defi niti o n of a n A E will be rec or de d o n t he A E 
secti o n of t h e e C R F. 
 
Vit al  si g ns 
Vital si g ns will i ncl u de t he c oll ecti o n of b o d y t e m p erat ure (rec or d e d i n ° C), bl o o d press ure 
( B P) a n d p ulse meas ure me nts. 
 
L a b or at or y  e v al u ati o ns  
Details re gar di n g c oll ecti o n m et h o ds a n d pr ocessi n g are o utli ne d i n t h e Ce ntral La b orat or y 
Ma n ual.  D uri n g  t he e xte nsi o n peri o d, all safet y la b orat or y e val u ati o ns will b e  perf or me d  
l ocall y. 
Cli nic all y  rel e va nt de vi ati o ns  of  la b orat or y test res ults occ urri n g  d uri n g  or  at c o m pleti o n  of  t he 
st u d y s h o ul d be e val u ate d f or criteri a defi ni n g a n A E a n d r e p orte d as s uc h if t he criteri a are 
met.  Re pe ate d  e val u ati o ns  are m a n dat or y  u ntil  n or malizati o n  of  t he res ult(s) or  u ntil  t he c ha n g e 
is n o l o n ger cli nic all y r ele va nt. 
Cli nic all y si g nifi ca nt a b n or m alities m ust be rec or d e d o n t h e rele va nt secti o n of t he e C R Fs 
ca pt uri n g Me dical hist or y/ C urre nt me dical c o n diti o ns/ A Es.  
He m at ol o g y  
He m o gl o bi n,  he mat o crit,  r e d bl o o d  cell ( R B C) c o u nt,  mea n  c or p usc ular  v ol u me  ( M C V), me a n 
c or p usc ular he m o gl o bi n ( M C H), mea n c or p usc ular he m o gl o bi n c o nce ntrati o n ( M C H C), re d 
cell distri b uti o n wi dt h ( R D W), w hite bl o o d c ell ( W B C) c o u nt wit h differe ntials a n d plat elet 
c o u nt will b e me as ure d.  
Cli nic al  c he mistr y  
S o di u m, p otassi u m, cr eati ni ne, B U N/ ure a, uric aci d, c hl ori d e, al b u mi n, c alci u m, al kali ne 
p h os p hatase, t ot al bilir u bi n, bi car b o nate/ H C O 3, A S T, A L T, gl uc ose, t ot al c h olester ol, a n d 
tri gl yc eri des will  b e  meas ure d.  If t h e t ot al bilir u bi n  c o nce ntr ati o n  is > 2 x  t h e U L N,  direct  a n d 
i n direct rea cti n g bilir u bi n s h o ul d be differ e nti ate d. 
F or  t h e p ur p oses  of  t his st u d y, cr eati ni ne cle ara nc e ( Cr Cl) will  be  esti mate d  b y  t he C oc kcr oft - 
Ga ult e q uati o n as f oll o ws:  
 

A nt h os  T hera pe utics  
Pa ge 3 5  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
Cr Cl  (ml / mi n )  =  
(1 4 0  − a g e ) x  w ei g ht  (k g )
7 2  x  s er u m Cr e ati ni n e  (m g / d L )  x  0 .8 5  (𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒) 
 
C o a g ul ati o n  pr ofile  
Sa m ples f or sta n dar d a P T T as well as P T/I N R will be c olle cte d at t h e visits n ote d i n t he 
assess me nt sc he d ul e. T h e res ults of t hese tests will b e bli n d e d t o sit e staff d uri n g t he tre at m e nt  
peri o d,  b ut  a v ail a ble d uri n g  t he scre e ni n g a n d p ost -tr eat m e nt f oll o w u p  peri o d.  
Uri n al ysis  
Uri ne  will  be  c oll ect e d  f or m eas ure me nts  f or s pecifi c gra vit y,  pr ot ei n,  gl uc ose,  a n d bl o o d  will 
be perf or me d. Mi cr osc o p y, W B C, R B C, a n d se di m e nts will als o be assesse d i n c ase of a n 
a b n or mal di pstic k test.  
 
Electr o c ar di o gr a m  ( E C G) 
E C Gs  m ust  be  c oll ect e d,  i nter pr ete d l ocall y b y  a q ualifie d  p h ysicia n,  a p pr o priatel y  si g n e d, a n d 
arc hi ve d at t h e st u d y site.  
 
Pre g n a nc y  a n d  assess me nts  of  fertilit y 
All  fe male st u d y parti ci pa nts  will  ha ve  ser u m pre g na nc y  testi n g at scr ee ni n g. W o me n  w h o  are 
p ost -me n o pa usal or w h o ha ve ha d o o p h orect o m y wit h o ut h ystere ct o m y will ha ve h or m o nal 
stat us c o nfir m e d at scr ee ni n g b y F S H. 
Fe m ale st u d y p arti ci pa nts w h o are c o nsi dere d t o be W O C B P after t he scre e ni n g peri o d will 
c o nti n ue t o ha ve l ocal uri ne pr e g na nc y t esti n g t hr o u g h o ut t he st u d y as per t he Assess me nt 
Sc he d ule ( A p pe n di x 3 ); a d diti o nal pre g n a nc y testi n g m a y be perf or m e d t o me et l ocal 
re q uire m e nts. Patie nts  will  n ot  rec ei ve st u d y me dicati o n  if t he res ults of  t he pre g na nc y  test are 
p ositi ve.  
5. 4  
Cli nic al E n d p oi nts  
 
Blee di n g  
All s us pecte d blee di n g e ve nts eit h er re p ort e d b y t h e s u bject or o bser ve d b y t he I n vesti gat or 
s h o ul d be rec or de d. 
O vert blee di n g e ve nts will be a dj u di cat e d a n d/ or classifie d  b y a n i n d e pe n de nt a n d bli n de d  C E C  
(Secti o n 3. 1. 6 ). T he C E C will classif y bl ee di n g e v e nts i n acc or d a nce wit h t he I nter nati o nal 
S ociet y o n T hr o m b osis a n d Hae m ostasis (I S T H) defi niti o ns a n d g ui d a nce ( Kaatz et al 2 0 1 5 ). 
T he defi niti o ns will be detaile d i n t he C E C C harter.   
T he details of all re p orte d ble e di n g e ve nts will be s u b mitt e d t o t he C E C as descri be d i n t h e 
e n d p oi nt re p orti n g g ui d eli n es. T hese det ails m a y i ncl u de, b ut are n ot li m it e d t o, 
• L ocati o n  of  t he blee di n g  
• D urati o n  of  t he blee di n g  
• Treat me nt of t he ble e di n g e ve nt i ncl u di n g n ot es or s u m maries of rec o m me n d ati o ns 
fr o m a h ealt hcar e pr ofessi o nal fr o m w h o m m e dic al treat me nt was o bt ai ne d s uc h as 
ot olar y n g ol o g y c o ns ults  f or ear, n ose, or t hr oat blee ds; ur ol o g y c o ns ults f or he mat uri a 
or ur o ge nital tra ct blee ds; s ur gical c o ns ults f or s ki n, s oft tiss ue, or i nter nal blee ds; 

A nt h os  T hera pe utics  
Pa ge 3 6  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
g y nec ol o g y  c o ns ults  f or uteri n e  or  v a gi nal  bl ee ds;  ne ur ol o g y  or  ne ur os ur gic al  c o ns ults 
f or i ntracr a nial blee ds; or op ht hal m ol o g y c o ns ults f or oc ular bl ee ds  
• N u m ber  of  bl o o d  pr o d uct  tra nsf usi o ns 
• Ma g nit u de  of  t h e blee di n g  (e. g., size if s ki n or  s u bc uta ne o us he mat o ma)  
• He m o gl o bi n ( H b) le v els at t he ti me of t h e ble e di n g e ve nt, l o west val ue, pre - a n d p ost- 
tra nsf usi o n val ues, a n d after res ol uti o n of t h e ble e di n g e ve nt 
• A n y  dia g n ostic  t ests d o ne  t o e v al uate t he ble e di n g  s uc h as e n d osc o p y f or 
gastr oi ntesti nal ( GI) bl ee ds  
• A n y dia g n ostic i ma gi n g, e. g., x -ra y, c o m p ute d t o m o gra p h y ( C T), ma g n eti c res o na nce 
i ma gi n g (M RI), or ultras o u n d, perf or me d t o e val uat e t he ble e di n g  
• A n y ot her i nf or mati o n t h at c o ul d be of hel p t o t he C E C i n a dj u dicati n g t h e ble e di n g  
e ve nt. 
 
E n d p oi nt  Re p orti n g  G ui deli nes  will  pr o vi de  d etail e d  i nstr ucti o ns f or sites o n  t h e 
d oc u me nt ati o n, d ata c olle cti o n, a n d re p orti n g re q uir e d f or eac h s us pecte d blee di n g e ve nt.  
 
Effic ac y  
T he  i n de p e n de nt a n d bli n de d  C E C  will  a dj u dic ate a n d classif y  t he f oll o wi n g e ve nts: 
• Isc he mic str o ke 
• Tra nsie nt  isc he mic attac k  ( TI A) 
• N o n -C N S  (s yste mic) arterial  e m b olic e ve nts 
• M y ocar dial  i nfar cti o n ( MI) 
• Ve n o us  t hr o m b oe m b olis m ( V T E) e ve nts 
• Deat h  
A dj u dicat e d res ults will be use d f or t he fi nal a nal ysis. Defi niti o ns a n d f urt her details will be 
d oc u me nt e d i n t h e C E C c h arter.  
5. 5  
Ot her assess m e nts  
 
P h ar m ac o ki netics  
Bl o o d sa m pl es f or P K will b e c olle cte d bef ore a d mi nistrati o n of st u d y dr u g o n st u d y visits as 
defi ne d  i n t he Assess me nt  Sc he d ule  (A p pe n di x  3 ). C o nce ntrati o ns  of  plas ma  t otal a belaci ma b 
(i.e., a bela ci m a b t hat is b o u n d t o F XI or n ot b o u n d t o F XI) will be deter mi ne d b y a vali d ate d 
L C -M S/ M S met h o d. A detaile d descri pti o n of t he m et h o d use d t o q ua ntif y t he c o nce ntr ati o n 
of  t otal a bela ci m a b  will  be  i ncl u de d i n t he bi oa n al yti cal ra w data  a n d i n t he Bi oa nal ytic al  Data 
Re p ort. All c o nc e ntrati o ns bel o w t he L L O Q or missi n g data will be la bele d as s uc h i n t he 
c o nce ntr ati o n d ata listi n gs.  
F oll o w  i nstr ucti o ns o utli ne d i n t he Ce ntral L a b orat or y Ma n ual re g ar di n g sa m ple c oll ecti o n, 
n u m beri n g, pr oc essi n g, a n d s hi p me nt.  

A nt h os  T hera pe utics  
Pa ge 3 7  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
 
P h ar m ac o d y n a mic  assess me nts  
P D  sa m ples will  be  c ollecte d  at t he ti me p oi nts defi n e d  i n t he assess me nt  sc he d ule. I nstr ucti o ns 
f or bi o-sa m ple pr o cessi n g will b e c o nt ai ne d i n t he Ce ntral L a b orat or y Ma n u al re g ar d i n g sa m ple 
c olle cti o n, n u m beri n g, pr o cessi n g, a n d s hi p me nt.  
P D  Bi o mar kers  i ncl u di n g b ut  n ot  li mite d t o t he f oll o wi n g ma y  be  st u die d: 
• Free  F XI  –  F XI  t hat is n ot  b o u n d  t o a b ela ci m a b will  be  meas ure d  i n plas ma  
• T otal  F XI  –  F XI  t hat is eit her b o u n d  t o a b ela ci m a b  or  free will  be  me as ure d  i n plas ma  
• a P T T 
 
 
 
A  detail e d  descri pti o n  of  t he assa y  m et h o ds  will  be  i ncl u de d i n t he Bi oa n al ytical  Data  Re p ort.  
 
I m m u n o ge nicit y 
A n i m m u n oassa y -base d met h o d will be use d t o det ect a nti -a bel aci ma b a nti -dr u g a nti b o di es 
( A D As). T he  a nal ytical met h o d  will  be  descri be d  i n detail  i n t he I G Bi oa nal yti cal  Dat a  Re p ort. 
I G sa m ples will b e c olle cte d bef ore a d mi nistrati o n of st u d y dr u g o n st u d y visits as defi n e d i n 
t he Assess me nt sc he d ule (A p pe n di x 3 ). 
F oll o w i nstr ucti o ns o utli n e d i n t he Ce ntral La b orat or y Ma n ual re gar di n g sa m ple c olle cti o n, 
n u m beri n g, pr oc essi n g, a n d s hi p me nt.  
 
A d diti o n al  bi o m ar kers  ( bl o o d) 
A d diti o nal  bl o o d  sa m ples will  be  c olle cte d  at  ti me p oi nts def i n e d i n t h e Assess me nt  sc he d ule 
a n d ba n ke d f or p ot e nti al f ut ure e x pl orat or y a nal ysis ( A p pe n di x 3 ). 
A d diti o nal  bi o mar kers  ma y  i ncl u d e, b ut  are n ot  necessaril y  li mite d t o: 
• 
 
 
 
 
 
T he  list ma y  be  c ha n ge d  or  e x pa n d e d  f urt h er, as  it is rec o g nize d t hat m or e  rel e va nt or  n o v el 
bi o mar kers ma y be disc o v ere d d uri n g t he c o n d u ct of  t he st u d y. T his ma y be c o n d ucte d i n a 
s u bset of patie nts. 
 
 
 
 
 
 
 
 
 
 
 

A nt h os  T hera pe utics  
Pa ge 3 8  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 6  
 
 
 
 
 
 
 
6  
Tre at me nt  
6. 1  
St u d y tre at m e nt  
F or  m ore  det ails  ple ase  refer t o t he P har m ac y  Ma n ual.  
 
A bel aci m a b  ( M A A 8 6 8) 
A nt h os  T hera pe utics,  or  a dele g ate  w or ki n g  o n  t heir be half,  will  pr o vi de  A belaci ma b  
 
 
 
 Details o n t he 
re q uire m e nts f or st ora ge a n d ma na ge me nt of st u d y treat m e nt, a n d i nstr ucti o ns t o be f oll o we d 
f or st u d y treat me nt pr e parati o n a n d a d mi nistr ati o n ar e o utli n e d i n t h e P har ma c y Ma n ual.  
 
Ri v ar o x a b a n  
Ri var o xa ba n  1 5  m g  a n d 2 0  m g  will  be  pr o vi de d  as  c o m merciall y  a vail a ble  fil m-c oate d  ta bl ets. 
St ora ge c o n diti o ns descri b e d o n t he la bel m ust be f oll o we d.  
 
A d diti o n al  st u d y tre at me nt 
N o  a d diti o nal tre at m e nt be y o n d  i n vesti gati o nal dr u g  a n d ri var o x a ba n are i ncl u de d i n t his trial. 
6. 2  
Tre at m e nt assi g n m e nt a n d r a n d o miz ati o n  
Patie nts  will  be  ra n d o miz e d o n  Da y  1  t o o ne  of  t he f oll o wi n g tr eat me nt ar ms  i n a 1: 1: 1 rati o: 
• A belaci ma b  ( M A A 8 6 8) 9 0 m g  s.c. m o nt hl y  
• A belaci ma b  ( M A A 8 6 8) 1 5 0 m g  s.c. m o nt hl y  
• Ri var o xa ba n  2 0 m g p. o. o nc e  per da y  wit h  e ve ni n g  meal  

A nt h os  T hera pe utics  
Pa ge 3 9  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
[ N ote: Patie nts  wit h  a  Cr Cl  ≤5 0  ml/ mi n  b y  t he C oc k cr oft -Ga ult  e q uati o n  will  ha v e  a 
d ose a da ptati o n t o ri var o xa ba n 1 5 m g p. o. dail y.]  
Ra n d o miz ati o n i nt o treat me nt gr o u ps will be stratifi e d b y t he use of c o nc o mita nt a nti pl atelet 
use at baseli ne ( yes/ n o) a n d re n al f u ncti o n ( Cr Cl ≤5 0 ml/ mi n or Cr Cl > 5 0 ml/ mi n). Patie nts 
ra n d o miz e d t o t he ri v ar o xa ba n ar m ma y be d ose a dj uste d bet wee n t he 1 5 m g d ose a n d 2 0 m g 
d o ses de pe n di n g o n Cr Cl val ues. 
O nce a s u bje ct is stratifi e d a n d r a n d o mi ze d, t h e s u bject will st a y i n t hat st arti n g str at u m, 
ra n d o miz e d treat me nt gr o u p,  a n d treat me nt re gi m e n f or a nal yses  p ur p oses  e ve n  if t heir d ose  is 
s u bse q ue ntl y a dj ust e d. 
O nce I n vesti g at o rs ha v e asc ertai ne d t hat t he patie nt is eli gi ble f or t h e st u d y, t he y will c o nt act 
t he I nteracti ve W e b or V oice  Res p o nse  S yste m  (I x R S) bef ore  t he first a d mi nistrati o n  of  st u d y 
dr u g. T he I x R S will re q uir e t he f oll o wi n g i nf or mati o n i n or der t o ra n d o mize a pat ie nt t o t he 
c orrect stratifi cati o n: ye ar of birt h, Cr Cl ( C oc k cr oft -Ga ult) a n d w het h er t he patie nt ta kes 
a nti pl atelet m e dic ati o ns (i. e., as piri n a n d/ or a P 2 Y 1 2  i n hi bit or) as a c o nc o mita nt me dicati o n. 
T he I x R S will all oc ate t he tre at m e nt gr o u p assi g n m e nt f or  t he patie nt. 
E mer ge n c y u n bli n di n g will be d o ne t hr o u g h t h e I x R S s yste m. T he treat me nt c o d e s h o ul d n ot 
be br o ke n e x ce pt i n m e dic al e mer ge n cies w he n t he a p pr o priat e m a na ge me nt of t he p ati e nt 
re q uires k n o wle d ge  of  t h e treat me nt assi g n me nt.  T he  decisi o n  of  w het her  or  n ot  t o u n bli n d  lies 
wit h t he i n vesti gat or a n d it is t he s ole res p o nsi bilit y of t he i n vesti g at or t o deter mi n e t he ne e d 
f or i m me di ate u n bli n di n g. H o we ver, if ti m e a n d circ u msta n ces per mit, t he I n vesti gat or is 
e nc o ura ge d t o c o nt act t h e 
 
 
 
T he s pecifi cati o ns f or ge ne rati o n of t he ra n d o miz ati o n sc he d ule will b e pre pare d b y t h e st u d y 
bi ostatistici a n a n d t he c o ntract researc h or ga ni zati o n ( C R O) i n c har ge of t he I x R S. A n 
i n de pe n de nt bi ostatisticia n, n ot ot her wise part of t he cli nical st u d y e xec uti o n tea m, will 
ge nerat e t h e ra n d o miz ati o n sc h e d ule. T h e ra n d o mizati o n n u m bers will be ge ner ate d t o e ns ure 
t hat tr eat me nt assi g n me nt is u n biase d. 
6. 3  
Tre at m e nt bli n di n g  
Patie nts, I n v esti gat ors, a n d S p o ns or st aff dir ectl y i n v ol ve d i n t he st u d y ma y b e a war e of t he 
treat me nt assi g n me nt bet wee n  a bel aci ma b  a n d ri var o xa ba n b ut  will  re mai n bli n de d  t o t h e d ose 
of a bela ci m a b assi g ne d. A n i n de pe n d e nt D M C will m o nit or t he d ata ( A Es, S A Es, ble e di n g 
e ve nts,  str o ke, s yste mic e m b olic e ve nts,  a n d deat h)  i n a n u n bli n de d  ma n ner  o n  a peri o dic  basis. 
A n  i n de pe n de nt statistic al gr o u p,  n ot  ot her wise  i n v ol ve d i n t he st u d y, will  pre pare  a n d pr o vi de 
t he re q uir e d re p orts t o t he D M C as per t he D M C C harter. 
T he st u d y’s pri mar y safet y a n d effic ac y e n d p oi nts will be a dj u di cat e d b y t he C E C w h ose 
m e m bers will re m ai n bli n de d t o treat me nt assi g n me nt.   
A d mi nistrati o n of st u d y tre at m e nt d uri n g t he e xt e nsi o n peri o d will b e o pe n -l a bel. 
6. 4  
Tre ati n g t he p atie nt  
 
Dis pe nsi n g  t he st u d y dr u g A bel aci m a b  
 
Eac h  st u d y site will  b e  s u p plie d wit h  a belaci ma b  as  si n gle-use  vials  via  t h e I x R S s yste m. A  
u ni q ue kit n u m b er is pri nte d o n t he vi al l a bel w hic h c orres p o n ds t o t he a bel aci ma b tre at m e nt 

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ar m. I n vesti gat or staff will  i de ntif y t he st u d y dr u g  vial  t o be  use d  f or t he patie nt  b y  c o ntacti n g 
t he I x R S a n d o btai ni n g th e kit n u m ber c o ntai ni n g t hat vial.  
At t he Da y 1 a n d Da y 3 0 visits, a bela ci m a b will b e a d mi nist ere d t o t he patie nt b y q u alifie d 
me dic al pers o n nel at t he st u d y ce nter vi a s.c. i njecti o n as s pecifie d i n t he P har mac y Ma n ual. 
F or t hese first t w o d oses, pati e nt s m ust re mai n at t he st u d y ce nt er f or at least 1 h o ur after 
a d mi nistr ati o n  of  st u d y dr u g  t o m o nit or  f or a n y I S Rs, h y perse nsiti vit y  r eacti o ns, or  ot her  A Es. 
Starti n g  wit h  t he t hir d d ose,  patie nts  will  eit her ret ur n t o t he st u d y ce nter  e ver y m o nt h  t o recei ve 
s.c. a d mi nistrati o n  of  st u d y dr u g  or  o pt  t o ha ve  st u d y dr u g  a d mi nister e d  o utsi de  t he st u d y c e nter 
b y a visiti n g n urse or ot h er assi g ne d i n di vi d ual q ualifie d t o a d mi nist er s.c. st u d y me dicati o n 
( or a c o m bi n ati o n of visit sce nari os de pe n di n g o n p atie nt a n d site a v ail a bilit y).  
Patie nts partici p ati n g i n t he e xt e nsi o n peri o d t hat rec ei ve d  ri var o x a ba n or a bel aci ma b 9 0 m g i n 
t he ra n d o mize d peri o d s h o ul d be m o nit ore d as descri be d a b o ve after t he first d ose of 
a bela ci m a b  1 5 0 m g . 
 
Ri v ar o x a b a n  
Eac h st u d y site will be s u p plie d wit h cart o ns of ri var o xa ba n 2 0 m g ta bl ets a n d 1 5 m g ta blets 
via t he I x R S s yste m. O n Da y 1, patie nts assi g ne d t o ri var o xa ba n will b e gi ve n a s u p pl y of 
ri var o xa ba n a n d will  be  i nstr ucte d t o t a ke t h e first d ose  t hat e ve ni n g  wit h  f oo d.  T hr o u g h o ut  t he 
st u d y, ri var o xa b a n will be dis pe nse d at a p pr o priate i nter vals t o e ns ure patie nts h a ve a de q uate 
q ua ntities of st u d y dr u g bet we e n st u d y visits.  
I n case of circ u msta nces  pre ve nti n g  a patie nt fr o m atte n di n g  o n -site visits, sites ma y, wit h t he 
patie nt’s c o nse nt, arra n g e t h e s hi p m e nt of ri var o x a ba n dir ectl y t o t he patie nt’s h o me as 
per mitte d  b y  l ocal re g ulati o ns. I n t his case,  t he I n v esti gat or a n d/ or  del e gat e d  staff will  arra n g e 
f or t he c o urier  ser vi ce a n d will  pr o vi de  t he patie nt’s  na me  a n d s hi p pi n g a d dress  t o t he c o urier. 
 
H a n dli n g  of  st u d y tre at me nt 
St u d y treat me nt m ust be re cei v e d b y a desi g n ate d pers o n at t he st u d y sit e, ha n dl e d a n d st ore d 
safel y a n d pr o perl y,  a n d ke pt  i n a sec ure d l ocati o n t o w hic h  o nl y  t he i n vesti gat or a n d desi g nees 
ha ve ac cess. U p o n recei pt, all st u d y treat me nt m ust be st ore d a cc or di n g t o t he i nstr u cti o ns 
s pecifie d o n t he l a bels. Cli nic al s u p pli es are t o b e dis pe nse d o nl y i n a cc or da n ce wit h t he 
pr ot oc ol.  
St u d y me di cati o n l a bels will be i n t he l ocal l a n g ua g e  a n d c o m pl y wit h t h e l e gal re q uir e me nts 
of  eac h  c o u ntr y.  T he y  will  i ncl u de st or a ge c o n diti o ns  f or t he st u d y tre at m e nt b ut  n o  i nf or mati o n 
a b o ut t h e p ati e nt  e xce pt f or t he kit  n u m ber.  T he  la b els will  h a ve  a n o pe n  fi el d f or sit es t o write 
i n t he patie nt’s ra nd o mi zati o n n u m ber f or re c o nciliati o n p ur p oses.  
T he i n vesti gat or m ust m ai nt ai n a n ac c urate rec or d of t he s hi p m e nt a n d dis pe nsi n g of st u d y 
treat me nt i n a dr u g  acc o u nta bilit y  l o g. M o nit ori n g  of  dr u g  acc o u nta bilit y  will  be  perf or me d  b y 
m o nit ors d uri n g sit e visits or re m otel y a n d at t he c o m pleti o n of t he trial.  
At t he c o ncl usi o n of t he st u d y, a n d as a p pr o priate d uri n g t he c o urse of t he st u d y ( o nl y after 
i nstr ucte d t o d o  s o), t he i n vesti gat or will  eit her l o call y destr o y  t h e u n use d  st u d y treat me nt (if 
l ocal S O P s per mit)  or  ret ur n all u n use d  st u d y treat m e nt, pac ka gi n g,  dr u g  la bels, a n d a c o p y of 
t he c o m plet e d dr u g acc o u nta bilit y l o g t o t h e  
m o nit or t o arra n ge f or destr ucti o n. 
 
I nstr ucti o ns f or a d mi nisteri n g  st u d y tre at me nt 
A belaci ma b  i nje cti o n will  be  pre par e d  b y  t he P har macist  or  q ualifie d  desi g n ate d  site staff 
acc or di n g t o i nstr ucti o ns i n t h e P har mac y Ma n u al a n d a d mi nist ere d s u bc ut a ne o usl y.  

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Ri var o xa ba n  will  be  self-a d mi nistere d  b y  t he patie nt.  
 
Met h o d  of  assessi n g  tre at me nt c o m pli a nce 
T he  i n v esti gat or s h o ul d pr o m ote  c o m plia nc e wit h  st u d y me dicati o ns  b y  i nstr ucti n g t h e patie nt 
t o ta ke t he st u d y tr eat me nt e xactl y  as  i nstr ucte d a n d b y  stati n g t h at c o m pli a nce is necessar y  f or 
t he patie nt’s  safet y a n d t he vali dit y  of  t he st u d y. T he  patie nt  m ust  als o be  i nstr ucte d t o c o ntact 
t he i n vesti gat or if he/s he is u na ble f or a n y r eas o n t o t a ke t he st u d y treat me nt as i nstr uct e d. 
Patie nts assi g ne d t o ri var o x a ba n will be as ke d t o bri n g all use d a n d u n use d st u d y dr u g 
c o ntai n ers  t o e ver y  visit,  i ncl u di n g re m ote ( vi de o-call)  visits  as  a p pli ca bl e.  C o m pli a nce  will  be 
assesse d at eac h visit b y m ea ns of ta bl et c o u nts a n d d oc u me nt e d o n t he r ele va nt e C R F pa ge.  
6. 5  
St u d y tre at m e nt i nterr u pti o ns  
St u d y  dr u g  ma y  be  i nterr u pt e d at t h e I n vesti gat or’s discreti o n  f or me dical or  s urgical  reas o ns. 
Reas o ns f or te m p orar y st u d y dr u g i nterr u pti o n ma y i ncl u de a pla n n e d i n vasi ve pr oce d ure or 
s ur ger y f or w hic h o ne w o ul d t y pic all y st o p oral a ntic oa g ul ati o n (se e Secti o n 6. 5. 2 ); cli nical 
i n dicati o n f or a pr o hi bite d m e dic ati o n (see Secti o n 6. 7. 1 ); a blee di n g A E  (see Secti o n 8. 2 ); or 
a n y ot her me dical c o n diti o n w her e t h e I n vesti gat or j u d ges t hat it is t he i n t he b est i nterests of 
t he patie nt t o te m p oraril y i nterr u pt st u d y dr u g. 
Si nce  patie nts  wit h  A F  are at u n derl yi n g  ris k of  str o ke a n d s yste mic e m b olis m,  t h e d urati o n  of 
a n y st u d y dr u g i nterr u pti o n s h o ul d b e ke pt t o t h e mi ni m u m p ossi ble u nless t here is a 
c o ntrai n dicati o n t o a ntic oa g ulati o n. Patie nts w h o ha ve i nterr u pte d st u d y dr u g s h o ul d be re - 
e val uate d re g ul arl y b y t he I n vesti g at or t o deter mi n e  t he ris ks a n d be nefits of res u mi n g st u d y 
dr u g.  
F or patie nts assi g ne d t o ri var o x a ba n, t he e C R F pa ge f or st u d y dr u g i nterr u pti o n s h o ul d be 
c o m plete d f or a n y t e m p orar y st u d y tr eat me nt i nterr u pti o ns of 2 or m ore c o nsec uti ve da ys a n d 
i ncl u de t he dat e/ti me of t he last d ose, t he reas o n f or t he t e m p orar y i nt err u pti o n (e. g ., 
pr oce d ures), a n d ot her r e q uire d d etails.  
F or patie nts assi g ne d t o a bel aci ma b, t h e e C R F f or st u d y dr u g i nterr u pti o n is re q uire d f or a n y 
misse d st u d y treat me nt > 4 5 da ys fr o m t he pre vi o us d ose a n d i ncl u de t h e date/ti me of t he l ast 
d ose, t he reas o n f or t h e te m p or ar y i nt err u pti o n ( e. g., pr oce d ures), a n d ot her r e q uire d d etails.  
T here is n o li mit o n eit h er t he n u m b er of st u d y dr u g te m p orar y i nterr u pti o ns or t he m a xi m u m 
le n gt h of a st u d y dr u g te m p orar y i nterr u pti o n. As l o n g as t h e st u d y h as n ot c o m plet e d , a patie nt 
w h o has i nterr u pte d st u d y dr u g ca n res u me st u d y dr u g as s o o n as it is deter mi ne d t o be 
a p pr o priat e b y t he I n vesti gat or.  
A patie nt w h o c o nti n ues t o be o n st u d y tre at m e nt i nt err u pt i o n w he n t he r a n d o mi ze d peri o d of 
t he st u d y has c o m plete d will  b e  c o nsi dere d  t o h a ve  per ma ne ntl y  disc o nti n ue d st u d y dr u g , 
will n ot be eli gi ble f or t he e xte nsi o n  a n d s h o ul d c o m plete a P S D D visit a n d a E o S visit 
a p pr o xi matel y 3 0 d a ys lat er (s ee Secti o n 6. 6 ). 
I n vesti gat ors are str o n gl y e nc o ur a ge d  t o call t h e 
 
 
 
 
 
F oll o w -u p  of  p atie nts  wit h  St u d y  Tre at me nt  I nterr upti o ns  
All  patie nts  w h o  te m p oraril y i nterr u pt st u d y dr u g  s h o ul d c o nti n ue t o be  f oll o we d. D uri n g  st u d y 

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dr u g te m p orar y i nterr u pti o ns, patie nts will be f oll o we d f or S A Es a n d e n d p oi nts b y t ele p h o n e 
c o ntact ( or visit  if nec essar y)  a p pr o xi mat el y  o nc e  a  m o nt h  u ntil  st u d y dr u g  treat me nt is r es u me d 
al o n g wit h re g ularl y sc h e d ule d pr ot o c ol -s pecifie d visits. 
If a patie nt t e m p oraril y i nt err u pts st u d y dr u g d ue t o a n A E, t he I n vesti gat or will att e m pt t o 
f oll o w t he e ve nt u ntil it has res ol v e d or st a bilize d. If t he p ati e nt a n d I n vesti gat or a gre e t h at 
st u d y dr u g  ca n be  res u me d wit h o ut  i ncrease d ris k t o t he patie nt,  st u d y dr u g  ma y  be  res u me d at 
a n y ti m e.  
 
St u d y  tre at me nt i nterr u pti o ns f or i n v asi ve pr oce d ures  
D uri n g t heir partici p ati o n i n t he st u d y, patie nts 
ma y 
nee d t o u n der g o a n i n v asi ve 
pr oce d ure/s ur ger y. T h e peri -pr oc e d ural ma na ge me nt of st u d y dr u g a ntic oa g ulati o n will var y 
de pe n di n g o n t he t y p e a n d ti mi n g (ele cti v e, ur ge nt, or e mer ge nt) of pr oc e d ure/s ur ger y, t he 
assi g ne d tre at m e nt ar m, a n d a c o nsi derati o n of t he pati e nt’s ris k of he m orr h a ge v ers us t he 
patie nt’s ris k of str o ke a n d s yste mic e m b olis m. Det aile d r ec o m me n dati o ns ar e pr o vi de d i n a 
Peri pr oce d ural  G ui d a nce  D oc u me nt.  I n vesti gat ors ar e str o n gl y e nc o ura ge d  t o c o ntact t he 
 
 f or g ui da nce  wit h  re gar ds  t o w het her  st u d y dr u g  i nterr u pti o n is rec o m me n d e d f or a 
gi ve n pr oce d ur e/s ur ger y.  
I n t he e ve nt of  a n ur ge nt/e m er ge nt  pr o ce d ure,  i n v esti gat ors are str o n gl y e nc o ura ge d  t o c o ntact 
t he 
 f or g ui da nc e wit h re g ar ds t o re v ersal strat e gies. 
L ocal a P T T res ults pri or t o a n y i n vasi ve pr oce d ure/s ur ger y s h o ul d be sa ve d al o n g wit h 
pr oce d ure/ o p erati v e re p orts as s o urce d o c u me nts.  
After  c o m pleti o n  of  t he pr oce d ur e/s ur ger y  a n d w he n  he m ostasis  has  bee n  ac hie ve d,  t he s h ort- 
ter m use  of  pare n teral a ntic oa g ulati o n  or  oral  a ntic oa g ulati o n  is per mitt e d  u ntil  t he p ati e nt  c a n 
be see n i n t h e st u d y ce nter a n d res u m e st u d y dr u g.  
6. 6  
Per m a ne nt st u d y dr u g disc o nti n u ati o n  
Per ma ne nt st u d y dr u g disc o nti n uati o n ( P S D D) is all o we d at t he I n vesti gat or’s discreti o n  or 
patie nt’s re q uest at a n y ti me. T he I n vesti g at or s h o ul d call t he 
 i n case of 
p ote nti al P S D Ds.  
If a patie nt has w hat is e x pe cte d t o be a per ma ne nt disc o nti n uati o n of st u d y dr u g, t h e patie nt 
s h o ul d c o m plete P S D D  visit  pr oce d ures  o utli ne d  i n t he Assess me nt  Sc he d ule  (A p pe n di x  3 ). At 
t he P S D D visit, u nless t he patie nt has a c o ntrai n dicati o n t o a ntic o a g ulati o n, I n vesti gat ors 
s h o ul d arra n ge patie nts  t o be  tra nsiti o ne d t o a p pr o priate S o C  a ntic oa g ul ati o n t hera p y 
mi ni mizi n g a n y ga p i n a nti c oa g ulati o n si nce patie nts wit h A F ar e at u n d erl yi n g ris k of str o ke 
a n d s yste mic e m b olis m (see Secti o n 7. 1 ). 
Patie nts  w h o  per ma ne ntl y  disc o nti n u e  st u d y dr u g  will  ha ve  a n E o S  visit  a p pr o xi matel y  3 0  da ys 
after t h e P S D D visit a n d t he n will b e c o nta cte d p eri o dicall y, a p pr o xi matel y e ver y 1 2 we e ks, 
b y tel e p h o ne f or S A Es a n d e n d p oi nts (see Secti o n 7. 2 ) u ntil t he site has b ee n n otifi e d b y t he 
S S C  t hat t he ra n d o mize d peri o d of t he trial has e n de d at w hic h p oi n t t he patie nt’s parti ci pati o n 
i n t he st u d y ca n be c o nsi dere d c o m pl ete d. Sites s h o ul d n ot e nter t h e patie nt as “c o m plet e” i n 
t he e C R F u ntil t he st u d y has be e n de clar e d c o m plet e, u nless t h e patie nt has wit h dr a w n t heir 
c o nse nt t o be f oll o we d b y all p ossi ble m et h o ds (i.e., i n pers o n, re m otel y, via t hir d part y) a n d 
ref uses t o per mit re vi e w of t he me dical rec or ds. 
I n cert ai n sit uati o ns, patie nts w h o h a ve pre vi o usl y p er ma ne ntl y disc o nti n u e d st u d y dr u g a n d 
ha d a n P S D D Visit ca n be all o we d t o res u me st u d y dr u g.  T he I n vesti gat or s h o ul d c o ntact t he 
 t o deter mi ne  w het her  or  n ot  a patie nt  w h o  c o m plete d  a P S D D  visit  ca n res u me 

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st u d y dr u g. 
A n y  patie nt  w h o  per m a ne ntl y  disc o nti n u es  st u d y dr u g  a n d als o wis hes  t o wit h dra w  c o nse nt f or 
partici pati o n i n t he st u d y 
m ust c o m pl ete t h e pr ot oc ol -s pecific 
wit h dr a wal of c o nse nt 
pr oce d ures (see Secti o n 7. 3 ). T he I n v esti gat or s h o ul d c o ntact t h e 
 t o disc uss 
cases i n w hi c h a patie nt wis hes t o wit h dra w bef ore t he decisi o n is ma de a n d wit h dra wal 
pr oce d ures  are be g u n.  Wit h dra wal  pr oc e d ures  ca n be gi n  o nl y  after disc ussi o n  a n d c o nfir mati o n 
t hat t h e patie nt’s desir e t o wit h dra w f ull c o nse nt. 
6. 7  
C o nc o mit a nt tre at m e nt  
T he I n vesti g at or m ust i nstr u ct t h e patie nt t o n otif y t he st u d y st aff of a n y ne w me dicati o ns 
he/s he ta k es after bei n g e nr olle d i nt o t he st u d y.  
All prescri pti o n m e dic ati o ns, O T C dr u gs i ncl u di n g her bal s u p ple m e nts, a n d si g nific a nt n o n - 
dr u g  t hera pies (i n cl u di n g p h ysical  t hera p y  a n d bl o o d  tra nsf usi o ns) a d mi nist ere d  or  ta k e n wit hi n 
t he ti m efra m e defi ne d i n t h e e ntr y criteri a pri or t o t h e start of t he st u d y a n d d uri n g t he st u d y, 
m ust be rec or d e d o n t h e C o nc o mita nt me dicati o ns/ Si g nifica nt n o n -dr u g t her a pies e C R F. 
Me dicati o n e ntries s h o ul d be s pecific t o tra de a n d g e neric na m e, t he si n gle d ose a n d u nit, t h e 
fre q ue nc y a n d r o ute of a d mi nistrati o n, t he st art a n d disc o nti n uati o n date a n d t he r eas o n f or 
t hera p y. 
Eac h c o nc o mit a nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bit e d 
me dic ati o n. If i n d o u bt, t he I n vesti gat or s h o ul d c o nt act t h e 
 d uri n g scr ee ni n g 
or, if t he patie nt is alre a d y e nr oll e d, t o deter mi ne if t he patie nt s h o ul d c o nti n ue wit h st u d y 
treat me nt. 
 
Pr o hi bite d  me dic ati o n  
I n case a n y of t he f oll o wi n g me di cati o ns are cli nicall y necessar y, n o f urt h er d osi n g of t he st u d y 
dr u g s h o ul d  occ ur u ntil t he i n vesti g at or has deter mi n e d t hat it  is safe f or t he pati e nt t o res u me 
st u d y dr u g: 
• A ntic oa g ul a nts,  ot her  t ha n t h e assi g ne d  st u d y dr u gs,  b y  a n y r o ute 
• Pare nteral  a nti platel et dr u gs  (e xc e pt N S AI Ds)  
• T hr o m b ol ytic  a ge nts. 
F or patie nts i n t h e ri var o x a ba n ar m: use of c o m bi n e d P -g p a n d str o n g C Y P 3 A i n hi bit ors s uc h 
as  at aza na vir,  clarit hr o m y ci n,  dr o ne dar o ne,  i n di na vir, itr ac o na z ole, ket o c o naz ole,  nefaz o d o n e, 
nelfi na vir, rit o na vir, sa q ui na vir, telit hr o m y ci n, a n d v oric o naz ole is pr o hi bit e d as well as ot her 
dr u gs i n acc or da n ce wit h l o cal r e g ulati o ns d uri n g t h eir ti m e i n t h e st u d y.  
F or pati e nts i n t he ri var o xa ba n ar m: use of c o m bi ne d P -g p a n d str o n g C Y P 3 A i n d ucers s uc h as 
rifa m pi n/rifa m pici n, rifa buti n, rifa p e nti n, p he n yt oi n, p he n o bar bital, pri mi d o ne, St. J o h n’s 
W ort, a n d car b a ma ze pi n e is pr o hi bite d, as well as ot her dr u gs i n acc or da n ce wit h l ocal 
re g ulati o ns d uri n g t heir ti me i n t he st u d y. 
 
Ot her  P r o hi biti o ns  a n d  Restricti o ns  
• W o me n of c hil d b eari n g p ote ntial ( W O C B P) m ust a gree t o r e mai n o n a n effe cti v e m et h o d 
of c o ntrace pti o n d uri n g t h eir ti me i n t h e st u d y a n d f or at least 1 0 wee ks aft er t he last d os e 
of a bela ci m a b f or W O C B P ra n d o miz e d t o a b ela ci m a b.  
• Me n  m ust a gree  n ot  t o fat her a c hil d or  d o nate s per m  d uri n g t heir  ti m e i n t h e st u d y. 

A nt h os  T hera pe utics  
Pa ge 4 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
6. 8  
Ris ks a n d be nefits  
T he ris ks a n d be nefits of usi n g ri var o xa ba n i n patie nts wit h atrial fi brill ati o n ar e descri be d i n 
t he S u m m ar y of Pr o d uct C h aracteristics [ Xarelt o (ri var o xa ba n) S m P C ] a n d Prescri bi n g 
I nf or mati o n [ X ar elt o (ri var o xa b a n) –  Pac ka g e I nsert ]. 
T he  ris ks ass ociate d  wit h  t he use  of  a belaci ma b  are t h ose i nferre d b y  t he bi ol o g y  of  a n d cli nical 
e x perie n ce wit h a b ela ci m a b, a n d t h ose ass ociat e d wit h st u d y pr oce d ures.  
T here  ma y  b e  u n k n o w n  ris ks of  a belaci ma b  w hic h  m a y  be  seri o us a n d u nf oresee n.  Ref er  t o t he 
I B f or f urt her det ails re gar di n g ris ks base d o n e x peri e nce a n d bi ol o g y of a belaci ma b.  
 
Ris ks  ass oci ate d  wit h  t he C O VI D -1 9  p a n de mic  
T he st u d y tre at m e nts, i ncl u di n g a b ela ci m a b, are n ot e x pecte d t o alt er t he n at ural defe ns e 
mec ha nis ms or de v el o pi n g i m m u nit y t o C O VI D -1 9. A ntic oa g ulati o n t h era p y ma y ha ve 
be neficial effects i n pr e ve nti n g t hr o m b o e m b olic c o m plicati o ns of C O VI D -1 9.  
T he C O VI D -1 9 pa n de mic ma y pr ese nt a d de d c hall e n ges f or trial partici p a nts w h o ma y ris k 
e x p os ure t o C O VI D -1 9 d uri n g tra vel t o researc h ce nters a n d i ntera cti o ns wit h resear c h staff. 
I n or der t o mi ni mize ris k t o trial p arti ci pa nts, o nl y criti cal st u d y tas ks were m ai nt ai ne d. 
F urt her m ore,  st u d y pr oce d ures  were  desi g n e d  t o be  a da pta bl e t o c ha n gi n g  c o n diti o ns  rel ate d t o 
t he C O VI D-1 9 pa n de mic.  
I n vesti gat ors s h o ul d ma ke e ver y eff ort t o e ns ure t h at t he y are f oll o wi n g l ocal g ui deli nes t o 
pre ve nt t he s prea d of C O VI D -1 9 as well as pr o vi de a p pr o priat e me di cal o versi g ht t o pati e nts 
e nr olle d i nt o t his st u d y, w het her visits are ta ki n g place o n -sit e or usi n g o ne of t he fle xi ble 
o pti o ns  t hat are a v ail a ble i n cl u di n g: 
• I n-h o me  visits  i n lie u of  o n -site visits  f or t he s.c. a d mi nistrati o n  of  a belaci ma b; 
• re m ote ( via tel e p h o ne or vi de o-c alls) visits i n lie u of o n -sit e visits w he n s.c. 
a d mi nistr ati o n of a bel aci ma b is n ot re q uire d;  
• I x R S dis pe nsi n g of m ulti ple m o nt hs of ri var o x a ba n s u p plies rat her t ha n re q uiri n g 
ri var o xa ba n patie nts t o ret ur n t o t he sit e t o o btai n t h ese s u p plies e ver y m o nt h, as well 
as direct-t o-patie nt s hi p m e nt (fr o m site t o p ati e nt’s h o me) of ri var o xa b a n s u p plies as 
nee d e d a n d l ocall y per mitt e d.  
If a pati e nt c o ntracts C O VI D-1 9 w hile e nr olle d i n t h e st u d y, t he patie nt s h o ul d be m a na ge d  
acc or di n g  t o us ual  me di cal  practice.  C O VI D -1 9  s h o ul d be  re c or de d i n t he a d v erse e ve nts  pa ge.  
Vacci nati o n  f or C O VI D -1 9  is per mitte d  d uri n g  the  st u d y c o urse. 
Patie nts  s h o ul d n ot  recei ve t heir i njecti o n of  a bel aci ma b  wit hi n  3  da ys  of  re cei vi n g a  C O VI D - 
1 9 vacci n e.  
 
Ris ks  B ase d  o n  Pri or  Cli nic al  E x perie nce  wit h  A bel aci m a b  
A belaci ma b has bee n g e nerall y well -t ol erat e d i n t h e t hree cli nical st u dies c o m plet e d t o date 
( C M A A 8 6 8 X 2 1 0 1, C M A A 8 6 8 A 1 1 0 1, a n d A N T-0 0 3) as well as i n  t he m ulti pl e  d ose st u d y  i n 
l o w-ris k A F  patie nts  ( A N T-0 0 4)  a n d i n patie nts  u n der g oi n g  ele cti v e T K A  s ur ger y ( A N T-0 0 5). 
T o date, acr oss t he P hase 1 a n d P hase 2 st u di es perf or me d  wit h a b elaci ma b, m ore t h a n 2 5 0 
s u bjects ha v e be e n a d mi nister e d a b ela ci m a b. A Es ha ve be e n i nfre q u e nt a n d well -bal a nce d 
bet wee n t he tre at m e nt a n d plac e b o ar ms. N o d ose -de pe n de nt safet y fi n di n gs ha ve bee n 
o bser ve d. W hile f ecal o cc ult bl o o d tests ha ve be e n p o siti ve i n a fe w st u d y partici p a nts, n o ne of 
t hese p ositi ve t est res ults re mai ne d p ositi ve o n re p eat testi n g or were ass ociate d wit h a n y 

A nt h os  T hera pe utics  
Pa ge 4 5  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
cli ni cal or la b orat or y si g nals i n dicati n g acti ve ble e di n g. T h us, n o s pecific ris ks ha ve bee n 
i de ntifie d base d o n pri or cli nical e x perie nc e f or a bel aci m a b. 
 
Ris ks  b ase d  o n  
 
 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Ris k  b ase d  o n  t he bi ol o g y  of  a bel aci m a b  
6. 8. 4. 1  
Blee di n g  ris k  
Si nce  a bel aci ma b  is a n i n hi bit or of  F XI  a n d F XIa,  it a cts  as  a n a ntic oa g ula nt.  T he  ble e di n g  ris k 
of a belaci ma b i n patie nts wit h A F is u n k n o w n; h o we ver, treat me nt wit h a belaci ma b c a n be 
e x pect e d t o res ult i n a ble e di n g p h e n ot y pe c o m par a ble t o t he bl ee di n g p h e n ot y pe i n patie nts 
wit h se vere F XI deficie nc y.  
Patie nts wit h se vere F XI d eficie nc y ge nerall y d o n ot e x perie nce s p o nta ne o us blee di n g, a n d 
s p o nta ne o us m uscle  or  j oi nt ble e di n g  or  i ntracr a nial bl ee di n g  e ve nts  are rare (B olt o n -
Ma g gs  2 0 0 0 , D u ga  a n d Sal o m o n  2 0 1 3 ). Bl ee di n g e ve nts t hat occ ur ar e ofte n i nj ur y- or tr a u ma -
relat e d, partic ul arl y i n tiss ues wit h i ncr ease d fi bri n ol ytic acti vit y s uc h as t he oral m uc osa, n asal 
m uc osa, a n d uri n ar y tract.  
A n F XI -A S O was als o e val uat e d i n a FI H st u d y i n healt h y s u bj ects ( Li u et al 2 0 1 1 ) a n d i n 
patie nts u n der g oi n g electi ve  u nilateral T K A ( B üller et al 2 0 1 5 ). R o b ust a n d s ustai ne d 
re d ucti o ns of  F XI  greater  t ha n 8 0 %  f or a d urati o n  e xcee di n g  6  t o 8  wee ks  were  ac hie ve d  at t he 
hi g hest d ose wit h se veral s u bjects reac hi n g u n det ect a ble le v els of F XI. N o blee di n g occ urre d 
i n s u bjects w h o  rec ei ve d F XI -A S O  i n t he FI H  st u d y. F urt her m ore,  a d mi nistr ati o n  of  F XI -A S O 
t o pati e nts u n der g oi n g u nil ateral T K A at a d ose t h at ac hie v e d a mea n 8 0 % r e d ucti o n i n F XI 
acti vit y a p pe are d t o be ass ociat e d wit h a tre n d t o war ds a l o wer i nci de nce of maj or or C R N M 
blee di n g  e v e nts  c o m par e d  t o s.c. e n o xa pari n  (B üller  et al 2 0 1 5 ). Si milar  res ults were  o bser ve d 
i n a cli nic al st u d y of a m o n ocl o nal a nti b o d y i n hi bit or of acti vate d F XI, os oci ma b, w hic h 
s h o we d n o e vi de nce of e xcess ris k of blee di n g wit h os oci ma b i n pati e nts u n der g oi n g ele cti v e 
T K A ( Weitz et al 2 0 2 0 ). 
I n t he P hase 1 st u di es of a b ela ci m a b ( C M A A 8 6 8 X 2 1 0 1, C M A A 8 6 8 A 1 1 0 1, a n d A N T-0 0 3), 
greater t h a n 9 5 % i n hi biti o n of F XI was n ot ass ociat e d wit h blee di n g ma nif estati o ns, a n d n o 
clini call y rele v a nt de creases i n he m o gl o bi n or he m at ocrit were o bser ve d at a n y ti me -p oi nt 
d uri n g t he st u d y. T o date, i n t he A N T -0 0 4 st u d y, n o maj or or cli nicall y r ele v a nt n o n -maj or 
blee di n g e ve nts ha ve o cc urre d wit h m ulti ple s.c. a d mi nistrati o n of a bel aci ma b;  h o we ver, 1 
cli ni call y  rele va nt ble e di n g  e ve nt at t he s ur gic al site has  bee n  re p orte d i n a patie nt  ra n d o miz e d 

A nt h os  T hera pe utics  
Pa ge 4 6  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
t o a bel aci ma b i n t he A N T-0 0 5 st u d y i n patie nts u n der g oi n g T K A.  
A t hera pe utic strate g y f or t h e ma n a ge me nt of bl ee di n g e ve nts i n t h e st u d y is pr o vi d e d i n Secti o n 
8. 2  a n d A p pe n di x 2 . 
6. 8. 4. 2  
P ote nti al  ris k  ass oci ate d  wit h  h y perse nsiti vit y  re acti o ns 
I nf usi o n of t hera p e uti c pr otei ns ca n r es ult i n i m me di ate or d ela y e d h y perse nsiti vit y reacti o ns. 
I m me di ate re acti o ns a p pear d uri n g  t he first h o urs  after dr u g  a d mi nistrati o n.  Cli nic al  
prese ntati o n ma y i ncl u de a wi de of ra n g e of s y m pt o ms e. g ., fe ver, c hills, na usea, c utan e o us 
s y m pt o ms, br o nc h os pas m, d ys p nea, dizzi ness, hea dac h es, 
m yal gia, t ac h yc ar dia a n d/ or  
h y p ote nsi o n.  A na p h yl a xis,  urticari a,  a n d  a n gi oe de ma  were  als o re p ort e d. Del a ye d 
h y perse nsiti vit y re acti o ns ca n a p pear bet we e n 1 -2 h o urs a n d u p t o 1 4 da ys after a d mi nis trati o n, 
ofte n 
wit h ser u m sic k ness – li ke s y m pt o ms (C or o mi nas  et al 2 0 1 4 ). T he i nci de nc e of 
h y perse nsiti vit y reacti o ns wit h m o n ocl o nal a nti b o dies ( m A bs) de pe n ds o n t he de gree  of  
h u ma niz ati o n,  t he cell  li n e fr o m w hi c h  t he y were  o btai ne d  a n d e xci pie nts. N o  
h y perse nsiti vit y rea cti o ns wer e o bser ve d i n t h e 1 3 -w ee k t o xicit y st u d y or i n t h e P hase 1 st u dies 
( C M A A 8 6 8 X 2 1 0 1, C M A A 8 6 8 A 1 1 0 1 a n d A N T-0 0 3).  
Ma na ge me nt of h y p erse nsiti vit y r eacti o ns  de pe n ds o n t he cli nical prese ntati o n a n d se verit y. 
Treat me nt i nterr u pti o n (if a p plic a ble); fl ui ds, v as o press ors, c ortic oster oi ds, a nti hista mi nes, 
br o nc h o dilat ors, e pi ne p hri ne, a n d o x y ge n ma y be us e d, as i n dic ate d.  
6. 8. 4. 3  
P ote nti al  ris k  ass oci ate d  wit h  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. 8. 4. 4  
P ote nti al  ris k  ass oci ate d  wit h  s.c. i njecti o n 
 
 
  
  
  
 I njecti o n sit e reacti o ns ca n res ult i n h e mat o ma, 
he m orr ha ge, br uisi n g, er yt he ma, disc ol orati o n, s welli n g a n d e de ma f or m ati o n, partic ul arl y 
f oll o wi n g s.c. a d mi nistrati o n. T he first a n d sec o n d i nje cti o ns of t he st u d y dr u g will be 
a d mi nist ere d at t he st u d y site w here patie nts will be m o nit ore d f or i nje cti o n site rea cti o ns.  
A  t hera pe utic strate g y f or t he m a na ge me nt  of  i nj ecti o n site reacti o ns is pr o vi de d  i n Secti o n  8. 3 . 

A nt h os  T hera pe utics  
Pa ge 4 7  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
6. 8. 4. 5  
P ote nti al  ris ks  ass oci ate d  wit h  st u d y pr oce d ures  
Bl o o d  sa m ples will  b e  c ollecte d  d uri n g  t he st u d y eit h er  via  ve ni p u nct ure  or  i. v. ca n n ul a.  Ris ks 
ass ociate d wit h bl o o d c oll ecti o n i ncl u d e p ai n, s welli n g a n d/ or br uisi n g at t he i nserti o n sit e of 
t he nee dle. Alt h o u g h r are, l o calize d cl ot f or mati o n, i nfecti o ns a n d ner ve d a ma g e ma y o cc ur. 
Li g ht he a de d ness a n d/ or fai nti n g ma y als o occ ur d uri n g or s h ortl y after t he bl o o d dr a w.  
P ote nti al  be nefits  ass oci at e d  wit h  a bel aci m a b  use  
F XI deficie nc y h as bee n ass oci ate d wit h a l o wer ris k f or V T E a n d str o ke c o m p are d t o t he 
ge neral p o p ulati o n ( Sal o m o n et al 2 0 0 8 , Sal o m o n et al 2 0 1 1 , Preis et al 2 0 1 7 ). F urt her m ore, 
F XI s u p pressi o n usi n g a n a ntise nse ol i g o n ucl e oti d e or m o n ocl o nal a nti b o d y a gai nst F XIa 
de m o nstrat e d a l o wer rat e of t ot al V T E i n patie nts u n der g oi n g u nilateral T K A wit h n o 
c o nc o mita nt i ncre ase i n ble e di n g e v e nts c o m pare d t o e n o xa pari n ( B üll er et al 2 0 1 5 ; Weitz et  
al 2 0 2 0 ). Preli mi nar y data fr o m t he A N T-0 0 5 st u d y are c o nsiste nt wit h t he res ults o btai n e d 
wit h F XI -A S O a n d t he F XIa m o n ocl o nal a nti b o d y a n d s u g gest t hat a bel aci ma b has r o b ust 
a ntit hr o m b oti c effi cac y c o m pare d t o e n o xa p ari n s.c. wit h o ut a n i n crease i n blee di n g e ve nts.  
7  
St u d y C o m pleti o n a n d Disc o nti n u ati o n  
7. 1  
St u d y c o m pleti o n a n d p ost -st u d y tre at m ent  
T he  S S C  will  c o m m u nic ate  t o st u d y sit es w he n  t he st u d y is e n di n g. S ites will be i nstr ucte d t o 
sc he d ule a n e n d of treat m e nt peri o d ( E o T) visit f or ra n d o miz e d patie nts  or e n d of e xte nsi o n 
treat me nt ( E o E) visit f or e xte nsi o n p ati e nts, as rel e va nt: 
•
Patie nts assi g ne d t o o n e of t he a b elaci ma b treat me nt ar ms s h o ul d ha ve t heir E o T  or E o E
visit sc he d ul e d a p pr o xi mat el y 3 0 da ys aft er t heir last s.c. i njecti o n of st u d y m e dic ati o n .
•
Patie nts  assi g ne d  t o t he ri v ar o xa ba n tre at m e nt ar m s h o ul d c o m plet e t heir E o T  visit  starti n g
a p pr o xi matel y t w o wee ks aft er n otific ati o n fr o m t he S S C. T hese patie nts s h o ul d c o nti n u e
t o ta ke t heir assi g ne d tre at m e nt u p t o t he d a y pri or t o t he E o T visit, at w hi c h ti me
ri var o xa ba n s u p plies m ust be c olle cte d.
At  t he E o T visit or E o E (f or patie nts c o m pleti n g t he e xte nsi o n peri o d), all st u d y dr u g s u p plies 
m ust be c ollecte d fr o m t he patie nt a n d t he I n vesti gat or m ust be gi n pla ns t o tra nsiti o n t he 
patie nt t o S o C a ntic oa g ulati o n t hera p y acc or di n g t o t he g ui deli nes i n Ta ble  7- 1 , u nless t he 
patie nt has a c o ntrai n dicati o n t o a ntic oa g ulati o n t hera p y. 
T a ble 7 -1  
E n d of S t u d y T r a nsiti o n G ui d eli nes  
T r a nsiti o ni n g  t o 
I nstr ucti o ns 
Direct  oral  a ntic oa g ula nt ( D O A C) 
Patie nts  s h o ul d i nitiate oral  D O A C  o n  t he s a me da y  of  t he E o T / E o E 
visit.  
Vita mi n  K  a nta g o nist ( V K A) 
Patie nts  s h o ul d be  gi ve n  a  s u p pl y of  V K A  a n d i nstr ucte d t o be gi n  
t hera p y 3 t o 5 da ys bef ore t he E o T visit. At t he E o T visit, meas ure 
P T/I N R a n d re peat as fre q ue ntl y as necessar y u ntil t he P T/I N R is 
t hera pe utic. Sites ma y c ollect re peat I N R s a m ples usi n g p oi nt of 
care de vices or s e n d f or  
l ocal a nal ysis,  i n w hic h  case  res ults will  re mai n as  part  of  s o urce 
d oc u me ntati o n o nl y.  
T he E o S visit (i n -pers o n or t ele p h o n e/ vi d e o -call) will ta ke plac e a p pr o xi mat el y 4 -wee ks after 
t he E o T/E o E  visit. T his visit will assess patie nts f or a ge neral he alt h a n d safet y c hec k pri or t o 
c o ncl u di n g t heir p arti ci pati o n i n t h e st u d y.  

A nt h os  T hera pe utics  
Pa ge 4 8  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
7. 2  
Disc o nti n u ati o n of st u d y tre at m e nt  
Disc o nti n uati o n  of  st u d y treat me nt f or a patie nt  o c c urs  w he n  st u d y dr u g  is per ma ne ntl y  st o p pe d 
earli er  t ha n t he pr ot oc ol  pla n ne d  d urati o n.  St u d y  dr u g  disc o nti n uati o n  ca n be  i niti ate d b y  eit h er 
t he patie nt or t he I n vesti gat or. 
St u d y  treat m e nt s h o ul d be  disc o nti n ue d  fr o m f urt her st u d y treat m e nt f or a n y of  t he f oll o wi n g: 
• Patie nt  re q uest 
• T he  i n vesti gat or j u d ges t hat c o nti n ue d  st u d y dr u g  a d mi nistr ati o n  is n ot  i n t he b est 
i nterest of t he patie nt 
• Pre g na nc y  (Secti o n  8. 6 ) 
If a pati e nt has w hat is e x pect e d t o be a per m a ne nt disc o nti n uati o n of st u d y dr u g, t he p ati e nt 
s h o ul d c o m plete t h e P S D D Visit pr oce d ures (see Secti o n 6. 6 ). 
 
After st u d y treat me nt disc o nti n uati o n, at a mi ni m u m, i n a b bre vi ate d visits, t he f oll o wi n g data 
s h o ul d be c oll ect e d at cli nic visits or vi a tele p h o ne/ vi de o-call visits:  
• si g ns a n d s y m pt o ms s u g gesti ve of  blee di n g,  str o ke, or  TI A  
• ne w/c o nc o mita nt  treat me nts 
• A Es/ S A Es  
If t he patie nt  ca n n ot or  is u n willi n g  t o atte n d  a n y visit(s),  t he site staff s h o ul d mai nt ai n  re g ul ar 
tele p h o n e c o ntact 
wit h t he patie nt, or 
wit h a pers o n pre-desi g nate d b y t he patie nt, 
a p pr o xi matel y e ver y 1 2 w ee ks.  
7. 3  
Wit h dr a w al of i nf or m e d c o nse nt  
Patie nt’s m a y v ol u nt aril y wit h dra w c o nse nt t o parti ci pate i n t he st u d y f or a n y r eas o n at a n y  
ti me. Sites s h o ul d c o nt act t he 
E bef or e re gisteri n g a wit h dr a wal of c o nse nt.  
Wit h dra wal  of  c o nse nt fr o m t he st u d y ca n oc c ur  w he n  a patie nt:  
• d oes  n ot  wa nt  t o partici pat e  i n t h e st u d y a n y l o n ger, a n d 
• d oes  n ot  wa nt  a n y f urt her visits  or  assess me nts,  a n d 
• d oes  n ot  wa nt  a n y f urt her st u d y rel ate d c o ntacts,  a n d 
• d oes n ot all o w a n al ysis of alr ea d y o btai ne d bi ol o gic material w hi c h h as n ot alrea d y  
bee n a nal yze d, a n d  
• d oes  n ot  all o w  f urt her use  of  alre a d y  o btai ne d  bi ol o gic  mat erial  f or f ut ure researc h. 
I n t his sit uati o n, t h e I n vesti gat or m ust ma ke e ver y eff ort ( e. g., t ele p h o n e, e-mail, letter) t o 
deter mi ne  t he pri mar y  reas o n f or t he pati e nt’s  decisi o n  t o wit h dra w  his/ her  c o nse nt a n d rec or d 
t his i nf or mati o n i n t he e C R F a n d i n t he s o urc e d oc u me nt. 
All eff ort s h o ul d b e ma de t o c o m pl ete t h e assess me nts pri or t o st u d y wit h dra wal. A fi nal 
e val uati o n at t he ti me of t he patie nt’s st u d y wit h dra wal s h o ul d be ma de as detaile d i n t he 
assess me nt sc he d ule ( A p pe n di x 3 ). 
If wit h dra wal  occ urs  pri or  t o st u d y dr u g  d osi n g,  st u d y treat me nt m ust  n ot  be  a d mi nistere d,  a n d 
n o  f urt her assess me nts  c o n d ucte d.  T he  data  t hat w o ul d  ha ve  bee n  c ollecte d  at s u bse q ue nt visits 
will  be  c o nsi dere d  missi n g.  F urt her  att e m pts  t o c o nta ct t he patie nt  are n ot  all o we d  u nless  safet y 
fi n di n gs re q uire c o m m u nicati o n  or f oll o w -u p.  

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7. 4  
L ost t o f oll o w -u p  
F or  patie nts  w h ose  stat us is u nclear  beca use  t he y fail t o a p pear  f or st u d y visits  wit h o ut  stati n g 
a n i nte nti o n t o disc o nti n u e or wit h dra w, t he I n vesti gat or s h o ul d d oc u me nt i n t he s o urce 
d oc u me n ts ste ps t a ke n t o c o nta ct t he patie nt, e. g. dates of tele p h o ne calls, re gister e d letters, etc. 
If l ocal re g ulati o ns per mit, a searc h of l ocal, re gi o nal, nati o nal p u blic rec or ds, a n d/ or i nter n et 
sites ma y be c hec k e d t o l oc ate a patie nt or i n vesti g at e vital stat us. 
A  patie nt ca n n ot be f or mall y c o nsi der e d  l ost t o f oll o w-u p u ntil  his/ her  sc he d ule d e n d of st u d y 
visit w o ul d ha ve o cc urre d.  
7. 5  
E arl y st u d y ter mi n ati o n b y t he S p o ns or  
T he st u d y ca n be ter mi nate d b y t he S p o ns or at a n y ti me f or a n y reas o n. T his ma y i ncl u de  
reas o ns relate d t o t he be n efit/ris k assess me nt of partici p ati n g i n t h e st u d y, practic al reas o ns 
(e. g., i ncl u di n g sl o w e nr oll me nt),  or  f or re g ulat or y or  me dical  re as o ns. S h o ul d  t his be  
necessar y, pati e nts m ust be see n as s o o n as p ossi ble a n d treat e d as a pre mat urel y wit h dr a w n 
patie nt. T he  I n vesti g at or ma y be i nf or m e d of a d diti o nal pr oce d ur es t o be f oll o we d i n or der t o 
e ns ure t hat a de q uate c o nsi d erati o n  is gi ve n  t o t he pr otecti o n  of  t he p ati e nt’s  i nt erests. T h e 
I n vesti gat or will be r es p o nsi ble f or i nf or mi n g t he I R B/ E C of t he earl y ter mi nati o n of t he trial. 
8  
S afet y m o nit ori n g  
8. 1  
A d verse e ve nts  
A n  A E  is t he a p peara nce  or  w orse ni n g  of  a n y u n desir a ble  si g n, s y m pt o m, or  me di cal  c o n diti o n 
occ urri n g  aft er starti n g t he st u d y dr u g  e v e n  if t he e ve nt is n ot  c o nsi der e d  t o be  relat e d t o st u d y 
dr u g. 
Me dical c o n diti o ns/ diseases t hat are pr ese nt bef ore starti n g st u d y dr u g are o nl y 
c o nsi dere d A Es if t h e y w orse n after starti n g st u d y dr u g. A b n or mal la b or at or y val ues or test 
res ults c o nstit ut e A Es  o nl y  if t he y i n d uce cli ni cal si g ns or  s y m pt o ms, are c o nsi dere d  cli nic all y 
si g nifica nt, or re q uir e t hera p y. 
I n a d diti o n, all re p orts of i nt e nti o n al mis use a n d a b use of t h e st u d y tr eat me nt are als o 
c o nsi dere d  a n A E  irres pecti ve if a cli nic al e ve nt has  occ urre d.  See  Secti o n  8. 6  f or a n o ver vie w 
of t he re p orti n g re q uire me nts.  
T he  occ urre nc e  of  A Es  m ust  be  s o u g ht b y  n o n -directi ve  q uesti o ni n g  of  t he pati e nt  at eac h visit 
d uri n g  t he st u d y. A Es  als o ma y  be  detecte d  w he n  t he y are v ol u nteere d  b y  t he pati e nt  d uri n g  or 
bet wee n visits or t hr o u g h p h ysical e xa mi nati o n fi n di n g, la b orat or y t est fi n di n g, or ot h er 
assess me nts. All A Es m ust be re c or de d o n t he A d vers e E ve nts e C R F u n d er t he si g ns, s y m pt o ms 
or dia g n osis as s ociat e d wit h t h e m, a n d a cc o m p a nie d b y t he f oll o wi n g i nf or mati o n:  
1.  t he se verit y gra de  
• mil d:  us uall y  tr a nsie nt i n nat ur e  a n d ge ner all y  n ot  i nt erferi n g wit h  n or mal  acti vities 
• m o derat e:  s ufficie nt disc o mf ort  t o i nterf ere wit h  n or mal  acti vities 
• se vere: pre ve nts  n or mal  acti vities 
2.  its relati o ns hi p t o t he st u d y treat me nt 
• Relate d  
• P ossi bl y  relate d 
• N ot  relate d 

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3.  its d urati o n  (start a n d e n d dates)  or  if t he e ve nt is o n g oi n g  a n o utc o m e  of  n ot  rec o vere d/ n ot 
res ol ve d m ust be r e p orte d. 
4.  w het her  it c o nstit utes  a S A E  (see Secti o n  8. 4. 1  f or defi niti o n  of  S A E)  a n d w hic h 
seri o us ness criteri a ha ve be e n met 
5.  Acti o n  t a ke n r e gar di n g i n vesti gati o nal treat me nt. 
All  A Es  m ust  be  tre ate d a p pr o priat el y.  Tr eat me nt  ma y  i ncl u de o ne  or  m ore  of  t he 
f oll o wi n g: 
• n o  acti o n  t a ke n (e. g., f urt h er o bser vati o n o nl y)  
• c o nc o mita nt me di cati o n  or  n o n -dr u g  t h era p y gi ve n  
• h os pitali zati o n/ pr ol o n g e d  h os pitaliz ati o n  (see Secti o n  8. 4. 1  f or defi niti o n  of  S A E)  
6.  Its o utc o me  ( n ot rec o v ere d/ n ot r es ol ve d; r ec o ver e d/res ol ve d; rec o veri n g/res ol vi n g, 
rec o vere d/res ol ve d wit h se q u ela e; fatal; or u n k n o w n). 
I nf or mati o n a b o ut c o m m o n si de effe cts alre a d y k n o w n a b o ut t he i n vesti gati o nal dr u g c a n be 
f o u n d i n t he I B. O nce a n A E is detecte d, it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is 
j u d ge d t o be per ma n e nt, a n d assess me nt s h o ul d be ma de at e ac h visit ( or m or e fre q ue ntl y, if 
necessar y) of a n y c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o t he i n vesti gati o nal dr u g, 
t he int er ve nti o ns re q uire d t o treat it, a n d t he o utc o m e.  
T he I n vesti gat or m ust als o i nstr u ct e ac h p ati e nt t o r e p ort a n y ne w A E ( be y o n d t he pr ot oc ol 
o bser vati o n p eri o d) t hat t he patie nt, or t h e patie nt’s pers o nal p h ysi cia n, belie ves mi g ht 
reas o na bl y be relate d to st u d y tr eat me nt. T his i nf or mati o n 
m ust b e rec or d e d i n t he 
I n vesti gat or’s s o urce d oc u m e nts; h o we ver, if t he A E meets t he criteria of a n S A E, it m ust be 
re p orte d t o 
 
8. 2  
R ec o m m e n de d tre at m e nt of blee di n g a d verse e ve nts  
T he ma na g e me nt of a s us pecte d blee di n g A E is at t he discreti o n of t he I n vesti g at or a n d will 
de pe n d o n t he s o urce/l oc ati o n of t h e blee di n g a n d t he se verit y. I n all cases of bl ee di n g A Es, 
t he I n vesti g at or s h o ul d use cli ni cal j u d g me nt i n assessi n g t he ris k t o t h e patie nt a n d m o nit or 
w het her t he bl ee di n g is res ol vi n g or w orse ni n g. F urt her g ui da n ce f or t he ma na g e me nt of 
blee di n g A Es i n t his trial c a n be f o u n d i n A p pe n di x 2 . I n vesti g at ors ar e als o e n c o ura ge d t o 
c o ntact t he 
 
 
 
All  s us pecte d blee di n g  e ve nts  m ust  be  rec or de d o n  t h e a p pr o priate e C R F pa ge.  
8. 3  
R ec o m m e n de d tre at m e nt of ot her a d verse e ve nts  
T he  I n vesti gat or a n d site staff m ust  o bser ve  t he patie nts  f or a n y A Es.  All  A Es  s h o ul d be  treate d 
acc or di n g t o cli nical practic e.  
 
H y perse nsiti vit y  re acti o ns 
H u ma n  m o n ocl o nal  a nti b o dies  s uc h as  a b ela ci m a b  h a ve  a l o w ris k of  ca usi n g  h y p erse nsiti vit y 
reacti o ns. 
H y perse nsiti vit y rea cti o ns mi g ht occ ur e ve n after i nitial d osi n g. I m me diat e h y perse nsiti vit y 
reacti o ns ma y  a p pe ar  d uri n g  t he first h o urs  aft er dr u g  a d mi nistr ati o n;  cli nical prese ntati o n  m a y 

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i ncl u de a wi de of ra n g e of s y m pt o ms, e. g., fe ver, c hills, i nfl u e nza-li ke s y n dr o me, na use a, 
v o miti n g, c ut a ne o us s y m pt o ms, br o nc h os pas m, d ys p nea, diz zi ness, he a dac hes, 
m yal gia, 
tac h yc ar dia, h y p ote nsi o n, urtic aria, a ngi o e de ma a n d ac ut e a na p h yla xis, w hi c h c o ul d be life - 
t hreat e ni n g. Dela ye d h y p erse nsiti vit y r eacti o ns m a y a p pear bet wee n 1-2 h o urs a n d u p t o 1 4 
da ys after a d mi nistr ati o n, ofte n wit h ser u m si c k ness -li ke s y m pt o ms. 
Treat me nt of h y perse nsiti vit y rea cti o ns is ge nerall y s y m pt o matic a n d de pe n ds o n t he se verit y 
of t he i niti al reacti o n a n d t he res p o nse t o treat me nt. A nti hista mi nes, s yste mic c ortic oster oi ds, 
a n d/ or n o n -ster oi d a nt-i nfla m mat or y dr u gs 
m a y be c o nsi d ere d i n 
mil der cases of 
h y perse nsiti vit y reacti o ns. I ntr a ve n o us ac cess, car di ac m o nit ori n g, hi g h -fl o w o x y ge n, fl ui ds, 
vas o press ors,  c ortic oster oi ds,  a nti hista mi nes,  br o nc h o dilat ors,  a n d e pi ne p hri n e ma y  b e  use d  i n 
case of a seri o us of a na p h yla xis or a n a p h yla ct oi d r ea cti o ns.  
 
I njecti o n site re acti o ns 
S u bc uta ne o us i nje cti o ns c a n occasi o n all y b e ass ociat e d wit h br uisi n g, he mat o ma, a n d 
s u perficial vei n  t hr o m b osis. Ma na ge me nt  of  br uisi n g  ca n i ncl u d e resti n g t he l o cal ar ea a n d c ol d 
c o m presses. Heat pa c ks or a was hcl ot h s oa ke d i n war m water ma y be a p plie d t o t he br uise d 
area f or se v eral d a ys  aft er t he i nf usi o n or  i njecti o n t o pr o m ote  res or pti o n. Aceta mi n o p he n  ma y 
be use d t o alle vi ate pai n.  
I nfecti o us c o m plic ati o ns  “c ell ulitis -li ke re acti o ns” ar e us uall y  tre ate d wit h  l o cal a ntise ptics  a n d 
ma y occ asi o nall y re q uire s yste mic a nti bi oti cs.  
I m m u n ol o gi c i nf usi o n sit e reacti o ns c o ul d b e ac ut e, dela ye d or b ot h. Cli ni cal s y m pt o ms ma y 
i ncl u de re d n ess, s welli n g, i n d urati o n, it c hi n g, te n d er ness, or pai n. I m m u n ol o gi c i nf usi o n site 
reacti o ns are us uall y self-li mite d a n d ma y be treate d wit h c ol d c o m pr esses, a nti hista mi nes, 
acet a mi n o p h e n, a n d t o pic al a nti -i nfla m mat or y dr u gs. T o pical c ortic ost er oi ds m a y be use d if 
t he rea cti o n w orse ns o ver se veral da ys. Oral c ortic oster oi ds are sel d o m re q uire d. 
8. 4  
Seri o us a d verse e ve nt re p orti n g  
 
Defi niti o n  of  S A E  
A n S A E is defi ne d as a n y A E [a p pear a nce of ( or w orse ni n g of a n y pre -e xisti n g) u n desira ble 
si g n(s), s y m pt o m(s), or me dic al c o n diti o ns(s)] w hic h meets a n y o n e of t he f oll o wi n g criteri a:  
• is fatal or  life-t hreate ni n g 
• res ults i n persiste nt  or  si g nifica nt disa bilit y/i nca pacit y  
• c o nstit ut es  a c o n ge nital a n o mal y/ birt h  defect  
• re q uires i n patie nt h os pit ali zati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitalizati o n,  u nless 
h os pitali zati o n is f or:  
o  electi ve  or  pre -pla n ne d  tre at m e nt f or a pre -e xisti n g c o n diti o n  a n d has  n ot  w orse ne d 
si nce t he st art of st u d y dr u g 
o  treat me nt o n a n e mer g e nc y o ut p ati e nt basis f or a n e v e nt n ot f ulfilli n g a n y of t h e 
defi niti o ns of a S A E gi ve n a b o v e a n d n ot res ulti n g i n h os pital a d missi o n  
o  s ocial re as o ns a n d res pite c are i n t he abse n ce of a n y deteri or ati o n i n t he p atie nt’s 
ge neral c o n diti o n  
• 
is me di call y  si g nifi ca nt, e. g. defi ne d  as  a n e v e nt t hat je o par di zes t h e patie nt  or  ma y 
re q uire a c ute me dic al or s ur gic al i nter ve nti o n t o pr e v e nt per m a ne nt i m pair me nt. 

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All  mali g n a nt  ne o plas ms  wi ll be  assesse d  as  seri o us u n der  “ me dicall y  si g nifica nt” if ot her 
seri o us ness criteri a are n ot met. 
Life -t hr eat e ni n g i n t he c o nte xt of  a S A E  refers t o a reacti o n i n w hic h  t he patie nt  was  at ris k of 
deat h at t he ti me of t h e re acti o n; it d oes n ot ref er t o a rea cti o n t h at h y p ot heticall y mi g ht ha v e 
ca use d deat h if it were m ore se v ere (see A n ne x I V, I C H -E 2 D G ui deli ne).  
Me dical a n d scie ntific j u d g me nt s h o ul d be e x ercis e d i n deci di n g w het her ot her sit uati o ns 
s h o ul d be c o nsi d ere d seri o us r eacti o ns, s uc h as i m p orta n t me di cal e ve nts t hat mi g ht n ot be 
i m me diat el y life t hre ate ni n g or r es ult i n d eat h or h os pitali zati o n b ut mi g ht je o par di ze t he 
patie nt or mi g ht re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes list e d a b o ve. 
E xa m pl es  of  s uc h e ve nts  are i nte nsi ve treat me nt i n a n e mer ge nc y  r o o m or  at h o me  f or all er gic 
br o nc h os pas m, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitaliz ati o n or 
de vel o p m e nt of de p e n de nc y or a b use (se e A n ne x I V, I C H -E 2 D G ui deli ne).  
A n y  s us pecte d tra ns missi o n via  a me dici nal  pr o d uct  of  a n i nfecti o us a ge nt is als o c o nsi dere d  a 
seri o us a d verse reacti o n. 
All A Es (seri o us a n d n o n -seri o us) are ca pt ure d o n t he e C R F; S A Es als o re q uire i n di vi d ual 
re p orti n g t o 
 as per Secti o n 8. 4. 2 . 
 
S A E  re p orti n g 
T o e ns ure pati e nt safet y, e ver y S A E, re gar dl ess of ca usalit y, occ urri n g after t h e patie nt has 
pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da ys after t h e last pla n n e d st u d y assess me nt, m ust be 
re p orte d t o 
wit hi n  2 4  h o urs  of  lear ni n g of  its occ urre nc e  as  descri be d  b el o w. A n y  
S A Es e x perie nc e d after t his peri o d s h o ul d o nl y be r e p orte d t o 
 if t h e I n vesti gat or 
s us pects a ca usal r elati o ns hi p t o st u d y treat me nt.  
N ote: S A Es re p ort e d b y patie nts dee me d t o be scree n fail ur es m ust b e re p ort e d t o  
p as 
o utli ne d h ere wit h a p pr o priat e i nf or m ati o n als o ca pt ure d i n t he e C R Fs.  
All  f oll o w-u p  i nf or mati o n f or t h e S A E  i n cl u di n g i nf or mati o n o n  c o m plic ati o ns,  pr o gr essi o n  of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w -u p t o t he ori gi nal e pis o de 
wit hi n 2 4 h o urs of t he I n vesti gat or re cei vi n g t he f oll o w -u p i nf or mati o n. A n S A E occ urri n g at 
a differe nt  ti m e i nt er val or  ot h er wise  c o nsi dere d  c o m pletel y  u nrelate d  t o a pre vi o usl y  re p ort e d 
o ne m ust be re p orte d se paratel y as a ne w e ve nt.  
F oll o w -u p  i nf or mati o n pr o vi de d  m ust  descri be  w het her  t he e ve nt has  res ol ve d or  c o nti n ues,  if 
a n d h o w  it was  treate d a n d w het her  t he patie nt  c o nti n ue d  or  wit h dre w  fr o m st u d y partici pati o n. 
Eac h re-o cc urre n ce, c o m pli cati o n, or pr o gressi o n of t he ori gi nal e ve nt m ust be re p orte d as a 
f oll o w-u p t o t hat e ve nt re gar dl ess of w he n it occ urs.  
If t he S A E  is n ot  pre vi o usl y  d oc u m e nte d  i n t he I B ( ne w occ urre nce)  a n d is t h o u g ht t o be  rel ate d 
t o t he st u d y treatme nt  a 
 ass ociate ma y ur ge ntl y  re q uire f urt her i nf or mati o n fr o m 
t he I n vesti gat or f or Healt h A ut h orit y re p orti n g.  
 ma y nee d t o iss ue a n I n vesti gat or 
N otificati o n (I N) t o i nf or m all i n vesti g at ors i n v ol ve d i n a n y st u d y wit h t he sa me st u d y 
treat me nt t h at t his S A E has bee n re p orte d. S us pecte d U ne x pecte d Seri o us A d verse Reacti o ns 
( S U S A Rs) will be c ollecte d a n d re p orte d t o t he c o m pete nt a ut h orities a n d rel e va nt E Cs i n 
acc or da n ce wit h E U G ui da nc e 2 0 1 1/ C 1 7 2/ 0 1 or as per nati o nal re g ulat or y  re q uir e me nts i n 
partici pati n g c o u ntries.  
Cli nic al e n d p oi nts descri be d i n Secti o n 5. 4 , s uc h as blee di n g e ve nts, isc he mic str o ke, 
he m orr ha gi c str o ke, TI A, n o n -C N S s yste mic e m b oli c e ve nts, ve n o u s t hr o m b oe m b olic e ve nts 
or  m y ocar dial  i nfar cti o n, t hat als o meet  S A E  crit eria  will  be  c ollecte d  as  part  of  t he e n d p oi nt  

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e C R F. T h ese  pr ot oc ol -s pecifi c S A Es  will  n ot  be  r e p orte d o n  a n i n di vi d ual b asis  i n a n e x p e dit e d 
ma n ner  a n d  i nste a d will  be  a dj u di cate d  b y  a n i n de pe n de nt C E C.  Fatal e ve nts will b e re p ort e d 
re gar dless of a dj u dicati o n o n a n a g gre gate basis t o healt h a ut h orities as r e q uire d b y l ocal 
re g ulati o ns. Ot her S A Es will be e v al uate d o n a case -b y -case basis t o deter mi ne w het her t here 
is reas o na ble p ossi bilit y t h at t he st u d y dr u g ca use d t he e ve nt. If t he e ve nt is c o nsi dere d b y t he 
s p o ns or or desi g nee t o me et t he crit eria f or e x pe dite d re p orti n g, t he e ve nt will be r e p orte d i n 
a n e x pe dit e d ma n ner. St u d y e n d p oi nts a n d safet y data will be re g ular l y re vie we d b y a n 
i n de pe n de nt D M C i n a n u n bli n de d ma n ner t o e ns ure pr o m pt i de ntificati o n of a n y cli nicall y 
c o ncer ni n g saf et y iss ues.  
T he  i n vesti g at or still has  t h e res p o nsi bilit y t o re p ort all S A Es  t o t he s p o ns or as  descri be d  a b o ve. 
F oll o w t he detaile d i ns tr ucti o ns re gar di n g t he s u b missi o n pr ocess f or re p orti n g S A Es t o 
N ote:  S A Es  m ust  be  re p orte d t o 
wit hi n  2 4  h o urs  of  t he I n vesti gat or lear ni n g 
of its occ urre n ce/re cei vi n g f oll o w -u p i nf or mati o n.  
8. 5  
R e p orti n g Me dic ati o n err ors i ncl u di n g mis us e/ a b use  
Me dicati o n  err ors  are u ni nte nti o nal  err ors i n t he prescri bi n g,  d is pe nsi n g, a d mi nistr ati o n  or 
m o nit ori n g of a me dici n e w hile u n der t he c o ntr ol of a healt hc are pr ofessi o nal, pati e nt/s u bj ect, 
or c o ns u mer ( E M A defi niti o n). 
Mis use refers t o sit u ati o ns w here t he me di ci nal pr o d uct is i nte nti o nally an d i na p pr o pri atel y 
use d n ot in ac c or da nce w it h t he pr o t oc ol. 
A b use c orres p o n ds t o t he persist e nt or s p ora dic, i nte nti o n al e x cessi ve use of a m e dici n al 
pr o d uct, w hi c h is a cc o m p a nie d b y har mf ul p h ysic al or ps yc h ol o gical effects. 
All st u d y treat me nt err ors a n d uses o utsi de of w hat i s f oresee n in t he pr ot oc ol will be c ollect e d 
i n t he D ose  A d mi nistrati o n  Re c or d  e C R F.  St u d y  treat m e nt err ors  are  o nl y  t o b e  re p orte d t o 
 de partm e nt if t he tre at m e nt err or is ass ociat e d wit h a n S A E. 
All  i nsta nces of mis use  or a b use  m ust  be  d oc u m e nte d i n t he A E  e C R F irres pe cti v e of t he 
mis use/a b use bei n g ass ociat e d wit h a n A E/ S A E. I n  a d diti o n, all i nst a nces of mis use or a b use 
m ust be re p orte d t o t he 
 de part me nt. As s uc h, i nsta nces of mis use or a b use 
are als o t o 
be re p orte d 
usi n g t he 
S A E f or m/e C R F. 
Ta ble 8- 1  s u m marizes t he 
re p orti n g re q uire me nts. 
T a ble 8 -1  
S u m m ar y of R e p orti n g R e q uir e me nts f or M e dic ati o n E r r ors 
T re at m e nt  err or  t y pe 
D oc u m e nt  i n D ose  
A d mi nistr ati o n 
e C R F 
D oc u m e nt  i n A E e C R F 
C o m plete  S A E  f or m/e C R F 
U ni nte nti o nal  st u d y 
treat me nt err or 
Yes  
O nl y  if ass ociate d  wit h a n 
A E  
O nl y  if ass ociate d  wit h  a n S A E  
Mis use/ A b use  
Yes  
Yes  
Yes,  e ve n if n ot  ass ociate d  
wit h a S A E  
F or m or e i nf or mati o n o n A E a n d S A E defi niti o n a n d r e p orti n g r e q uire me nts, please see Secti o n 
8. 1  a n d Secti o n 8. 4 , r es pecti vel y. 
8. 6  
Pre g n a nc y re p orti n g  
Re pr o d ucti v e t o xicit y a n d ter at o ge nicit y data ar e n ot a vaila ble f or t his a nti b o d y at t his ti m e; 
t heref ore, n o g ui deli nes o n t hera pe uti c rec o m me n dati o ns i n case of pre g na nc y are a vaila ble. 

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T his  st u d y e nr olls  w o me n  w h o  are eit her of  n o n -c hil d-beari n g  p ote ntial  or  w h o  ha ve  a gree d  t o 
hi g hl y effe cti v e c o ntra ce pti o n as o utli ne d i n t he eli gi bilit y criteri a; t h us pre g na n c y is n ot a n 
e x pect e d  o utc o m e  f or a n y fe male st u d y parti ci pa nt.  H o we ver,  i n t he case t hat a pre g n a nc y  i n a 
fe mal e st u d y parti ci pa nt s h o ul d occ ur ple ase f oll o w t he bel o w re p orti n g g ui d eli n es. T he 
a p pr o priat e cli nical f oll o w -u p f or t his pati e nt a n d f or t he fet us is at t he discr eti o n of t he 
I n vesti gat or. 
T o  e ns ure patie nt  safet y, eac h  pre g na nc y  oc c urri n g  after  si g ni n g t he i nf or me d c o nse nt m ust  be 
re p orte d  t o
 wit hi n  2 4  h o urs  of  lear ni n g of  its occ urre nce.  T he  pre g n a nc y  s h o ul d be 
f oll o we d u p t o deter mi ne o ut c o me, i ncl u di n g s p o nta ne o us or v ol u ntar y ter mi nati o n, details  of 
t he birt h,  a n d t he prese n ce  or  a bse nce  of  a n y birt h  d ef ects,  c o n ge nital a b n or maliti es,  or  mater nal 
a n d/ or ne w b or n c o m plic ati o ns.  
Pre g na nc y m ust be rec or de d o n t he P har mac o vi gil a nce Pre g na nc y F or m a n d re p orte d b y t h e 
I n vesti gat or t o t he 
 de part me nt. Pre g na nc y f oll o w -u p s h o ul d be rec or de d o n t he 
sa me f or m a n d s h o ul d i ncl u de a n assess me nt  of  t he p ossi ble  relati o ns hi p t o t he st u d y treat me nt. 
A n y S A E e x perie nce d d uri n g t he pre g na n c y a n d u nrelat e d t o t he pre g na nc y m ust be re p orte d 
o n a S A E f or m . 
If t he I n vesti gat or bec o mes a ware of a pre g na nc y occ urri n g i n t he part ner of a s u bject 
partici pati n g  i n t he st u d y, t he pre g na nc y s h o ul d be re p orte d  t o  
 wit hi n 2 4  h o urs of 
bec o mi n g a ware, usi n g Pre g na nc y R e p ort F or m. I nf or mati o n re gar di n g t he pre g n a nt part n er 
m ust o nl y be s u b mitte d after o bt ai ni n g writte n c o nse nt fr o m t he pre g n a nt part ner. T h e 
pre g na nc y s h o ul d be f oll o we d u p t o deter mi n e o ut c o me, i ncl u di n g s p o nt a ne o us or v ol u nt ar y 
ter mi n ati o n, d etails of t h e birt h, a n d t h e prese nc e or a bse nce of a n y birt h defects, c o n ge nital 
a b n or maliti es, or mat er nal a n d/ or ne w b or n c o m plic ati o ns.  
All  assess me nts  t hat ar e c o nsi dere d  as  a ris k d uri n g  pre g na nc y  m ust  n ot  be  perf or me d,  s uc h as 
ve n o gra p h y. T he p ati e nt ma y c o nti n u e all ot her pr ot oc ol assess me nts.  
9  
D at a re vi e w a n d d at a b ase m a n a ge me nt  
9. 1  
Site m o nit ori n g  
Bef ore st u d y i niti ati o n, at a (re m ote or i n -pers o n) site i nitiati o n visit or at a n i n vesti g at or’s 
meeti n g, t he S p o ns or or S p o ns or re prese ntati ve will re vie w t he pr ot oc ol a n d e C R Fs wit h t he 
I n vesti gat or(s) a n d t heir staff. D uri n g  t he st u d y 
 e m pl o ys  se veral met h o ds  of  e ns uri n g 
pr ot oc ol  a n d G C P  c o m plia nc e a n d t he q ualit y/i nt e grit y  of  t he sites’ data.  T he  m o nit or  will  visit 
t he site t o c he c k  t he c o m plet e ness  of  patie nt  rec or ds, t he acc ur ac y  of  e ntries  o n  t he e C R Fs,  t he 
a d here nc e t o t he pr ot oc ol a n d t o G C P, t he pr o gress of e nr oll me nt, a n d e ns ure t hat st u d y dr u g 
is bei n g  st ore d, dis pe nse d,  a n d  acc o u nte d  f or acc or di n g  t o s pecifi cati o ns. Ke y  st u d y pers o n nel 
m ust be a vaila ble t o assist t h e m o nit or d uri n g t hese visits.  
T he I n vesti gat or m ust mai ntai n s o urce d oc u m e nts f or eac h patie nt i n t he st u d y, c o nsisti n g of 
case a n d visit n ot es ( h os pital or cli nic me dical re c or ds) c o ntai ni n g de m o gra p hi c a n d m e dic al 
i nf or mati o n, l a b orat or y dat a, ele ctr ocar di o gra ms, a n d t he res ults of a n y ot h er t ests or 
assess me nts. All i nf or mati o n o n e C R Fs m ust be tra cea bl e t o t hese s o urce d o c u me nts i n t he 
patie nt 's file. T h e I n vesti gat or m ust als o ke e p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y 
t he patie nt ( a si g ne d c op y is gi ve n t o t he patie nt).  
T he  I n vesti gat or m ust  gi ve  t he m o nit or  acc ess  t o all rele va nt s o urce d oc u me nts  t o c o nfir m t heir 
c o nsiste nc y wit h t h e e C R F e ntries. 
 m o nit ori n g sta n dar ds re q uire f ull verificati o n f or 
t he prese n ce  of  i nf or me d c o nse nt,  a d here n ce  t o t he eli gi bilit y criteria,  d o c u me ntati o n  of  S A Es, 

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a n d t he rec or di n g of data t h at will be use d f or all pri mar y a n d safet y varia bles. A d diti o n al 
c hec ks of t he c o nsiste n c y of t he s o urce d ata wit h t h e e C R Fs ar e perf or me d acc or di n g t o t he 
st u d y-s pecific m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u me nts a b o ut t he i de ntit y of t he 
patie nts will be discl ose d.  
9. 2  
D at a c ollecti o n  
Desi g nate d i n vesti g at or st aff will e nter t he dat a re q uire d b y t he pr ot oc ol i nt o t h e Electr o nic 
Case Re p ort F or ms usi n g f ull y vali dat e d s oft ware t hat c o nf or ms t o 2 1 C F R Part 1 1 
re q uire m e nts. Desi g nate d i n vesti g at or site staff will n ot be gi ve n ac cess t o t he ele ctr o ni c d ata 
ca pt ure ( E D C) s yste m u ntil t he y ha ve bee n trai ne d. A ut o mati c vali d ati o n pr o gra ms c hec k f or 
data discre p a n cies a n d, b y g e nerati n g a p pr o priat e err or m essa ges, all o w t he dat a t o be 
c o nfir me d  or  c orrecte d  bef ore  tra nsfer of  t he data  t o t he c o ntract researc h or ga nizati o n  ( C R O) 
w or ki n g o n be half of A nt h os T hera pe utics. T he  I n vesti gat or m ust c ertif y t hat t h e data e nter e d 
i nt o t he Ele ctr o ni c  Case  R e p ort  F or ms  (e C R Fs) are c o m plet e a n d a cc urate.  After  data base  l oc k, 
t he I n vesti g at or will recei ve c o pies of t he p ati e nt dat a f or arc hi vi n g at t he i n vesti gati o nal site. 
Data  n ot  re q uiri n g a se parate writt e n  rec or d are n ote d  o n  t he Assess me nt Sc he d ule  a n d ca n be 
rec or de d dir ectl y o n t he e C R Fs. All ot her dat a ca pt ure d f or t his st u d y will ha ve a n e xter nal 
ori gi nati n g  s o urce (eit h er writte n  or  el ectr o nic)  wit h  t he e C R F n ot  bei n g  c o nsi dere d  as  s o urce. 
All data s h o ul d be rec o r de d, ha n dle d, a n d st ore d i n a wa y t hat all o ws its acc urate re p orti n g, 
i nter pretati o n a n d verificati o n. 
9. 3  
D at a b ase m a n a ge m e nt a n d q u alit y c o ntr ol  
 will r e vie w t h e data e nter e d i nt o t h e e C R Fs b y i n vesti gati o nal st aff f or c o m pl ete n ess 
a n d acc ura c y  a n d instr uct  t he site p ers o n nel  t o ma k e  a n y re q uire d c orr ecti o ns  or  a d diti o ns. 
Q ueries are se nt t o t he i n vesti gati o nal sit e usi n g a n electr o nic dat a q uer y. Desi g nate d 
i n vesti gat or site st aff is re q uire d t o res p o n d t o t h e q u er y a n d c o nfir m or c orrect t he d ata.  
C o nc o mit a nt m e dic ati o ns e ntere d i nt o t h e dat a bas e will be c o de d usi n g t h e 
W H O Dr u g 
Refere nc e List, w hic h e m pl o ys t he A nat o mical T hera pe uti c C he mi cal classific ati o n s yste m. 
Me dical  hist or y/c urre nt  m e dic al  c o n diti o ns  a n d  a d v erse e ve nts  will  b e  c o de d  us i n g t h e me di cal  
dicti o n ar y f or re g ul at or y acti vities ( Me d D R A) ter mi n ol o g y.  
E xce pt f or t he e xt e nsi o n peri o d, l a b or at or y sa m ples will be pr o cesse d c e ntrall y,  a n d t he r es ults 
will be se nt electr o nic all y t o
. D uri n g t he e xte nsi o n peri o d, safet y la b orat ories will b e 
perf or me d l o call y.  
At  t he c o ncl usi o n  of  t he st u d y, t he occ urre nce  of  a n y e mer ge nc y c o de brea ks  will  be  deter mi ne d 
after ret ur n of all c o de bre a k re p orts a n d u n use d dr u g s u p plies t o 
 
T he  occ urre nce of a n y pr ot oc ol de viati o ns will be d eter mi ne d. After t hese acti o ns ha ve bee n 
c o m plete d a n d t he d ata b ase has bee n declare d t o be c o m plete a n d acc ur ate, it will be l oc k e d, 
a n d t he treat me nt c o des will b e ma de a v ail a ble f or d ata a nal ysis. A n y c ha n ges t o t he dat a base 
after t h at ti m e c a n o nl y b e  m a de b y j oi nt writt e n a gr ee me nt bet we e n t h e A nt h os T her a pe utics 
Hea d of Re g ulat or y a n d t he C hief Me di cal Offi cer.  
1 0  
D at a a n al ysis  
A ge neral d escri pti o n of t h e statistic al met h o ds t o be use d t o a n al yz e t his st u d y is o utli ne d 
bel o w. F urt h er det ails c a n be f o u n d i n t h e Statistic al A nal ysis Pla n ( S A P).  

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1 0. 1  
A n al ysis sets  
• 
O n -Treat m e nt: will c o nsist of all ra n d o miz e d patie nts w h o recei ve d at least o ne d ose of 
st u d y dr u g. Patie nts will b e c o nsi d ere d t o be o n-tr e at me nt if wit hi n 6 0 d a ys of t heir l ast 
d ose of st u d y dr u g u p t o t he E o T visit  of t he ra n d o mi ze d tre at m e nt peri o d . 
• 
I nte nt-t o-Treat (I T T): all p ati e nts ra n d o miz e d a n d d ose d t o b e a n al yz e d a cc or di n g t o 
ra n d o miz e d treat me nt assi g n me nt.  E v e nts  occ urri n g  fr o m ra n d o miz ati o n t hr o u g h E o S  of 
t he ra n d o mize d treat me nt p eri o d will be i n cl u de d i n t he a nal ysis.  
• 
Per  Pr ot oc ol:  All  ra n d o mize d patie nts  wit h  a treat m e nt c o m plia n ce rate of  at least 8 0 %  a n d 
d o n ot ha ve a n y maj or pr ot oc ol vi olati o ns as defi ne d i n t he fi n al S A P.  
• 
O n -Treat m e nt E xte nsi o n: will c o nsist of all p ati e nts w h o recei ve d at le ast o ne d ose of 
a bela ci m a b i n t he e xte nsi o n p eri o d. Patie nts will b e c o nsi dere d t o be o n -tr eat me nt if wit hi n 
6 0 da ys of t heir l ast d ose of st u d y dr u g t o t h e E o E visit of t he e xte nsi o n p eri o d . 
1 0. 2  
P atie nt de m o gr a p hics a n d ot her b aseli ne c h ar acteristics  
Data  f or bac k gr o u n d  a n d de m o gra p hic  varia bl es  will  be  liste d b y  treat m e nt gr o u p  a n d patie nt. 
S u m mar y statistics will be pr o vi d e d b y tre at me nt gr o u p.  
Rele va nt me di cal hist or y, c urre nt me di cal c o n diti o ns, res ults of la b orat or y scree ns, dr u g tests 
a n d a n y ot her  rele v a nt i nf or m ati o n will  be  liste d b y  treat m e nt gr o u p  a n d pati e nt,  a n d s u m mar y 
statisti cs will als o be pr o vi de d b y treat me nt gr o u p.  
1 0. 3  
Tre at m e nts  
Data  f or st u d y dr u g  a d mi nistrati o n  an d  c o nc o mita nt t hera pies will  be  list e d b y  tr eat me nt gr o u p 
a n d pati e nt.  
1 0. 4  
A n al ysis of t he pri m ar y v ari a ble(s)  
T he pri m ar y a nal ysis will c o m par e ea c h a belaci ma b re gi me n wit h ri var o x a ba n f or t he ti me t o 
first occ urre nc e of maj or or C R N M blee di n g i n t h e O n -Treat m e nt A nal ysis Set. F or e ac h 
treat me nt r e gi m e n, t he e ve nt rat e will be esti mate d wit h 9 5 % c o nfi d e nce i nter v als ( CIs). T he 
ti me t o first e ve nt will be a nal y ze d usi n g t he C o x pr o p orti o nal ha zar ds m o del i ncl u di n g 
treat me nt a n d t he f oll o wi n g t w o stratific ati o n f act ors as c o variates: 
• Pla n ne d use of c o nc o mita nt a nti platel et me di cati o n use (e. g ., as piri n a n d/ or P 2 Y 1 2 
i n hi bit or) f or t he d urati o n of t h e trial 
• Cr Cl  ( C oc kcr oft-Ga ult)  ≤ 5 0  ml/ mi n  
T he haz ar d rati os ( H R) wit h 9 5 % CIs will b e re p orte d f or b ot h d oses of a belaci ma b vs. 
ri var o xa ba n. A si g nific a nce le vel of α = 0. 0 5, wit h o ut a dj ust me nt f or m ulti plic ati v e testi n g, will 
be use d. A se nsiti vit y a nal ysis will be perf or me d i n t he I T T p o p ul ati o n.  
T he pr o p orti o n al ha zar ds ass u m pti o n i n t h e C o x m o del will be assesse d. A piec e wise C o x 
m o del will be c o nsi d ere d gi v e n e vi de n ce of n o n -pr o p orti o nal h azar ds.  
1 0. 5  
A n al ysis of se c o n d ar y v ari a bles  
Sec o n dar y  e n d p oi nts  will  be  a nal yz e d  f oll o wi n g t he t esti n g pr oce d ur e  o utli ne d  i n Se cti o n  1 0. 4 . 
 

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S afet y  v ari a bles  
1 0. 5. 1. 1  Blee di n g  e ve nts 
All  i nf or m ati o n o bt ai ne d  o n  ble e di n g  e ve nts  will  be  dis pla ye d  b y  tr eat me nt gr o u p.  
T he  n u m ber  a n d perce nta g e  of  pati e nts  wit h  blee di n g  e ve nts  will  be  ta b ulat e d b y  b o d y  s yste m 
a n d preferr e d ter m wit h a brea k d o w n b y tr eat me nt. A patie nt wit h m ulti pl e ble e di n g e v e nts is 
o nl y  c o u nte d o nce  t o war ds t he per ce nt a ge  of  pati e nts  wit h  blee di n g  e v e nts.  A d diti o nal  a n al ysis 
b y ne gati ve bi n o mial m a y be carrie d o ut t o c o m pare blee di n g e ve nt rates a m o n g tre at m e nt 
gr o u ps if s ufficie nt blee di n g e ve nts oc c ur.  
Blee di n g e ve nts occ urri n g d uri n g t h e e xte nsi o n peri o d will be s u m mari ze d as descri be d i n t h e 
S A P.  
1 0. 5. 1. 2  A d verse e ve nts  
All  i nf or mati o n o btai ne d  o n  A Es  will  be  dis pla ye d  b y  treat me nt gr o u p  a n d patie nt  a n d will be 
s u m mariz e d se paratel y f or t he O n-Treat me nt A nal ysis Set a n d t he O n -Tre at m e nt E xte nsi o n 
A nal ysis Set . 
T he n u m ber a n d perc e nta g e of patie nts wit h A Es will be t a b ulate d b y b o d y s yste m a n d 
preferre d ter m wit h a brea k d o w n b y treat me nt. A pa tie nt wit h m ulti ple A Es wit hi n a b o d y 
s yste m is o nl y c o u nte d o nc e t o war ds t he t otal of t his b o d y s yste m.  E x p os ure -a dj ust e d A E rates 
will als o be s u m marize d f or b ot h t he O n -Treat m e nt A nal ysis Set a n d t he O n -Tre at m e nt 
E xte nsi o n A nal ysis Set.  
 
Vit al  si g ns 
All vit al si g ns d ata will be liste d b y tre at m e nt gr o u p, pati e nt, a n d visit/ti me a n d if ra n ges are 
a vail a ble a b n or malities (a n d r ele v a nt ort h ost ati c c h a n ges) will be fla g ge d. S u m mar y statistics 
will be pr o vi d e d b y tre at m e nt a n d visit/ti me.  
 
E C G  e v al u ati o ns  
All E C G data will be liste d b y treat me nt gr o u p, patie nt a n d visit/ti m e, a b n or malities will be 
fla g ge d. S u m m ar y statistics will be pr o vi d e d b y treat me nt a n d visit/ti m e. 
 
Cli nic al  l a b or at or y e v al u ati o ns 
All  la b orat or y data  will  be  liste d b y  tr eat m e nt gr o u p,  p atie nt,  a n d visit/ti m e  a n d if n or mal  ra n g es 
are a vaila bl e a b n or malities will be fla g ge d. S u m m ar y statistics will be pr o vi de d b y tr eat me nt 
a n d visit/ti m e.  
 
Ot her  s afet y e v al u ati o ns  
All i nje cti o n site re acti o n dat a will b e list e d b y tre at me nt gr o u p, p ati e nt,  a n d visit/ti m e, a n d 
s u m mariz e d b y tre at me nt gr o u p a n d visit/ti me as nee de d. 
1 0. 6  
 
  
  
  
  
  
  
  
  
  
 
 
 

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P h ar m ac o d y n a mics  
All p har ma c o d y na mic e n d p oi nts will be s u m mari ze d b y visit a n d tr eat me nt gr o u p i ncl u di n g 
t he rati o t o baseli ne f or e ac h tr eat me nt al o n g wit h t h eir ass ociate d c o nfi de nce i nter v als.  
 
P h ar m ac o ki netics  
Plas ma t ot al a b elaci ma b c o nce ntrati o n dat a will be liste d b y d ose, patie nt, a n d visit/sa m pli n g 
ti me p oi nt. Descri pti ve s u m mar y statisti cs will b e pr o vi de d b y d ose a n d visit/sa m pli n g ti m e 
p oi nt,  i ncl u di n g t he fre q u e nc y ( n, %)  of  c o nce ntrati o ns  bel o w  t he L L O Q a n d re p orte d as zer o. 
 
P h ar m ac o ki netic  / p h ar m ac o d y n a mic  i nter acti o ns 
Gra p hi cal  de picti o ns  of  t he relati o ns hi p bet wee n  plas ma  a bel aci ma b  c o nc e ntrati o ns  a n d/ or P K 
para meters a n d P D varia bles (f or e xa m ple: free F XI a n d a P T T) ma y be prese nte d f or t he 
cli ni cal st u d y r e p ort.  
T he rel ati o ns hi p bet we e n i n di vi d ual P K pr ofiles or deri ve d P K para met ers a n d vari o us 
effica c y/ P D meas ure me nts or deri ve d v aria bl es (f or e xa m ple: fre e F XI a n d a P T T) will be 
e x pl ore d as a p pr o priat e. A d diti o nall y, t he effect of rele va nt baseli ne c hara cteristics (a ge, 
ge n der,  b o d y  wei g ht,  baseli ne  fact or XI  le vels, baseli ne  a P T T, etc.) o n  P K  para meters  a n d P D 
res p o nses will  be  as sesse d as  nee de d  usi n g  a m o del -base d  a p pr oac h  t hat i nc or p orat es data  fr o m 
ot her st u dies wit h a belaci ma b. If a v aila ble, t h ese res ults ma y be s u m mari ze d i n t h e cli nical 
st u d y re p ort; h o we ver,  a se p arat e a nal ysis  pla n  a n d fi nal re p ort f or t his a nal ysis  will  be  iss ue d. 
 
I m m u n o ge nicit y 
All  i m m u n o ge nicit y res ults will  be  liste d b y  treat me nt gr o u p,  patie nt,  a n d  visit/ti me.  
 
E x pl or at or y  bi o m ar kers  
 
 
 
 
 
 
 
 
 
 
 
 
 
S a m ple size c alc ul ati o n  
T he  pri mar y  e n d p oi nt is t h e c o m p osit e of  maj or  or  C R N M  blee di n g.  T he  st u d y is e ve nt dri ve n.  
Ass u mi n g a H R of 0. 6 0 f or eac h d ose of a bel aci ma b c o m par e d wit h ri var o xa b a n, at l east 1 6 6 
e ve nts  will  pr o vi de  at least 8 0 %  p o wer  f or e ac h a b ela ci ma b  ar m vs.  ri var o xa ba n wit h  a 2 -si de d 
al p ha of  0. 0 5.  Gi ve n  a n e x pecte d  1 5 %  per  year  e ve nt rate i n t he ri var o xa ba n ar m, a 1 0 %  a n n ual 
dr o p o ut rate ( deat h, wit h dra wal of c o nse nt, l ost-t o-f oll o w-u p), a p pr o xi mat el y 1, 2 0 0 patie nts 
s h o ul d pr o vi de  t he re q uisit e n u m ber  of  e ve nts  o ver  a t otal trial d urati o n  of  2 7  m o nt hs.  We  will 

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f oll o w t he e ve nt r ates wit h t he p ossi bilit y of e xte n di n g e nr oll m e nt p hase t o preser v e t he pla n ne d 
d urati o n of t h e tri al.  
1 0. 8  
A d h oc d at a re vie ws  
A d  h oc  data  re vie ws of  u n bli n de d  dat a  ma y  be  c o n d u cte d  b y  a S p o ns or  tea m d uri n g  t he c o n d uct 
of  t he st u d y t o s u p p ort decisi o n -ma ki n g  c o ncer ni n g  t he c urre nt st u d y or  t he S p o ns or’s  cli nical 
de vel o p m e nt pr o gra m  i n ge neral. T hese re vie ws will be c o n d ucte d b y a li mite d S p o ns or te a m 
n ot i n v ol ve d i n t he c o n d uct of t he st u d y  d uri n g t he ra n d o mize d p eri o d of t h e st u d y . 
1 1  
Et hic al c o nsi der ati o ns  
1 1. 1  
R e g ul at or y a n d et hic al c o m pli a nce  
T his cli nical st u d y was desi g n e d a n d s hall b e i m ple m e nte d, e xec ute d a n d re p ort e d i n 
acc or da n ce wit h t he I C H Har m o ni ze d Tri partite G ui deli n es f or G C P, wit h a p plic a ble l oc al 
re g ulati o ns (i ncl u di n g E ur o pea n  Directi ve  2 0 0 1/ 2 0/ E C,  U S  C o de  of  Fe der al  R e g ulati o ns  Titl e 
2 1, a n d Ja pa nese Mi nistr y of Healt h, La b or, a n d Welfare), a n d wit h t he et hic al pri nci ples l ai d 
d o w n i n t he Decl arati o n of H elsi n ki.  
1 1. 2  
R es p o nsi bilities of t he i n vesti g at or a n d et hics c o m mittee  
Bef ore i niti ati n g a trial, t he I n vesti g at or/i nstit uti o n m ust o bt ai n a p pr o val/fa v ora bl e o pi ni o n 
fr o m t he et hi cs  c o m mitte e ( E C) f or t he trial pr ot oc ol,  writte n  i nf or m e d c o nse nt f or m, c o nse nt 
f or m u p dates, patie nt re cr uit me nt pr oc e d ures (e. g., a d vertise m e nts) a n d a n y ot her writte n 
i nf or mati o n t o be pr o vi d e d t o patie nts. Pri or t o st u d y start, t he I n vesti gat or is re q uire d t o si g n 
a pr ot oc ol  si g nat ure pa g e  c o nfir mi n g  his/ h er  a gree me nt t o c o n d uct t he st u d y i n acc or da n ce  wit h 
t hese d oc u m e nts a n d all of t he i nstr ucti o ns a n d pr oc e d ures f o u n d i n t his pr ot oc ol a n d t o gi v e 
access t o all rel e va nt dat a a n d r ec or ds t o 
m o nit ors, a u dit ors,  
Q ualit y 
Ass ura nce re prese ntati ves, d esi g nate d a ge nts of A nt h os T hera pe utics, E Cs, a n d re g ulat or y 
a ut h orities  as  re q uire d. If a n i ns pecti o n of  t he cli nical site is re q ueste d b y  a re g ulat or y a ut h orit y, 
t he I n vesti gat or m ust i nf or m A nt h os T hera pe utics or a dele gate w or ki n g o n t heir be half 
i m me diat el y t h at t his re q uest has bee n ma de. 
F or  m ulti -c e nter  trials, a C o or di nati n g  I n vesti g at or will  be  selecte d b y  A nt h os  T h era pe utics  or 
a del e gat e w or ki n g o n t h eir b e ha lf ar o u n d t he ti me of Last Patie nt Last Visit t o be a r e vie wer 
a n d si g nat or y f or t h e C S R.  
1 1. 3  
P u blic ati o n of st u d y pr ot oc ol a n d res ults  
T he ke y desi g n ele m e nts  of  t his pr ot oc ol will be p oste d i n  a p u blicl y ac cessi ble dat a base s uc h 
as cli nic altrials. g o v. U p o n s t u d y c o m pleti o n a n d fi n aliz ati o n of t he st u d y re p ort t h e res ults of 
t his tri al will be p oste d i n a p u blicl y ac cessi ble dat a base of cli nical trial res ults i n acc or d a nce 
wit h l ocal re g ul ati o ns.  
N o p u blicati o n or discl os ure of st u d y res ults will b e per mitte d e xc e pt u n der t he ter ms a n d 
c o n diti o ns  of  a se parate writt e n  a gree me nt bet wee n  t he S p o ns or  a n d t he I n vesti gat or a n d/ or t he 
I n vesti gat or's i nstit uti o n. A  P u blicati o n  C o m mittee,  l e d b y  t he TI MI  St u d y  Gr o u p,  will  o versee 
p u blicati o n of pri mar y a n d se c o n dar y res ults. F urt her details of t he c o m p ositi o n, r ol es, 
res p o nsi bilities, a n d pr ocesses of t he P u blicati o n C o m mittee will be d oc u me nte d i n t h e 
P u blicati o n C o m mitt ee C harter.  
T he i nf or mati o n de v el o pe d fr o m  t his cli nical st u d y will be use d b y t he S p o nsor i n c o n necti o n 
wit h  t he d e vel o p me nt  of  a bel aci ma b  a n d ot her  dr u gs  a n d dia g n ostics,  a n d t h us ma y  be  discl ose d 

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as  re q uire d t o ot her  cli nic al i n vesti g at ors, b usi ness  part ners,  or  re g ulat or y a ge nci es.  T o  per mit 
t he i nf or mati o n deri ve d fr o m t he cli ni cal st u dies t o be use d, t he I n vesti gat or is o bli gate d t o 
pr o vi de t he S p o ns or wit h all data o bt ai ne d i n t he st u d y.  
1 2  
Pr ot oc ol a d here nce  
T his pr ot oc ol defi n es t he st u d y o bjecti v es, t he st u d y pr oce d ures, a n d t he data t o be c ollecte d 
o n st u d y parti ci pa nts. A d diti o n al assess me nts r e q uir e d t o e ns ure safet y of pati e nts s h o ul d b e 
a d mi nist ere d as dee m e d necessar y o n a case b y c ase basis. U n der n o circ u msta nces is a n 
i n vesti gat or all o we d t o c ollect a d diti o nal d ata or c o n d uct a n y a d diti o nal pr oce d ures f or a n y 
researc h rel ate d p ur p ose i n v ol vi n g a n y i n vesti gati o n al dr u gs u n der t he pr ot oc ol. 
I n vesti gat ors asc ertai n t he y will a p pl y d ue dili ge nce t o a v oi d pr ot oc ol de vi ati o ns. If a n 
i n vesti gat or fe els a pr ot oc ol de vi ati o n w o ul d i m pr o ve t he c o n d uct of t he st u d y t his m ust be 
c o nsi dere d a pr ot o c ol a m e n d me nt, a n d u nless s uc h a n a me n d m e nt is a gre e d u p o n b y A nt h os 
T hera pe utics a n d a p pr o v e d b y t he E C a n d h ealt h a ut h orities, w here re q uir e d, it ca n n ot be 
i m ple me nte d. 
1 2. 1  
Pr ot oc ol A m e n d m e nts  
A n y c ha n ge t o t he pr ot o c ol c a n o nl y b e ma d e i n a writte n pr ot o c ol a me n d m e nt t hat m ust be 
a p pr o ve d b y A nt h os T hera pe utics, Healt h A ut h oriti es w here re q uire d, a n d t he I R B pri or t o 
i m ple me ntati o n. 
A me n d me nts t h at ar e i nte n de d t o eli mi n ate a n a p p ar e nt i m me di ate h azar d t o patie nts ma y be 
i m ple me nt e d i m me di atel y, pr o vi de d t h e Healt h A ut h oriti es are s u bse q ue ntl y n otifi e d b y 
pr ot oc ol a me n d m e nt a n d t he re vi e wi n g E C is n otifie d.  
N ot wit hsta n di n g t he ne e d f or a p pr o v al of f or mal pr ot oc ol a me n d m e nts, t h e I n vesti gat or is 
e x pect e d t o t a ke a n y i m m e diate a cti o n r e q uire d f or t he safet y of a n y p ati e nts i ncl u de d i n t his 
st u d y, e ve n if t his acti o n re pr ese nts a de viati o n fr o m  t he pr ot oc ol. I n s uc h cases, t he re p orti n g 
re q uire m e nts i de ntifie d i n Secti o n  8  ( Safet y M o nit ori n g)  m ust  be  f oll o we d a n d t he St u d y  Lea d 
i nf or me d. 
 

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1 3  
Ref ere nces  
Refere nc es  are a v ail a ble u p o n  re q uest 
Ber g J, Li n d gre n P, Nie u wla at R, et al ( 2 0 1 0) Fact ors deter mi ni n g utilit y m eas ure d wit h t h e 
E Q -5 D i n patie nts wit h atrial fi brillati o n. Q ual . Lif e Res.; 3: 3 8 1-3 9 0  
B olt o n -Ma g gs  ( 2 0 0 0) Fact or  XI  deficie nc y  a n d  its m a na ge m e nt.  Hae m o p hilia;  6  ( S 1): 1 0 0-9.  
B üller H R, Bet h u n e C, B ha n ot S, et al ( 2 0 1 5) Fact or XI a ntise nse oli g o n ucle oti de f or 
pre ve nti o n of v e n o us t hr o m b osis. N. E n gl. J. Me d.; 3 7 2: 2 3 2 -4 0.  
Ca n o SJ, La m pi n g D L, B a m ber L, et al ( 2 0 1 2) T h e A nti -Cl ot Tr eat me nt Scal e ( A C T S) i n 
cli ni cal tri als: cr oss -c ult ural vali dati o n i n v e n o us t hr o m b oe m b olis m patie nts. Healt h a n d 
Q ualit y Of  Lif e O utc o m es; 1 0: 1 2 0 -1 3 0.  
C he n g  Q,  T uc ker  EI,  Pi ne  M S,  et al (2 0 1 0)  A  r ole f or fact or XIIa -me di ate d  fa ct or XI  acti vati o n 
i n t hr o m b us f or mati o n i n vi v o. Bl o o d; 1 1 6: 3 9 8 1-9.  
C or o mi nas  M,  Gasta mi n za G,  L o bera T  ( 2 0 1 4) H y perse nsiti vit y  re acti o ns t o bi ol o gical dr u gs.  
J. I n vesti g. Aller g ol.  Cli n.  I m m u n ol.; 2 4:  2 1 2 -2 2 5.  
Cr os b y J R, Marzec U, Re ve n k o A S, et al ( 2 0 1 3) A ntit hr o m b otic effe ct of a ntise nse fact or XI 
oli g o n ucl e oti d e tre at m e nt i n pri mat es. Arteri oscl er T hr o m b Vasc Bi ol. 3 3( 7): 1 6 7 0 -8.  
D u ga S, Sal o m o n O ( 2 0 1 3) C o n g e nit al fact or XI defici e nc y: a n u p d ate. Se mi n. T hr o m b. 
He m ost. 3 9: 6 2 1 – 6 3 1  
Gaila ni D, Re n né T ( 2 0 0 7) I ntri nsic p at h wa y of c oa g ul ati o n a n d arteri al t hr o m b osis. 
Arteri oscler. T hr o m b. Vasc. Bi ol.; 2 7: 2 5 0 7 -1 3.  
Hi n dric ks G, P ot par a T, Da gres N et al ( 2 0 2 0) 2 0 2 0 E S C G ui deli nes f or t h e dia g n osis a n d 
ma na ge me nt  of  atrial fi brillati o n de v el o pe d  i n c olla b orati o n  wit h  t he E ur o pea n  Ass ociati o n  of 
Car di o -T h ora cic S ur ger y ( E A C T S) E ur He art J. A u g 2 9;e haa 6 1 2.  
H uis ma n M V, R ot h ma n KJ, Pa q uett e M, et al ( 2 0 1 7) T he C h a n gi n g La n dsca pe f or Str o ke 
Pre ve nti o n i n A F: Fi n di n gs Fr o m t h e G L O RI A -A F Re gistr y P hase 2. J A m C oll Car di ol. 
6 9( 7): 7 7 7 -7 8 5.  
I d us o gie E E, Presta L G,  Gazz a n o -Sa nt or o H, et  al ( 2 0 0 0) Ma p pi n g of  t he C 1 q bi n di n g  site o n 
Rit u xa n, a c hi m eric a nti b o d y wit h a h u ma n I g G 1  Fc. J. I m m u n ol. 1 6 4: 4 1 7 8 -4 1 8 4.  
Ja n uary C T, 
W a n n L S, Al pert J S,  et al ( 2 0 1 4) 2 0 1 4 A H A/ A C C/ H R S g ui deli ne f or t h e 
ma na ge me nt of patie nts wit h atrial fi brillati o n: a re p ort of t he A meri ca n C oll e ge of 
Car di ol o g y/ A m eric a n Heart Ass ociati o n Tas k F orc e o n Practic e G ui d eli n es a n d t he Heart 
R h yt h m S oci et y. J A m C oll Car di ol.; 6 4( 2 1):e 1 -7 6  
Ja n uar y C T, Wa n n L S, Cal ki ns H, et al ( 2 0 1 9) 2 0 1 9 A H A/ A C C/ H R S F oc use d U p date of t he 
2 0 1 4 A H A/ A C C/ H R S G ui deli ne f or t h e Ma na g e me nt of Patie nts Wit h Atrial Fi brillati o n: A 
Re p ort of t he A merica n C olle g e of Car di ol o g y/ A m er ica n Heart Ass ociati o n Tas k F or ce o n 
Cli nic al  Practic e  G ui d eli n es  a n d t he Heart  R h yt h m  S ociet y.  J A m  C oll  Car di ol.; 7 4( 1): 1 0 4 -1 3 2.  
J P A C - J oi nt U nite d Ki n g d o m Bl o o d Tr a nsf usi o n a n d Tiss ue Tra ns pla ntati o n Ser vices 
Pr ofessi o nal A d vis or y C o m mitt ee ( 2 0 1 4) 5 t h Ha n d b o o k of Tra nsf usi o n Me dici ne; Ja n uar y 
2 0 1 4; T S O; N or wic h  
Kaatz  S,  A h ma d D,  S p yr o p o ul os  A C,  et al ( 2 0 1 5) Defi niti o n  of  cli nicall y  rele va nt n o n -maj or 
blee di n g  i n st u dies of  a ntic o a g ula nts  i n atrial fi brillati o n a n d ve n o us  t hr o m b oe m b oli c disease 

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i n n o n-sur gical p ati e nts: c o m m u ni cati o n fr o m t he S S C of t he I S T H. J T hr o m b Hae m ost.  
1 3( 1 1): 2 1 1 9 -2 6.  
K oc h A W, Sc hieri n g N, Mel k k o S, et al ( 2 0 1 9) M A A 8 6 8, a n o vel F XI a nti b o d y wit h a 
u ni q ue  bi n di n g  m o de,  s h o ws d ura bl e  effe cts  o n  mar k ers  of  a ntic oa g ul ati o n  i n h u ma ns.  Bl o o d. 
1 3 3( 1 3): 1 5 0 7 -1 5 1 6.  
Li p  G Y,  Ras m usse n  L H,  Olss o n  S B,  et al  ( 2 0 0 9) Oral  dire ct  t hr o m bi n i n hi bit or A Z D 0 8 3 7  f or 
t he pre ve nti o n of str o ke a n d s yste mic e m b olis m i n p atie nts wit h n o n-val v ular atrial 
fi brill ati o n: a ra n d o miz e d d ose-g ui di n g, safet y, a n d t olera bilit y st u d y of f o ur d oses of 
A Z D 0 8 3 7 vs. vita mi n K a nt a g o nists. E ur Heart J; 3 0( 2 3): 2 8 9 7 -9 0 7.  
Li p  G Y, Nie u wlaat  R,  Pisters  R,  et al ( 2 0 1 0) Refi ni n g  cli nical ris k stratificati o n f or pre dicti n g 
str o ke a n d t hr o m b oe m b olis m i n atrial fi brillati o n usi n g  a n o vel  ris k fact or-base d  a p pr oac h: t he 
e ur o heart s ur ve y o n atrial fi brillati o n. C hest.; 1 3 7( 2): 2 6 3 -7 2.  
Li p G Y, Hal peri n J L, Peterse n P, et al ( 2 0 1 5) A P hase II, d o u ble -bli n d, ra n d o mize d, par all el 
gr o u p,  d ose -fin di n g  st u d y of  t he saf et y a n d  t ol era bilit y of  dare xa b a n  c o m pare d  wit h  warfari n 
i n patie nts  wit h  n o n -val v ular  atrial fi brillati o n: t he or al  fact or Xa  i n hi bit or f or pr o p h yla xis  of 
str o ke i n atrial fi brillati o n st u d y 2 ( O P A L-2). J T hr o m b Hae m ost; 1 3( 8): 1 4 0 5 -1 3.  
Li u  Q,  Bet h u n e  C,  Dess o u ki  E,  et al ( 2 0 1 1) I SI S-F XI R x,  a n o vel  a n d s pecific a ntise nse i n hi bit or 
of fact or XI, ca use d si g nifi ca nt re d ucti o n i n F XI a nti ge n a n d a cti vit y a n d i n crease d a P T T 
wit h o ut  ca usi n g  blee di n g  i n healt h y  v ol u nteers.  Pa per  prese nte d  at t he 5 3r d  A merica n  S ociet y 
of  He mat ol o g y  a n n ual meeti n g  a n d e x p ositi o n,  Sa n  Die g o,  Calif or ni a.  Bl o o d;  1 1 8:  2 0 9  –  2 0 9.  
Li v nat  T,  Ta mari n  I, M or  Y,  et al ( 2 0 0 9) Rec o m bi na nt  acti vat e d  fact or VII  a n d tra ne xa mi c aci d 
are hae m ostatic all y  effecti ve  d uri n g  m aj or  s ur ger y i n fact or XI -defici e nt  p ati e nts  wit h  i n hi bit or 
a nti b o di es. T hr o m b. Hae m ost.; 1 0 2: 4 8 7 – 4 9 2.  
Meijers  J C, Te kele n b ur g W L, et al ( 2 0 0 0) Hi g h Le v els  of C oa g ulati o n Fact or  XI  as  a  Ris k 
Fact or f or Ve n o us T hr o m b osis N  E n gl J Me d. 2 0 0 0 Mar 9; 3 4 2( 1 0): 6 9 6 -7 0 1.  
M u mf or d A D, Ac kr o y d S, et al ( 2 0 1 4) G ui d eli ne f or t he dia g n osis a n d ma na g e me nt of t he 
rare c oa g ulati o n dis or ders: a U nit e d Ki n g d o m Hae m o p hilia C e ntre D oct ors' Or ga niz ati o n 
g ui deli n e  o n  be h alf  of  t he Britis h  C o m mitte e  f or Sta n dar ds  i n Hae mat ol o g y.  Br  J Hae mat ol. 
1 6 7( 3): 3 0 4 -2 6.  
O' C o n nell  N M,  Ri d dell  A F,  Pasc oe  G,  et al ( 2 0 0 8) Re c o m bi na nt  fa ct or VIIa  t o pre v e nt  s ur gi cal 
blee di n g i n fact or XI defici e nc y. Hae m o p hilia. ; 1 4( 4): 7 7 5 -8 1.  
Patel M R, Ma haffe y K W, Gar g J, et al ( 2 0 1 1) Ri v ar o xa ba n vers us warfari n i n n o n val v ular  
atrial fi brillati o n. N E n gl J Me d. 3 6 5( 1 0): 8 8 3 -9 1.  
Preis M,  Hirsc h J, K otler  A, Z oa bi A, Stei n N, et  al. ( 2 0 1 7) Fact or  XI deficie n c y is  ass ociate d 
wit h  l o wer ris k f or car di o vasc ular  a n d v e n o us  t hr o m b oe m b olis m e ve nts.  Bl o o d.  1 2 9( 9):  1 2 1 0 - 
1 2 1 5. Sal o m o n  O,  Stei n ber g  D M,  K ore n -M ora g  N,  et al ( 2 0 0 8) Re d uce d  i nci de nc e of  isc he mic 
str o ke i n patie nts wit h se v ere fact or XI deficie nc y. Bl o o d; 1 1 1: 4 1 1 3 -7.  
Ra h ma n F, K wa n G F, a n d Be nja mi n E ( 2 0 1 4) Gl o bal e p i de mi ol o g y of atri al fi brillati o n. Nat 
Re v Car di ol. 1 1( 1 1): 6 3 9 -5 4.  
Ri d dell A, A b d ul -Ka dir R, P ollar d D, et al ( 2 0 1 1) M o nit ori n g l o w d ose rec o m bi na nt fact or 
VIIa t hera p y i n patie nts wit h se vere f act or XI d efici e nc y u n der g oi n g s ur ger y. T hr o m b. 
Hae m ost. 1 0 6: 5 2 1 – 5 2 7.  
R uff C T, Gi u gli a n o R P, Bra u n wal d E, et al ( 2 0 1 4) C o m paris o n of t he Effic ac y a n d Safet y of 

A nt h os  T hera pe utics  
Pa ge 6 3  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
Ne w  Oral  A ntic oa g ula nts  Wit h  W arfari n  i n Patie nts  Wit h  Atrial  Fi brillati o n:  A  Meta -A nal ysis 
of Ra n d o mise d Trials. L a ncet. 3 8 3( 9 9 2 1): 9 5 5 -6 2.  
Sal o m o n O, Stei n ber g D M, Z uc ker M, et al ( 2 0 1 1) Patie nts wit h se vere fa ct or XI defici e nc y 
ha ve a re d u ce d i nci de nc e of dee p -v ei n t hr o m b osis. T hr o m b. Hae m ost.; 1 0 5: 2 6 9 -7 3.  
S hiel ds R L, Na me n u k A K, H o n g, K, et al ( 2 0 0 1) Hi g h res ol uti o n ma p pi n g of t he bi n di n g site 
o n h u m a n I g G 1  f or Fc γ RI, Fcγ RII, Fcγ RIII, a n d Fc R n a n d desi g n of I g G1  vari a nts wit h 
i m pr o ve d bi n di n g t o t h e Fc g R. J. Bi ol. C he m. 2 7 6: 6 5 9 1-6 6 0 4.  
S uri M F K, Ya m a gis hi K, et al ( 2 0 1 0) N o vel He m ostati c Fact or L e vels a n d Ris k of Isc he mic 
Str o ke: 
T he 
At her oscl er osis 
R is k i n 
C o m m u nities ( A RI C) St u d y. 
Cere br o vasc 
Dis. 
2 0 1 0; 2 9( 5): 4 9 7 -5 0 2.  
Weit z JI, C o n n oll y SJ, Patel I, et al ( 2 0 1 0) R a n d o mise d, p arallel -gr o u p, 
m ultice ntre, 
m ulti n ati o n al  p hase  2  st u d y c o m pari n g  e d o xa b a n,  a n oral  fact or Xa  i n hi bit or, wit h  warf ari n  f or 
str o ke pre ve nti o n i n patie nts wit h atrial fi brill ati o n. T hr o m b Hae m ost; 1 0 4: 6 3 3 -4 1.  
Weit z  JI, Ba uersa c hs  R,  Bec k er  B,  et al ( 2 0 2 0) Effe ct  of  Os oci ma b  i n Pre v e nti n g  Ve n o us 
T hr o m b oe m b olis m A m o n g Patie nts U n der g oi n g K ne e Art hr o plast y: T he F O X T R O T 
Ra n d o miz e d C li nical Tri al. J A M A. 3 2 3( 2): 1 3 0-1 3 9.  
Xarelt o ®  (ri var o xa ba n) 1 5 m g fil m-c oate d t a blets –  S u m mar y of Pr o d uct C h aracteristi cs 
2 0 1 9.  Me dici ne. or g. u k.  htt ps:// w w w. me dici n es. or g. u k/e mc/ me dici n e/ 2 5 5 9 2 # S T O R A G E . 
Accesse d 2 0 Oct 2 0 2 0.  
Xarelt o ®  (ri var o xa ba n) 2 0 m g fil m-c oate d t a blets –  S u m mar y of Pr o d uct C h aracteristi cs 
2 0 1 9.  Me dici ne. or g. u k.  htt ps:// w w w. me dici n es. or g. u k/e mc/ pr o d uct/ 2 7 9 3/s m pc . Acc esse d 
2 0 Oct 2 0 2 0.  
Xarelt o ®  (ri var o xa ba n) [ Pac ka g e I nsert]. Ja nsse n P har mace utic als,  I nc. Tit us ville,  NJ  a n d 
Ba yer Healt h Care A G Le ver k use n, Ger m a n y; r e vise d Marc h  
2 0 2 0.  ht t p:// w w w.ja nsse nla bels.c o m/ pa c ka ge-i nsert/ pr o d uct-m o n o gra p h/ prescri bi n g - 
i nf or mati o n/ X A R E L T O-pi. p df . Ac cesse d 2 0 Oct 2 0 2 0. 

A nt h os  T hera pe utics  
Pa ge 6 4  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
1 4  
A p pe n di x 1 –  C o m p o ne nts of t he C H A 2 D S 2 -V A Sc Sc ore  
T a ble 1 4 -1  
C o m p o n e nts of t he C H A 2 D S 2 -V A S c S c or e ( Li p et al 2 0 1 0)  
 
Ite m 
P oi nts  
C  
C o n gesti ve  he art  fail ur e ( or left ve ntric ul ar  s yst olic d ysf u ncti o n)  
1  
H  
H y perte nsi o n:  bl o o d  press ure  c o nsiste ntl y  a b o ve 1 4 0/ 9 0  m m H g  ( or 
treat e d h y pert e nsi o n o n me di cati o n)  
1  
A 2 
A ge  ≥7 5 years  
2  
D  
Dia betes  Mellit us  
1  
S 2 
Pri or  Str o ke  or  TI A  or  s yste mic arteri al t hr o m b oe m b olis m 
2  
V  
Vasc ular  disease  (e. g., p eri p her al  arter y  dise ase,  m y ocar dial  i nfarcti o n, 
a ortic pla q ue)  
1  
A  
A ge  6 5 – 7 4 years  
1  
Sc  
Se x  cate g or y  (i.e., fe m ale se x) 
1  

A nt h os  T hera pe utics  
Pa ge 6 5  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
1 5  
A p pe n di x 2 –  M a n a ge m e nt of Bl ee di n g  
T he  ma na ge me nt  of  s us pecte d bl ee di n g  is at t he discreti o n  of  t h e I n vesti g at or a n d will  de pe n d 
o n  t he s o urce/l ocati o n of  t he ble e di n g  a n d t he se verit y. I n all cases  of  blee di n g,  t he I n vesti gat or 
s h o ul d use cli nic al j u d g me nt i n assessi n g t he ris k t o t h e patie nt a n d m o nit or w het her t h e 
blee di n g is res ol vi n g or w orse ni n g.  
 
See bel o w f or s u g geste d g ui da n ce f or patie nts ra n d o mize d t o a b ela ci m a b or ri var o x a ba n. 
Re gar dless of st u d y dr u g assi g n me nt, i n t he e v e nt of se vere or life -t hr eat e ni n g blee di n g s uc h 
as  blee di n g  res ulti n g i n he m o d y n a mi c  c o m pr o mise r e q uiri n g i nt er ve nti o n (s uc h as  e n d osc o p y, 
a n gi o gra p h y, or s ur ger y) or a n i ntra cra ni al he m orr ha ge, t he f oll o wi n g ste ps s h o ul d be 
c o nsi dere d: 
• Wi t h h ol d st u d y dr u g  a n d all a nti pl atelet a ge nts  / o pe n  la bel a ntic oa g ula nts 
• I nstit ute sta n dar d of car e f or life-t hreat e ni n g blee di n g (e. g., l ar ge b ore i. v. or ce ntral 
ve n o us  access,  t y pe a n d cr oss matc h  bl o o d,  a d mit t o t he i nte nsi v e care u nit,  a n d pr o vi de 
he m o d y na mic a n d r es pirat or y s u p p ort, as ne e de d)  
• A d mi nister  p ac ke d  re d bl o o d  cells  ( or w h ole  bl o o d)  as  nee de d  
• C o nsi der  meas ures  s pecific t o t he patie nt’s  st u d y treat me nt as  descri b e d  bel o w  
I n cases of se vere or life-t hreate ni n g bl ee di n g, t h e i n vesti gat or is e nc o ur a ge d t o c o nt act t h e 
 
 
1 5. 1  
A bel aci m a b  
Ma na ge me nt  of  acti ve bl ee di n g  i n patie nts  a d mi nistere d  a bela ci ma b  s h o ul d be gi n,  if p ossi ble, 
wit h l ocal m eas ures (e. g., press ure or pac ki n g) at t h e site t o c o ntr ol a n y blee di n g, if p ossi ble. 
Mi n or blee di n g e ve nts, s uc h as e pista xis or s u perficial blee di n g, ca n us uall y be ma n a ge d 
c o nser vati v el y usi n g l ocal me as ures wit h o ut i nterr u pti o n  of st u d y dr u g treat me nt. As n ote d 
a b o ve,  treat me nt of  m o derate  t o se ver e ble e di n g  ma y  re q uire i ntr a ve n o us fl ui d re plac e me nt a n d 
bl o o d tra nsf usi o ns. T here is c urre ntl y n o s pecific re versal a ge nt f or a bela ci m a b. I n vesti gat ors 
are e nc o ura g e d t o c all t he 
 f or f urt h er g ui da nc e. 
Base d  o n  cli nical e x perie n ce ma n a gi n g  F XI  deficie nt  i n di vi d uals, treat m e nt o pti o ns  f or patie nts 
ra n d o miz e d t o a bel aci ma b i ncl u d e a nti-fi bri n ol ytic a ge nts s uc h as tra n e xa mic aci d ( T X A), 
t o pical he m ostatic a ge nts s uc h as fibri n gl u e, a n d pr o -he m ostatic bl o o d c o m p o ne nts s uc h as 
l o w d ose  rec o m bi n a nt a cti v ate d  f act or VII  (r F VIIa), pr ot hr o m bi n  c o m ple x  c o n ce ntr ate  ( P C C), 
fres h fr oze n plas ma ( F F P), a n d acti vate d P C C [e. g., fact or VIII i n hi bit or b y pass acti vit y 
( F EI B A)]. 
Of n ote, F XI c o nce ntrates are a v aila ble i n s o me c o u ntries ( n ot mar kete d i n t h e U S);  h o we ver, 
F XI c o nce ntr ates are n ot li kel y t o be effe cti v e i n patie nts o n a belaci ma b be ca use t he e x cess 
free a b elaci ma b a nti b o d y i n t h e circ ulati o n is e x pe cte d t o q ui c kl y n e utraliz e t he e x o g e n o us F XI.  
A ntifi bri n ol ytic  a g e nts  ha ve  be e n  use d  e xte nsi vel y  i n F XI  deficie nt  p ati e nts.  Si nce  ble e di n g  i n 
F XI defi cie nt patie nts t y pic all y occ ur i n ar eas of hi g h fi bri n ol yti c acti vit y s uc h as t he or al 
m uc osa, nasal m uc osa, a n d uri nar y tr act, 
pr oc e d ures s uc h as de ntal e xtracti o ns ca n be 
perf or me d  wit h  oral  a ntifi bri n ol yti c t her a p y al o ne starti n g t h e ni g ht  bef ore  a n d c o nti n ui n g  f or 
7  da ys  (D u ga  et al 2 0 1 3 ). Tra ne xa mi c  aci d ( T X A) is t he m ost  fre q ue ntl y use d  a ge nt a n d ca n be 
gi ve n  orall y  as  a ta blet or  a 5 %  m o ut h was h,  as well  as  i ntra ve n o usl y. Fi bri n  gl ue  has  als o bee n 
use d  t o rest ore l ocal he m ostasis  d uri n g  de ntal  s ur ger y i n patie nts  wit h  F XI  deficie nc y  (D u ga  et 

A nt h os  T hera pe utics  
Pa ge 6 6  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
  
al 2 0 1 3 ) a n d is a n o pti o n f or patie nts a d mi nistere d a b elaci ma b. 
T X A,  fi bri n gl ue,  a n d r F VIIa al o ne or  i n c o m bi nati o n  ha ve  bee n  use d  t o tre at seri o us blee di n g 
i n F XI d efici e nt p ati e nts un der g oi n g maj or s ur ger y a n d ma y be c o nsi dere d i n t h e e v e nt of 
se vere or life-t hre ate ni n g blee di n g i n patie nts a d mi nistere d a bel aci ma b. St u dies s h o w t hat a 
re gi me n of l o w-d ose r F VIIa at a d ose of 3 0 μ g/ k g f oll o we d b y a d mi nistrati o n of r F VIIa at a 
d ose  of  1 5 – 3 0  μ g/ k g  e ver y 2 – 4  h o urs  f or 2 4 – 4 8  h o urs  i n a d diti o n t o T X A  1  g  e ver y  6  h o urs  f or 
5  t o 7  da ys  ca n b y pass  t he eff ect of  F XI  defici e nc y,  rest ore c oa g ul ati o n  par a meters,  a n d pre v e nt 
seri o us blee di n g after maj or s ur ger y i n F XI defi cie nt pati e nts ( Ri d d ell et al 2 0 1 1 , Li v nat et al  
2 0 0 9 ). 
I n vitr o t hr o m b oel ast ometr y  st u dies s h o we d t hat r F VIIa is ca pa ble of  b y passi n g  t he i n hi biti o n 
of F XIa pr o d uce d b y a bela ci m a b i n h u ma n bl o o d a n d i n plas ma fr o m c y n o m ol g us m o n ke ys. I n  
bl o o d  fr o m he alt h y  h u ma n  d o n ors,  t he pr ol o n gati o n  of  cl otti n g ti me i n d uc e d b y  a b ela ci m a b was 
s h orte ne d u p o n a d diti o n of r F VIIa (see a belaci ma b I B). Rec o m bi na nt F VIIa carri es a b o xe d  
war ni n g  f or t hr o m b osis, s o t his t hera p y s h o ul d o nl y  be  use d  i n cases  of  se vere blee di n g w here 
t he tre ati n g p h ysi cia n j u d ges t he be n efit-ris k t o fa v or treat me nt wit h r F VIIa.  
As a last r es ort, t h era pe utic plas ma p h eresis t o re m o ve a belaci ma b ma y b e a n o pti o n w here 
defi niti ve re m o val of a b ela ci m a b is re q uir e d. T h era pe utic pl as ma p heresis usi n g F F P i n 
e xc ha n ge of patie nt’s o w n plas ma t o re m o ve free a n d t otal a b elaci ma b a n d t o rest ore F XI t o 
desire d le vels i n lif e -t hreate ni n g blee di n g c o ul d l e a d t o defi niti ve n e utralizati o n of t h e P D 
effects of a b elaci ma b if nec essar y. Cli ni cal e x peri e nc e wit h t his a p pr o ac h, h o we ver, is c urre ntl y 
lac ki n g. 
1 5. 2  
Ri v ar o x a b a n  
Acti ve bl ee d i n g i n p ati e nts ra n d o mize d t o ri var o xa b a n s h o ul d be ma na g e d ac c or di n g t o l ocal 
sta n dar d of care a n d g ui deli nes (Hi n dri c ks et al 2 0 2 0 ). 
Acti ve ble e di n g i n pati e nts a d mi nistere d ri v ar o xa ba n s h o ul d be gi n wit h l ocal meas ures (e. g., 
press ure  or  pac ki n g)  at t he site t o c o ntr ol a n y blee di n g,  if p ossi ble.  Mi n or  blee di n g  e ve nts,  s uc h 
as  e pista xis  or  s u perficial ble e di n g,  ca n us uall y  be  ma na ge d  c o nser vati vel y  wit h o ut  i nterr u pti o n 
of st u d y dr u g treat me nt.  
As n ote d a b o ve,  treat me nt of m o derat e t o se vere blee di n g m a y re q uir e i ntra v e n o us fl ui d 
re plac e me nt a n d bl o o d tr a nsf usi o ns. If t he last d ose of ri var o xa b a n was wit hi n 2-4 hr, t he use 
of acti v ate d c harc o al m a y be c o nsi d ere d t o re d u ce f urt her e x p os ure. S pecific tr eat me nt 
i nter ve nti o ns t o i d e ntif y a n d m a na ge t he c a use of blee di n g ( e. g., gastr osc o p y) s h o ul d b e 
perf or me d pr o m ptl y.  
I n cases of se vere or life-t hre ate ni n g blee di n g, re v ersal of t he effects of ri var o xa ba n wit h 
a n de xa net alf a ca n be c o nsi dere d t o rest ore p h ysi ol o gical h e m ostasis. If u na v ail a ble, g e neral 
he m ostatic a g e nts, s uc h as 4 -f act or pr ot hr o m bi n c o m ple x c o n ce ntr ates ( P C C) m a y be use d. 
Acti vat e d pr ot hr o m b i n c o m pl e x c o nce ntrat es (a P C C), or r F VIIa ca n be c o nsi der e d; h o we ver, 
t hese ca n als o i ncre ase t he ris k of t hr o m b osis. 
I n vesti gat ors ar e e nc o ura g e d  t o call  t he 
 f or f urt her g ui da nce.  

A nt h os  T hera pe utics  
Pa ge 6 7  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
 
 
1 6  
A p pe n di x 3 –  Assess me nt Sc he d ul es  
T a ble 1 6 -1  
Assess me nt Sc he d ule ( Ye ar 1)  
P eri o d  
S cr e e ni n g  
Tr e at m e nt  P eri o d  ( Y e ar 1)  
 
D a y  
M o nt h  
 
-3 0  t o -1  
1  
8  
3 0  
6 0  
3  
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
Vi sit  Wi n d o w  ( d a y s) 
 
 
± 2  
± 3  
± 3  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
I nf or m e d c o n s e nt/ G e n eti c  c o n s e nt 1  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I n cl u si o n/ E x cl u si o n crit eri a  
x  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
D e m o gr a p h y/ M e di c al  Hi st or y  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h y si c al  E x a m  
S  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H ei g ht  a n d  W ei g ht  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vit al  si g n s  
x  
x  
 
x  
 
 
 
 
x  
 
 
 
 
 
x  
1 2 -l e a d E C G  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HI V,  H e p atiti s  B,  H e p atiti s  C  
S  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S er u m  Pr e g n a n c y  a n d  F S H  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Uri n e  Pr e g n a n c y  - W O C B P  o nl y  
 
S  
 
S  
 
S  
 
 
S  
 
 
S  
 
 
S  
H e m at ol o g y  
x  
x  
 
 
 
x  
 
 
x  
 
 
x  
 
 
x  
C h e mi str y  
x  
 
 
 
 
 
 
 
x  
 
 
 
 
 
x  
Uri n al y si s  
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P T/I N R,  a P T T  
x  
x  
 
x  
 
x  
 
 
x  
 
 
x  
 
 
x  
P K 2  a n d  Fr e e  F XI  / T ot al  F XI 2  
 
x  
 
x  
 
x  
 
 
x  
 
 
x  
 
 
x  
A nti dr u g  a nti b o di e s  ( A D A)2  
 
x  
 
x  
 
x  
 
 
x  
 
 
x  
 
 
x  
F a ct or  XI  C o a g ul ati o n  A cti vit y 3  
 
x  
 
x  
 
x  
 
 
x  
 
 
x  
 
 
x  
E x pl or at or y  bi o m ar k er s 3  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
x  
G e n eti c  s a m pl e 1  
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
 
E Q -5 D -5 L  a n d  A C T S  P R O s 3  
 
x  
 
 
 
 
 
 
x  
 
 
 
 
 
x  
T el e p h o n e  c all  vi sit  o nl y  
 
 
x  
 
 
 
 
 
 
 
 
 
 
 
 
St u d y  dr u g  s. c.  a d mi ni str ati o n 4  
 
x  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
St u d y  dr u g  p. o.  a c c o u nt a bilit y 5  
 
 
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
I nj e cti o n sit e  i n s p e cti o n4  
 
x  
 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
C o n c o mit a nt  m e di c ati o n s  
x  
x  
A E a s s e s s m e nt  
 
x  

A nt h os  T hera pe utics  
Pa ge 6 8  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
 
S  =  r e s ult s ar e  d o c u m e nt e d  i n s o ur c e  d o c u m e nt s  o nl y  
 
1  T h e g e n eti c i nf or m e d c o n s e nt i s f or a n o pti o n al s u b -st u d y; t h e g e n eti c s a m pl e c a n b e c oll e ct e d at a n y ti m e aft er t h e o pti o n al g e n eti c i nf or m e d c o n s e nt i s o bt ai n e d  
2  O nl y c oll e ct e d fr o m p ati e nt s a s si g n e d t o a b el a ci m a b  
3  M a y b e c oll e ct e d i n a s u b s et of p ati e nt s  
4  P ati e nt s a s si g n e d t o a b el a ci m a b o nl y; D o s e c a n b e a d mi ni st er e d at i n -cli ni c or i n -h o m e vi sit s b y m e di c all y q u alifi e d, u n -bli n d e d st u d y st aff or d e si g n e e s a s l o c all y p er mitt e d. If a d mi ni st er e d i n -
h o m e, a s s e s s m e nt s f or c o n c o mit a nt m e di c ati o n s, A E s, a n d ot h er c h a n g e s i n h e alt h st at u s will b e c o n d u ct e d b y sit e s vi a t el e p h o n e or vi d e o c all a s l o c all y p er mitt e d  
5  P ati e nt s a s si g n e d t o ri v ar o x a b a n o nl y; A c c o u nt a bilit y c a n b e a s s e s s e d at i n -cli ni c vi sit or vi a virt u al ( e. g. vi d e o c all) vi sit a s a p pr o pri at e a n d l o c all y p er mitt e d  
 
 

A nt h os  T hera pe utics  
Pa ge 6 9  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
 
 
T a ble 1 6 -2  
Assess me nt Sc he d ule ( Ye ar 2 ) 
P eri o d  
Tr e at m e nt  P eri o d  ( Y e ar 2) 1  
P S D D  
Vi sit  
E o T  
Vi sit 6 
E o S  
4 -w k p o st - 
tr a n siti o n 
vi sit/ c all  
 
M o nt h  
 
1 3  
1 4  
1 5  
1 6  
1 7  
1 8  
1 9  
2 0  
2 1  
2 2  
2 3  
2 4  
Vi sit  Wi n d o w  ( d a y s) 
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
P h y si c al  E x a m  
 
 
 
 
 
 
 
 
 
 
 
 
S  
S  
 
Vit al  si g n s  
 
 
 
 
 
x  
 
 
 
 
 
x  
x  
x  
 
1 2 -l e a d E C G  
 
 
 
 
 
 
 
 
 
 
 
 
x  
x  
 
Uri n e  Pr e g n a n c y  - W O C B P  o nl y  
 
 
S  
 
 
S  
 
 
S  
 
 
S  
S  
S  
 
H e m at ol o g y  
 
 
x  
 
 
x  
 
 
x  
 
 
x  
x  
x  
 
C h e mi str y  
 
 
 
 
 
x  
 
 
 
 
 
x  
 
 
 
P T/I N R,  a P T T  
 
 
x  
 
 
x  
 
 
x  
 
 
x  
x  
x  
 
P K 2  a n d  Fr e e  F XI  / T ot al  F XI 2  
 
 
x  
 
 
x  
 
 
x  
 
 
x  
x  
x  
 
A nti dr u g  a nti b o di e s  ( A D A)2  
 
 
x  
 
 
x  
 
 
x  
 
 
x  
x  
x  
 
F a ct or  XI  C o a g ul ati o n  A cti vit y 3  
 
 
x  
 
 
x  
 
 
x  
 
 
x  
x  
x  
 
E x pl or at or y  bi o m ar k er s 3  
 
 
 
 
 
 
 
 
 
 
 
x  
 
x  
 
E Q -5 D -5 L  a n d  A C T S  P R O s 3  
 
 
 
 
 
x  
 
 
 
 
 
x  
 
 
 
St u d y  dr u g  s. c.  a d mi ni str ati o n 4  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
x  
 
St u d y  dr u g  p. o.  a c c o u nt a bilit y 5  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
I nj e cti o n sit e  i n s p e cti o n4  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
C o n c o mit a nt  m e di c ati o n s  
x  
x  
x  
x  
A E a s s e s s m e nt  
x  
x  
x  
x  
S  =  r e s ult s ar e  d o c u m e nt e d  i n s o ur c e  d o c u m e nt s  o nl y;  P S D D  =  p er m a n e nt  st u d y  dr u g  di s c o nti n u ati o n;  E o T  =  e n d  of  tr e at m e nt p eri o d;  E o S  =  e n d  of  st u d y  
 
1  S u b s e q u e nt  tr e at m e nt y e ar s  will  f oll o w t h e s a m e  a s s e s s m e nt  s c h e d ul e  a s  Y e ar  2  
2  O nl y  c oll e ct e d  fr o m p ati e nt s  a s si g n e d  t o a b el a ci m a b  
3  M a y  b e  c oll e ct e d  i n a  s u b s et  of  p ati e nt s  
4  P ati e nt s a s si g n e d t o a b el a ci m a b o nl y; D o s e c a n b e a d mi ni st er e d at i n -cli ni c or i n -h o m e vi sit s b y m e di c all y q u alifi e d, u n -bli n d e d st u d y st aff or d e si g n e e s a s l o c all y p er mitt e d.  If a d mi ni st er e d  i n-
h o m e,  a s s e s s m e nt s  f or c o n c o mit a nt  m e di c ati o n s,  A E s,  a n d  ot h er  c h a n g e s  i n h e alt h  st at u s will  b e  c o n d u ct e d  b y  sit e s  vi a  t el e p h o n e or  vi d e o c all a s l o c all y p er mitt e d  
5  P ati e nt s  a s si g n e d  t o ri v ar o x a b a n o nl y;  A c c o u nt a bilit y  c a n  b e  a s s e s s e d  at  i n-cli ni c  vi sit  or  vi a  virt u al  ( e. g. vi d e o  c all)  vi sit  a s  a p pr o pri at e  a n d  l o c all y p er mitt e d  
6  T h e E o T vi sit f or t h e r a n d o mi z e d tr e at m e nt p eri o d will al s o s er v e a s D a y 1 f or t h e o pti o n al e xt e n si o n p eri o d. R ef er t o T a bl e 1 7 -3 f or t h e o pti o n al e xt e n si o n p eri o d a s s e s s m e nt s. If a p ati e nt 
el e ct s n ot t o e nt er t h e e xt e n si o n, t h e y will h a v e t h e E o S vi sit a s  d e s cri b e d  i n t h e pr ot o c ol. 

A nt h os  T hera pe utics  
Pa ge 7 0  
P has e  2  Atrial  Fi brillati o n  Pr ot oc ol  
 
Pr ot oc ol  N o.  A N T -0 0 6  
T a ble 1 6 -3  
O pti o n al E xte nsi o n Pe ri o d Assess me nt S c h e d ule