A Prospective, Randomized, Open-Label, Blinded Endpoint Evaluation (PROBE) Parallel Group Study Comparing Edoxaban vs. VKA in Subjects Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation (ELIMINATE-AF)
Phase: PHASE3
Conditions: Atrial Fibrillation
Sponsor: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

C LI NI C A L S T U D Y P R O T O C O L 
A P R O S P E C TI V E, R A N D O MI Z E D, O P E N- L A B E L, 
B LI N D E D E N D P OI N T E V A L U A TI O N ( P R O B E) 
P A R A L L E L G R O U P S T U D Y C O M P A RI N G E D O X A B A N 
V S. V K A I N S U B J E C T S U N D E R G OI N G C A T H E T E R 
A B L A TI O N O F N O N- V A L V U L A R A T RI A L 
FI B RI L L A TI O N ( E LI MI N A T E- A F) 
 
 
D S E- E D O- 0 1- 1 6- E U 
E u dr a C T N U M B E R 2 0 1 6- 0 0 3 0 6 9- 2 5 
 
V E R SI O N 3. 0, 2 7 J ul y 2 0 1 7 
 
 
D AII C HI S A N K Y O E U R O P E G m b H 
ZI E L S T A T T S T R A S S E 4 8, 8 1 3 7 9 M U NI C H, G E R M A N Y 
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T 
I nf or mati o n c o ntai ne d i n t his d oc u me nt pre pare d b y D AII C HI S A N K Y O E U R O P E G m b H 
Gl o bal Me dical Affairs is pr o prietar y t o Daiic hi  Sa n k y o ( D S).  T he i nf or mati o n is pr o vi de d t o 
y o u i n c o nfi de nce w hic h is re q ueste d u n der a n  a gree d u p o n a n d si g ned C o nfi de ntialit y a n d 
Discl os ure A gree me nt.  D o n ot gi ve t his d oc u m e nt or a n y c o p y of it or re veal a n y pr o prietar y 
i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her t ha n t h ose i n y o ur or ga nizati o n w h o are 
assisti n g y o u i n t his w or k a n d are b o u n d b y t h e C o nfi de ntialit y a n d Discl os ure A gree me nt) 
wit h o ut t he pri or writte n pe r missi o n of a n a ut h orize d re prese ntati ve of D S. 
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 of 1 0 9 
 
I n vesti g at or’s Si g n at ure: 
I ha ve f ull y disc usse d t he o bjecti ves of t his st u d y a n d t he c o nt e nts of t his pr ot oc ol wit h 
t he S p o ns or’s re prese ntati ve. 
I u n dersta n d t hat i nf or mati o n c ontai ne d i n or pertai ni n g t o t h is pr ot oc ol is c o nfi de ntial 
a n d s h o ul d n ot be discl ose d, ot her t ha n t o t h os e directl y i n v ol ve d i n t he e xec uti o n or t he 
et hical re vie w of t he st u d y, wit h o ut writte n a ut h orizati o n fr o m t he S p o ns or.  It is, 
h o we ver, per missi ble t o pr o vi de i nf or mati o n t o  a s u bject i n or der t o o btai n c o nse nt. 
I a gree t o c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its 
re q uire me nts, s u bject t o et hical a n d safet y co nsi derati o ns a n d g ui deli nes, a n d t o c o n d uct 
t he st u d y i n acc or da nce wit h t he Declaratio n of Helsi n ki, I nter nati o nal C o u ncil o n 
Har m o nizati o n g ui deli nes o n G o o d Cli nical Pr actice (I C H E 6), a n d a p plica ble re gi o nal 
re g ulat or y re q uire me nts. 
I a gree t o ma ke a vaila ble t o S p o ns or perso n nel, t heir re prese nta ti ves a n d rele va nt 
re g ulat or y a ut h orities, m y s u bjects’ st u d y rec or ds i n or der t o verif y t he data t hat I ha ve 
e ntere d i nt o t he case re p ort f or ms.  I a m a ware of m y res p o nsi bilities as a Pri nci pal 
I n vesti gat or as pro vi de d b y t he S p o ns or. 
I u n dersta n d t hat t he S p o ns or ma y deci de t o s us pe n d or pre mat urely ter mi nate t he st u d y 
at a n y ti me f or w hate ver reas o n; s uc h a deci si o n will be c o m m u nicate d t o me i n writi n g.  
C o n versel y, s h o ul d I deci de t o wit h dr a w fr o m e xec uti o n of t he st u d y, I will 
c o m m u nicate m y i nte nti o n i m me diatel y i n writi n g t o t he S p o ns or. 
  
  
 
  
D ate 
  Si g n at ure 
 
  
 
 
 
 
  
Site n o.  
  I n vesti g at or’s n a me a n d a d dress ( pri nt or st a m p)  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 of 1 0 9 
 
P R O T O C O L S Y N O P SI S 
E u dra C T N u m ber:  
2 0 1 6- 0 0 3 0 6 9- 2 5 
Pr ot oc ol N u m ber:  
D S E- E D O- 0 1- 1 6- E U  
I n vesti gati o nal 
Pr o d uct: 
E d o xa ba n ( D U- 1 7 6 b) 
Acti ve I n gre die nt(s)/ 
i nter nati o nal 
n o n- pr o prietar y na me: 
N -( 5- C hl or o p yri di n- 2- yl)- N-[( 1 S, 2 R, 4 S)- 4-
( N, N- di met h ylcar ba m o yl)- 2-( 5- met h yl- 4, 5, 6, 7-
tetra h y dr o[ 1, 3]t hiaz ol o[ 5, 4-c] p yri di ne- 2-
car b o xa mi d o)c ycl o he x yl] o xa mi de m o n o ( 4- met h yl be nze nes ulf o nate) 
m o n o h y drate/ E d o xa ba n  
St u d y Title:  
A Pr os pecti ve, Ra n d o mize d, O pe n- La bel, Bli n de d E n d p oi nt 
E va luat io n ( P R O B E) Parallel Gr o u p St u d y C o m pari n g E d o xa ba n vs. 
V K A i n S u bjects U n der g oi n g Cat h eter A blati o n of N o n- val v ular 
A trial F i brillati o n ( E LI MI N A T E- A F) 
St u d y P hase:  
P hase 3 b 
I n dicati o n U n der 
I n vesti gati o n: 
N o n- val v ular atrial fi brillati o n ( A F) 
St u d y O bjecti ves: 
Pri m ar y o bjecti ves of t his st u d y: 
Pri m ar y effic ac y o bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of t he c o m p osite of all-ca use 
deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d Maj or 
Blee di n g (I nter nati o nal S ociet y o n T hr o m b osis a n d He m ostasis 
[I S T H] defi niti o n) i n t he e d o xa ba n gr o u p a gai nst t he vita mi n K 
a nta g o nist ( V K A) gr o u p i n s u bjects  u n der g oi n g cat heter a blati o n of 
atrial fi brillati o n ( A F) i n t he peri o d fr o m t he e n d of t he cat heter 
a blati o n pr oce d ure t o Da y 9 0/ e n d- of-treat me nt ( E O T). 
Pri m ar y s afet y o bjecti ve: 
T o c o m pare descri pti vel y t he i n ci de nce of Maj or Blee di n g (I S T H 
defi niti o n) i n t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p i n t he peri o d 
fr o m date of first i nta ke of st u d y me dicati o n t o Da y 9 0/ E O T. 
Sec o n d ar y o bjecti ves:  
I n s u bjects u n der g oi n g cat heter a blati o n of A F, t o c o m pare 
descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, wit h 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 of 1 0 9 
 
re gar ds t o t he i nci de nce of t he f oll o wi n g effic ac y e n d p oi nts  as liste d 
bel o w: 
 C o m p osite of all-ca use deat h, st r o ke (isc he mic, he m orr ha gic, 
or u n deter mi ne d, acc or di n g t o  alter nati ve defi niti o n (1 ); see 
Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
s yste mic e m b olic e ve nts ( S E E), a n d car di o vasc ular ( C V) 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d all-ca use m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
a n d tra nsie nt isc he mic attac k ( TI A) 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d) 
 
T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, 
wit h re gar ds t o t he i nci de nce of t he f oll o wi n g s afet y e n d p oi nts as 
liste d bel o w: 
 Maj or Blee di n g ( defi ne d b y T h r o m b ol ysis i n M y ocar dial 
I nfarcti o n [ TI MI], Blee di n g Aca de mic Researc h C o ns orti u m 
[ B A R C] 2 or hi g her) 
 Maj or a n d Cli nicall y Rele va nt  N o n- Maj or ( C R N M) Blee di n g 
(I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 of 1 0 9 
 
 A n y Blee di n g 
 I ntracra nial he m orr ha ge (I C H) 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or 
hi g her]) 
 Safet y para meters s uc h as a d verse e ve nts ( A Es), seri o us 
a d verse e ve nts ( S A Es), la b orat or y para meters, 
electr ocar di o gra m ( E C G) a n d vital si g ns. 
Ot her o bjecti ves:  
T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, 
wit h re gar ds t o t he f oll o wi n g:  
 Rele va nt Healt h Ec o n o mics O utc o me Researc h ( H E O R) 
para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of t he a blati o n 
pr oce d ure d ue t o i na d e q uate a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses 
( be y o n d a blati o n pr oce d ure), i ncl u di n g b ut n ot li mite d 
t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k: H os pital a d missi o ns d ue t o C V ca uses 
i ncl u de, b ut are n ot li mite d t o E mer ge nc y De part me nt 
( E D), I nte nsi ve Care U nit (I C U), C V war d. 
o  Mea n le n gt h of sta y ass ociat e d wit h t he differe nt t y pe 
of h os pital a d missi o ns, s uc h as E D, I C U a n d C V war ds
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are 
C V e ve nt relate d o utsi de sc he d ule d visits as defi ne d b y 
st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns ( S C L) as defi ne d b y Diff usi o n 
Wei g hte d Ma g netic Res o na nce I ma gi n g ( D W- M RI) p ost 
a blati o n pr oce d ure (at preselecte d ce nters) 
 Car diac mar kers 
St u d y Desi g n:  
T his is a m ulti nati o nal pr os pecti ve, ra n d o mize d, o pe n-la bel, bli n de d 
e n d p oi nt e val uati o n ( P R O B E) parallel gr o u p p hase 3 b st u d y 
c o m pari n g e d o xa ba n vs. V K A i n  s u bjects u n der g oi n g cat heter 
a blati o n of n o n- val v ular A F.  Af ter Scree ni n g a n d ra n d o mizati o n, 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 of 1 0 9 
 
eli gi ble s u bjects recei ve 2 1 da ys ( + 7) a ntic oa g ulati o n bef ore bei n g 
assesse d f or s uita bilit y f or t he cat het er a blati o n pr oce d ure.  S u bjects 
will recei ve 9 0 da ys a ntic oa g ulati o n p ost- pr oce d ure a n d are t he n 
f oll o we d- u p after a n a d diti o nal 3 0 da ys.  I n all s u bjects, ke y 
de m o gra p hic a n d ris k c haracteristic s of b ot h str o ke a n d blee di n g (f or 
e xa m ple, C H A 2D S 2- V A Sc sc ore, H A S- B L E D, t y pe of A F, prese nce 
of c or o nar y arter y disease ( C A D), heart fail ure ( H F), dia betes mellit us 
( D M), a n d h y perte nsi o n) will be c ollecte d. S u bjects will be 
ra n d o mize d i n a 2: 1 rati o t o e d o xa ba n vs. V K A i nt o o ne of t he t w o 
st u d y ar ms as descri be d bel o w. 
E d o x a b a n st u d y ar m 
S u bjects will be re q uire d t o c o m ple te at least 2 1 ( u p t o + 7) da ys of 
a ntic oa g ulati o n wit h e d o xa ba n. S u bj ects recei vi n g a ntic oa g ula nts at 
t he ti me of e nr oll me nt will be s witc he d t o e d o xa ba n (t he s witc hi n g 
p r oce d ure will f oll o w t he e d o xa ba n label a n d is descri be d i n Secti o n 
5. 2. 1. 3 ). It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y 
d ose of e d o xa ba n is ta ke n e ver y da y i n t he e ve ni n g. E d o xa ba n ca n be 
ta ke n wit h or wit h o ut f o o d. 
If a s u bject has ta ke n t he st u d y dr u g i n t he e ve ni n g, t he pr oce d ure ca n 
be perf or me d i n t he m or ni n g of t he ne xt da y. T he i nter val bet wee n t he 
last i nta ke of e d o xa ba n a n d t he pr oce d ure m ust n ot e xcee d 1 8 h o urs. 
After t he a blati o n, st u d y me dicati o n m u st be re-starte d o n t he da y of 
p r oce d ure b ut n o earlier t ha n 6 h o urs p ost-s heat h re m o val a n d o nl y 
o nce a de q uate he m ostasis has bee n ac hie ve d. 
Ti mi n g of t he last d ose of e d o xa ba n pri or t o t he cat heter a blati o n 
p r oce d ure a n d t he first d ose after t he pr oce d ure will be rec or de d i n t he 
electr o nic case re p ort f or m (e C R F). 
V K A st u d y ar m 
S u bjects e nr olle d i n t he V K A st u d y ar m will be re q uire d t o c o m plete 
at least 2 1 da ys ( u p t o + 7 da ys) of a ntic oa g ulati o n treat me nt wit h 
V K A. S u bjects will ta ke t he V K A acc o r di n g t o t he directi o n of t he 
I n vesti gat or. E ver y atte m pt will be ma de t o bri n g s u bjects i nt o t he 
t hera pe utic tar get ra n ge (I N R [Inter nati o nal N or malize d Rati o] 
2. 0- 3. 0) as fast as p ossi ble a n d t o mai ntai n t he tar get I N R ra n ge 
c o nsiste ntl y.  
I N R will nee d t o be meas ure d fre q ue ntl y at t he start of t he st u d y 
( u nless a s u bject is recei vi n g a n u n var yi n g V K A d ose at t he ti me of 
ra n d o mizati o n) t o rec or d t he ti me w he n I N R reac hes a le vel of ≥2. 0.  
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or 
t he last 1 0 da ys pri or t o t he cat heter a blati o n. T his will nee d t o be 
d oc u me nte d b y fre q ue nt I N R meas ure m e nts, at least o nce per wee k i n 
t he pre-a blati o n peri o d. O n t he day of, or t he da y pri or t o, t he 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 of 1 0 9 
 
sc he d ule d a blati o n pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 
2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 t he 
p r oce d ure ma y be perf or me d at t he I n vesti gat or’s discreti o n. 
Ot her wise, t he s u bject is n ot eli g i ble f or perf or mi n g t he cat heter 
a blati o n (t he s u bject will be s witc he d fr o m st u d y me dicati o n t o 
sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A will be use d wit h o ut 
i nterr u pti o n a n d bri d gi n g wit h l o w m olec ular wei g ht he pari n 
( L M W H) will n ot be all o we d at t his ti me. 
Tr a nses o p h a ge al ec h oc ar di o gr a m  bef ore c at heter a bl ati o n 
Tra nses o p ha geal ec h ocar di o gra m ( T E E)  or alter nati vel y i ntra-car diac 
ec h ocar di o gra m will be perf or me d bef ore cat heter a blati o n d uri n g t he 
h os pital sta y relate d t o t he pr oce d ure or t he da y bef ore t o i de ntif y 
p ote ntial cl ots. If T E E or t he i ntr a-car diac ec h ocar di o gra m is p ositi ve, 
i.e., s h o ws cl ots, t he a blati o n pr oce d ure will be ca ncele d a n d t he 
s u bject will be s witc he d fr o m st u d y me dicati o n t o sta n dar d of care 
a n d will e nter t he 3 0- da y f oll o w- u p peri o d. 
A ntic o a g ul ati o n d uri n g c at heter a bl ati o n 
Acc or di n g t o sta n dar d of care a n d as rec o m me n de d i n c urre nt 
treat me nt g ui deli nes (1 5 ) he pari n s h o ul d be a d mi nistere d ( 1 0 0 U/ k g 
b ol us) pri or t o or i m me diatel y f o ll o wi n g tra ns-se ptal p u nct ure d uri n g 
A F a blati o n pr oce d ures a n d a dj ust e d t o ac hie ve a n d mai ntai n a n 
acti vate d cl otti n g ti me ( A C T) of 3 0 0- 4 0 0 sec o n ds. A C T le vels s h o ul d 
be c hec ke d at 1 5- 2 0- mi n ute i nter val s u ntil t hera pe utic a ntic oa g ulati o n 
is ac hie ve d a n d t he n at 3 0- mi n ute i nter vals f or t he d urati o n of t he 
p r oce d ure. He pari n a ntic oa g ulati o n will be partiall y re verse d wit h 
p r ota mi ne a n d s heat hs re m o ve d at a n A C T < 2 5 0 sec o n ds. 
A ntic o a g ul ati o n p ost c at heter a bl ati o n 
F oll o wi n g c o m pleti o n of t he cat heter a blati o n pr oce d ure, all s u bjects 
will c o nti n ue recei vi n g treat me nt wit hi n t heir st u d y ar m u ntil Da y 9 0 
p ost- pr oce d ure.  
At t he E n d of Tre at me nt 
At Da y 9 0 p ost- pr oce d ure, t he s u bject will disc o nti n ue t he st u d y 
treat me nt c o m pletel y a n d will be c o nti n ue d o n a n y of t he a p pr o ve d 
oral a nti-c oa g ulati o n ( O A C) dr u gs or a ntic oa g ulati o n st o p pe d 
acc or di n g t o sta n dar d of care per p h ysicia n's discreti o n. Detaile d 
s witc hi n g pr ot oc ols acc or di n g t o me dicati o n la bel will be pr o vi de d.  
All s u bjects re gar dless of t heir p ost-st u d y treat me nt will ha ve a n 
a d diti o nal 3 0- da y safet y f oll o w- u p peri o d after w hic h t heir 
p artici pati o n i n t he st u d y will be c o m plete d. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 of 1 0 9 
 
St u d y D urati o n:  
T otal f or eac h s u bject 5- 6 m o nt hs. Pre-a blati o n treat me nt peri o d of at 
least 2 1 da ys ( u p t o + 7 da ys). P ost-a blati o n treat me nt peri o d of 9 0 
da ys ( ± 7 da ys) pl us 3 0- da y f oll o w- u p peri o d ( u p t o + 5 da ys).  
Pr ojecte d 1 6 m o nt hs e nr oll me nt 
St u d y Sites a n d 
L ocati o n: 
It is pla n ne d t o e nr oll a p pr o x. 5 6 0 s u bjects wit h 2: 1 ra n d o mizati o n 
rati o (e d o xa ba n: V K A) b y a p pr o xi matel y 7 5 st u d y sites l ocate d i n 
Ca na da, E ur o pe ( Bel gi u m, Czec h Re p u blic, Fra nce, Ger ma n y, 
H u n gar y, Ital y, Net herla n ds, P ola n d, S pai n, U nite d Ki n g d o m), K orea, 
a n d Tai wa n t o ac hie ve a p pr o x. 4 5 0 s u bjects u n der g oi n g t he cat heter 
a blati o n pr oce d ure a n d c o m pleti n g t he st u d y.  
S u bject Eli gi bilit y 
Criteria: 
I ncl usi o n criteria: 
1.  Male or fe male at least 1 8 years of a ge wit h d oc u me nte d 
hist or y of par o x ys mal (lasti n g ≤7 da ys), persiste nt (lasti n g 
> 7 da ys b ut ≤1 2 m o nt hs) or l o n g-sta n di n g [l o n g-lasti n g] 
persiste nt ( > 1 2 m o nt hs) n o n- val v ular A F. D urati o n of A F ca n 
be c o nfir me d b y a n y electrical traci n g or a rec or di n g i n t he 
s u bject’s me dical rec or ds (e. g., me dical c hart, h os pital 
disc har ge s u m mar y). 
2.  S u bject is eli gi ble a n d is sc he d ule d f or eit her ra di o fre q ue nc y 
( R F) or cr y o ball o o n cat heter a blati o n ( b ot h first a n d re peate d 
pr oce d ure i ncl u de d).  
3.  Si g ne d i nf or me d c o nse nt f or m (I C F). 
E xcl usi o n criteria: 
1.  A F c o nsi dere d t o be of a tra nsie n t or re versi ble nat ure (s uc h as 
i n m y ocar ditis, p ost-s ur ger y, i o nic dist ur ba nces, 
t h yr ot o xic osis, p ne u m o nia, se vere a ne mia etc.). 
2.  S u bject p ost str o ke, or wit h a s yste mic t hr o m b oe m b olic e ve nt 
wit hi n t he past 6 m o nt hs pri or t o ra n d o mizati o n.  
3.  S u bject has a t hr o m b us i n t he le ft atrial a p pe n da ge ( L A A), left 
atri u m ( L A), left ve ntricle ( L V), or a orta, or a n i ntracar dial 
mass. 
4.  S u bject ha d a m y ocar dial i nfarc ti o n ( MI) wit hi n t he 2 m o nt hs 
pri or t o ra n d o mizati o n or c or o nar y arter y b y pass graft ( C A B G) 
s ur ger y wit hi n 3 m o nt hs pri or t o t he ra n d o mizati o n. 
5.  S u bject has si g ns of blee di n g, hi st or y of cli nicall y-rele va nt 
blee di n g acc or di n g t o I S T H, or c o n diti o ns ass ociate d wit h 
hi g h ris k of blee di n g s uc h as past hist or y of i ntracra nial 
(s p o nta ne o us or tra u matic), or sp o nta ne o us i ntra o c ular, s pi nal, 
retr o perit o neal, or i ntra-artic ular blee di n g; o vert 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 1 of 1 0 9 
 
gastr oi ntesti nal ( GI) blee di n g or acti ve ulcer wit hi n t he 
pre vi o us year; rece nt se vere tra u ma, maj or s ur ger y, or dee p 
or ga n bi o ps y; acti ve i nfecti v e e n d ocar ditis; u nc o ntr olle d 
h y perte nsi o n ( bl o o d press ure [ B P] a b o ve 1 7 0/ 1 0 0 m m H g); or 
he m orr ha gic dis or der i ncl u di n g k n o w n or s us pecte d here ditar y 
or ac q uire d blee di n g or c oa g ul ati o n dis or der i n t he last 
1 2 m o nt hs pri or t o ra n d o mizati o n.  
6.  S u bjects wit h mec ha nical heart va l ves, s u bjects wit h m o derate 
t o se vere mitral ste n osis a n d s u bjects w h o ha ve ne w 
i m pla ntati o n ( wit hi n 3 m o nt hs pri or t o ra n d o mizati o n) of a 
bi o pr ost hetic heart val ve, wit h or wit h o ut A F.  
7.  S u bjects wit h a hist or y of L A A occl usi o n/e xcl usi o n (eit her b y 
s ur ger y or b y a pr oce d ure). 
8.  S u bjects wit h a n y c o ntrai n dicati o n f or e d o xa ba n, V K A, 
L M W H, he pari n t hera p y i ncl u di n g k n o w n aller gies, 
h y perse nsiti vit y, or i nt olera nce t o a n y c o m p o ne nt of t hese 
dr u gs or its e xci pie nts. 
9.  S u bjects recei vi n g d ual a nti platelet t hera p y ( D A P T, i.e., 
as piri n a n d P 2 Y 1 2 a nta g o nist) or pla n ne d t o recei ve D A P T 
d uri n g t he st u d y. 
1 0.  U nfracti o nate d he pari n ( U F H), l o w m olec ular wei g ht he pari ns 
( L M W H; e n o xa pari n, dalte pari n, etc.), he pari n deri vati ves 
(f o n da pari n u x, etc.), a n d oral a ntic oa g ula nts ( warfari n, 
da bi gatra n ete xilate, ri var o xa ba n, a pi xa ba n etc.) ca n n ot be 
use d c o nc o mita ntl y t o st u d y me dicati o n. A n y bri d gi n g wit h 
L M W H ar o u n d t he C A pr oce d ure is pr o hi bite d. D uri n g t he C A 
pr oce d ure, U F H will be use d acc o r di n g t o sta n dar d of care t o 
ac hie ve A C T of 3 0 0 t o 4 0 0 sec. S u bjects w h o re q uire c hr o nic 
use of me dici nes affecti n g he m ost asis s uc h as hi g her d oses of 
as piri n (acet ylsalic ylic aci d [ A S A]) ( A S A u p t o 1 0 0 m g per 
da y all o we d) or c hr o nic oral or pare nteral i nta ke  of n o n-as piri n 
n o n-ster oi dal a nti-i nfla m mat or y dr u gs ( N S AI D) o n ≥4 
da ys/ wee k ( use of N S AI Ds via ot her r o utes is n ot restricte d). 
1 1.  S u bjects wit h acti ve li ver diseas e or persiste nt (c o nfir me d b y 
re peat assess me nts at least a wee k a part) ele vati o n of li ver 
e nz y mes/ bilir u bi n: 
―  Ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase 
( A S T) ≥2 ti mes t he u p per li mit of n or mal ( U L N) 
―  T otal bilir u bi n ( T B L) ≥1. 5 ti mes t he U L N (s u bjects w h ose 
ele vate d T B L is d ue t o k n o w n Gil bert’s s y n dr o me ma y be 
i ncl u de d i n t he st u d y) 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 2 of 1 0 9 
 
―  He patic disease ass ociate d wit h c oa g ul o pat h y a n d 
cli nicall y rele va nt blee di n g ris k. 
1 2.  S u bjects wit h ki d ne y fail ure (c alc ulate d creati ni ne cleara nce 
[ Cr C L] < 1 5 m L/ mi n). 
1 3.  S u bjects wit h he m o gl o bi n < 1 0 g/ d L or platelet c o u nt < 1 0 0, 0 0 0 
cells/ µ L or w hite bl o o d cell ( WB C) c o u nt < 3 0 0 0 cells/ µ L. 
1 4.  S u bjects wit h pre- pla n ne d i n vasi ve dia g n ostic or t hera pe utic 
pr oce d ures/i nter ve nti o ns ( ot her  t ha n e n d osc o p y) d uri n g t he 
st u d y peri o d i n w hic h blee di n g is a ntici pate d. 
1 5.  Partici pati o n i n a n y ot her i nte r ve nti o nal trial (s u bjects w h o 
recei ve d a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys 
pri or t o ra n d o mizati o n, or pla n t o recei ve s uc h i n vesti gati o nal 
t hera p y d uri n g t he st u d y peri o d). 
1 6.  Pre vi o us ra n d o mizati o n i n t his st u d y. 
1 7.  Fe male s u bjects of c hil d beari n g p ote ntial wit h o ut  usi n g hi g hl y 
effecti ve c o ntrace pti o n (fe male of c hil d beari n g p ote ntial is 
defi ne d as o ne w h o has n ot bee n p ost me n o pa usal f or at least 
o ne year, or has n ot bee n s ur gicall y sterilise d, or has n ot ha d a 
h ysterect o m y at least t hree m o nt hs  pri or t o t he start of t his 
st u d y). Fe males ta ki n g oral c o ntrace pti ves s h o ul d ha ve bee n 
o n t hera p y f or at least t hree m o nt hs. A de q uate  c o ntrace pti ves 
i ncl u de: C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) 
oral, i ntra va gi nal or tra n s der mal h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n; pr o gest o ge n- o nl y oral, 
i njecta ble or i m pla nta ble h or m o nal c o ntrace pti o n ass ociate d 
wit h i n hi biti o n of o v ulati o n; i ntra uteri ne de vice (I U D); 
i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal 
occl usi o n; vasect o mize d pa rt ner; se x ual a bsti ne nce. 
1 8.  Pre g na nt or breast- fee di n g s u bjects. 
1 9.  S u bjects wit h t he f oll o wi n g dia g n oses or sit uati o ns: 
―  Acti ve ca ncer u n der g oi n g c he m ot hera p y, ra diati o n or 
maj or s ur ger y wit hi n t he ne xt 5 m o nt hs 
―  Si g nifica nt acti ve/ u nc o ntr olle d c o nc urre nt me dical ill ness 
―  Life e x pecta nc y < 6 m o nt hs. 
2 0.  S u bjects w h o are u nli kel y t o c o m pl y wit h t he pr ot oc ol (e. g., 
u nc o o perati ve attit u de, i na bilit y t o  ret ur n f or s u bse q ue nt visits, 
a n d/ or ot her wise c o nsi dere d b y t h e I n vesti gat or t o be u nli kel y 
t o c o m plete t he st u d y). 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 3 of 1 0 9 
 
2 1.  S u bjects wit h a k n o w n dr u g or al c o h ol de pe n de nce wit hi n t he 
past 1 2 m o nt hs pri or t o ra n d o mizati o n as j u d ge d b y t he 
I n vesti gat or. 
2 2.  S u bjects wit h a n y c o n diti o n t hat, i n t he o pi ni o n of t he 
I n vesti gat or, w o ul d place t he s u bject at i ncrease d ris k of har m 
if he/s he partici pate d i n t he st u d y. 
2 3.  Pla n ne d pr oce d ure usi n g laser cat heter a blati o n or ot her f or ms 
of cat heter a blati o n differe nt fr o m R F or cr y o ball o o n (i.e. hi g h 
i nte nsit y f oc use d ultras o u n d [ HI F U], micr o wa ves, h ot ball o o n, 
etc). 
D osa ge F or m, D ose, 
a n d R o ute of 
A d mi nistrati o n: 
E d o xa ba n: 6 0 m g a n d 3 0 m g pr o vi de d as fil m c oate d ta blets f or oral 
use ( 3 0 m g or 1 5 m g as tra nsi ti o n me dicati o n if a p plica ble). 
T he d ose of e d o xa ba n is 6 0 m g o nce- dail y a n d will be re d uce d t o 
3 0 m g o nce- dail y, if t he s u bject has o ne of t he f oll o wi n g:   
 M o derate or se vere re nal i m pair me nt ( Cr C L ≥1 5 t o 
≤5 0 m L/ mi n as calc ulate d usi n g t he C oc kcr oft- Ga ult f or m ula 
 L o w b o d y wei g ht ( ≤6 0 k g) 
 Recei ves o ne of t he f oll o wi n g c o nc o mita nt P- g p i n hi bit ors: 
cicl os p ori n, dr o ne dar o ne, er yt hr o m yci n, ket oc o naz ole. 
Re mar k:   I n E U c o u ntries, acc or di n g t o t he S u m mar y of 
Pr o d uct C haracteristics ( S m P C) c o nc o mita nt use of e d o xa ba n 
wit h c ycl os p ori ne, dr o ne dar o ne, er yt hr o m yci n, or 
ket oc o naz ole re q uires d ose re d ucti o n t o 3 0 m g o nce- dail y. 
C o nc o mita nt use of e d o xa ba n wit h q ui ni di ne, ver a p a mil, or 
a mi o d ar o ne  d oes n ot re q uire  d ose re d ucti o n 
It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of 
e d o xa ba n is ta ke n e ver y da y i n t h e e ve ni n g. E d o xa ba n ca n be ta ke n 
wit h or wit h o ut f o o d. 
V K A: Oral V K A, as pre- defi ne d pe r c o u ntr y, wit h o nce- dail y d osi n g 
f or tar get I N R bet wee n 2. 0- 3. 0, i ncl usi ve. S u bjects will ta ke t he V K A 
o nce- dail y acc or di n g t o t he di recti o n of t he I n vesti gat or. 
V K A is s u p plie d as c o m merciall y a vaila ble ta blets of t he preferre d 
V K A f or eac h selecte d c o u ntr y partic i pati n g i n t he st u d y, bei n g eit her:
―  Warfari n: 1 a n d 2. 5 m g ta blets. 
―  P he n pr oc o u m o n: 3 m g ta blets. 
―  Fl ui n di o ne: 2 0 m g ta blets (e xcl usi ve t o Fra nce). 
―  Ace n oc o u mar ol: 4 m g ta blets. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 4 of 1 0 9 
 
T he I n vesti gat or m o nit ors t he I N R a n d a dj usts t he V K A d ose t o 
mai ntai n t he I N R wit hi n tar get. It is t he I n vesti gat or’s res p o nsi bilit y t o 
c ollect I N R assess me nts a n d rec o r d t hese t hr o u g h o ut t he st u d y. 
St u d y E n d p oi nts: 
Pri m ar y effic ac y e n d p oi nt  
C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d), a n d Maj or Blee di n g (I S T H), a nal yze d as ti me t o first 
occ urre nce of a n y c o m p o ne nt 
Pri m ar y s afet y e n d p oi nt  
Maj or Blee di n g (I S T H), a nal yze d as ti me t o first occ urre nce of Maj or 
Blee di n g  
Sec o n d ar y e n d p oi nts 
Effic ac y: 
 C o m p osite of all-ca use deat h, st r o ke (isc he mic, he m orr ha gic, 
or u n deter mi ne d, acc or di n g t o  alter nati ve defi niti o n (1 ); see 
Secti o n 7. 4. 2  f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
S E E, a n d all-ca use m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic, he m orr ha gic, or 
u n deter mi ne d) 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 5 of 1 0 9 
 
S afet y: 
 Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 Maj or a n d C R N M Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I C H 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or 
hi g her]) 
 Safet y para meters s uc h as A Es, S A Es, la b orat or y para meters, 
E C G a n d vital si g ns. 
All a dj u dicate d e n d p oi nts are a nal yz e d as ti me t o first occ urre nce 
of a n y of its c o m p o ne nts. 
F or all s pecific e n d p oi nts bli n dl y a dj u dicate d b y t he Cli nical 
E n d p oi nts C o m mittee ( C E C), t he C E C’s i nter pretati o n pre vails 
a n d is use d i n t he statistical a nal yses. 
Ot her e n d p oi nts:  
 Rele va nt H E O R para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of t he a blati o n 
pr oce d ure d ue t o i na d e q uate a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses 
( be y o n d a blati o n pr oce d ure), i ncl u di n g b ut n ot li mite d 
t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k:   H os pital a d missi o ns d ue t o C V ca uses 
i ncl u de, b ut are n ot li mite d t o E D, I C U, C V war d. 
o  Mea n le n gt h of sta y ass ociat e d wit h t he differe nt t y pe 
of h os pital a d missi o ns, s uc h as E D, I C U a n d C V war ds
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are 
C V e ve nt relate d o utsi de sc he d ule d visits as defi ne d b y 
st u d y pr ot oc ol 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 6 of 1 0 9 
 
 S C L as defi ne d b y D W- M RI p ost a blati o n pr oce d ure (at 
preselecte d ce nters)  
 Car diac mar kers 
Pla n ne d Sa m ple Size:  T he pri mar y e n d p oi nt wi ll be t he i nci de nce of a c o m p osite of all-
ca use deat h, str o ke (isc he mic str o ke, he m orr ha gic str o ke, or 
u n deter mi ne d str o ke), a n d Maj or Blee di n g e ve nts (I S T H defi niti o n) 
d uri n g t he peri o d fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o 
Da y 9 0/ E O T. A rate of u p t o 3 % of t he c o m bi ne d pri mar y e n d p oi nt 
ca n be e x pecte d i n t he V K A ar m as o bser ve d fr o m p u blis he d st u dies 
a n d retr os pecti ve a nal yses (f or m ore  details, please refer t o Secti o n 
1 0. 7 ).  
Base d u p o n t his l o w pre dicte d rate, a f or mal sa m ple size 
deter mi nati o n base d o n n o n-i nferi or it y or s u peri orit y of e d o xa ba n 
vers us V K A is n ot feasi ble. T he sa m ple size is pla n ne d base d u p o n 
t he pri mar y c o m p osite e n d p oi nt t o i ncl u de a n a de q uate n u m ber of 
s u bjects t hat will pr o vi de t he e x pecte d i nci de nce rates o n t he pri mar y 
e n d p oi nt. T heref ore, t he pla n is t o i ncl u de 4 5 0 s u bjects i n t he Per 
Pr ot oc ol ( P P) a nal ysis set, i.e.  s u bjects w h o ha ve u n der g o ne a n 
a blati o n pr oce d ure a n d wit h o ut a n y maj or pr ot oc ol vi olati o n.  
I n or der t o ac hie ve t his, a p pr o xi matel y 5 6 0 s u bjects will nee d t o be 
e nr olle d i n t he st u d y. T he st u d y wi ll be st o p pe d o nce t he n u m ber of 
4 5 0 s u bjects bel o n gi n g t o t he P P a nal ysis set is reac he d. 
Statistical A nal yses:  T he f oll o wi n g a nal ysis sets are defi ne d: 
T he I nte nti o n-t o-tre at (I T T) a n alysis set c o nsists of all ra n d o mize d 
s u bjects irres pecti ve w het her t he y recei ve d a si n gle d ose of st u d y 
me dicati o n or n ot. 
T he m o difie d I nte nti o n-t o-tre at ( mI T T) a n alysis set  c o nsists of all 
ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of st u d y 
me dicati o n. 
T he Per Pr ot oc ol ( P P) a n alysis set  c o nsists of all ra n d o mize d s u bjects 
w h o recei ve d at least o ne d ose of st u d y me dicati o n a n d d o n ot ha ve 
a n y of t he f oll o wi n g maj o r pr ot oc ol vi olati o ns: 
 N ot u n der g oi n g a cat heter a blati o n 
 N o A F 
 K n o w n c o ntrai n dicati o n f or O A C 
 A maj or vi olati o n of t he i ncl usi o n criteria 
 A maj or vi olati o n of t he e xcl usi o n criteria 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 7 of 1 0 9 
 
T he list of maj or pr ot oc ol vi olati o ns will be descri be d i n t he statistical 
a nal ysis pla n ( S A P) a n d fi nali ze d bef ore data base l oc k.  
T he S afety ( S A F) a n alysis set  c o nsists of all ra n do mize d s u bjects w h o 
recei ve d at least o ne d ose of st u d y me dicati o n.  
Defi niti o n of ter ms: 
‘Over all St u dy Peri o d ’:   T his peri o d is define d as t he ti me fr o m t he 
refere nce date ( date a n d ti me of ran d o mizati o n or date a n d ti me of 
first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T. 
‘Over all St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me 
fr o m t he refere nce date ( date a n d ti me of ra n d o mizati o n or date a n d 
ti me of first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T + 3 0 da ys. 
‘P ost- a bl ati o n St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m 
t he e n d of t he cat heter a blatio n pr oce d ure t o Da y 9 0/ E O T. 
‘P ost- a bl ati o n St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he 
ti me fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T + 
3 0 da ys.  
P l a n ne d A n alyses: 
Acc or di n g t o t he o bjecti ves of t h is st u d y, t he statistical a nal ysis 
s h o ul d be i nter prete d i n a p urel y e x pl orat or y- descri pti ve wa y. N o 
f or mal c o nfir mat or y statistical testi n g is pla n ne d. 
T he a nal ysis set a n d a nal ysis peri o d t o be use d f or t he mai n a nal ysis 
of t he vari o us a dj u dicate d e n d p oi nts is prese nte d bel o w: 
 
E n d p oi nt(s) 
pri m ar y  
a n al ysis set 
pri m ar y  
a n al ysis peri o d 
Pri mar y  
P P  
p ost-a blati o n peri o d
Pri mar y safet y  
mI T T  
o verall st u d y peri o d
Sec o n dar y efficac y  
P P  
p ost-a blati o n peri o d
Sec o n dar y safet y  
mI T T  
o verall st u d y peri o d
F or eac h of t he pri mar y a n d sec o n dar y a dj u dicate d e n d p oi nts, 
a p pr o priate s u m mar y statistics  (e. g. e ve nt rate) i ncl u di n g 9 5 % 
c o nfi de nce i nter val ( CI) will be pr o vi de d. 
F or eac h of t he e n d p oi nts, t he ti me fr o m refere nce date t o t he first 
occ urre nce of a n e ve nt ( base d o n C E C a dj u dicati o n), is a nal yze d 
usi n g a C o x pr o p orti o nal hazar d m o del wit h treat me nt re gi me n as a 
fact or, t o pr o vi de p oi nt esti mates a n d 9 5 % CI f or t he hazar d rati o 
( H R). De pe n di n g o n t he a nal ysis peri o d use d i n t he statistical a nal ysis, 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 8 of 1 0 9 
 
s u bjects wit h o ut a n occ urre nce of a n e ve nt will be ce ns ore d at t he last 
date of t he a nal ysis peri o d or at t he last date of k n o w n o utc o mes 
stat us. T he latter is deter mi ne d o n a n i n di vi d ual basis f or s u bjects wit h 
i nc o m plete f oll o w- u p. 
F or ti me t o first e ve nt a nal yses base d o n a n y of t he st u d y peri o ds 
defi ne d a b o ve, c u m ulati ve e ve nt rates o ver ti me are s u m marize d usi n g 
t he Ka pla n- Meier met h o d. 
T o e val uate t he r o b ust ness of t he ma i n a nal yses, t he a nal ysis will be 
re peate d usi n g t he mI T T, I T T a n d/ or P P a nal ysis set. I n a d diti o n, t he 
statistical res ults base d o n t he f oll o wi n g a nal ysis peri o ds: ‘ p ost-
a blati o n st u d y peri o d + 3 0 da ys’ a n d ‘ o verall st u d y peri o d + 3 0 da ys’ 
will be prese nte d. 
All details of t he statistical a nal ysis will be descri be d i n a S A P. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 9 of 1 0 9 
 
T A B L E O F C O N T E N T S 
I N V E S TI G A T O R A G R E E M E N T ................................................................................... 2 
P R O T O C O L S Y N O P SI S ................................................................................................. 5  
T A B L E O F C O N T E N T S ................................................................................................ 1 9  
LI S T O F I N- T E X T T A B L E S ......................................................................................... 2 5  
LI S T O F I N- T E X T FI G U R E S ....................................................................................... 2 6  
LI S T O F A B B R E VI A TI O N S ......................................................................................... 2 7  
1.  
I N T R O D U C TI O N ........................................................................................ 3 0 
1. 1.  
Bac k gr o u n d .................................................................................................... 3 0  
1. 2.  
Descri pti o n of I n ves ti gati o nal Pr o d uct .......................................................... 3 0 
1. 2. 1. 1.  
N o ncli nical St u dies ........................................................................................ 3 0  
1. 2. 1. 2.  
Cli nical E x perie nce ........................................................................................ 3 0  
1. 2. 1. 3.  
D ose Rati o nale ............................................................................................... 3 2  
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects ........................................................... 3 3  
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S .......................................... 3 5  
2. 1.  
St u d y O bjecti ves ............................................................................................ 3 5  
2. 1. 1.  
Pri mar y O bjecti ves ......................................................................................... 3 5  
2. 1. 2.  
Sec o n dar y O bjecti ves ..................................................................................... 3 5  
2. 1. 3.  
Ot her O bjecti ves ............................................................................................ 3 6  
3.  
S T U D Y D E SI G N .......................................................................................... 3 7  
3. 1.  
O verall Pla n .................................................................................................... 3 7  
3. 2.  
Disc ussi o n of St u d y Desi g n ........................................................................... 3 8  
4.  
S T U D Y P O P U L A TI O N .............................................................................. 4 0  
4. 1.  
E nr oll me nt ......................................................................................................  4 0  
4. 1. 1.  
I ncl usi o n Criteria ............................................................................................ 4 0 
4. 1. 2.  
E xcl usi o n Criteria .......................................................................................... 4 0  
4. 2.  
Scree ni n g Fail ures .......................................................................................... 4 2  
5.  
S T U D Y T R E A T M E N T S ............................................................................. 4 3  
5. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Re gi me ns ................................. 4 3  
5. 1. 1.  
Treat me nt Gr o u ps .......................................................................................... 4 3  
5. 1. 2.  
Met h o d of Treat me nt All ocati o n .................................................................... 4 3  
5. 1. 3.  
Bli n di n g ..........................................................................................................  4 4  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 0 of 1 0 9 
 
5. 2.  
St u d y Dr u gs .................................................................................................... 4 4  
5. 2. 1.  
E d o xa ba n ........................................................................................................  4 4  
5. 2. 1. 1.  
Descri pti o n ..................................................................................................... 4 4  
5. 2. 1. 2.  
D ose ............................................................................................................... 4 4  
5. 2. 1. 3.  
Tra nsiti o ni n g t o E d o xa ba n at Ra n d o mizati o n ................................................ 4 5  
5. 2. 1. 4.  
Tra nsiti o n fr o m E d o xa ba n at E n d of Treat me nt ............................................ 4 6  
5. 2. 2.  
Vita mi n K A nta g o nist .................................................................................... 4 7  
5. 2. 2. 1.  
D ose ............................................................................................................... 4 7  
5. 2. 2. 2.  
Tra nsiti o ni n g t o St u d y Vita mi n K A nta g o nist at Ra n d o mizati o n .................. 4 8  
5. 2. 2. 3.  
I nter nati o nal N or malize d Rati o Ma na ge me nt ................................................ 4 8 
5. 2. 2. 4.  
Tra nsiti o n fr o m Vita mi n K A nta g o ni st at E n d of Treat me nt ......................... 4 9 
5. 2. 3.  
I nterr u pti o ns a n d Disc o nti n uati o ns of St u d y Treat me nt ................................ 4 9 
5. 3.  
La beli n g a n d Pac ka gi n g ................................................................................. 4 9  
5. 4.  
Pre parati o n ..................................................................................................... 5 0  
5. 5.  
A d mi nistrati o n ............................................................................................... 5 0  
5. 6.  
St ora ge ........................................................................................................... 5 0  
5. 7.  
Dr u g Acc o u nta bilit y ....................................................................................... 5 1  
5. 8.  
Met h o d of Assessi n g Re gi me n C o m plia nce .................................................. 5 1  
5. 9.  
Pri or a n d C o nc o mita nt Me dicati o ns .............................................................. 5 2  
5. 9. 1.  
Pr o hi bite d Me dicati o ns .................................................................................. 5 2  
5. 1 0.  
S u bject Wit h dra wal/ Disc o nti n uati o n ............................................................. 5 3  
5. 1 0. 1.  
Reas o ns f or Wit h dra wal ................................................................................. 5 3  
5. 1 0. 2.  
Wit h dra wal Pr oce d ures .................................................................................. 5 3  
6.  
S T U D Y P R O C E D U R E S .............................................................................. 5 4  
6. 1.  
Pre-scree ni n g ..................................................................................................  5 4  
6. 2.  
S u bject E nr oll me nt ( Scree ni n g/ Ra n d o mizati o n, Visit 1, Da y - 2 1 ( ma x. 
Da y - 2 8) a n d O pti o nal Visit 2 Da y - 1 4) ........................................................ 5 4  
6. 2. 1.  
E d o xa ba n St u d y Ar m ..................................................................................... 5 6  
6. 2. 2.  
V K A St u d y Ar m ............................................................................................ 5 7  
6. 3.  
Cat heter A blati o n ( Peri pr oce d ural  Visit, Visit 3, Da y 0) ............................... 5 7 
6. 3. 1.  
E d o xa ba n St u d y Ar m ..................................................................................... 5 8  
6. 3. 2.  
V K A St u d y Ar m ............................................................................................ 5 8  
6. 3. 3.  
A ntic oa g ulati o n D uri n g Cat heter A blati o n .................................................... 5 9  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 1 of 1 0 9 
 
6. 3. 4.  
A ntic oa g ulati o n P ost Cat heter A blati o n ........................................................ 5 9  
6. 4.  
H os pital Disc har ge ( Visit 4; o pti o nal) ........................................................... 5 9  
6. 5.  
Diff usi o n- Wei g hte d Ma g ne tic Res o na nce I ma gi n g ( Selecte d sites o nl y) 
( Visit 5, Da y 4) ............................................................................................... 5 9 
6. 6.  
Site Visit ( Visit 6, Da y 3 0) ............................................................................. 6 0  
6. 7.  
O pti o nal Site Visit/ Tele p h o ne Asse ss me nt ( Visit 7, Da y 6 0) ........................ 6 0 
6. 8.  
E n d of Treat me nt ( Visit 8, Da y 9 0) ............................................................... 6 0  
6. 9.  
E n d of St u d y Visit, P ost-treat me nt F oll o w- u p ( Visit 9, Da y 1 2 0) ................. 6 1  
6. 1 0.  
Misse d Visits .................................................................................................. 6 1  
6. 1 1.  
M o dificati o n of I C after Ra n d o mizati o n ........................................................ 6 1  
6. 1 1. 1.  
S u bjects L ost t o F oll o w- U p ........................................................................... 6 2  
6. 1 2.  
E n d of Trial Defi niti o n ................................................................................... 6 2  
7.  
O U T C O M E A S S E S S M E N T S ..................................................................... 6 3  
7. 1.  
Pri mar y Efficac y E n d p oi nt ............................................................................. 6 3  
7. 2.  
Pri mar y Safet y E n d p oi nt ................................................................................ 6 3  
7. 3.  
Sec o n dar y E n d p oi nts ...................................................................................... 6 3  
7. 3. 1.  
Ot her E n d p oi nts ............................................................................................. 6 4  
7. 4.  
E n d p oi nt Defi niti o ns ...................................................................................... 6 4  
7. 4. 1.  
Blee di n g ......................................................................................................... 6 5  
7. 4. 2.  
Efficac y E n d p oi nt Defi niti o ns ....................................................................... 6 5  
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S. ... 6 6  
8. 1.  
P har mac o ki netic Varia ble(s) .......................................................................... 6 6  
8. 2.  
Car diac Mar kers ............................................................................................. 6 6  
9.  
S A F E T Y A S S E S S M E N T S .......................................................................... 6 7  
9. 1.  
A d verse E ve nt C ollecti o n a n d Re p orti n g ....................................................... 6 7  
9. 2.  
Defi niti o ns ......................................................................................................  6 8  
9. 2. 1.  
A d verse E ve nt ................................................................................................ 6 8  
9. 2. 2.  
U ne x pecte d A d verse E ve nt ............................................................................ 6 8  
9. 2. 3.  
E x pecte d A d verse E ve nt ................................................................................ 6 8  
9. 2. 4.  
Seri o us A d verse E ve nt ................................................................................... 6 8  
9. 2. 5.  
A d verse E ve nts of S pecial I nterest ................................................................ 6 9  
9. 2. 5. 1.  
C o m bi ne d Ele vati o ns of A mi n ot ra nsferases a n d Bilir u bi n ............................ 6 9 
9. 3.  
Classificati o n f or A E assess me nt ................................................................... 6 9  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 2 of 1 0 9 
 
9. 3. 1.  
Se verit y Assess me nt ...................................................................................... 6 9  
9. 3. 2.  
Ca usalit y Assess me nt ..................................................................................... 6 9  
9. 3. 3.  
Acti o n Ta ke n Re gar di n g t he Assi g ne d A ntit hr o m b otic Re gi me n ................. 7 0  
9. 3. 4.  
Ot her Acti o n Ta ke n f or E ve nt ........................................................................ 7 0  
9. 3. 5.  
A d verse E ve nt O utc o me ................................................................................ 7 0  
9. 4.  
Ti mi n g of A d verse E ve nt Re p orti n g .............................................................. 7 1  
9. 5.  
Re p orti n g S A Es/ A Es ...................................................................................... 7 1  
9. 5. 1.  
D oc u me ntati o n ............................................................................................... 7 1  
9. 5. 2.  
N otif yi n g Re g ulat or y A ut h orities, I n ve sti gat ors a n d I nstit uti o nal Re vie w 
B oar d/I n de pe n de nt Et hics C o m mittee ........................................................... 7 2  
9. 6.  
Re p orti n g of Pre g na nc y/ E x p os ure i n Uter o .................................................. 7 3  
9. 7.  
Cli nical La b orat or y E val uati o ns .................................................................... 7 3  
9. 8.  
Vital Si g ns ...................................................................................................... 7 4  
9. 9.  
Electr ocar di o gra ms ........................................................................................ 7 4  
9. 1 0.  
P h ysical E xa mi nati o n Fi n di n gs ...................................................................... 7 4  
9. 1 1.  
Ma g netic Res o na nce I ma gi n g: Di ff usi o n- Wei g hte d I ma gi n g ....................... 7 5 
1 0.  
S T A TI S TI C A L M E T H O D S ....................................................................... 7 6  
1 0. 1.  
A nal ysis Sets .................................................................................................. 7 6  
1 0. 1. 1.  
I nte nt-t o- Treat A nal ysis Set ........................................................................... 7 6 
1 0. 1. 2.  
M o difie d I nte nt-t o- Tr eat A nal ysis Set ........................................................... 7 6  
1 0. 1. 3.  
Per Pr ot oc ol A nal ysis Set ............................................................................... 7 6  
1 0. 1. 4.  
Safet y A nal ysis Set ........................................................................................ 7 7  
1 0. 2.  
Ge neral Statistical C o nsi derati o ns ................................................................. 7 7  
1 0. 3.  
St u d y P o p ulati o n Data ................................................................................... 7 9  
1 0. 4.  
Statistical A nal ysis ......................................................................................... 7 9  
1 0. 4. 1.  
A nal ysis of A dj u dicate d Efficac y E n d p oi nts ................................................. 7 9  
1 0. 4. 2.  
A nal ysis of A dj u dicate d Safet y E n d p oi nts .................................................... 8 0  
1 0. 4. 3.  
A nal ysis of Ot her Para meters ........................................................................ 8 1  
1 0. 4. 4.  
Safet y A nal yses .............................................................................................. 8 1  
1 0. 4. 4. 1.  
A d verse E ve nt A nal yses ................................................................................ 8 1  
1 0. 4. 4. 2.  
Cli nical La b orat or y E val uati o n A nal yses ...................................................... 8 1  
1 0. 4. 4. 3.  
Vital Si g ns A nal yses ...................................................................................... 8 1  
1 0. 4. 4. 4.  
Electr ocar di o gra m A nal yses .......................................................................... 8 2  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 3 of 1 0 9 
 
1 0. 4. 4. 5.  
P h ysical E xa mi nati o n A nal yses ..................................................................... 8 2  
1 0. 4. 5.  
Ot her A nal yses ............................................................................................... 8 2  
1 0. 5.  
I nteri m A nal yses ............................................................................................ 8 2 
1 0. 6.  
Data a n d Safet y M o nit ori n g B oar d ................................................................ 8 2  
1 0. 7.  
Sa m ple Size Deter mi nati o n ............................................................................ 8 2  
1 1.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E .............................. 8 4  
1 1. 1.  
M o nit ori n g a n d I ns pecti o ns ........................................................................... 8 4  
1 1. 2.  
Data C ollecti o n .............................................................................................. 8 4  
1 1. 3.  
Data Ma na ge me nt .......................................................................................... 8 4  
1 1. 4.  
St u d y D oc u me ntati o n a n d St ora ge ................................................................. 8 5  
1 1. 5.  
Rec or d Kee pi n g .............................................................................................. 8 6  
1 2.  
FI N A N CI N G A N D I N S U R A N C E .............................................................. 8 7  
1 2. 1.  
Fi na nces ......................................................................................................... 8 7  
1 2. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ura nce .................................................... 8 7  
1 3.  
P U B LI C A TI O N P O LI C Y ........................................................................... 8 8  
1 4.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N ............. 8 9  
1 4. 1.  
C o m plia nce State me nt, Et hics a n d Re g ulat or y C o m plia nce ......................... 8 9  
1 4. 2.  
S u bject C o nfi de ntialit y .................................................................................. 8 9  
1 4. 3.  
I nf or me d C o nse nt Pr oce d ure ......................................................................... 8 9 
1 4. 4.  
Re g ulat or y C o m plia nce .................................................................................. 9 0  
1 4. 5.  
Pr ot oc ol De viati o ns ........................................................................................ 9 0  
1 4. 6.  
S u p pl y of Ne w I nf or mati o n Affec ti n g t he C o n d uct of t he St u d y .................. 9 0 
1 4. 7.  
Pr ot oc ol A me n d me nts .................................................................................... 9 1  
1 4. 8.  
A d dress List ................................................................................................... 9 1  
1 4. 8. 1.  
S p o ns or ...........................................................................................................  9 1  
1 4. 8. 1. 1.  
D S E Pr oject Lea der ........................................................................................ 9 1  
1 4. 8. 1. 2.  
D S E Me dical E x pert ...................................................................................... 9 1  
1 4. 8. 2.  
C R O ............................................................................................................... 9 2  
1 4. 8. 2. 1.  
C R O Me dical M o nit or ................................................................................... 9 2  
1 4. 8. 2. 2.  
C R O Pr oject Ma na ger .................................................................................... 9 2  
1 4. 8. 3.  
Dr u g Safet y .................................................................................................... 9 2  
1 4. 8. 3. 1.  
D S E ................................................................................................................ 9 2  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 4 of 1 0 9 
 
1 4. 8. 3. 2.  
C R O ............................................................................................................... 9 2  
1 4. 8. 4.  
Bi ostatistics & Data Ma na ge me nt .................................................................. 9 2  
1 4. 8. 4. 1.  
D S E Data Ma na ge me nt .................................................................................. 9 2  
1 4. 8. 4. 2.  
D S E Bi ostatisticia n ........................................................................................ 9 3  
1 4. 8. 5.  
Bi ol o gical S peci me ns ..................................................................................... 9 3  
1 4. 8. 6.  
I nteracti ve We b V oice Res p o nse S yste m (I X R S) .......................................... 9 3 
1 4. 8. 7.  
Bi oa nal ytical La b orat or y ................................................................................ 9 3  
1 4. 8. 8.  
e C R F Pr o vi der ................................................................................................ 9 3  
1 4. 8. 9.  
Ot her ...............................................................................................................  9 3  
1 5.  
R E F E R E N C E S ............................................................................................. 9 4  
1 6.  
A P P E N DI C E S .............................................................................................. 9 7  
1 6. 1.  
St u d y Or ga nizati o n ........................................................................................ 9 7  
1 6. 1. 1.  
Data a n d Safet y M o nit ori n g B oar d ................................................................ 9 7  
1 6. 1. 2.  
Cli nical E ve nts C o m mitt ee ............................................................................ 9 7  
1 6. 1. 3.  
E xec uti ve C o m mittee ..................................................................................... 9 7  
1 6. 1. 4.  
O perati o ns C o m mittee ................................................................................... 9 8  
1 6. 2.  
S u b-st u d y ....................................................................................................... 9 8  
1 6. 3.  
Blee di n g Criteria ............................................................................................ 9 9  
1 6. 4.  
Defi niti o n of ter ms ....................................................................................... 1 0 2  
1 6. 5.  
C o m p o ne nts of t he C H A D S 2, C H A2D S 2- V A Sc Sc ore a n d H A S- B L E D Sc ore 1 0 3 
1 6. 6.  
Esti mati o n of Creati ni ne Cleara nce ( Cr C L) ................................................. 1 0 4  
1 6. 7.  
M o difie d Ra n ki n Scale ................................................................................. 1 0 5  
1 6. 8.  
Re gi o nal G ui deli ne Rec o m me n dati o ns f or I N R .......................................... 1 0 6  
1 6. 9.  
Sc he d ule of E ve nts ....................................................................................... 1 0 7  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 5 of 1 0 9 
 
LI S T O F I N- T E X T T A B L E S 
Ta ble 1. 1:  
S u m mar y of t he H o k usai V T E a n d E N G A G E A F- TI MI 4 8 St u dies ........ 3 1  
Ta ble 2:  
Tra nsiti o ni n g t o E d o xa ba n at Ra n d o mizati o n ........................................... 4 5  
Ta ble 3:  
Tra nsiti o ni n g fr o m E d o xa ba n  at E n d of Treat me nt .................................. 4 6 
Ta ble 1 6. 1:  
I S T H Blee di n g Criteria ............................................................................. 9 9 
Ta ble 1 6. 2:  
TI MI Blee di n g Criteria .............................................................................. 9 9  
Ta ble 1 6. 3:  
B A R C Blee di n g Criteria ......................................................................... 1 0 0  
Ta ble 1 6. 4:  
C o m p o ne nts of t he C H A D S 2 Sc ore ........................................................ 1 0 3 
Ta ble 1 6. 5:  
C o m p o ne nts of t he C H A 2D S 2- V A Sc Sc ore ............................................ 1 0 3 
Ta ble 1 6. 6:  
C o m p o ne nts of t he H A S- B L E D Sc ore .................................................... 1 0 3  
Ta ble 1 6. 7:  
M o difie d Ra n ki n Scale ............................................................................ 1 0 5  
Ta ble 1 6. 8:  
Re gi o nal G ui deli ne Rec o m me n dati o ns f or I N R ..................................... 1 0 6  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 6 of 1 0 9 
 
LI S T O F I N- T E X T FI G U R E S 
Fi g ure 3. 1 St u d y Desi g n .................................................................................................... 3 8  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 7 of 1 0 9 
 
LI S T O F A B B R E VI A TI O N S 
A B B R E VI A TI O N  
D E FI NI TI O N 
A C T 
Acti vate d cl otti n g ti me 
A E
 A d verse
 
e ve nt
 
A E SI 
A d verse e ve nt of s pecial i nterest 
A F
 Atrial
 
fi brillati o n
 
A L P
 Al kali ne
 
p h os p hatase
 
A L T
 Ala ni ne
 
tra nsa mi nase
 
A R C 
Aca de mic Researc h C o ns orti u m 
A S A
 Acet ylsalic ylic
 
aci d
 
A S T
 As partate
 
tra nsa mi nase
 
B A R C 
Blee di n g Aca de mic Researc h C o ns orti u m 
B P
 Bl o o d
 
press ure
 
C A B G 
C or o nar y arter y b y pass graft 
C A D
 C or o nar y
 
arter y
 
disease
 
C E C 
Cli nical E ve nts C o m mittee 
C H A D S 2 
C o n gesti ve heart fail ure, H y perte nsi o n, A ge,  Dia betes, pre vi o us Str o ke ris k sc ore 
CI
 C o nfi de nce
 
i nter val
 
C N S 
Ce ntral ner v o us s yste m 
C O X
 C y cl o o x y ge nase
 
Cr C L
 Creati ni ne
 
cleara nce
 
C R F 
Case re p ort f or m 
C R N M 
Cli nicall y rele va nt n o n- maj or 
C R O 
C o ntract Researc h Or ga nizati o n 
c T n- hs 
car diac tr o p o ni n hi g h se nsiti vit y  
C V
 Car di o vasc ular
 
D A P T 
D ual A nti platelet T hera p y (e. g., as piri n a n d P 2 Y 1 2 a nta g o nist) 
D M
 Dia betes
 
mellit us
 
D S E 
Daiic hi Sa n k y o E ur o pe 
D S M B 
Data a n d Safet y M o nit ori n g B oar d 
D V T 
Dee p vei n t hr o m b osis 
D WI 
Diff usi o n wei g hte d i ma gi n g  
D WI- F L AI R  
Diff usi o n wei g hte d i ma gi n g fl ui d atte n uate d i n versi o n rec o ver y 
D W- M RI 
Diff usi o n wei g hte d ma g netic res o na nce i ma gi n g 
E C
 Et hics
 
C o m mittee
 
E C G
 Electr ocar di o gra m
 
e C R F 
Electr o nic case re p ort f or m 
E D
 E mer ge nc y
 
de part me nt
 
E D C 
Electr o nic data ca pt ure 
E H R A 
E ur o pea n Heart R h yt h m Ass ociati o n 
E O T
 E n d- of- Treat me nt
 
E U
 E ur o pea n
 
U ni o n
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 8 of 1 0 9 
 
A B B R E VI A TI O N  
D E FI NI TI O N 
E u dra C T 
E ur o pea n u ni o n dr u g re g ulati n g a ut h orities cli nical trials 
F Xa
 Fact or
 
Xa
 
G C P 
G o o d Cli nical Practice (refers t o I C H) 
GI
 Gastr oi ntesti nal
 
G M
 Gre y
 
matter
 
H E O R 
Healt h Ec o n o mics O utc o me Researc h 
H F
 Heart
 
fail ure
 
HI F U 
Hi g h i nte nsit y f oc use d ultras o u n d 
H R
 Hazar d
 
rati o
 
I B
 I n vesti gat or
 
Br oc h ure
 
I C 
I nf or me d c o nse nt  
I C F 
I nf or me d C o nse nt F or m 
I C H
 I ntracra nial
 
he m orr ha ge
 
I C U 
I nte nsi ve Care U nit 
I D
 I de ntificati o n
 
I E C
 I n de pe n de nt
 
Et hics
 
C o m mittee
 
I N R
 I nter nati o nal
 
n or malize d
 
rati o
 
I R B
 I nstit uti o nal
 
Re vie w
 
B oar d
 
I S T H 
I nter nati o nal S ociet y o n T hr o m b osis a n d He m ostasis 
I T T 
I nte nt-t o-treat (a nal ysis set) 
I X R S 
I nteracti ve we b/ v oice res p o nse s yste m 
L A
 Left
 
atri u m
 
L A A 
Left Atrial A p pe n da ge 
L M W H 
L o w m olec ular wei g ht he pari n 
L V
 Left
 
ve ntricle
 
Me d D R A 
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
MI
 M y ocar dial
 
i nfarcti o n
 
mI T T 
M o difie d I T T (a nal ysis set) 
M RI 
Ma g netic res o na nce i ma gi n g 
m R S 
m o difie d Ra n ki n Scale 
N O A C 
N o n- vita mi n K a nta g o nist oral a ntic oa g ula nt 
N S AI D
 N o n-ster oi dal
 
a nti-i nfla m mat or y
 
dr u g
 
N T- pr o B N P  
N-ter mi nal fra g me nt B-t y pe natri uretic pe pti de  
O A C
 Oral
 
a ntic oa g ula nt
 
P D
 P har mac o d y na mic
 
P E
 P ul m o nar y
 
e m b olis m
 
P- g p
 P- gl y c o pr otei n
 
P K
 P har mac o ki netic
 
P P
 Per
 
pr ot oc ol
 
P R O B E desi g n  
Pr os pecti ve, Ra n d o mize d, O pe n-la bel st u d y wit h Bl i n de d E val uati o n of e n d p oi nts 
R F
 Ra di o
 
fre q ue nc y
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 2 9 of 1 0 9 
 
A B B R E VI A TI O N  
D E FI NI TI O N 
S A E 
Seri o us a d verse e ve nt 
S A F 
Safet y (a nal ysis set) 
S A P 
Statistical a nal ysis pla n 
S C E 
sile nt cere bral e ve nts 
S C L 
sile nt cere bral lesi o ns 
S E E 
S yste mic e m b olic e ve nts 
S m P C 
S u m mar y of Pr o d uct C haracteristics 
S O P 
Sta n dar d o perati n g pr oce d ures 
S U S A R 
S us pecte d, u ne x pecte d, seri o us a d verse reacti o n 
T B L
 T otal
 
bilir u bi n
 
T E A E 
Treat me nt-e mer ge nt a d verse e ve nt 
T E E
 Tra nses o p ha geal
 
ec h ocar di o gra m
 
 
TI A 
Tra nsie nt isc he mic attac k 
TI MI 
T hr o m b ol ysis i n M y ocar dial I nfarcti o n  
T T R 
Ti me i n t hera pe utic ra n ge 
U L N 
U p per li mit of n or mal 
V K A 
Vita mi n K a nta g o nist 
vs
 Vers us
 
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
 
cells
 
 
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 0 of 1 0 9 
 
1.  
I N T R O D U C TI O N  
1. 1.  
B ac k gr o u n d  
Atrial fi brillati o n ( A F) is t he m o st c o m m o n arr h yt h mia i n a d ults, affecti n g 0. 5 % t o 1 % of t he t otal 
p o p ulati o n a n d > 8 % of s u bjects ol der t ha n 8 0 years. S u bjects s ufferi n g fr o m A F are at a n i ncrease d 
ris k of str o ke, pr o gressi n g heart fail ure a n d s u d de n deat h. Cat heter a blati on as a met h o d of treati n g 
A F is m ore a n d m ore fr e q ue ntl y perf or me d i n cli nical practice d ue t o its effecti ve ness o n A F-
relate d s y m pt o ms a n d q ualit y of life (3 ). H o we ver, t his pr oce d ure is ass ociate d wit h a si g nifica nt 
t hr o m b oe m b olic ris k d uri n g a n d sh ortl y after t he pr oce d ure. T he ca uses of t hr o m b oe m b olic e ve nts 
d uri n g a n d after t he a blati o n are m ulti ple a n d as s u c h, t he use of oral a ntic oa g ula nts d uri n g t he 
cat heter a blati o n pr oce d ure is t heref ore warra nte d (2 ).  
Vita mi n  K  a nta g o nists  ( V K As)  ha ve  bee n  tra dit i o nall y  use d  t o  pre ve nt  pr oce d ure-relate d  
t hr o m b oe m b olis m (4 ).  T he tra diti o nal a ntic oag ulati o n a p pr oac h is t o i n terr u pt a d mi nistrati o n of 
a n oral V K A a n d use he pari n bri d gi n g.  M ore rece ntl y, st u dies ha ve i n dicat e d t hat u ni nterr u pte d 
a ntic oa g ulati o n  ma y  be  safer  a n d  m ore  effecti ve  ( 5 ).  C urre nt  A F  g ui deli nes  rec o m me n d  
c o nsi derati o n of u ni nterr u pte d oral a ntic oa g ulati o n f or patie n ts u n der g oi n g cat heter a blati o n (2 ). 
I n  a  E ur o pea n  Heart  R h yt h m  Ass ociati o n  s ur ve y,  7 1. 6 %  of  res p o n de nts  re p orte d  usi n g  t he  
u ni nterr u pte d V K A strate g y f or cat heter a blati o n ( 6 ).  
N o n- vita mi n K oral a ntic oa g ul a nts ( N O A Cs) offer i m p orta nt a d va nta ges o ver V K A be y o n d t heir 
ease of a d mi nistrati o n, s uc h as fe wer i nteracti o ns  a n d n o nee d of la b orat or y m o nit ori n g, a n d ha ve 
bec o me wi del y a vaila ble a n d re prese nt a n  attracti ve alter nati ve i n t his setti n g. 
 
1. 2.  
Descri pti o n of I n vesti g ati o n al Pr o d uct 
E d o xa ba n t os ylate ( D U- 1 7 6 b) is a n a ntit hr o m b otic a ge nt, a n orall y acti ve, se lecti ve, direct, a n d 
re versi ble  i n hi bit or  of  Fact or  Xa  ( F Xa),  ma n ufact ure d  b y  Daiic hi  Sa n k y o  C o.,  Lt d.,  Ja pa n.   
I n hi biti o n of F Xa i n t he c oa g ulati o n casca de prol o n gs cl otti n g ti me a n d p ote ntiall y re d uces t he 
ris k of s p o nta ne o us or i n d uce d t hr o m b us f or mati o n. 
I nter nati o nal n o n- pr o prietar y na me: E d o xa ba n (D U- 1 7 6) refers t o t he a n h y dr o us free base of 
e d o xa ba n t os ylate. S u bjects are gi ve n e d o xa ba n t o s ylate (a m o n o h y drate salt) b ut all d oses a n d 
plas ma c o nce ntrati o ns are e x presse d i n ter ms of e d o xa ba n, t he a n h y dr o us free base. 
F or si m plicit y, t his pr ot oc ol uses t he ter m “e d o xa ba n” t o refer t o ei t her or b ot h f or ms. 
1. 2. 1. 1.  
N o ncli nic al St u dies 
I n n o ncli nical st u dies, e d o xa ba n s h o we d e xcelle nt p ote ntial as a n a n tit hr o m b otic a ge nt.  Res ults 
of n o n-cli nical t o xic o l o g y st u dies d o n ot i n dicate a n y maj or cli nicall y c o ncer ni n g a d verse effects 
i n  st u d y  a ni mals  e x p ose d  t o  e d o xa ba n.  A d diti o nal  details  ar e  a vaila ble  i n  t he  e d o xa ba n  
I n vesti gat or’s Br oc h ure (I B) (7 ). 
1. 2. 1. 2.  
Cli nic al E x perie nce 
E d o xa ba n was i nitiall y a p pr o ve d i n Ja pa n f or t h e pre ve nti o n of ve n o us t hr o m b oe m b olis m ( V T E) 
i n patie nts u n der g oi n g a n y of t he f oll o wi n g ort h o pe dic pr oce d ures o n  t he l o wer li m b: t otal k nee 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 1 of 1 0 9 
 
re place me nt,  t otal  hi p  re place me nt,  a n d  hi p  fract ure  s ur ger y  a n d  t he n  s u bse q ue ntl y  f or  t he  
pre ve nti o n of isc he mic str o ke a n d s yste mic e m b olis m i n patie nts wit h n o n- val v ular A F; treat me nt 
a n d rec urre nce pre ve nti o n of V T E. I n 2 0 1 5, e d o xa ba n was a p pr o ve d i n t he E ur o pea n U ni o n ( E U) 
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 a d ult patie nts wit h n o n val v ular A F wit h 
o ne or m ore ris k fact ors (s uc h as c o n gesti ve heart fail ure, h y perte nsi o n, a ge ≥7 5 years, dia betes 
mellit us, pri or str o ke or tra nsie nt isc hae mic attac k  ( TI A), a n d f or t he treat me nt a n d pre ve nti o n of 
rec urre nt dee p vei n t hr o m b osis ( D V T) a n d p ul m o nar y e m b olis m ( PE). Si milar i n dicati o ns were 
als o a p pr o ve d i n t he U nite d States a n d ot her c o u ntries a n d re gi o ns.   
T he efficac y a n d safet y of e d o xa ba n f or re d uci n g t h e ris k of str o ke a n d s yste mic e m b olic e ve nts 
( S E Es) i n s u bjects wit h n o n- val v ular A F was de m o nstrate d i n a lar ge pi v otal P hase 3 st u d y 
( E N G A G E A F- TI MI 4 8) (1 ). Si milarl y, t he efficac y a n d safet y of e d o xa ba n f or t he treat me nt of 
V T E, i ncl u di n g D V T a n d P E, a n d t he pre ve nti o n of  rec urre nt V T E was de m o nstrate d i n t he P hase 
3 H o k usai V T E st u d y ( 8 ). 
Feat ures of t he H o k usai V T E a n d E N G A G E A F- TI MI 4 8 st u dies are s u m marize d i n Ta ble 1. 1 . 
T a ble 1. 1:  S u m m ar y of t he H o k us ai V T E a n d E N G A G E A F- TI MI 4 8 St u dies 
St u d y 
P o p ul ati o n 
Me di a n 
D ur ati o n 
of 
Tre at me nt 
Tre at me nt Gr o u ps  N 
Pri m ar y Effic ac y O utc o me  
Pri m ar y S afet y O utc o me 
E n d p oi nt
H R ( 9 5 % CI) 
E d o x a b a n vs 
W arf ari n 
E n d p oi nt 
H R ( 9 5 % CI) 
E d o x a b a n vs 
W arf ari n 
H o k usai 
V T E (ac ute 
V T E) 
0. 7 y ears 
E d o xa ba n 6 0 m g  
4 1 1 8 
Rec urre nt 
V T E 
0. 8 9 ( 0. 7 0, 1. 1 3) 
mI T T, o verall st u d y 
peri o d 
Maj or + 
C R N M 
Blee di n g 
0. 8 1 ( 0. 7 0 5, 0. 9 3 6) 
mI T T, o n-treat me nt 
peri o d 
Warfari n
 4 1 2 2
 
E N G A G E 
A F- TI MI 
4 8 ( n o n-
val v ular 
A F) 
2. 5 y ears 
E d o xa ba n  
Hi g h D ose 
Re gi me n *  
7 0 1 2 
Str o ke 
a n d S E E 
0. 7 9 ( 0. 6 3, 0. 9 9) 
mI T T, o n-treat me nt 
peri o d 
Maj or 
Blee di n g 
0. 8 0 ( 0. 7 1, 0. 9 1) 
mI T T, o n-treat me nt 
peri o d 
E d o xa ba n  
L o w D ose 
Re gi me n * * 
7 0 0 2 
1. 0 7 ( 0. 8 7, 1. 3 1) 
mI T T, o n-treat me nt 
peri o d 
0. 4 7 ( 0. 4 1, 0. 5 5) 
mI T T o n-treat me nt 
peri o d 
Warfari n
 7 0 1 2
  
-
 
-
 
A b bre viati o ns: A F = atrial fi brillati o n; CI = c o nfi de nce i nter val; C R N M = cli nicall y rele va nt n o n- maj or; H R = 
Hazar d Rati o; S E E = s yste mic e m b olic e ve nt; vs = vers us; V T E = ve n o us t hr o m b oe m b olis m; mI T T = m o difie d 
i nte nti o n-t o-treat; N = n u m ber of treate d s u bjects 
* Hi g h D ose Re gi me n = 6 0 m g e d o xa ba n o nce- dail y wit h re d ucti o n t o 3 0 m g o nce- dail y i n s u bjects wit h l o w b o d y 
wei g ht, m o derate re nal i m pair me nt, or s pecifie d c o nc o mita nt me dicati o ns; 
* * L o w D ose Re gi me n = 3 0 m g e d o xa ba n o nce- dail y wit h re d ucti o n t o 1 5 m g o nce- dail y i n s u bjects wit h l o w b o d y 
wei g ht, m o derate re nal i m pair me nt, or s pecifie d c o nc o mita nt me dicati o ns. 
 
Ot her c o m plete d st u dies i ncl u d e P hase 1 cli nical p har mac ol o g y st u dies, P hase 2 d ose-ra n gi n g 
st u dies i n s u bjects wit h n o n- val v ular A F a n d s u bjects u n der g oi n g l o wer-e xtre mit y ort h o pe dic 
s ur ger y, a n d P hase 3 st u dies i n s u bjects u n der g oi n g l o wer-e xtre mit y ort h o pe dic s ur ger y. 
I n t he c o urse of t he e d o xa ba n cli nical de vel o p me nt pr o gra m, o ver 2 3, 5 0 0 s u bjects have bee n gi ve n 
e d o xa ba n  e nc o m passi n g  o ver  3 4, 1 0 0  s u bject- years  of  e x p os ure.  T he  safet y  a n d  efficac y  of  
e d o xa ba n has bee n e val uate d i n t he f oll o wi n g pr o gra ms: 
 P hase 1 st u dies (i ncl u di n g 1 6 2 7 s u bjects fr o m p har mac o ki netic ( P K)- p har mac o d y na mic 
( P D) st u dies, P K i n s u bjects wit h re nal i m pair me nt, a n d dr u g- dr u g i nteracti o n st u dies):  
Res ults of t hese st u dies ha ve s h o w n t hat e d o xa ba n is ra pi dl y a bs or be d wit h ra pi d o nset of 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 2 of 1 0 9 
 
acti o n a n d t he d ose c o nce ntrati o n relati o ns hi p is ge nerall y li near. T he mea n ter mi nal 
half-life is bet wee n 1 0- 1 4 h o urs.  T he P D effect as meas ure d b y a nti- Xa acti vit y or 
i n hi biti o n of F Xa acti vit y lasts f or 2 4 h o urs.  D ose-relate d i ncreases i n P K c o nce ntrati o ns 
a n d a nti-t hr o m b otic acti vit y were o bser ve d, as meas ure d b y a nti- Xa acti vit y.  T he 
bi oa vaila bilit y is ~ 6 0 % a n d 5 0 % of t he a bs or b e d dr u g is e xcrete d b y re nal cleara nce.  T he 
a bs or pti o n, distri b uti o n, meta b olis m, a n d e x creti o n are als o me diate d t hr o u g h t he P 
gl yc o pr otei n ( P- g p) tra ns p ort s yste m a n d dr u gs wit h P- g p i n hi bit or y effects ma y alter 
e d o xa ba n e x p os ure. 
 P hase 2 st u dies i n A F s u bjects (i ncl u di n g 1, 9 7 3 s u bjects):  T hese st u dies pri maril y 
e val uate d safet y of differ e nt d ose re gi me ns of e d o xa ba n wit h a p pr o xi matel y 1 2 wee ks of 
treat me nt.  Res ults of t hese st u dies s h o we d t hat t he t wice a da y re gi me n ha d hi g her 
blee di n g t ha n o nce- dail y re gi me n of e d o xa ba n.  C o nse q ue ntl y, t he o nce- dail y re gi me n of 
e d o xa ba n was teste d i n t he s u bse q ue nt P hase 3 trials. 
 P hase 3 A F pi v otal trial ( E N G A G E A F- TI MI 4 8) i n v ol vi n g 2 1, 0 2 6 treate d s u bjects wit h 
a me dia n f oll o w- u p of 2. 8 years ( me dia n tr eat me nt 2. 5 years). T w o o nce- dail y re gi me ns 
of e d o xa ba n were c o m pare d wit h warfari n f o r t he pre ve nti o n of str o ke a n d s yste mic 
e m b olis m i n patie nts wit h n o n- val v ular A F. B ot h  re gi me ns were n o n-i nferi or t o warfari n 
f or t he pre ve nti o n of str o ke a n d s yste mic e m b olis m a n d were ass ociate d wit h 
si g nifica ntl y l o wer rates of blee di n g a n d deat h fr o m cardi o vasc ular ( C V) ca uses. 
E d o xa ba n has bee n a p pr o ve d f or mar keti n g i n t he U nite d States a n d E U f or t his 
i n dicati o n. 
 P hase 2/ 3 V T E pr o p h yla xis st u dies i n s u bjec ts u n der g oi n g ort h o pe dic s ur ger y (i ncl u di n g 
3, 6 7 8 s u bjects).  E d o xa ba n has bee n a p pr o ve d f o r mar keti n g i n Ja pa n f or t his i n dicati o n. 
 P hase 3 V T E pi v otal trial ( H o k usai- V T E) i n v ol vi n g 8, 2 4 0 treate d s u bjects.  E d o xa ba n 
a d mi nistere d o nce- dail y after i n itial treat me nt wit h he pari n was n o n-i nferi or t o sta n dar d 
t hera p y a n d ca use d si g nifica ntl y less blee di n g i n patie nts wit h V T E. E d o xa ba n has bee n 
a p pr o ve d f or mar keti n g i n t he U S  a n d E U f or t his i n dicati o n. 
1. 2. 1. 3.  
D ose R ati o n ale 
Base d o n t he res ults of t he E N G A G E A F- TI MI 4 8 a n d H o k usai- V T E st u dies, a n e d o xa ba n d ose 
t hat is c o nsi dere d as safe a n d effecti ve f or patie nts wit h A F or V T E a n d is i ncl u de d i n t he la bel 
( prescri bi n g i nf or mati o n) has bee n selecte d f or t his trial.  E d o xa ba n has n ot bee n e val uate d i n 
patie nts wit h A F u n der g oi n g cat heter  a blati o n of n o n- val v ular A F b ut n o e vi de nce e xists s u g gesti n g 
f urt her t hat d ose a da ptati o n is re q uire d. 
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 3 of 1 0 9 
 
 
1. 3.  
Ris ks a n d Be nefits f or St u d y S u bjects 
Atrial fi brillati o n ( A F) is t he m o st fre q ue nt s ustai ne d arr h yt h mia i n cli nical practice. Cat heter 
a blati o n of A F has bee n esta blis he d as a n effecti v e t hera p y f or t he treat me nt of s y m pt o ms i n t hese 
patie nts ( 3 ). H o we ver, t his pr oce d ure is ass ociate d wit h a si g nifica nt t hr o m b oe m b olic ris k. I n a 
rece nt w orl d- wi de s ur ve y (9 ), t he o verall i nci de nce of maj or c o m plicati o ns of car diac a blati o n 
was 4. 5 % a n d t he deat h rate was 0. 1 5 %. Ta m p o na de was t he m ost fre q ue nt c o m plicati o n ( 1. 3 1 %), 
f oll o we d b y t otal fe m oral pse u d oa ne ur ys m ( 0. 9 3 %), TI As ( 0. 7 1 %), t otal arter o- ve n o us fist ulae 
( 0. 5 4 %), p ul m o nar y vei n ste n osis re q uiri n g i nter ve nti o n ( 0. 2 9 %) a n d str oke ( 0. 2 3 %). T he ca uses 
of t hr o m b oe m b olic e ve nts d uri n g a n d after t he a blati o n are m ulti ple a n d i ncl u de (I) c har f or mati o n 
at t he cat heter ti p, (II) m o bilizati o n of pre-e xisti n g left atrial t hr o m bi, (III) t hr o m b us f or mati o n i n 
left atrial s heat hs, (I V) t he t hr o m b o ge nic p ote ntial of left atrial e n d ocar dial lesi o ns, a n d ( V) 
electrical car di o versi o n d uri n g t he pr oce d ure. 
A ntic oa g ulati o n t hera p y is t heref ore re q uire d bef ore, d uri n g, a n d f o r a peri o d after t he pr oce d ure 
(as defi ne d b y g ui deli nes), a n d ma y be c o nti n ue d i n defi nitel y i n pa tie nts wit h o n g oi n g ris k fact ors 
f or str o ke ( C o n gesti ve heart fail ure, H y perte nsi o n, A ge, Dia betes, pre vi o us Str o ke ris k sc ore 
[ C H A D S2]  ≥1 or C H A 2D S 2- V A Sc ≥2).  
Tra diti o nall y, V K As (e g, c o u mari ns a n d i n da ne di o nes) are use d as a ntic oa g ula nt me dicati o ns 
(s o meti mes wit h e n o xa pari n a d mi nistere d as a ‘ brid ge’ d uri n g t he pr oce d ure)  t o re d uce t he ris k 
of str o ke a n d t hr o m b oe m b olic c o m plicati o ns i n s u bjects wit h A F u n der g oi n g cat heter a blati o n. 
G ui deli nes rec o m me n d u ni nterr u pte d V K A t hera p y, f or e xa m ple wit h warfari n, d ose d t o a n 
I nter nati o nal N or malize d Rati o (I N R of 2. 0 – 2. 5). H o we ver, t hese V K As (a ntic oa g ula nt a ge nts) 
are i n direct t hr o m bi n i n hi bit ors w hic h act b y bl oc ki n g t he vita mi n K- de pe n de nt li ver pr o d ucti o n 
of plas ma cl otti n g fact ors, pr ot hr o m bi n ( Fact or II), a n d Fact ors VII,  I X, a n d X. T he use of warfari n 
is c o m plicate d b y se veral i n here nt pr o ble ms, i ncl u di n g a dela ye d o nset of a ntit hr o m b otic acti o n, 
narr o w  t hera pe utic  i n de x  t hat  re q uires  cl os e  a ntic oa g ulati o n  m o nit ori n g  usi n g  t he  I N R,  
u n pre dicta ble  a n d  varia ble  p ha r mac ol o gical  res p o nse,  a n d  man dat or y  re g ular  la b orat or y  
m o nit ori n g  t o  c o ntr ol  its  a ntic oa g ula nt  effect  a n d  mi ni mize  t he  ris k  of  seri o us  blee di n g.  
F urt her m ore, n u mer o us dr u gs, certai n dietar y s u p ple me nts, alc o h ol, a n d s o me f o o ds mar ke dl y 
affect warfari n d ose res p o nse. T his is i n a d diti o n t o t he fi n di n g t hat warfari n use i ncreases b ot h 
t he ris k of de vel o pi n g i ntra cere bral he m orr ha ge a n d m ortalit y. 
H o we ver, as V K As ma y be diffic ult t o ma na ge , t he fi xe d- d ose N O A Cs are i ncreasi n gl y use d 
i nstea d of V K As a n d t heir use i n patie nts u n der goi n g a blati o n is t heref or e of i nterest als o. 
T he N O A Cs offer t he be nefits of pre dicta ble e ffect wit h o ut nee d f or m o nit ori n g, fe wer f o o d a n d 
dr u g i nteracti o ns, s h orter plas ma half-life, a n d a n i m pr o ve d effic ac y/safet y rati o. Se veral s mall, 
n o n-ra n d o mize d, o bser vati o nal st u di es a n d meta-a nal yses (e. g. 1 0, 1 1, 1 2, 1 3, 1 4 ) ha ve s u g geste d 
a si milar safet y a n d efficac y pr ofile f or t he dire ct F Xa i n hi bit ors ri var o xa ba n a n d a pi xa ba n, a n d 
t he direct t hr o m bi n i n hi bit or da bigatra n, c o m pare d t o warfari n.  
I n a s u b-a nal ysis of t he lar ge, ra n d o mize d R O C K E T A F st u d y, a relati vel y s mall gr o u p of patie nts 
u n der g oi n g  cat heter  a blati o n  or  car di o versi o n  ha d  si milar  o ut c o mes  w he n  recei vi n g  eit her  
ri var o xa ba n or warfari n (1 6 ). T he use of ri var o xa ba n was i n vesti gate d i n patie nts u n der g oi n g 
cat heter a blati o n f or n o n- val v ular  A F i n t he V E N T U R E A F st u d y, w hic h s h o we d si milar safet y 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 4 of 1 0 9 
 
o utc o mes wit h u ni nterr u pte d oral ri var o xa ba n a n d u ni nterr u pte d st a n dar d V K A t hera p y. T he 
i nci de nce  of  Maj or  Blee di n g  e ve nts  was  ver y l o w  i n  b ot h  treat me nt  gr o u ps,  a n d  re mai ne d  
c o nsiste nt t hr o u g h o ut t he st u d y peri o d (3 ). 
T heref ore, t here e xists a nee d f or a safer, m ore ef fecti ve, a n d easil y ma na gea ble oral a ntic oa g ula nt 
( O A C) a ge nt f or t he pre ve nti o n of ac ute str o ke i n s u bjects wit h A F w h o are sc he d ule d f or cat heter 
a blati o n. It is e x pecte d t hat e d o xa ba n will pr o vi de  c o m para ble efficac y t o warfari n, b ut wit h a 
pre dicta ble a n d faster a ntit hr o m b otic res p o ns e a n d wit h n o nee d f or la b orat or y m o nit ori n g. 
E d o xa ba n is a selecti ve F Xa i n hi bit or wit h ra pi d o nset of acti o n a n d pre dicta ble a n d e xcelle nt 
a ntit hr o m b otic pr o perties. I n m o re t ha n 3 5, 0 0 0 s u bjects treate d t o date, e d o xa ba n a p pears t o be 
well t olerate d u p t o a d ose of 9 0 m g dail y, wit h  e x pecte d tra nsie nt a n d ma na gea ble blee di n g 
a d verse e ve nts ( A Es) a n d tra nsie nt a n d re versi b le li ver e nz y me a n d bilir u bi n ele vati o ns.   
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 5 of 1 0 9 
 
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S 
2. 1.  
St u d y O bjecti ves 
2. 1. 1.  
Pri m ar y O bjecti ves 
Pri m ar y Effic ac y O bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of t he c o m p osite of all-ca use deat h, str o ke (isc he mic, 
he m orr ha gic, or u n deter mi ne d) a n d Maj or Blee di n g (I nter nati o nal S ociet y o n T hr o m b osis a n d 
He m ostasis  [I S T H]  defi niti o n)  i n  t he  e d o xa ba n  gr o u p  a gai nst  t he  V K A  gr o u p  i n  s u bjects  
u n der g oi n g cat heter a blati o n of A F, i n t he peri o d fr o m t he e n d of t he cat heter a blati o n pr oce d ure 
t o Da y 9 0/ E n d- of- Treat me nt ( E O T). 
Pri m ar y S afet y O bjecti ve: 
T o c o m pare descri pti vel y t he i nci de nce of Ma j or Blee di n g (I S T H defi niti o n) i n t he e d o xa ba n 
gr o u p a gai nst t he V K A gr o u p i n t he peri o d fr o m t he date of first i nta ke of st u d y me dicati o n t o 
Da y 9 0/ E O T. 
2. 1. 2.  
Sec o n d ar y O bjecti ves 
I n s u bjects u n der g oi n g cat heter a blati o n of A F, t o c o m pare descri pti vel y t he e d o xa ba n gr o u p 
a gai nst t he V K A gr o u p, wit h re gar ds t o t he i nci de nce of t he f oll o wi n g effic ac y e n d p oi nts  as liste d 
bel o w: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g [I S T H 
defi niti o n] 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d), S E E, a n d C V m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic,  he m orr ha gic, or u n deter mi ne d) 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 6 of 1 0 9 
 
 
T o c o m pare descri pti vel y t he e d o xa ba n gr o u p a gai nst t he V K A gr o u p, wit h re gar ds t o t he i nci de nce 
of t he f oll o wi n g s afet y e n d p oi nts as liste d bel o w: 
 Maj or Blee di n g ( defi ne d b y T hr o m b ol ysis i n  M y ocar dial I nfarcti o n [ TI MI], Blee di n g 
Aca de mic Researc h C o ns orti u m [ B A R C] ( 2 or hi g her)) 
 Maj or a n d Cli nicall y Rele va nt N o n- Ma j or ( C R N M) Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I ntracra nial he m orr ha ge (I C H) 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d  b y TI MI, B A R C [ 2 or hi g her]) 
 Safet y para meters s uc h as A Es, seri o us a d verse e ve nts ( S A Es), la b orat or y para meters, 
electr ocar di o gra m ( E C G) a n d vital si g ns. 
2. 1. 3.  
Ot her O bjecti ves  
T o  c o m pare  descri pti vel y  t he  e d o xa ba n  gr o u p  a gai nst  t he  V K A  gr o u p,  wit h  re gar ds  t o  t he  
f oll o wi n g:  
 Rele va nt Healt h Ec o n o mics O utc o me Researc h ( H E O R) para meters: 
o  N u m ber of s u bjects wit h ca n cellati o n of t he a blati o n pr o ce d ure d ue t o i na de q uate 
a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses ( be y o n d a blati o n pr oce d ure), 
i ncl u di n g b ut n ot li mite d t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
( Re mar k:   H os pital a d missi o ns d ue t o C V ca uses i ncl u de, b ut are n ot li mite d t o 
E mer ge nc y De part me nt ( E D), I nte nsi ve Care U nit (I C U), C V war d.) 
o  Mea n le n gt h of sta y ass ociate d wit h t he differe nt t y pe of h os pital a d missi o ns, s uc h 
as E D, I C U a n d C V war ds 
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are C V e ve nt relate d o utsi de 
sc he d ule d visits as defi ne d b y st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns as defi ne d b y diff usi o n wei g hte d ma g netic res o na nce i ma gi n g 
( D W- M RI) p ost a blati o n pr oce d ure (at preselecte d ce nters) 
 Car diac mar kers. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 7 of 1 0 9 
 
3.  
S T U D Y D E SI G N 
3. 1.  
O ver all Pl a n 
T his  is  a  m ulti nati o nal,  pr os pecti ve,  ra n d o m ize d,  o pe n-la bel,  bli n de d  e n d p oi nt  e val uati o n  
( P R O B E) parallel gr o u p p hase 3 b st u d y c o m pari n g e d o xa ba n vs. V K A i n s u bjects u n der g oi n g 
cat heter a blati o n of n o n- val v ular A F. I n all s u bjec ts ke y de m o gra p hic a n d ris k c haracteristics of 
b ot h str o ke a n d blee di n g (f or e xa m ple, C H A 2D S 2- V A Sc sc ore, H A S- B L E D, t y pe of A F, prese nce 
of c or o nar y arter y disease ( C A D), heart fail ure ( H F), dia betes mellit us ( D M), a n d h y perte nsi o n) 
will be c ollecte d.  
It is pla n ne d t o e nr oll a p pr o x. 5 6 0 s u bjects at 7 5 st u d y sites l ocate d i n Ca na da, E ur o pe ( Bel gi u m, 
Czec h Re p u blic, Fra nce, Ger ma n y, H u n gar y, Ital y,  Net herla n ds, P ola n d, S pai n, U nite d Ki n g d o m), 
K orea, a n d Tai wa n t o ac hie ve a p pr o x. 4 5 0 s u bjects u n der g oi n g t he cat heter a blati o n pr oce d ure 
a n d c o m pleti n g t he st u d y. E nr oll me nt is a ntici pate d t o occ ur o ver a peri o d of a p pr o xi matel y 1 6 
m o nt hs. 
S u bjects eli gi ble t o partici pate m ust pr o vi de wr itte n i nf or me d c o nse nt (I C) bef ore ra n d o mizati o n 
or a n y st u d y-s pecific pr oce d ures  are perf or me d. O nce t he i nf or me d c o nse nt f or m (I C F) has bee n 
si g ne d, eli gi ble s u bjects are ra n d o mize d wit h o ut dela y t o o ne of t he t w o st u d y ar ms ( 2: 1 e d o xa ba n 
vs. V K A)  
E nr oll me nt of s u bjects will occ ur bet wee n 2 1 t o 2 8 da ys bef ore t he car diac a blati o n pr oce d ure. 
T he baseli ne visit ma y be s plit i nt o t w o ste ps as  per l ocal re q uire me nts.  I n t he pre-a blati o n 
treat me nt peri o d, a n o pti o nal visit ma y occ ur f or th ose patie nts w h o d o n ot ha ve t he o pti o n of I N R 
meas ure me nt i n a n a m b ulat or y setti n g.   
S u bjects will be re q uire d t o ha ve  c o m plete d at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n wit h 
st u d y treat me nt (e d o xa ba n or V K A) pri or t o t he cat heter a blati o n visit / peri pr oce d ural visit ( Da y 
0). S u bjects ra n d o mize d t o V K A m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last 1 0 da ys pri or t o 
t he cat heter a blati o n visit / peri pr oce d ural visit ( Da y 0). T his will nee d t o be d oc u me nte d b y 
fre q ue nt I N R meas ure me nts, at least o nce per wee k i n t he pre-a blati o n peri o d. O n t he da y of, or 
t he da y pri or t o, t he sc he d ule d a blati o n pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0-
3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 t he pr oce d ure ma y be perf or me d at t he 
I n vesti gat or’s discreti o n. Ot her wise, t he s u bject is n ot eli gi ble f or perf or mi n g t he cat heter a blati o n 
(t he s u bject will be s witc he d fr o m st u d y me dicatio n t o sta n dar d of care a n d will e nter t he 3 0- da y 
f oll o w- u p peri o d).  
Tra nses o p ha geal ec h ocar di o gra m ( T E E) or alter nati vel y i ntra-car diac ec h ocar di o gra m will be 
perf or me d bef ore cat heter a blati o n d uri n g t he h os pital sta y relate d t o t he pr oce d ure or t he da y 
bef ore t o i de ntif y p ote ntial cl ots. If T E E or t h e i ntra-car diac ec h ocar di o gra m is p ositi ve, i.e., 
s h o ws cl ots, t he a blati o n pr oce d ure will be ca ncele d a n d t he s u bject will be s witc he d fr o m st u d y 
me dicati o n t o sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d.  
T he ra n d o mize d treat me nt re gi me ns are c o nti n ue d f or 9 0 da ys, w he n t he sc he d ule d E O T is 
reac he d. I n s u bjects ra n d o mize d t o V K A, w he n after a blati o n, t he s u bject s’ a ntic oa g ulati o n is 
m ore c o nsta nt, t he fre q ue nc y of I N R meas ure me nts  ma y be l o wer t ha n i n t he pre-a blati o n peri o d. 
H o we ver, i n t he p ost-a blati o n pe ri o d, at least m o nt hl y I N R c o ntr ols are re q uire d. S u bject cli nical 
visits are pla n ne d at 3 0, a n d 9 0 da ys after ca r diac a blati o n.  A tele p h o ne assess me nt ( pers o nal 
visit as a n alter nati ve o pti o n) will be ma de at Da y 6 0. All ra n d o mize d s u bjects w h o are o n st u d y 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 8 of 1 0 9 
 
me dicati o n (st u d y e d o xa ba n or V K A) at 9 0 da ys, will ha ve a p ost-treat me nt c o ntact at 2 5- 3 5 da ys 
after t he E O T visit t o c ollect data o n c o nc o mita nt me dicati o ns, S A Es, a n d ot her safet y e ve nts of 
i nterest.  T he  o verall  d urati o n  of  s u bject  partici pati o n  fr o m  scree ni n g  t hr o u g h  f oll o w- u p  is  
t heref ore a p pr o x. 4 ½- 5 m o nt hs. 
A sc he matic prese ntati o n of t h e st u d y desi g n is pr o vi de d i n Fi g ure 3. 1.  
At Da y 9 0, t he s u bject will eit her disc o nti n ue t he treat me nt c o m pletel y or will be tra nsiti o ne d t o 
a n a vaila ble mar kete d O A C of t he I n vesti gat or’s c h oice. T he I n vesti gat or will f oll o w t he tra nsiti o n 
strate g y i n t he a p pr o ve d pr o d uct la bel.  
All i nf or mati o n m ust be ca pt ure d i n t he electr o nic case re p ort f or m (e C R F) a n d st u d y assess me nts 
are  perf or me d  acc or di n g  t o  t he  vi sit  sc he d ule  pr o vi de d  u n der  Secti o n1 6. 9 .  S u bjects  w h o  
pre mat urel y disc o nti n ue st u d y O A C ar e re q ueste d t o c o nti n ue cli nic al f oll o w- u p wit h st u d y visits 
acc or di n g t o t his sc he d ule. 
T he  st u d y  or ga nizati o n,  i ncl u di n g  t he  Cli nical  E ve nts  C o m m ittee  ( C E C),  Data  a n d  Safet y  
M o nit ori n g B oar d ( D S M B), E xec uti ve C o m mitt ee a n d Steeri n g C o m mittee are descri be d i n 
a p pe n di x Secti o n  1 6. 1. A n i n de pe n de nt D S M B re vie ws perti ne nt st u d y data t o pr otect t he safet y 
of t he s u bjects partici pati n g i n t he st u d y. 
 
Fi g ure 3. 1 St u d y Desi g n 
 
N ote: F or patie nts t o u n der g o a blati o n, I N R wa s t o be bet wee n 2. 0 t o 3. 0. If I N R was ≥1. 5 a n d 
< 2. 0 or > 3. 0 a n d ≤3. 5, a blati o n c o ul d be perf or me d at  t he I n vesti gat or’s discreti o n o nl y 
3. 2.  
Disc ussi o n of St u d y Desi g n 
T his st u d y is desi g ne d t o e val uate descri pti vel y t he safet y a n d t o e x pl ore t he efficac y of a n 
e d o xa ba n- base d a ntit hr o m b otic re gi me n vers us a V K A- base d a ntit hr o m b otic re gi me n i n s u bjects 
u n der g oi n g cat heter a blati o n of n o n - val v ular A F. A parallel gro u p desi g n wit h V K A ser vi n g as 
t he c o ntr ol ar m has bee n selecte d t o pr o vi de c o m parati ve data. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 3 9 of 1 0 9 
 
T he d urati o n of a ntic oa g ula nt treat me nt pri or t o cat heter a blati o n of  2 1 ( u p t o + 7) da ys is i n 
acc or da nce wit h t he E ur o pea n Heart R h yt h m Ass ociati o n ( E H R A) p ositi o n pa per ( 1 7 ), w hic h 
states ‘ All patie nts u n der g oi n g A F a blati o n w h o prese nt i n A F f or t he pr oce d ure s h o ul d be 
a ntic oa g ulate d f or at least 3 wee ks pri or t o A F a bla ti o n. If t he y ha ve n ot bee n a ntic oa g ulate d pri or 
t o  a blati o n,  a  T E E  s h o ul d  be  perf or me d.   I n  a d diti o n  t o  a d heri n g  t o  t hese  well-esta blis he d  
a ntic oa g ulati o n g ui deli nes t hat  a p pl y t o car di o versi o n, t he 2 0 1 2 H R S/ E H R A/ E C A S c o nse ns us 
d oc u me nt rec o m me n ds t hat all patie nts bei n g a ntic oa g ulate d d uri n g A F a bla ti o n wit h he pari n t o 
ac hie ve a n acti vate d cl otti n g ti me ( A C T) of at least 3 0 0 s. T his writi n g gr o u p f ull y s u p p orts t hese 
pri or mi ni m u m rec o m me n dati o ns f or a ntic oa g ula ti o n.’ Li ke wise, t he re q uire me nt f or patie nts 
treate d wit h a V K A or a N O A C t o have at least 3 wee ks of effec ti ve sta ble I N R at t hera pe utic 
le vels ( bet wee n 2 a n d 3 f or V K A) is als o i n-li ne wit h t hese rec o m me n dati o ns. T he treat me nt 
d urati o n after t he a blati o n pr oce d ure is i n-li ne wit h t he rece nt E S C g ui deli nes t hat rec o m me n d 
t hat a ntic oa g ulati o n s h o ul d be mai ntai ne d f or at least 8 wee ks after a blati o n f or all patie nts (2 ). 
T his st u d y re q uires T E E or alter n ati vel y i ntracar diac ec h ocar di o gra m  i n all patie nts t o e ns ure 
a p pr o priate a ntic oa g ulati o n i n t he 3 wee ks bef ore t he i nter ve nti o n i n b ot h ar ms. 
T he  e n d p oi nts  selecte d  are  rele va nt  f or  t he  st u d y.  Blee di n g  is  a  ce ntra l  safet y  o utc o me  i n  
car di o vasc ular cli nical trials, es peciall y f or a nti t hr o m b otic strate gies a n d i n vasi ve pr oce d ures (1 8, 
1 9, 2 0 ).  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 0 of 1 0 9 
 
4.  
S T U D Y P O P U L A TI O N 
4. 1.  
E nr oll me nt 
I n vesti gat ors will mai ntai n a c o nfi de ntial pre-scree ni n g l o g of all p ote ntial st u d y ca n di dates t hat 
i ncl u des li mite d i nf or mati o n of t he s u bjects (a ge, se x), date a n d o utc o me of scree ni n g pr ocess 
(e. g., e nr oll i n t he st u d y, reaso n f or n ot partici pati n g). 
I n vesti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt L o g of all s u bjects e nr olle d i n t he st u d y 
i n dicati n g t heir assi g ne d st u d y n u m ber. 
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n (I D) c o de list.  T his c o nfi de ntial 
list of na mes of all s u bjects all ocate d t o st u d y n u m bers o n e nr olli n g i n t he st u d y, all o ws t he 
I n vesti gat or t o re veal t he i de ntit y of a n y s u bject w he n necessar y. 
A s u bject is c o nsi dere d t o be e nr olle d after t he I C F has bee n si g ne d. A u ni q ue st u d y I D n u m ber 
is  pr o vi de d  t hr o u g h  t he  i nteracti ve  we b/ v oice  res p o nse  s yste m  (I X R S)  t o get her  wit h  t he  
ra n d o mize d treat me nt assi g n me nt. 
4. 1. 1.  
I ncl usi o n Criteri a 
S u bjects m ust satisf y all of t he f oll o wi n g cr iteria t o be i ncl u de d i n t he st u d y: 
1.  Male or fe male at least 1 8 years of a ge wit h d oc u me nte d hist or y of par o x ys mal (lasti n g 
≤7 da ys), persiste nt (lasti n g > 7 da ys b ut ≤1 2 m o nt hs) or l o n g-sta n di n g [l o n g-lasti n g] 
persiste nt ( > 1 2 m o nt hs) n o n- val v ular A F. D urati o n of A F ca n be c o nfir me d b y a n y 
electrical traci n g or a rec o r di n g i n t he s u bject’s me dical rec or ds (e. g., me dical c hart, 
h os pital disc har ge s u m mar y). 
2.  S u bject is eli gi ble a n d is sc he d ule d f or eit h er ra di ofre q ue nc y ( R F) or cr y o ball o o n cat heter 
a blati o n ( b ot h first a n d re peate d pr oce d ure i ncl u de d).  
3.  Si g ne d I C F. 
4. 1. 2.  
E xcl usi o n Criteri a 
S u bjects w h o meet a n y of t he f oll o wi n g criteria  will be dis q ualifie d fr o m e nteri n g t he st u d y: 
1.  A F c o nsi dere d t o be of a tra nsie nt or re ve rsi ble nat ure (s uc h as i n m y ocar ditis, p ost-
s ur ger y, i o nic dist ur ba nces, t h yr ot o xic osis, p ne u m o nia, se vere a ne mia etc.). 
2.  S u bject p ost str o ke, or wit h a s yste mic t hr o m b oe m b olic e ve nt wit hi n t he past 6 m o nt hs 
pri or t o ra n d o mizati o n.  
3.  S u bject has a t hr o m b us i n t he left atrial a p pe n da ge ( L A A), left atri u m ( L A), left ve ntricle 
( L V), or a orta, or a n i ntracar dial mass. 
4.  S u bject ha d a m y ocar dial i nfarcti o n ( MI) wit hi n  t he 2 m o nt hs pri or t o ra n d o mizati o n or 
c or o nar y arter y b y pass graft ( C A B G) s u r ger y wit hi n 3 m o nt hs pri or t o t he 
ra n d o mizati o n. 
5.  S u bject has si g ns of blee di n g, hist or y of cli nicall y-rele va nt blee di n g acc or di n g t o I S T H, 
or c o n diti o ns ass ociate d wit h hi g h ris k of bl ee di n g s uc h as past hi st or y of i ntracra nial 
(s p o nta ne o us or tra u matic), or s p o nta ne o us i ntra oc ular, s pi nal, retro perit o neal, or i ntra-

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 1 of 1 0 9 
 
artic ular blee di n g; o vert gastr o i ntesti nal ( GI) blee di n g or acti ve ulcer wit hi n t he pre vi o us 
year; rece nt se vere tra u ma, maj or s ur ger y, or dee p or ga n bi o ps y; acti ve i nfecti ve 
e n d ocar ditis; u nc o ntr olle d h y perte nsi o n ( bl o o d press ure [ B P] a b o ve 1 7 0/ 1 0 0 m m H g); or 
he m orr ha gic dis or der i ncl u di n g k n o w n or s us p ecte d here ditar y or ac q uire d blee di n g or 
c oa g ulati o n dis or der i n t he last 1 2 m o nt hs pri or t o ra n d o mizati o n.  
6.  S u bjects wit h mec ha nical heart val ves, s u bjects  wit h m o derate t o se vere mitral ste n osis 
a n d s u bjects w h o ha ve ne w i m pla ntati o n ( wit hi n 3 m o nt hs pri or t o ra n d o mizati o n) of a 
bi o pr ost hetic heart val ve, wit h or wit h o ut A F.  
7.  S u bjects wit h a hist or y of L A A occl usi o n/ e xcl usi o n (eit her b y s ur ger y or b y a 
pr oce d ure). 
8.  S u bjects wit h a n y c o ntrai n dicati o n f or e d o xa ba n, V K A, l o w m olec ular wei g ht he pari n 
( L M W H), he pari n t hera p y i ncl u di n g k n o w n aller gies, h y perse nsiti vit y, or i nt olera nce t o 
a n y c o m p o ne nt of t hese dr u gs or its e xci pie nts. 
9.  S u bjects recei vi n g d ual a nti platelet t h era p y ( D A P T, i.e., as piri n a n d P 2 Y 1 2 a nta g o nist) or 
pla n ne d t o recei ve D A P T d uri n g t he st u d y 
1 0.  U nfracti o nate d he pari n ( U F H), l o w m olec ula r wei g ht he pari ns ( L M W H; e n o xa pari n, 
dalte pari n, etc.), he pari n deri vati ves (f o n da pari n u x, etc.), a n d oral a ntic oa g ula nts 
( warfari n, da bi gatra n ete xilate, ri var o xa ba n, a pi xa ba n etc.) ca n n ot be use d c o nc o mita ntl y 
t o st u d y me dicati o n. A n y bri d gi n g wit h L M W H ar o u n d t he C A pr oce d ure is pr o hi bite d. 
D uri n g t he C A pr oce d ure, U F H will be use d acc or di n g t o sta n dar d of care t o ac hie ve 
A C T of 3 0 0 t o 4 0 0 sec. S u bjects w h o re q uire  c hr o nic use of me dici nes affecti n g 
he m ostasis s uc h as hi g her d oses of as piri n (acet ylsalic ylic aci d [ A S A]) ( A S A u p t o 1 0 0 
m g per da y all o we d) or c hr o ni c oral or pare nteral i nta ke of n o n-as piri n n o n-ster oi dal 
a nti-i nfla m mat or y dr u gs ( N S AI D) o n ≥4 da ys/ wee k ( use of N S AI Ds via ot her r o utes is 
n ot restricte d) 
1 1.  S u bjects wit h acti ve li ver diseas e or persiste nt (c o nfir me d b y re peat assess me nts at least 
a wee k a part) ele vati o n of li ver e nz y mes/ bilir u bi n: 
―  Ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase ( A S T) ≥2 ti mes t he u p per li mit 
of n or mal ( U L N) 
―  T otal bilir u bi n ( T B L) ≥1. 5 ti mes t he U L N (s u bjects w h ose ele vate d T B L is d ue t o 
k n o w n Gil bert’s s y n dr o me ma y be i ncl u de d i n t he st u d y) 
―  He patic disease ass ociate d wit h c oa g ul o pat h y a n d cli nicall y rele va nt blee di n g ris k.  
1 2.  S u bjects wit h ki d ne y fail ure (calc ulate d cr eati ni ne cleara nce [ Cr C L] < 1 5 m L/ mi n). 
1 3.  S u bjects wit h he m o gl o bi n < 1 0 g/ d L or platelet c o u nt < 1 0 0, 0 0 0 cells/ µ L or w hite bl o o d 
cell ( W B C) c o u nt < 3 0 0 0 cells/ µ L. 
1 4.  S u bjects wit h pre- pla n ne d i n vasi ve dia g n osti c or t hera pe utic pr oce d ures/i nter ve nti o ns 
( ot her t ha n e n d osc o p y) d uri n g t he st u d y peri o d i n w hic h blee di n g is a ntici pate d. 
1 5.  Partici pati o n i n a n y ot her i nter ve nti o nal trial (s u bjects w h o recei ve d a n y i n vesti gati o nal 
dr u g or de vice wit hi n 3 0 da ys pri or t o ra n d o mizati o n, or pla n t o recei ve s uc h 
i n vesti gati o nal t hera p y d uri n g t he st u d y peri o d). 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 2 of 1 0 9 
 
1 6.  Pre vi o us ra n d o mizati o n i n t his st u d y. 
1 7.  Fe male s u bjects of c hil d beari n g p ote ntial w it h o ut usi n g hi g hl y effecti ve c o ntrace pti o n 
(fe male of c hil d beari n g p ote ntial is defi ne d as o ne w h o ha s n ot bee n p ost me n o pa usal f or 
at least o ne year, or has n ot bee n s ur gicall y  sterilise d, or has n ot ha d a h ysterect o m y at 
least t hree m o nt hs pri or t o t he start of t his st u d y). Fe males ta ki n g oral c o ntrace pti ves 
s h o ul d ha ve bee n o n t hera p y f or at least t hree m o nt hs. A de q uate  c o ntrace pti ves i ncl u de: 
C o m bi ne d (estr o ge n a n d pr o ge st o ge n c o ntai ni n g) oral, i ntra va gi nal or tra ns der mal 
h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n; pr o gest o ge n- o nl y oral, 
i njecta ble or i m pla nta ble h or m o nal c o ntrace pti o n ass ociate d wit h in hi biti o n of o v ulati o n; 
i ntra uteri ne de vice (I U D); i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal 
occl usi o n; vasect o mize d part ner; se x ual a bsti ne nce. 
1 8.  Pre g na nt or breast- fee di n g s u bjects. 
1 9.  S u bjects wit h t he f oll o wi n g dia g n oses or sit uati o ns: 
- 
Acti ve ca ncer u n der g oi n g c he m ot hera p y, ra diati o n or maj or s ur ger y wit hi n t he ne xt 5 
m o nt hs 
- 
Si g nifica nt acti ve/ u nc o ntr olle d c o nc urre nt me dical ill ness 
- 
Life e x pecta nc y < 6 m o nt hs. 
2 0.  S u bjects w h o are u nli kel y t o c o m pl y wit h t he pr ot oc ol (e. g., u nc o o perati ve attit u de, 
i na bilit y t o ret ur n f or s u bse q ue nt visits, an d/ or ot her wise c o nsi dere d b y t he I n vesti gat or 
t o be u nli kel y t o c o m plete t he st u d y). 
2 1.  S u bjects wit h a k n o w n dr u g or alc o h ol de pe n de nce wit hi n t he past 1 2 m o nt hs pri or t o 
ra n d o mizati o n as j u d ge d b y t he I n vesti gat or. 
2 2.  S u bjects wit h a n y c o n diti o n t hat, i n t he o pi ni o n of t he I n vesti gat or, w o ul d place t he 
s u bject at i ncrease d ris k of har m if he/s he partici pate d i n t he st u d y. 
2 3.  Pla n ne d pr oce d ure usi n g laser cat heter a bla ti o n or ot her f or ms of cat heter a blati o n 
differe nt fr o m R F or cr y o ball o o n (i.e. hi g h i nte nsit y f oc use d ultras o u n d [ HI F U], 
micr o wa ves, h ot ball o o n, etc). 
4. 2.  
Scree ni n g F ail ures 
S u bjects are scree ne d base d o n t he i nf or mati o n a v aila ble fr o m t he sta n dar d care. F or s u bjects 
f ulfilli n g t he eli gi bilit y criteria, si g nat ure of t he I C F m ust ta ke place bef ore a n y st u d y-s pecific 
scree ni n g pr oce d ures occ ur. A s u bject w h o with dra ws I C bef ore ra n d o mizati o n or w h o fails t he 
i ncl usi o n/e xcl usi o n criteria bef ore ra n d o mizati o n is defi ne d as a scree ni n g fail ure. N o f urt her 
cli nical f oll o w- u p is perf or me d f or t hese s u bjects. 
If s u bjects fail t he scree ni n g pr oced ure, i n vesti gat ors ca n disc uss w it h t he me dical m o nit or if t he y 
feel a s u bject mi g ht be s uita ble f or rescree ni n g.  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 3 of 1 0 9 
 
5.  
S T U D Y T R E A T M E N T S 
5. 1.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nt Re gi me ns 
5. 1. 1.  
Tre at me nt Gr o u ps  
 E d o xa ba n 6 0 m g o nce- dail y or 3 0 m g o nce- da il y i n selecte d s u bjects (see Secti o n 
5. 2. 1. 2 ). 
 Oral V K A, as pre- defi ne d pe r c o u ntr y, wit h o nce- dail y d osi n g f or tar get I N R bet wee n 
2. 0- 3. 0, i ncl usi ve. 
 
T he V K A pr e- defi ne d f or t he vari o us  c o u ntries are s h o w n bel o w: 
C o u ntr y 
Pre- defi ne d V K A 
Bel gi u m 
P he n pr oc o u m o n & Warfari n 
Ca na da
 Warfari n
 
Czec h Re p u blic 
Warfari n 
Fra nce
 Fl ui n di o ne
 
( Pre visca n ®)
Ger ma n y
 P he n pr oc o u m o n
 
H u n gar y
 Warfari n
 
Ital y
 Warfari n
 
K orea
 Warfari n
 
Net herla n ds
 P he n pr oc o u m o n
 
P ola n d
 Warfari n
 
S pai n
 Ace n oc o u mar ol
 
( Si ntr o m ®)
Tai wa n
 Warfari n
 
U nite d Ki n g d o m 
Warfari n 
 
5. 1. 2.  
Met h o d of Tre at me nt All oc ati o n 
After t he I C has bee n si g ne d a n d eli gi bilit y c o nfir me d, t he I n vesti gat or c o ntacts t he I X R S t o 
re gister a ne w s u bject a n d assig n a n i n di vi d ual st u d y I D n u m ber. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 4 of 1 0 9 
 
T he I n vesti gat or s h o ul d be pre pare d t o pr o vi de  s u bject i nf or mati o n, i ncl u di n g, b ut n ot li mite d t o: 
date of I C, s u bject’s ye ar of birt h, a n d ge n der. 
T he n t he I n vesti gat or c o ntacts I X R S t o ra n d o mize s u bject i nt o t he st u d y. T he i n vesti gat or s h o ul d 
be pre pare d t o c o nfir m t he s u bj ect’s eli gi bilit y criteria a n d i nf or mati o n a b o ut b o d y wei g ht, a n d 
Cr C L usi n g C oc kcr oft- Ga ult (i n t h e c o urse of t he st u d y, ot her f or m ula will als o be use d, e. g., 
C K D- E PI E q uati o n; see Secti o n 1 6. 6 ). Als o t he i n vesti gat or will be as ke d t o pr o vi de i nf or mati o n 
w het her t he s u bject is ta ki n g c o nc o mita nt P- g p i n hi bit ors re q uiri n g e d o xa ba n d ose re d ucti o n ( or 
ot her d ose re d ucti o n rele va nt me di cati o n acc or di n g t o l ocal la bell i n g or I B, as a p plica ble). 
S u bjects will be assi g ne d ra n d o ml y via t he a b o ve me nti o ne d I X R S s uc h t hat t he st u d y has a 2: 1 
rati o of s u bjects i n t he e d o xa ba n: V K A treat me nt ar ms. 
T he s pecificati o ns f or ge nerati o n of t he ra n d o m izati o n sc he d ule will be pre pare d b y t he st u d y 
bi ostatisticia n a n d t he I X R S ve n d or. A n i n de pe n de nt  bi ostatisticia n, n ot ot her wise part of t he 
st u d y tea m, will ge nerate t he ra n d o mizati o n sc he d ule.  F or t his st u d y, t he ra n d o mizati o n sc he d ule 
refers  t o  a  list  t hat  i ncl u des  at  least  t he  s u bject  I D,  ra n d o mizat i o n  bl oc k  n u m ber,  a n d  
ra n d o mizati o n treat me nt.  
5. 1. 3.  
Bli n di n g 
T his is a n o pe n-la bel st u d y w it h bli n de d e n d p oi nt e val uati o n. 
 
5. 2.  
St u d y Dr u gs 
5. 2. 1.  
E d o x a b a n 
All dis pe nsati o ns m ust ta ke place t hr o u g h t he I X R S, w hic h will pr o vi de t he a p pr o priate dr u g 
s u p pl y kit n u m ber. 
5. 2. 1. 1.  
Descri pti o n 
E d o xa ba n  t os ylate  ( D U- 1 7 6 b,  tra de  na mes  Li xi a na ®,  Sa va ysa ®),  re ferre d  t hr o u g h o ut  t his  
pr ot oc ol b y t he ter m “e d o xa ba n” f or si m plicit y. Please refer t o Secti o n 5. 3 . 
I m p orta ntl y, it is ma n dat or y i n t his st u d y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of 
e d o xa ba n is ta ke n e ver y da y i n t he e ve ni n g. Patie nts will be i nstr ucte d t o s wall o w t he ta blet, 
prefera bl y wit h water. E d o xa ba n ca n  be ta ke n wit h or wit h o ut f o o d (7 ). 
If a d ose of e d o xa ba n is misse d, t he d ose m ust be ta ke n as s o o n as p ossi ble as l o n g as o n t he sa me 
da y. T he d ose of e d o xa ba n m ust n ot be d o u ble d t o ma ke u p f or a misse d d ose. 
5. 2. 1. 2.  
D ose 
T he d ose of e d o xa ba n is 6 0 m g o nce- dail y b ut will be re d uce d t o 3 0 m g o nce- dail y, if t he s u bject 
has o ne of t he f oll o wi n g:   
- 
M o derate t o se vere re nal i m pair me nt ( Cr C L ≥1 5 t o ≤5 0 m L/ mi n as calc ulate d 
usi n g t he C oc kcr oft- Ga ult f or m ula 
- 
L o w b o d y wei g ht ( ≤6 0 k g) 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 7 of 1 0 9 
 
 
5. 2. 2.  
Vit a mi n K A nt a g o nist  
All V K A m ust be dis pe nse d via t he I X R S t hat  will pr o vi de t he a p pr o priate dr u g s u p pl y kit 
n u m ber.  
5. 2. 2. 1.  
D ose 
T he I n vesti gat or m o nit ors t he I N R a n d a dj usts t he V K A d ose t o mai ntai n t he I N R wit hi n tar get. 
It is t he I n vesti gat or’s res p o nsi bilit y t o c ollect I N R assess me nts a n d rec or d t hese t hr o u g h o ut t he 
st u d y.  A preferre d V K A is selecte d f or eac h partici pati n g c o u ntr y (f or m ore  details, please refer 
t o Secti o n 5. 1. 1 ) w hic h is pr o vi de d as st u d y me dicati o n: 
―  W arf ari n  
L oa di n g d ose fr o m 2- 5 m g o nce- dail y f or 2- 4 da ys f oll o we d b y a mai nte na nce d ose of 
2- 1 0 m g o nce- dail y a dj uste d b y I N R val ues  t o mai ntai n tar get I N R bet wee n 2. 0- 3. 0 
i ncl usi ve. 
―  P he n pr oc o u m o n  
Wee kl y d ose calc ulati o n of u p t o 9 m g o n Da y 1, 6 m g o n Da y 2 a n d mai nte na nce d oses 
bet wee n 1. 5- 6. 0 m g o nce- dail y t hereafter, a dj ust e d b y I N R val ues t o mai ntai n tar get I N R 
bet wee n 2. 0- 3. 0 i ncl usi ve. 
―  Fl ui n di o ne  
T he i nitial dail y d ose of 2 0 m g is a dj uste d b y I N R val ues t o mai ntai n tar get I N R bet wee n 
2. 0- 3. 0 i ncl usi ve. I n s u bjects at partic ular ris k of blee di n g ( wei g ht < 5 0 k g, el derl y, 
he patic i m pair me nt), t he i nitial d ose is us uall y l o wer. N o l oa di n g d ose s h o ul d be use d. 
T he d ose a dj ust me nt is perf or me d i n acc or da nce t o t he pac ka ge i nsert a n d us uall y b y 
i ncre me nts of 5 m g ( 1/ 4 ta blet). 
―  Ace n oc o u m ar ol  
T he us ual starti n g d ose i n a n or mal wei g ht pers o n is bet wee n 2- 4 m g/ da y wit h o ut 
a d mi nistrati o n of a l oa di n g d ose, if t he I N R va l ue bef ore t he start of treat me nt is wit hi n 
t he n or mal ra n ge. Treat me nt ma y als o be i nitiate d wit h a l oa di n g d ose re gi me n, us uall y 
6 m g o n t he first da y f oll o we d b y 4 m g o n t he sec o n d da y. T he mai nte na nce d ose 
ge nerall y lies bet wee n 1- 8 m g o nce- dail y, a dj uste d b y I N R val ues t o mai ntai n tar get I N R 
bet wee n 2. 0- 3. 0 i ncl usi ve. 
T he d osi n g of t he af ore me nti o ne d V K As m ust be i n di vi d ualize d. T he mai nte na nce d ose varies 
fr o m s u bject t o s u bject a n d its a p pr o priate ness m ust be c hec ke d i n di vi d uall y o n basis of I N R 
val ues. 
S u bjects will ta ke t he V K A acc or di n g t o  t he directi o n of t he I n vesti gat or. 
T he I n vesti gat or or desi g nee is res p o nsi ble f o r dis pe nsi n g t he V K A a nta g o nist a n d m ust e ns ure 
t hat dr u g s u p plie d b y S p o ns or is use d i n acc or da nce wit h t he pr ot oc ol a n d t he V K A pac ka ge i nsert.  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 8 of 1 0 9 
 
5. 2. 2. 2.  
Tr a nsiti o ni n g t o St u d y Vit a mi n K A nt a g o nist at R a n d o miz ati o n 
S u bjects are tra nsiti o ne d t o a n a vaila ble st u d y V K A (c o u ntr y s pecific as pr o vi de d b y I X R S, see 
Secti o n 5. 1. 1 . f or details). T he I n vesti gat or will f oll ow t he tra nsiti o n strate g y i n t he a p pr o ve d 
pr o d uct la bel.  
F or  s u bjects  n ot  pre vi o usl y  o n  V K A,  c o m m o nl y  i nitial  d oses  of  V K A  are  hi g her  t ha n  t he  
mai nte na nce d oses w hic h will be use d after t he I N R is sta bilize d. F or t hese s u bjects bri d gi n g wit h 
pare nteral a ntic oa g ulati o n is per missi ble.  F or i nitiati o n of V K A t hera p y an d relate d bri d gi n g wit h 
pare nteral  a ntic oa g ulati o n,  f oll o w  l ocall y  esta blis he d  g ui deli nes  a n d  l ocal  a p pr o ve d  la bel  
( prescri bi n g i nf or mati o n) fro m t he V K A ma n ufact urer. 
F or s u bjects ra n d o mize d t o  V K A: If s u bject is o n: 
 V K A, c o nti n ue wit h st u d y V K A w he n I N R ≤2. 5. 
 N O A C, disc o nti n ue t he N O A C a n d start st u d y V K A at t he ti me of t he ne xt sc he d ule d 
N O A C d ose. 
F or s u bjects ra n d o mize d t o V K A w h o re q uire s witc hi n g fr o m a n ot her a ntic oa g ula nt (a n ot her V K A, 
ot her n o n- V K A O A C dr u gs or pare nt eral a ntic oa g ula nts), f oll o w t he g ui da nce f or s witc hi n g i n t he 
l ocall y a p pr o ve d la bels of t hese pr o d ucts. Ca pt ure t he date a n d ti mi n g of first st u d y d ose i n e C R F. 
5. 2. 2. 3.  
I nter n ati o n al N or m alize d R ati o M a n a ge me nt 
E ver y atte m pt will be ma de t o bri n g s u bjects i nt o  t he t hera pe utic tar get ra n ge (I N R 2. 0- 3. 0) as 
fast as p ossi ble a n d t o mai ntai n t he tar get I NR ra n ge c o nsiste ntl y. Cl ose atte nti o n t o t he I N R 
ma na ge me nt pla n a n d fre q ue nt m o nit ori n g of I N R val ues is str o n gl y r ec o m me n de d t o o pti mize 
t he  V K A  treat me nt  a n d  mai ntai n  t he  s u bject’s  I N R  val ues  bet wee n  2. 0- 3. 0  i ncl usi ve.   T he  
I n vesti gat or  will  e ns ure  t he  V K A  is  use d  acc or di n g  t o  t he  a p pr o ve d  la bel  ( prescri bi n g  
i nf or mati o n). 
Fre q ue nt I N R deter mi nati o ns u p o n i nitiati o n s h o ul d  be o btai ne d u ntil s u bject’s I N R is sta ble i n 
t he t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits will be pla n ne d f or ‘ de n o v o’ s u bjects 
o n V K A t o a dj ust t he d ose wit h t he g oal of reac h i n g I N R 2. 0- 3. 0 wit hi n 6- 8 da ys after e nr ol me nt. 
O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns a n d g ui deli nes pr o vi de d i n t he 
l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A ma n ufact urer. 
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last  1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. O n t he da y of, or t he da y pri or t o, t he sc he d ule d a blati o n 
pr oce d ure, s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is 
> 3. 0 a n d ≤3. 5 t he pr oce d ure ma y be perf or me d at t he I n vesti gat or’s discreti o n.  
After  a blati o n,  w he n  t he  s u bjects’  a ntic oa g ula ti o n  is  m ore  c o nsta nt,  t he  fre q ue nc y  of  I N R  
meas ure me nts ma y be l o wer t ha n i n t he pre-a bla ti o n peri o d. H o we ver, i n t he p ost-a blati o n peri o d, 
at least m o nt hl y I N R c o ntr ols are re q uire d. 
I N R val ues a n d V K A d ose are c ollecte d eit her d uri n g t he o n-site vi sits or b y l ocal la b orat or y 
deter mi nati o n. I N R val ues a n d V K A d oses c ollecte d  t hr o u g h t he ge neral practiti o ner or l ocal 
a ntic oa g ulati o n cli nic m ust als o be c o nsi dere d a n d c ollecte d b ut t his d oes n ot c o nstit ute a wai ver 
f or s u bjects’ pla n ne d I N R deter mi nati o n d uri n g o n-site visits. I n a n y case t he st u d y p h ysicia n is 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 4 9 of 1 0 9 
 
res p o nsi ble f or c hec ki n g t he I N R val ue, a da ptin g t he V K A d ose acc or di n gl y, a n d f or e nteri n g all 
t he data i nt o t he e C R F. 
5. 2. 2. 4.  
Tr a nsiti o n fr o m Vit a mi n K A nt a g o nist at E n d of Tre at me nt 
S u bjects  are  tra nsiti o ne d  t o  a n  a vaila ble  mar k ete d  O A C  of  t he  I n vesti gat or’s  c h oice.  T he  
I n vesti gat or  will  f oll o w  t he  tra nsiti o n  strate g y i n  t he  a p pr o ve d  pr o d uct  la bel.  S u bjects  w h o  
pre mat urel y disc o nti n ue st u d y O A C ar e re q ueste d t o c o nti n ue cli nic al f oll o w- u p wit h st u d y visits 
acc or di n g t o t his sc he d ule. 
 
5. 2. 3.  
I nterr u pti o ns a n d Disc o nti n u ati o ns of St u d y Tre at me nt 
T he i nte n de d d urati o n of t he t w o st u d y treat me nts after a blati o n is 9 0 da ys. S u bjects sta y o n t he 
assi g ne d re gi me n as m uc h as p ossi ble. 
Per ma ne nt  disc o nti n uati o n  of  t he  assi g ne d  re gi me n  is  ma n dat or y  if  t he  Cr C L  falls  bel o w  
1 5 m L/ mi n o n t w o c o nsec uti ve occasi o ns  or if s u bject is place d o n dial ysis. If t he I n vesti gat or 
d o u bts t he acc urac y of t he Cr C L val ue calc ulate d wit h t he C oc kcr oft- Ga ult f or m ula, he/s he ma y 
c o nsi der calc ulati n g Cr C L usi n g a 2 4- h o ur uri n e c ollecti o n, f or c o nfir mat or y p ur p oses. If a 
s u bject’s Cr C L, calc ulate d wit h eit her t he C oc kcr oft- Ga ult f or m ula or 2 4- h o ur uri ne c ollecti o n, 
rec o vers t o ≥1 5 m L/ mi n, t he s u bject s h o ul d res u me st u d y re gi me n i n li ne wit h t he a p plica ble 
la bels. 
F or s u bjects wit h a s us pecte d tra nsie nt decreas e i n Cr C L < 1 5 m L/ mi n it is rec o m me n de d t hat 
re peat testi n g of Cr C L occ ur after c orrecti ve acti o n is ta ke n or w he n t he me dical c o n diti o n t hat 
ca use d t he w orse ni n g re nal f u ncti o n  res ol ves. T he ti mi n g of t he re peat testi n g is at t he discreti o n 
of t he I n vesti gat or a n d will var y de pe n di n g o n t he nat ure of t he me dical c o n diti o n (e. g., 1- 2 wee ks 
f or uri nar y tract i nfecti o n or o ver di uresis vs. se veral wee ks t o m o nt hs f or gl o mer ul o ne p hritis). 
If ot her cli nical c o ntrai n dicati o ns f or a n y st u d y me dicati o n de vel o p (acc or di n g t o t he la bel of t he 
res pecti ve dr u g), t he st u d y me dicatio n m ust be disc o nti n ue d ( or d ose decrease d if a p plica ble). If 
t he  c o ntrai n dicati o n  res ol ves,  t he  res pecti ve  st u d y  me dicati o n  is  restarte d.  D uri n g  eac h  
i nterr u pti o n of a ntic oa g ula nt t hera p y, s u bjects are e val uate d t o deter mi ne w het her t he s u bject ca n 
safel y res u me t he st u d y dr u g. A p ost-ra n d o mizati o n c ha n ge i n healt h stat us  t hat res ults i n t he 
s u bject  meeti n g  o ne  or  m ore  of  t he  e xcl usi o n  criteria  s h o ul d  o nl y  lea d  t o  i nterr u pti o n  or  
disc o nti n uati o n  of  t he  assi g ne d  me dicati o ns  if  t he  c ha n ge  i n  healt h  stat us  i m plies  a  
c o ntrai n dicati o n acc or di n g t o t he dr u g la bels. 
St u d y  me dicati o ns  are  per ma ne ntl y  disc o nti n ue d  if  t he  s u bject  ref uses  c o nti n uati o n  of  a n y  
me dicati o n i n t he assi g ne d st u d y re gi me ns.  
All st u d y me dicati o n start a n d st o p  dates are ca pt ure d i n e C R F t o get her wit h t he reas o n f or 
i nterr u pti o n or disc o nti n uati o n. 
 
5. 3.  
L a beli n g a n d P ac k a gi n g 
T he I n vesti gat ors/st u d y c o or di nat ors m ust e ns ure  t hat t he a p pr o priate fiel ds o n t he la bel are 
c o m plete d, i ncl u di n g u ni q ue s u bject I D a n d i nitials. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 0 of 1 0 9 
 
T he I n vesti gat or pr o vi des t he s u bjects wit h s ufficie nt st u d y me dicati o ns t o last u ntil t he ne xt 
sc he d ule d dis pe nsi n g visit. 
E d o xa ba n is s u p plie d as 3 0 or 6 0 m g  fil m c oate d ta blets ( 3 0 m g or 1 5 m g as tra nsiti o n me dicati o n 
if a p plica ble) f or oral use a n d will be pr o vi de d t o all sites via I X R S. Materials are s u p plie d a n d 
la belle d wit h a si n gle pa nel m ultili n g ual b o o klet. 
V K A me dicati o n f or oral use a n d will be pr o vi de d t o all sites via I X R S. Materials are s u p plie d 
a n d la belle d wit h a si n gle pa nel m ultili n g ual b o o kl et. T he S p o ns or will pr o vi de a n oral preferre d 
V K A as pre-selecte d b y c o u ntr y, bei n g eit her: 
- 
W arf ari n  s u p plie d as c o m merciall y a vaila ble ta blets of 1 m g, a n d 2. 5 m g i n wallets wit h 
blisters. 
- 
P he n pr oc o u m o n  s u p plie d as c o m merciall y a vaila ble ta blets of 3 m g stre n gt h i n wallets wit h 
blisters. 
- 
Fl ui n di o ne  s u p plie d as c o m merciall y a vaila ble ta blets of 2 0 m g stre n gt h i n wallets wit h 
blisters. Fl ui n di o ne s u p pl y is e xcl usi ve t o Fra nce a n d will n ot be a vaila ble i n ot her 
partici pati n g c o u ntries. Fl ui n di o n e is o nl y la belle d i n Fre nc h. 
- 
Ace n oc o u m ar ol  s u p plie d as c o m merciall y a vaila ble ta blets of 4 m g stre n gt h i n wallets wit h 
blisters. 
 
5. 4.  
Pre p ar ati o n 
All i n vesti gati o nal pr o d ucts will be s u p plie d as ta blets t hat nee d n o f urt her pre parati o n at t he sites. 
 
5. 5.  
A d mi nistr ati o n 
E d o xa ba n will be a d mi nistere d i n acc or da nce wit h t he l ocal la bel or I B, a n d V K A will be 
a d mi nistere d i n acc or da nce wit h t he a p pr o ve d l ocal la bel. 
 
5. 6.  
St or a ge 
W he n a dr u g s hi p me nt is recei ve d, t he I n vesti gat or or desi g nee will d o t he f oll o wi n g wit hi n 
4 8 h o urs of recei pt: c hec k t he a m o u nt a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal 
la n g ua ge o n t he la bel, c hec k t he dr u g e x pirati o n date, a n d si g n t he Recei pt of S hi p me nt F or m 
pr o vi de d.  T he site will ac k n o wle d ge recei pt of t he s hi p me nt i n t he I X R S.  All i nstr ucti o ns o n t he 
Recei pt of S hi p me nt F or m will be f oll o we d, a n d t he f o r m will be fille d i n at t he site.  I n a d diti o n, 
t he I n vesti gat or or desi g nee will c o ntact t he site m o nit or as so o n as p ossi ble b ut wit hi n 4 8 h o urs, 
if t here is a pr o ble m wit h t he s hi p me nt. 
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n der t he rec o m me n de d 
st ora ge  c o n diti o ns  as  meas ure d  b y  a  mi nim u m/ ma xi m u m  t her m o meter.  Te m perat ure  
meas ure me nt will be rec or de d dail y o n a te m perat ure l o g, e xcl u di n g wee ke n ds a n d h oli da ys.  T he 
s p o ns or a n d site m o nit or m ust be c o ntacte d i n t he e ve nt of a te m perat ure e xc ursi o n o utsi de of t he 
rec o m me n de d st ora ge c o n diti o ns. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 1 of 1 0 9 
 
 
5. 7.  
Dr u g Acc o u nt a bilit y 
T he e C R F c o ntai ns a dr u g acc o u nta bilit y m o d ule f o r me dicati o ns s u p plie d b y t he s p o ns or.  T he 
I n vesti gat or or desi g nee e nters t he re q uire d i nf or mati o n i n t his m o d ule. 
At t he e n d of t he st u d y, or as di recte d, all me dicati o ns s u p plie d b y t he s p o ns or, i ncl u di n g u n use d, 
partiall y use d, or e m pt y c o ntai ners, will be ret ur n e d t o a desi g nee as i nstr ucte d b y Daiic hi Sa n k y o 
E ur o pe ( D S E) or destr o ye d at t he site.  I n vest i gati o nal Pr o d uct will be ret ur ne d o nl y after t he 
st u d y m o nit or has c o m plete d a fi nal in ve nt or y t o verif y t he q ua ntit y t o  be ret ur ne d.  T he ret ur n of 
all st u d y me dicati o ns m ust be d oc u me nte d a n d t he d oc u me ntati o n i ncl u de d i n t he s hi p me nt.  At 
t he e n d of t he st u d y, a fi nal st u d y me dicati o n rec o nciliati o n state me nt m ust be c o m plete d b y t he 
I n vesti gat or or desi g nee a n d pr o vi de d t o t he s p o ns or.  Dr u g s u p plies ma y be destr o ye d b y t he 
I n vesti gat or w he n a p pr o ve d i n writi n g b y D S E a n d D S E has recei ve d c o pies of t he site’s dr u g 
ha n dli n g a n d dis p ositi o n sta n dar d o perati n g pr oce d ures ( S O Ps).  
All i n ve nt or y f or ms m ust be ma de a vaila ble f or a u dits b y a s p o ns or a ut h or ize d re prese ntati ve or 
desi g nee a n d / or i ns pecti o ns b y re g u lat or y a ge nc y i ns pect ors.  T he I n vesti gat or is res p o nsi ble f or 
t he acc o u nta bilit y of all use d a n d u n use d me dicati o ns pr o vi de d  b y t he s p o ns or at t he site. 
 
5. 8.  
Met h o d of Assessi n g Re gi me n C o m pli a nce 
Eac h  s u bject  s h o ul d  d oc u me nt  misse d  d oses  i n  t he  s u bject  b o o klet.  T he  s u bject  s h o ul d  be  
i nstr ucte d b y t he I n vesti gat or t o bri n g t his b o o klet t o a n y visit s o t hat t he rele va nt i nf or mati o n ca n 
be ca pt ure d i n t he e C R F. 
At eac h visit, t he I n vesti gat or or desi g nee asse sses t he s u bject’s c o m plia nce wit h t he assi g ne d 
re gi me n b y as ki n g t he s u bject a b o ut misse d d oses a n d vis uall y i ns pecti n g t he dr u g s u p pl y t he 
s u bject br o u g ht t o t he visit. T he I n vesti gat or or desi g nee assesses t he c o m plia nce of e d o xa ba n, b y 
ta blet c o u nts, a n d ca pt ures i nf or mati o n i n t he e C R F. If zer o ta blets are ret ur ne d w hile a n o vera ge 
is e x pecte d, t he s u bject s h o ul d be as ke d w het her a n y were dis p ose d/t hr o w n a wa y, rat her t ha n 
ta ke n orall y. 
M ore o ver, t he I n vesti gat or ca pt ures t he e x p os ure t o e d o xa ba n a n d V K A i n t he e C R F: 
- 
T he i nf or mati o n pr o vi de d b y t he s u bject o n t heir me dicati o n l o g. 
- 
I nf or mati o n pr o vi de d b y s u bject d uri n g site visits or site tele p h o ne assess me nts c o ncer ni n g 
misse d d oses ( date, dr u g a n d reas o n). 
- 
F or V K A, t he I n vesti gat or assesses t he I N R at l ocal la b orat or y at eac h o n site visit a n d uses 
t he deter mi ne d I N R val ue i n t he assess me nt of V K A e x p os ure a n d tar get I N R bet wee n 
2. 0- 3. 0. It is t he I n vesti g at or’s res p o nsi bilit y: 
o  t o m o nit or t he I N R a n d a dj ust t he V K A d ose t o mai ntai n t he I N R wit hi n tar get, a n d 
o  t o c ollect at least m o nt hly I N R assess me nts a n d rec or d t hese t hr o u g h o ut t he st u d y. 
- 
I n case of a s us pecte d st u d y e n d p oi nt, a n a d diti onal assess me nt f or s u bject c o m plia nce t o t he 
assi g ne d re gi me n m ust be perf or me d. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 2 of 1 0 9 
 
 
5. 9.  
Pri or a n d C o nc o mit a nt Me dic ati o ns 
Pri or me dicati o ns t hat t he s u bject has ta ke n wit hi n 3 0 da ys bef ore ra n d o mizati o n are rec or de d i n 
t he e C R F. T hese me dicati o ns ta ke n b y t he s u bjects pri or t o ra n d o mizati o n or at a n y ti me d uri n g 
t he st u d y are re gar de d as c o nc o mita nt me dicati ons a n d m ust be d oc u me nte d o n t he a p pr o priate 
pa ges of t he e C R F. 
If t he s u bject e x perie nces a stu d y e n d p oi nt e ve nt (see Secti o n 7. 1 a n d 7. 3 , i ncl u di n g i n di vi d ual 
c o m p o ne nts) or a n S A E, t he n i nf or mati o n o n c o nc o mita nt me dicati o ns ta ke n wit hi n t he past 
3 0 da ys m ust be d oc u me nte d i n t he a p pr o priate e C R F pa ges. 
C o nc o mita nt me dicati o n use is ca pt ure d i n t he e C R F u ntil t he p ost-treat me nt f oll o w- u p visit. 
 
Me dicati o ns liste d bel o w are all o we d wit h t he f oll o wi n g restricti o ns: 
 A S A is all o we d if d ose ≤1 0 0 m g o nce- dail y 
 I n t he e d o xa ba n- base d re gi me n, e d o xa ba n d ose re d ucti o n t o 3 0 m g o nce- dail y is re q uire d 
d uri n g c o nc o mita nt use wit h t he P- g p i n hi bit o rs c ycl os p ori ne, dr o ne dar o ne, er yt hr o m yci n, 
or ket oc o naz ole ( please refer t o l ocal la belli n g or t o t he I B, as a p plic a ble); Re mar k: I n E U 
c o u ntries, acc or di n g t o t he S m P C c o nc o mita nt use of e d o xa ba n wit h c ycl os p ori ne, 
dr o ne dar o ne, er yt hr o m yci n, or ket oc o naz ole re q uires d ose re d ucti o n t o 3 0 m g o nce- dail y. 
C o nc o mita nt use of e d o xa ba n wit h q ui ni di ne, ver a p a mil, or a mi o d ar o ne d oes n ot re q uire  
d ose re d ucti o n. 
 
5. 9. 1.  
Pr o hi bite d Me dic ati o ns 
T he f oll o wi n g dr u gs are n ot per mitte d d uri n g t he treat me nt peri o d: 
 A d diti o nal a ntic oa g ula nts, ot her t ha n t he assi g ne d e d o xa ba n or V K A, b y a n y r o ute ( wit h 
t he e xce pti o n of pare nteral a ge nts use d t o treat a ne w cli nical e ve nt, s uc h as ac ute 
c or o nar y s y n dr o me, or as a bri d ge w h e n starti n g or res u mi n g t he assi g ne d V K A); 
 D ual a nti platelet t hera p y ( D A P T, i.e., as piri n a n d P 2 Y 1 2 a nta g o nist); 
 Fi bri n ol ytic a ge nts, u nless re q uire d t o treat a ne w cli nical e ve n t, s uc h as ac ute MI, P E, or 
str o ke, i n w hic h case t he ris ks a n d be nefits of s uc h treat me n t s h o ul d be c o nsi dere d a n d, if 
gi ve n, t he assi g ne d e d o xa ba n or V K A s h o ul d be te m p oraril y disc o nti n ue d;  
 C hr o nic use of me dici nes affecti n g he m ostasis  s uc h as hi g her d oses of A S A ( A S A u p t o 
1 0 0 m g per da y all o we d) or c hr o nic oral or pare nteral i nta ke of  n o n-as piri n N S AI Ds o n 
≥4 da ys/ wee k ( use of N S AI Ds via ot her r o utes is n ot restricte d); 
 Vita mi n K s u bstit uti o n me dicati o ns; 
 I n vesti gati o nal dr u gs ( ot her t ha n t he ra n d o mize d st u d y treat me nt re gi me n). 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 3 of 1 0 9 
 
S u bjects o n t hese dr u gs at t he ti me of ra n d o mi zati o n ca n n ot be i ncl u de d i nt o t he st u d y. After 
ra n d o mizati o n,  s h ort-ter m  c o nc o mita nt  use  of  t hese  dr u gs  ma y  re q uire  a  st u d y  me dicati o n  
i nterr u pti o n. All st u d y me dicati o n i nterr u pti o ns m ust be ca pt ure d i n t he e C R F. After c o m pleti o n of 
a s h ort c o urse of t hera p y wit h t he pr o hi bite d dr u g, t he i nterr u pte d st u d y me dicati o n ma y be 
res u me d. L o n ger-ter m c o nc o mita nt use of t hese dru gs (e. g., ne w i n dicati o n f or c hr o nic D A P T) will 
re q uire wit h dra wal of t he s u bject fr o m t he st u d y. 
5. 1 0.  
S u bject Wit h dr a w al/ Disc o nti n u ati o n 
I n acc or da nce wit h t he Declarati o n of Helsi n ki a n d ot her a p plica ble  re g ulati o ns, a s u bject has t he 
ri g ht t o wit h dra w c o nse nt f or partici pati o n i n  t he st u d y at a n y ti me a n d f or a n y reas o n wit h o ut 
prej u dice t o his or her f ut ure me dical car e b y t he p h ysicia n or at  t he i nstit uti o n. 
5. 1 0. 1.  
Re as o ns f or Wit h dr a w al 
A n y s u bject w h o is wit h dra w n fr o m  t he st u d y treat me nt f or a n y reas o n will ha ve t heir reas o ns f or 
wit h dra wal rec or de d. S u bjects ma y be wit h dra w n fr o m t he st u d y after si g ni n g t he I C F f or t he 
f oll o wi n g reas o ns: 
 A E 
 Wit h dra wal b y s u bject 
 P h ysicia n decisi o n 
 Deat h 
 Lac k of effi cac y 
 Pre g na nc y 
 Pr ot oc ol de viati o n 
 St u d y ter mi nate d b y s p o ns or 
 L ost t o f oll o w- u p 
 Ot her 
 
5. 1 0. 2.  
Wit h dr a w al Pr oce d ures 
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete an d re p ort t he o bser vati o ns 
as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra w al i ncl u di n g t he date of  last treat me nt a n d t he 
reas o n f or wit h dra wal. 
If t he s u bject is wit h dra w n d ue t o a n A E, t he I n vesti gat or will f oll o w t he s u bject u ntil t he A E has 
res ol ve d or sta bilize d. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y s h o ul d c o m plete prot oc ol-s pecifie d wit h dra wal 
pr oce d ures. S u bjects will be f oll o we d i n t he trial (f or all pr ot oc ol s pecifie d e val uati o ns of efficac y 
or safet y e ve nts, c o nc o mita nt t hera pies, etc) u nless t here is writte n d oc u me ntati o n of wit h dra w n 
c o nse nt ( b y t he s u bject a n d/ or  b y t he I n vesti gat or).   

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 4 of 1 0 9 
 
6.  
S T U D Y P R O C E D U R E S 
A ta b ular s u m mar y of t he visit sc he d ule f or t he st u d y is pr o vi de d i n Secti o n 1 6. 9 . T he me dicati o ns 
use d i n t he st u d y re gi me ns are pr o vi de d b y t h e S p o ns or a n d details o n dr u g acc o u nta bilit y are 
pr o vi de d i n Secti o n 5. 7 . 
S u bjects eli gi ble t o part ici pate i n t he st u d y m ust ha ve si g ne d t he I C F bef ore ra n d o mizati o n or a n y 
st u d y-s pecific pr oce d ures are perf or me d. After t he I C F is si g ne d, s u bjects are ra n d o mize d wit h o ut 
dela y t o o ne of t he t w o st u d y ar ms ( 2: 1 e d o xa ba n vs. V K A).  
 
6. 1.  
Pre-scree ni n g  
T he pre-scree ni n g will be d o ne o ut si de t he pr ot oc ol at t he site’s discreti o n t h o u g h i nf or mati o n 
re q uire d b y t he pr ot oc ol will nee d t o be rec or de d i n t he e C R F a n d s u bject n otes.   
 
6. 2.  
S u bject  E nr oll me nt  ( Scree ni n g/ R a n d o miz ati o n,  Visit  1,  D a y  - 2 1  ( m a x.  D a y - 2 8) 
a n d O pti o n al Visit 2 D a y - 1 4) 
T he scree ni n g peri o d will be 1- 3 da ys. Visits f or Scree ni n g a n d Ra n d o mizati o n ma y be c o m bi ne d 
if t he I ncl usi o n/ E xcl usi o n criteria ca n be c hec ke d o n t he basis of t h e patie nt's healt h rec or d a n d 
act ual la b orat or y res ults w it h s ufficie nt acc urac y a n d if t he s u bject has bee n ha n de d o ut t he I C F 
at least 1 da y bef ore ra n d o mizati o n a n d prec o n diti o ne d t hat all of t he s u bject's q uesti o ns c o ul d be 
a ns were d.  
E nr oll me nt of s u bjects will occ ur bet wee n 2 1 t o 2 8 da ys bef ore t he pr oce d ure. S u bjects will 
u n der g o st u d y s pecific pr oce d ures o nl y after t he I C F is si g ne d. T his  visit ma y be s plit i nt o t w o 
ste ps at baseli ne as per l ocal re q uire me nts. I n t he pre-a blati o n treat me nt peri o d, a n o pti o nal visit 
ma y occ ur f or t h ose patie nts w h o d o n ot ha ve t he o pti o n of I N R meas ure me nt i n a n a m b ulat or y 
setti n g ( o pti o nal Visit 2, Da y - 1 4).  
T he  f oll o wi n g  acti vities  a n d/ or  assess me nts  ar e  perf or me d  pri or  t o  ra n d o mizati o n  a n d  t he  
o utc o mes rec or de d i n t he e C R F: 
 I C F si g ne d; 
 C hec k t hat t he s u bject meets all of t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria 
(see Secti o n 4. 1 ); i n case t hat Ra n d o mizati o n is n ot at t he sa me da y as Scree ni n g, 
i ncl usi o n a n d e xcl usi o n criteria will be re-assesse d at Ra n d o mizati o n;   
 C ollect de m o gra p h y i nf or mati o n (a ge, b o d y wei g ht a n d ge n der)  
 Re vie w me dical hist or y i n cl u di n g blee di n g hist or y a n d hist or y of car di o versi o ns; 
 Rec or d pri or me dicati o n wit hi n t he 3 0 da ys pr i or t o ra n d o mizati o n; 
 P h ysical e xa mi nati o n; 
 Bl o o d dra w f or ce ntral la b at Scree ni n g:  
―  Creati ni ne, esti mate d Cr C L acc or di n g t o t he C oc kcr oft- Ga ult f or m ula (see Secti o n 
1 6. 6 ), 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 5 of 1 0 9 
 
―  Re d Bl o o d Cell c o u nt a n d stat us  (e. g., he m o gl o bi n, he mat ocrit), platelet c o u nt, W B C 
( wit h differe ntial if ele vate d), T B L (if ele vate d, deter mi ne c o nj u gate d/ u nc o nj u gate d 
bilir u bi n fracti o n), A L T, A S T, al kali ne p h os p hatase, I N R i n all s u bjects;  
―  T otal c h olester ol a n d tri gl yceri d es o nl y d o ne at scree ni n g;  
―  Bl o o d dra w f or ce ntral la b orat or y a nal ysis of car diac mar kers. 
If a vaila ble rece nt l ocal la b orator y res ults are of s ufficie nt acc urac y t o verif y t he patie nt’s 
eli gi bilit y a n d s u p p ort ra n d o mizati o n i n t he j u d g me nt of t he i n vesti gat or t he patie nt ca n be 
ra n d o mize d o n t he sa me da y as scree ni n g. 
 W o me n of c hil d beari n g p ote nti al m ust ha ve a ne gati ve uri ne test f or pre g na nc y at 
scree ni n g (a fe male of c hild beari n g p ote ntial is defi ne d as o ne w h o has n ot bee n 
p ost me n o pa usal f or at least o ne year, or has n ot bee n s ur gicall y sterilise d, or has n ot ha d a 
h ysterect o m y at least 3 m o nt hs pri or t o t he start of t his st u d y). T hese s u bjects m ust be 
willi n g a n d a ble t o use a de q uate c o ntrace pti o n a n d a d here t o t he f oll o wi n g pr o hi biti o ns 
a n d restricti o ns:  Fe males ta ki n g oral c o ntra ce pti ves s h o ul d ha ve bee n o n t hera p y f or at 
least t hree m o nt hs. A de q uate  c o ntrace pti ves i ncl u de: C o m bi ne d (estr o ge n a n d 
pr o gest o ge n c o ntai ni n g) oral, i ntra va gi nal  or tra ns der mal h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n; pr o ge st o ge n- o nl y oral, i njecta ble or i m pla nta ble 
h or m o nal c o ntrace pti o n ass ociate d wit h i n hi bi ti o n of o v ulati o n; i ntra uteri ne de vice (I U D); 
i ntra uteri ne h or m o ne-releasi n g s yste m (I U S); bilateral t u bal occl usi o n; vasect o mize d 
part ner; se x ual a bsti ne nce. T his test will be c o nfir me d at Visit 3 ( Baseli ne / Da y 0 / 
cat heter a blati o n da y) a n d Visit 6 ( Site Visi t Da y 3 0). F urt her m ore, pre g na nc y tests are 
carrie d o ut w he ne ver t here are cli nical i n di cati o ns f or t he e xiste nce of a pre g na nc y. 
Eli gi ble s u bjects s h o ul d be ra n d o mi ze d wit h o ut dela y. T he I n vesti gat or will c o ntact t he I X R S a n d 
pr o vi de t he f oll o wi n g i nf or mati o n: 
 C o nfir mati o n t hat I C F has bee n si g ne d a n d date; 
 De m o gra p h y ( year of birt h, b o d y wei g ht a n d ge n der); 
 C o nfir m if Cr C L is less or e q ual 5 0 m L/ mi n. or > 5 0 m L/ mi n.; 
 Usa ge of a P- g p i n hi bit or t hat re q uires a n e d o xa ba n d ose re d ucti o n (acc or di n g t o l ocal 
e d o xa ba n la belli n g or I B as a p plica ble); 
 C o nfir mati o n s u bject f ulfills all i ncl usi o n a n d n o ne of t he e xcl usi o n criteria. 
S u bject I D n u m ber will be assi g ne d t hr o u g h I X R S a n d t he f oll o wi n g if t he s u bject is 
ra n d o mize d: 
―  t he ra n d o mize d treat me nt re gi me n;  
―  prese nce of e d o xa ba n d ose re d ucti o n re q uire me nt; 
―  kit n u m bers of t he me dicati o ns t o be use d. 
After ra n d o mizati o n,  
 T he assi g ne d st u d y me dicati o n a n d t he pr o per dail y  d osi n g is e x plai ne d t o t he s u bject. It 
is als o e x plai ne d h o w t he dr u g acc o u ntabilit y is d oc u me nte d i n t he st u d y.  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 6 of 1 0 9 
 
 
F or s u bjects ra n d o mize d t o e d o xa ba n (see Secti o n 5. 2. 1 . f or m ore details): If s u bject is 
o n: 
     (a) V K A, disc o nti n ue t he V K A a n d start e d o xa ba n w he n I N R is ≤2. 5. 
     ( b) N O A C, disc o nti n ue N O A C a n d start e do xa ba n at t he ti me of  t he ne xt sc he d ule d 
     
N O A C d ose.  
I n t he pre-a blati o n peri o d, it is ma n dat or y t hat t he o nce- dail y d ose of e d o xa ba n is ta ke n 
i n t he e ve ni n g. 
 
F or s u bjects ra n d o mize d t o V K A (see Secti o n 5. 2. 2 . f or m ore details): If s u bject is o n: 
     (a) V K A, c o nti n ue wit h me dicati o n as pr o vi de d b y I X R S w he n I N R ≤2. 5. 
     ( b) N O A C, disc o nti n ue t he N O A C a n d start V K A at t he ti me of t he ne xt sc he d ule d 
           N O A C d ose. 
 I nstr ucti o n is pr o vi de d t o t he s u bject t o brin g all st u d y me dicati o n t o eac h visit, i ncl u di n g 
e d o xa ba n. Eac h s u bject s h o ul d d oc u me nt mi sse d d oses i n t he s u bject b o o klet. T he 
s u bject s h o ul d be i nstr ucte d b y t he I n vesti gat or t o bri n g t his b o o klet t o  a n y visit s o t hat 
t he rele va nt i nf or mati o n ca n be ca pt ure d a n d I n vesti gat or ca pt ures i nf or mati o n i n t he 
e C R F. 
 O nl y f or V K A s u bjects:   o btai n I N R a n d V K A d ose i nf or mati o n.  Fre q ue nt I N R 
deter mi nati o ns u p o n i nitiati o n s h o ul d be o btai ne d u ntil s u bject’s I N R is sta ble i n t he 
t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits  will be pla n ne d f or ‘ de n o v o’ 
s u bjects o n V K A t o a dj ust t he d ose wit h t he g oal of reac hi n g I N R 2. 0- 3. 0 wit hi n 6-
8 da ys after e nr ol me nt. O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns 
a n d g ui deli nes pr o vi de d i n t he l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A 
ma n ufact urer. 
 Vital si g ns ( heart rate, sitti n g bl o o d press u re, hei g ht [at ra n d o mizati o n o nl y], a n d b o d y 
wei g ht); 
 1 2-lea d E C G; 
 C o nc o mita nt me dicati o n; 
 A E a n d s us pecte d cli nic al e ve nts re p orti n g. 
T he S p o ns or will s u p pl y st u d y s u bj ects wit h e d o xa ba n a n d V K A f or t he pre-a blati o n st u d y peri o d 
acc or di n g t o assi g ne d re gi me n at ra n d o mizati o n. Me dicati o n kits are assi g ne d t hr o u g h t he I X R S. 
Acc o u nta bilit y f or me dicati o ns pr o vi de d b y D S E is perf or me d at dis pe nsi n g visits a n d t he E O T 
visit. 
All s u bjects will be re q uire d t o c o m plete at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n pri or t o t he 
car diac a blati o n. 
6. 2. 1.  
E d o x a b a n St u d y Ar m 
S u bjects recei vi n g a ntic oa g ula nts at t he ti me of  e nr oll me nt will be s witc he d t o e d o xa ba n (t he 
s witc hi n g pr oce d ure will f oll o w t he e d o xa ban la bel a n d is descri be d i n Secti o n 5. 2. 1. 3 ). It is 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 7 of 1 0 9 
 
ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose of e d o xa ba n is ta ke n i n t he 
e ve ni n g. 
6. 2. 2.  
V K A St u d y Ar m 
S u bjects e nr olle d i n t he V K A st u d y ar m will be re q uire d t o c o m plete at least 2 1 da ys ( + 7 da ys) 
of a ntic oa g ulati o n treat me nt wit h V K A. S u bject s will ta ke t he V K A acc or di n g t o t he directi o n 
of t he I n vesti gat or. E ver y atte m pt will be ma de t o  bri n g s u bjects i nt o t he t hera pe utic tar get ra n ge 
(I N R 2. 0- 3. 0) as fast as p ossi ble a n d t o mai ntai n t he tar get I N R ra n ge c o nsiste ntl y.  
I N R will nee d t o be meas ure d fre q ue ntl y at t he start of t he st u d y ( u nless a s u bject is recei vi n g a n 
u n var yi n g V K A d ose at t he ti me of ra n d o mizati o n) t o rec or d t he ti me w he n I N R reac hes a le vel 
of ≥2. 0.  
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last 1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. I N R m ust be meas ure d o n t he da y of or t he da y pri or t o t he 
sc he d ule d a blati o n pr oce d ure. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d ≤3. 5 o n t he da y of 
or t he da y pri or t o t he sc he d ul e d a blati o n pr oce d ure, t he pr oc e d ure ma y be perf or me d at t he 
I n vesti gat or’s discreti o n. Ot her wise, t he s u bject is n ot eli gi ble f or perf or mi n g t he cat heter 
a blati o n (t he s u bject will be s witc he d fr o m st u d y me dicati o n t o sta n dar d of care a n d will e nter 
t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A w ill be use d wit h o ut i nterr u pti o n a n d bri d gi n g 
wit h L M W H will n ot be all o we d at t his ti me. 
6. 3.  
C at heter A bl ati o n Visit ( Peri pr oce d ur al Visit, Visit 3, D a y 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 A d mi nister a n d dis pe nse st u d y me dicati o n; t h e S p o ns or will s u p pl y st u d y s u bjects wit h 
e d o xa ba n a n d V K A f or t he p os t-a blati o n st u d y peri o d; 
 S u bjects ra n d o mize d t o e d o xa ba n will ta ke e d o xa ba n i n t he e ve ni n g of t he da y bef ore t he 
a blati o n pr oce d ure. T he i nter v al bet wee n t he last i nta ke of e d o xa ba n a n d t he pr oce d ure 
m ust n ot e xcee d 1 8 h o urs. After t he a blati o n, st u d y me dicati o n m ust be re-starte d o n t he 
da y of pr oce d ure b ut n o earlier  t ha n 6 h o urs p ost-s heat h re mo val a n d o nl y after a de q uate 
he m ostasis has bee n ac hie ve d. 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 T E E or alter nati vel y i ntracar diac ec h ocar di o gra m - will be perf or me d d uri n g t he h os pital 
sta y relate d t o t he pr oce d ure directl y bef ore cat heter a blati o n or t he da y bef ore ( u p t o 
2 4 h o urs bef ore a blati o n). If T E E or i ntracar diac ec h ocar di o gra m is p ositi ve, i.e., s h o ws 
cl ots, t he car diac a blati o n pr oce d ure will be  ca ncele d a n d t he patie nt will be s witc he d 
fr o m st u d y me dicati o n t o sta n dar d of care a n d will e nter a 3 0- da y f oll o w- u p peri o d; 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 8 of 1 0 9 
 
 Cat heter a blati o n pr oce d ure; 
 U nfracti o nate d he pari n ( U F H) a d mi nistrati o n/ A C T m o nit ori n g;  
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis i ncl u di n g safet y para meters (I N R, li ver 
f u ncti o n, ser u m c he mistr y, a n d he mat ol o g y) as descri be d i n Secti o n 9. 7. 
 O nl y i n w o me n of c hil d beari n g p ote ntial: uri ne test f or pre g na nc y. F urt her m ore, 
pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of 
a pre g na nc y; 
 C o nc o mita nt me dicati o ns; 
 Re vie w of treat me nt c o m plia nce a n d i nterr u pti o ns. A ntit hr o m b otic re gi me n c o m plia nce is 
ac hie ve d b y assessi n g s u bject c o m plia nce ( b ot h b y pill c o u nt, self-re p orti n g/ p h ysicia n-
re p orti n g a n d b y I N R val ues f or V K A s u bjects o nl y). I n case of a s us pecte d st u d y 
e n d p oi nt, a n a d diti o nal assess me nt f or s u bject c o m plia nce t o t he assi g ne d re gi me n m ust 
be perf or me d. 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
 A Es (i ncl u di n g a b n or mal la b orat or y fi n di n gs a n d d uri n g u nsc he d ule d visits), e n d p oi nt 
e ve nts, a n d a d verse e ve nts of s pecial i ntere st ( A E SI) s h o ul d be re p orte d as s o o n as site 
pers o n nel lear n of t he e ve nt. E n d p oi nt  e ve nt a n d A E re p orti n g s h o ul d occ ur 
t hr o u g h o ut t he st u d y a n d n ot be restricte d t o s pecific visits. If A L T or A S T > 3 x U L N 
wit h si m ulta ne o us T B L > 2 x U L N is o bser ve d, t he n al kali ne p h os p hatase ( A L P) s h o ul d 
be deter mi ne d. 
6. 3. 1.  
E d o x a b a n St u d y Ar m 
S u bjects will be re q uire d t o ha ve  c o m plete d at least 2 1 ( u p t o + 7) da ys of a ntic oa g ulati o n wit h 
e d o xa ba n. It is ma n dat or y t hat i n t he pre-a blati o n peri o d, t he o nce- dail y d ose  of e d o xa ba n is ta ke n 
i n t he e ve ni n g.  
If a s u bject has ta ke n t he st u d y dr u g i n t he e ve ni n g a n d t he T E E/i ntracar diac ec h ocar di o gra m is 
ne gati ve, t he pr oce d ure ca n be pe rf or me d i n t he m or ni n g of t he ne xt da y. T he i nter val bet wee n 
t he last i nta ke of e d o xa ba n a n d t he pr oce d ure sh o ul d n ot e xcee d 1 8 h o urs. After t he a blati o n, st u d y 
me dicati o n m ust be re-starte d o n t he da y of pr o ce d ure n o earlier t ha n 6 h o urs p ost-s heat h re m o val 
a n d o nl y o nce a de q uate he m ost asis has bee n ac hie ve d. 
Ti mi n g of t he last d ose of e d o xa ba n pri or t o t he ca t heter a blati o n pr oce d ure a n d t he first d ose after 
t he pr oce d ure will be rec or de d i n t he e C R F. 
6. 3. 2.  
V K A St u d y Ar m 
Bef ore a blati o n, eac h s u bject m ust be i n t he I N R ra n ge of 2. 0- 3. 0 f or t he last  1 0 da ys pri or t o t he 
cat heter a blati o n. T his will nee d t o be d oc u me nte d b y fre q ue nt I N R meas ure me nts, at least o nce 
per wee k i n t he pre-a blati o n peri o d. I N R m ust be meas ure d o n t he da y of or t he da y pri or t o t he 
sc he d ule d a blati o n pr oce d ure. O n t he da y of, or t he da y pri or t o, t h e sc he d ule d a blati o n pr oce d ure, 
s u bjects I N R s h o ul d be wit hi n t he ra n ge 2. 0- 3. 0. If I N R is ≥1. 5 a n d < 2. 0 or if I N R is > 3. 0 a n d 
≤3. 5 t he pr oce d ure ma y be perf or me d at t he I n ves ti gat or’s discreti o n. Ot her wise, t he s u bject is 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 5 9 of 1 0 9 
 
n ot  eli gi ble  f or  perf or mi n g  t he  cat heter  a bla ti o n  (t he  s u bject  will  be  s witc he d  fr o m  st u d y  
me dicati o n t o sta n dar d of care a n d will e nter t he 3 0- da y f oll o w- u p peri o d).  
D uri n g t he cat heter a blati o n pr oce d ure, V K A will be  use d wit h o ut i nterr u pti o n a n d bri d gi n g wit h 
L M W H will n ot be all o we d at t his ti me. 
6. 3. 3.  
A ntic o a g ul ati o n D uri n g C at heter A bl ati o n 
D uri n g a blati o n, he pari n s h o ul d be gi ve n t o mai ntai n a n A C T > 3 0 0 s ( 2 ). He pari n (sta n dar d of 
care treat me nt) s h o ul d be a d mi nistere d ( 1 0 0 U/ k g b ol us) pri or t o or i m me diatel y f oll o wi n g tra ns-
se ptal p u nct ure d uri n g A F a blati o n pr oce d ures a n d a dj uste d t o ac h ie ve a n d mai ntai n a n A C T of 
3 0 0 t o 4 0 0 sec o n ds. A C T le vels s h o ul d be c hec ke d  at 1 5- 2 0- mi n ute i nter vals u ntil t hera pe utic 
a ntic oa g ulati o n is ac hie ve d a n d t he n at 3 0- mi n ute  i nter vals f or t he d urati o n of t he pr oce d ure. 
He pari n a ntic oa g ulati o n will be partiall y re verse d wit h pr ota mi ne a n d s heat hs re m o ve d at a n A C T 
< 2 5 0 sec o n ds ( 1 5 ). 
6. 3. 4.  
A ntic o a g ul ati o n P ost C at heter A bl ati o n 
F oll o wi n g c o m pleti o n of t he cat heter a blati o n pr oce d ure, all s u bjects will c o nti n ue recei vi n g 
treat me nt  wit hi n  t heir  st u d y  ar m  u ntil  Da y  9 0  p ost- pr oce d ure.  F or  patie nts  ra n d o mize d  t o  
e d o xa ba n, after t he a blati o n, st u d y me dicati o n m ust be re-starte d o n t he da y of pr oce d ure n o 
earlier t ha n 6 h o urs p ost-s heat h re m o val a n d o nl y o nce a de q uate he m ostasis has bee n ac hie ve d. 
F or s u bjects ra n d o mize d t o V K A w he n after a b lati o n, t he s u bjects’ a ntic oa g ulati o n is m ore 
c o nsta nt, t he fre q ue nc y of I N R meas ure me nts ma y be l o wer t ha n i n t he pre-a blati o n peri o d. 
H o we ver, i n t he p ost-a blati o n peri o d, at least m o nt hl y I N R c o ntr ols are re q uire d. 
6. 4.  
H os pit al Disc h ar ge ( Visit 4; o pti o n al) 
T his visit ma y be perf or me d at t he discreti o n of  t he I n vesti gat or. T he f oll o wi n g acti vities a n d/ or 
assess me nts are perf or me d at t he h os pital disc har g e visit a n d t he o utc o mes rec or de d i n t he e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 5.  
Diff usi o n- Wei g hte d  M a g netic  Res o n a nce  I m a gi n g  ( Selecte d  sites  o nl y)  ( Visit  5, 
D a y 4) 
At selecte d sites, t he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes 
rec or de d i n t he e C R F: 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 D W- M RI or diff usi o n wei g hte d i ma gi n g fl ui d atte n uate d i n versi o n rec o ver y 
( D WI- F L AI R) will be perf or me d 4 da ys ± 2 da ys p ost cat heter a blati o n; 
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 0 of 1 0 9 
 
6. 6.  
Site Visit ( Visit 6, D a y 3 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis of  safet y para meters (I N R, li ver f u ncti o n, 
ser u m c he mistr y, a n d he mat ol o g y); as descri be d i n Secti o n 9. 7 . 
 O nl y i n w o me n of c hil d beari n g p ote ntial: uri ne test f or pre g na nc y. F urt her m ore, 
pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of 
a pre g na nc y; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m p lia nce a n d i nterr u pti o ns;  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 7.  
O pti o n al Site Visit/ Tele p h o ne  Assess me nt ( Visit 7, D a y 6 0) 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F:  A  pers o nal  visit  is  o pti o nal  f or  t h ose  patie nts  w h o  d o  n ot  ha ve  t he  o pti o n  of  I N R  
meas ure me nt b y t heir ge neral practiti o ner. 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure , b o d y wei g ht; o nl y d o ne if perf or me d as 
pers o nal visit);  
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m plia nce a n d i nterr u pti o ns.  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
6. 8.  
E n d of Tre at me nt ( Visit 8, D a y 9 0) 
At Da y 9 0, t he s u bject will eit her  disc o nti n ue t he treat me nt c o m pletel y or will be c o nti n ue d o n 
a n y of t he a p pr o ve d O A C dr u gs per p h ysicia n's di screti o n. Detaile d s witc hi n g pr ot oc ols acc or di n g 
t o me dicati o n la bel will be pr o vi de d.  
T he E O T visit is perf or me d f or s u bjects w h o ha ve  a pre mat ure disc o nti n uati o n of t heir assi g ne d 
O A C- base d re gi me n or w h o ha ve m o difie d t heir I C  after ra n d o mizati o n wit h f ull wit h dra wal of 
I C (see details Secti o n 6. 1 1 ). F or t hese s u bjects, t he sc he d uli n g of t he E O T re mai ns u nc ha n ge d 
(i.e. 9 0 ± 5 da ys). I n s uc h cases, t he E O T visit is t he e n d- of-st u d y visit/c o ntact. 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 1 of 1 0 9 
 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 1 2-lea d E C G rec or di n g; 
 Bl o o d dra w f or ce ntral la b orat or y a nal ysis of  safet y para meters (I N R, li ver f u ncti o n, 
ser u m c he mistr y, a n d he mat ol o g y) as descri be d i n Secti o n 9. 7 ; 
 C o nc o mita nt me dicati o ns (c ha n ges); 
 Re vie w of treat me nt c o m p lia nce a n d i nterr u pti o ns;  
 ( S) A Es a n d s us pecte d cli nical e n d p oi nts e x perie nce d b y t he s u bject since t he last visit. 
 T he tra nsiti o n me dicati o n a n d t he pr o per dail y d osi n g is e x plai ne d t o t he s u bject i ncl u di n g 
c o nfir mati o n t hat t he s u bject u n der sta n ds t he pr o per dail y d osi n g;  
 Dis pe nsati o n of t he tr a nsiti o n st u d y me dicati o n. 
 
6. 9.  
E n d of St u d y Visit, P ost-tre at me nt F oll o w- u p ( Visit 9, D a y 1 2 0) 
All ra n d o mize d s u bjects will ha ve  a p ost-treat me nt c o ntact at 3 0-3 5 da ys after t he E O T visit t o 
c ollect data o n c o nc o mita nt me dicati o ns, S A Es , a n d ot her safet y e ve nts of i nterest. 
T he f oll o wi n g acti vities a n d/ or assess me nts are perf or me d a n d t he o utc o mes rec or de d i n t he 
e C R F: 
 O btai n I N R a n d V K A d ose i nf or mati o n ( V K A s u bjects o nl y); 
 Vital si g ns ( heart rate, sitti n g bl o o d press ure, b o d y wei g ht);  
 C o nc o mita nt me dicati o ns (c ha n ges); 
 ( S) A Es a n d e n d p oi nt e ve nts e x perie nce d b y t he s u bject si nce t he last visit. 
 
6. 1 0.  
Misse d Visits 
E ver y eff ort s h o ul d be ma de t o e ns ure s u bjects re t ur n f or t heir o n-site visits. If t he s u bject is 
u na ble t o ret ur n f or a n o n-site vi sit, t he I n vesti gat or, or desi g nee, m ust d oc u me nt i n t he e C R F t he 
reas o n t he s u bject was u na ble t o c om plete t he visit. T he I n vesti gat or s h o ul d als o ma ke e ver y eff ort 
t o c o ntact t he s u bject, wit hi n t he visit wi n d o w, t o c ollect t he s u bject’s vital stat us as well as 
i nf or mati o n relate d t o p ote ntial A Es, safet y data, an d h os pitalizati o ns. 
6. 1 1.  
M o dific ati o n of I C after R a n d o miz ati o n 
S u bjects are sc he d ule d t o ha ve re g ular st u d y c o ntacts e ver y m o nt h u ntil t he E n d of St u d y Visit is 
c o m plete d (i.e., 3 0 da ys after t he E O T Visit).  
I n acc or da nce wit h t he Declarati o n of Helsi n ki a n d ot her a p plica ble  re g ulati o ns, a s u bject has t he 
ri g ht  t o  wit h dra w  c o nse nt  fro m st u d y  partici pati o n  at  a n y  ti me  a n d  f or  a n y  reas o n  wit h o ut  
prej u dice t o his or her f ut ure me dical car e b y t he p h ysicia n or at  t he i nstit uti o n. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 2 of 1 0 9 
 
T his pr ot oc ol ma kes a disti ncti o n bet wee n re q uest  t o disc o nti n ue ( 1) a n y or all st u d y me dicati o n, 
( 2) o n site visits, ( 3) tele p h o ne c o ntacts, ( 4) c ollecti o n of cli nical f oll o w- u p data, ( 5) c ollecti o n of 
vital stat us a n d ( 6) f u ll wit h dra wal of I C. 
D uri n g t he treat me nt p hase, all s u bjects are f oll o we d  f or 9 0 da ys irres pecti ve of c ha n ges i n t he 
a ntit hr o m b otic re gi me n. He ncef ort h, d uri n g i n terr u pti o n or f oll o wi n g disc o nti n uati o n of st u d y 
me dicati o n, s u bjects c o nti n ue t o ha ve re g ular st u d y visits or tele p h o ne assess me nts u ntil t he 9 0-
da y E O T visit is c o m plete d. 
If t he s u bject ca n n ot ret ur n f or a n i n- pers o n visit, a tele p h o ne visit is sc he d ule d u nless s u bject 
re q uests n ot t o be c o ntacte d b y tele p h o ne. C ollecti o n of a vaila ble cli nical data or vital stat us, 
eit her at t he i nter ve nti o nal ce nter, at t he referri n g h os pital, wit h t he ge neral practiti o ner, or t he 
m u nici pal re gistries c o nti n ues u nle ss e x plicitl y disall o we d b y s u bject. 
C ollecte d data u p t o t he date of f ull wit h dra wal of I C are use d i n t he fi nal a nal ysis. 
Rec or ds i n t he e C R F d oc u me nt m o dificati o ns t o t h e I C as detaile d a b o ve (i ncl u di n g le vel a n d date 
of m o dificati o n or wit h dra wal). 
6. 1 1. 1.  
S u bjects L ost t o F oll o w- U p 
All s u bjects s h o ul d be e nc o ura ge d  t o ret ur n f or pr ot oc ol-re q uire d o n-site visits or tele p h o ne 
assess me nts f or e val uati o n d uri n g t he cli nical f oll o w- u p. If a s u bject is u na ble t o ret ur n f or a cli nic 
visit, s u bject s h o ul d be c o ntacte d  b y tele p h o ne t o o btai n s u bject re q uire d i nf or mati o n. All atte m pts 
s h o ul d be d oc u me nte d i n t he s o urce d oc u me nts. If t he s u bject d oes n ot res p o n d t o tele p h o ne calls, 
t he n t he I n vesti gat or m ust se n d a certifie d letter t o t he s u bject. O nl y after faili n g t o c o ntact t he 
s u bject at t he fi nal f oll o w- u p visit will t he s u bject be c o nsi dere d l ost t o f oll o w- u p after last c o ntact 
e xce pt f or m ortalit y if a vaila ble vi a m u nici palit y re gistries. It m ust be a hi g h pri orit y t o o btai n at 
least s ur vi val data o n all s u bjects l ost t o f oll o w- u p. W he n a s u bject is l ost t o f oll o w- u p a n E n d-
of- St u d y F or m is c o m plete d. 
6. 1 2.  
E n d of Tri al Defi niti o n 
All ra n d o mize d s u bjects will ha ve a c o ntact pla n ne d 3 0- 3 5 da ys after t h e E O T visit, t o c ollect data 
o n tar gete d c o nc o mita nt me dicati o ns, S A Es, a n d ot her A E SI. T he fi nal c o ntact is t he p ost-
treat me nt f oll o w- u p visit sc he d ule d at 3 0- 3 5 da ys after t he E O T visit. T he st u d y is dee me d 
c o m plete d as s o o n as t he fi nal c o ntact of t he last  s u bject is perf or me d i n all ce nters a n d i n all 
partici pati n g c o u ntries. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 3 of 1 0 9 
 
7.  
O U T C O M E A S S E S S M E N T S 
7. 1.  
Pri m ar y Effic ac y E n d p oi nt 
C o m p osite  of  all-ca use  deat h,  str o ke  (isc he mi c,  he m orr ha gic,  or  u n deter mi ne d),  a n d  Maj or  
Blee di n g (I S T H defi niti o n), a nal yze d as ti me t o first occ urre nce of a n y c o m p o ne nt. 
7. 2.  
Pri m ar y S afet y E n d p oi nt 
Maj or Blee di n g (I S T H defi niti o n), a nal yze d as ti me t o first occ urre nce of Maj or Blee di n g. 
7. 3.  
Sec o n d ar y E n d p oi nts 
Effic ac y: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2  f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d) S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic,  he m orr ha gic, or u n deter mi ne d) 
S afet y: 
 Maj or Blee di n g ( defi ne d b y TI MI, B A R C ( 2 or hi g her)) 
 Maj or a n d Cli nicall y Rele va nt N o n- Ma j or ( C R N M) Blee di n g (I S T H defi niti o n) 
 C R N M Blee di n g (I S T H defi niti o n) 
 Mi n or Blee di n g (I S T H defi niti o n) 
 A n y Blee di n g 
 I C H 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 4 of 1 0 9 
 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g (I S T H defi niti o n) 
 N o n-fatal Maj or Blee di n g (I S T H defi niti o n) 
 Fatal Maj or Blee di n g ( defi ne d b y TI MI, B A R C [ 2 or hi g her]) 
 N o n-fatal Maj or Blee di n g ( defi ne d  b y TI MI, B A R C [ 2 or hi g her]) 
 Safet y para meters s uc h as A Es, S A Es, la b orat or y para meters, E C G a n d vital si g ns. 
 
All a dj u dicate d e n d p oi nts are a nal yze d as ti me t o first occ urre nce of a n y of its c o m p o ne nts. 
F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal yses. 
7. 3. 1.  
Ot her E n d p oi nts 
 Rele va nt H E O R para meters: 
o  N u m ber of s u bjects wit h ca ncellati o n of a blati o n pr oce d ure d ue t o i na de q uate 
a ntic oa g ulati o n 
o  N u m ber of h os pital a d missi o ns d ue t o C V ca uses ( be y o n d a blati o n pr oce d ure), 
i ncl u di n g b ut n ot li mite d t o o verall, f or blee di n g, S E E, ve n o us t hr o m b osis, etc. 
Re mar k:   H os pital a d missi o ns d ue t o C V  ca uses i ncl u de, b ut are n ot li mite d t o 
E D, I C U, C V war d. 
o  Mea n le n gt h of sta y ass ociate d wit h t he differe nt t y pe of h os pital a d missi o ns, s uc h 
as E D, I C U a n d C V war ds 
o  A d diti o nal o ut patie nt p h ysicia n or n urse visits t hat are C V e ve nt relate d o utsi de 
sc he d ule d visits as defi ne d b y st u d y pr ot oc ol 
 Sile nt cere bral lesi o ns as de fi ne d b y D W- M RI p ost a blatio n pr oce d ure (at preselecte d 
ce nters) 
 Car diac mar kers 
 
7. 4.  
E n d p oi nt Defi niti o ns 
All s us pecte d cli nical e n d p oi nts are a dj u di cate d b y a n i n de pe n de nt C E C (see Secti o n 1 6. 1. 2 ) 
wit h o ut k n o wle d ge of t he act ual assi g ne d treat me n t. Mai n a dj u dicati o n criteria are me nti o ne d 
bel o w. F urt her details o n t hese defi niti o ns a n d h o w t he y will be a ssesse d are pr o vi de d i n t he C E C 
C harter.  
T he re q uire me nts f or c ollecti n g a n d s u b mitti n g t he s o urce d oc u me nts f or a p pr o priate a dj u dicati o n 
of t he re p orte d pri mar y a n d sec o n dar y e n d p oi nt e ve nts will be pr o vi de d t o t he sites/I n vesti gat ors 
se paratel y i n t he Stu d y O perati o ns Ma n ual. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 5 of 1 0 9 
 
F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal yses. 
 
7. 4. 1.  
Blee di n g 
Blee di n g will be classifie d acc or di n g t o t he I S T H defi niti o ns ( 1 6, 1 7 ). Blee di n g e ve nts will als o be 
classifie d acc or di n g t o B A R C ( 1 8 ) a n d TI MI (2 2, 2 3 ) classificati o ns f or descri pti ve p ur p oses o nl y 
(see Secti o n 1 6. 3  f or f urt her details) 
7. 4. 2.  
Effic ac y E n d p oi nt Defi niti o ns 
T he f oll o wi n g efficac y e n d p oi nt de fi niti o ns will be a p plie d: 
- 
A str o ke is defi ne d b y a n ac ute e pis o de of f ocal or gl o bal ne ur ol o gical d ysf u ncti o n 
ca use d b y brai n, s pi nal c or d, or reti nal vasc ular i nj ur y as a res ult of he m orr ha ge or 
i nfarcti o n. T he e ve nt classifies as a str o ke rat her t ha n a TI A base d o n a n y of t he 
f oll o wi n g: 
– D urati o n of ne ur ol o gical d ysf u ncti o n > 2 4 h o urs. 
– D urati o n of ne ur ol o gical d ysf u ncti o n < 2 4 h o urs i n case of i ma gi n g- d oc u me nte d ne w 
he m orr ha ge or i nfarcti o n. 
– A ne ur ol o gical d ysf u ncti o n res ulti n g i n deat h ( 2 4 ). 
Str o ke will be s u b- di vi de d i nt o isc he mic, he m orr ha g ic or u n deter mi ne d. Str o ke is 
cate g orize d as disa bli n g a n d n o n- disa bli n g str o ke usi n g t he m o difie d Ra n ki n Scale ( m R S) 
sc ore. 
- 
TI A  is defi ne d b y a n y ne ur ol o gical d ysf u ncti o n n ot satisf yi n g t he a b o ve criteria f or 
str o ke, s pecificall y if lasti n g < 2 4 h o urs wit h o ut i ma gi n g- d oc u me nte d ac ute brai n 
i nfarcti o n. 
T hese defi niti o ns of TI A a n d str o ke wi del y c orres p o n d wit h t he “ U p date d sta n dar dize d 
e n d p oi nt defi niti o ns f or tra nscat heter a ortic  val ve i m pla ntati o n” p u blis he d b y t he V A R C- 2 
gr o u p a n d wit h t h ose “ Defi niti o ns f or Car di o vasc ular E n d p oi nt E ve nts i n Cli nical Trials” 
p u blis he d b y a n A C C/ A H A tas k f orce ( 2 5, 2 6 ). 
- 
A n alter n ati ve defi niti o n of str o ke  will be a p plie d defi ni n g str o ke as a n a br u pt o nset, 
o ver mi n utes t o h o urs, of a f ocal ne ur ol o gical deficit i n t he distri b u ti o n of a si n gle brai n 
arter y t hat is n ot d ue t o a n i de ntifia ble n o n vasc ular ca use (i.e., brai n t u m or or tra u ma), a n d 
t hat eit her lasts at least 2 4 h o urs or res ults i n deat h wit hi n 2 4 h o urs of o nset (1 ). 
C orres p o n di n g t o t his  alter n ati ve defi niti o n, TI A is defi ne d as a n a br u pt o nset, o ver 
mi n utes t o h o urs, of a f ocal ne ur ol o gical deficit i n t he distri b uti o n of a si n gle brai n arter y, 
t hat lasts less t ha n 2 4 h o urs a n d is n ot d ue t o a n i de ntifia ble n o n- vascular ca use (i.e., brai n 
t u m or or tra u ma) a n d d oes n ot satisf y t he str o ke defi niti o n a b o ve (1 ). 
- 
A n S E E  is defi ne d as a n arterial e m b olis m res ulti n g i n cli nical isc he mia, e xcl u di n g t he 
ce ntral ner v o us s yste m ( C N S), c or o nar y  a n d p ul m o nar y arterial circ ulati o n (1 ). 
- 
C V m ort alit y , defi ne d as car diac or vasc ular deat h acc or di n g t o Aca de mic Researc h 
C o ns orti u m  ( A R C) (2 7 ). 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 6 of 1 0 9 
 
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S. 
8. 1.  
P h ar m ac o ki netic V ari a ble(s) 
N ot a p plica ble. 
 
8. 2.  
C ar di ac M ar kers  
E vi de nce s u g gests t hat t he car diac bi o mar kers N- ter mi nal fra g me nt B-t y pe natri uretic pe pti de 
( N T- pr o B N P) a n d car diac tr o p o ni n hi g h se nsiti vit y (c T n- hs) are i n de pe n de ntl y ass ociate d wit h 
ris k of str o ke i n A F (2 8 ). N o n- ge netic car diac bi o mar kers s uc h as N T- pr o B N P a n d c T n- hs will be 
a nal yze d i n all patie nts at scree ni n g/ra n d o mizati o n.   
T he res ults will be re vie we d a n d c o m pare d t o  t he ce ntral la b orat or y’s n or mal ra n ges. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 7 of 1 0 9 
 
9.  
S A F E T Y A S S E S S M E N T S 
Safet y  assess me nts  t hat  are  c o m p o ne nts  of  t he  st u d y  e n d p oi nt  assess me nts  (e. g.  blee di n g  
e n d p oi nts) are detaile d i n Secti o n 7. 4  a n d m ust be c ollecte d i n t he A E/ O utc o me e C R F pa ge(s). 
9. 1.  
A d verse E ve nt C ollecti o n a n d Re p orti n g 
All cli nical A Es (see Secti o n 9. 2 f or defi niti o ns) occ urri n g after t he s u bject si g ns t he I C F a n d u p 
t o 3 0 da ys after t he last d ose of st u d y me dicati o n (ie, t he f ollo w- u p peri o d), w het her o bser ve d b y 
t he I n vesti gat or or re p orte d b y t he s u bject, will be rec or de d o n t he A E e C R F pa ge.  Me dical 
c o n diti o ns (i ncl u di n g la b orat or y va l ues/ vital si g ns t hat are o ut of ra n ge) t hat were dia g n ose d or 
k n o w n t o e xist pri or t o I C will be rec or de d as part of me dical hist or y.   
All A Es, S A Es, A E SIs are t o be re p orte d acc or di n g t o t he pr oce d ures i n Secti o n 9. 5 .   
All  la b orat or y  res ults,  vital  si g ns,  a n d  E C G  re s ults  or  fi n di n gs  s h o ul d  be  a p praise d  b y  t he  
I n vesti gat or t o deter mi ne t heir cli nical si g nifica nce.  Is olate d a b n or mal la b orat or y res ults, vital 
si g n fi n di n gs, or E C G fi n di n gs (i.e., n ot part of a re p orte d dia g n osis) s h o ul d be re p orte d as A Es if 
t he y are s y m pt o matic, lea d t o st u d y dr u g disc o nti n uati o n, d os e re d ucti o n, re q uire c orrecti ve 
treat me nt, or c o nstit ute a n A E i n t he I n vesti gat or’s cli nical j u d g me nt. 
At eac h visit, t he I n vesti gat or will deter mi n e w het her a n y A Es ha ve occ urre d b y e val uati n g t he 
s u bject.  A Es ma y be directl y o bser ve d, re p orte d s p o nta ne o usl y b y t he s u bject or b y q uesti o ni n g 
t he s u bject at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g 
a b o ut t he occ urre nce of a n y s pecific s y m pt o ms.  T h e I n vesti gat or m ust assess all A Es t o deter mi ne 
seri o us ness, se verit y, a n d ca usalit y, i n acc or da nce wit h t he defi niti o ns i n Secti o ns 9. 2 a n d 9. 3 .  
T he I n vesti gat or’s assess me nt m ust be clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n wit h 
t he I n vesti gat or’s si g nat ure.   
Al wa ys re p ort t he dia g n osis as t he A E or S A E te r m.  W he n a dia g n osis is u na vaila ble, re p ort t he 
pri mar y si g n or s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve 
u ntil t he dia g n osis bec o mes a vaila bl e.  If t he si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest 
a c o m m o n dia g n osis, re p ort t he m as i n di vi d ual e ntries of A E or S A E.   
F or e ve nts t hat are seri o us d ue t o h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust be re p orte d 
as t he S A E ( dia g n osis or s y m pt o m re q uiri n g h os pitaliz ati o n).  A pr oce d ure is n ot a n A E or S A E, 
b ut t he reas o n f or t he pr oce d ure ma y be a n A E or  S A E.  Pre- pla n ne d ( pri or t o si g ni n g t he I C F) 
pr oce d ures or treat me nts re q uiri n g h os pitalizati o n f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n 
i n se verit y s h o ul d n ot be rep orte d as S A Es (see Secti o n 9. 2 f or Defi niti o ns).   
F or deat hs, t he u n derl yi n g or i m me di ate ca use of d eat h s h o ul d al wa ys be re p orte d as a n S A E.   
A n y  seri o us,  u nt o war d  e ve nt  t hat  ma y  occ ur  s u bs e q ue nt  t o  t he  re p orti n g  peri o d  t hat  t he  
I n vesti gat or assesses as relate d t o st u d y dr u g s h o ul d als o be rep orte d a n d ma na ge d as a n S A E. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 8 of 1 0 9 
 
9. 2.  
Defi niti o ns 
9. 2. 1.  
A d verse E ve nt  
A n y u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h 
d oes n ot necessaril y ha ve a ca usal relati o ns hi p wit h  t his treat me nt. A n A E ca n t heref ore be a n y 
u nfa v o ura ble  a n d  u ni nte n de d  si g n  (i ncl u di n g  a n  a b n or mal  la b or at or y  fi n di n g  f or  e xa m ple),  
s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal (in vesti gati o nal) pr o d uct, 
w het her or n ot c o nsi dere d relate d t o t he me dici nal (i n vesti gati o nal) pr o d uct. 
9. 2. 2.  
U ne x pecte d A d verse E ve nt 
A n u ne x pecte d A E is a n A E, t he nat ure or se verit y  of w hic h is n ot c o nsiste nt wit h t he refere nce 
safet y i nf or mati o n of a n y of t he st u d y me dicati o n. T he desi g nati o n of e x pecte d or u ne x pecte d 
m ust be deci de d fr o m t he pers pecti ve of pre vi o us l y descri be d A Es, n ot o n t he basis of w hat mi g ht 
be a ntici pate d fr o m p har mac ol o gical pr o perties of a me dici nal pr o d uct. T he i n vesti gat or ca n 
pr o vi de his j u d ge me nt o n t he e x pecte d ness/ u ne x pect e d ness of a re p orte d A E t o t he s p o ns or a n d 
t his will be ta ke n i nt o acc o u nt f or t he s p o ns or’s j u d ge me nt of e x pecte d ness. H o we ver, t he fi nal 
deter mi nati o n of e x pecte d ness is t he res p o nsi bilit y of D SE a n d n ot t he I n vesti gat or. 
9. 2. 3.  
E x pecte d A d verse E ve nt 
A n e x pecte d A E is a n e ve nt w h ic h is descri be d i n t he refere nce safet y i nf or mati o n of t he st u d y 
dr u gs i n nat ure, se verit y or i nci de nce. 
9. 2. 4.  
Seri o us A d verse E ve nt  
A n S A E or reacti o n is a n y u nt o war d me dical occ urre nce t hat at a n y d ose: 
 res ults i n deat h 
 is life-t hreate ni n g 
T he ter m “life-t hreate ni n g” i n t he defi niti o n of   “seri o us” refers t o a n e ve nt i n w hic h t he 
s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y mi g ht ha ve ca use d d eat h if it were m ore se vere 
 re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xis ti n g h os pitalizati o n 
 res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
 is a c o n ge nital a n o mal y/ birt h defect 
O R 
 is a n y ot her me dicall y i m p orta nt c o n diti o n (see bel o w). 
 
N ote:  Me dical  a n d  scie ntific  j u d ge me nt  s h o ul d  be  e xercise d  i n  deci di n g  w het her  e x pe dite d  
re p orti n g is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt medical e ve nts t hat ma y n ot be 
i m me diatel y life-t hreate ni n g or res ult i n deat h or h os pitalizati o n, b ut ma y je o par dise t he s u bject 
or ma y 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 liste d i n t he defi niti o n a b o ve. 
T hese  s h o ul d  als o  us uall y  be  c o nsi dere d  seri o u s.  E xa m ples  i ncl u de  aller gic  br o nc h os pas m,  
c o n v ulsi o ns, a n d bl o o d d yscrasias  or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 6 9 of 1 0 9 
 
 
N ote: 
 A pr oce d ure is n ot a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y be a n A E or 
S A E. 
 Treat me nt re q uiri n g h os pitaliza ti o ns f or pre-e xisti n g c o n diti o ns w hic h d o n ot w orse n i n 
se verit y are n ot S A Es. 
9. 2. 5.  
A d verse E ve nts of S peci al I nterest 
9. 2. 5. 1.  
C o m bi ne d Ele v ati o ns of A m i n otr a nsfer ases a n d Bilir u bi n 
T here was n o cli nicall y c o ncer ni n g si g nal of dr u g- i n d uce d li ver i nj ur y ass ociate d wit h e d o xa ba n 
base d o n t he e xte nsi ve gl o bal P hase 3 e x perie n ce i n v ol vi n g o ver 3 4, 1 0 0 e d o xa ba n s u bject- years 
e x p os ure ( wit h me dia n dr u g e x p os ure of ~ 2. 5 y ears a m o n g ~ 1 4, 0 0 0 e d o xa ba n s u bjects). H o we ver, 
t here  will  be  o n g oi n g  m o nit ori n g  of  he patic  e ve nts,  i ncl u di n g  c o m bi ne d  ele vati o ns  of  
a mi n otra nsferases a n d bilir u bi n ( A L T or A S T > 3 x U L N wit h si m ulta ne o us T B L > 2 x U L N), 
partic ularl y t h ose wit h o ut e vi de nce of c h olestasis ( A L P ≥2 x U L N is c o nsi dere d e vi de nce of 
p ossi ble c h olestasis) a n d wit h o ut alter n ati ve eti ol o g y f or he pat ocell ular da ma ge. 
C o m bi ne d  ele vati o ns  of  a mi n otra nsferases  a n d  bilir u bi n,  eit her  seri o us  or  n o n-seri o us  a n d  
w het her or n ot ca usall y relate d, s h o ul d al wa ys be re p orte d t o t he S p o ns or as s o o n as p ossi ble 
f oll o wi n g t he pr oce d ures o utli ne d i n Secti o n 9. 5  f or S A E re p orti n g. 
I n cases of li ver la b orat or y a b n or malities, or e vi de nce of li ver d ysf u ncti o n, it is i m p orta nt t o 
e ns ure t hat t he eti ol o g y of li ver i nj ur y is i de n tifie d a n d st u d y s u bjects are m o nit ore d u ntil t he li ver 
la b orat or y assess me nts ret ur n t o n or mal. 
 
9. 3.  
Cl assific ati o n f or A E assess me nt 
9. 3. 1.  
Se verit y Assess me nt 
T he se verit y of a n A E is gra de d as f oll o ws: 
Mil d:    
  
Disc o mf ort n ote d, b ut n o disr u pti o n of n or mal dail y acti vit y. 
M o derate:   
Disc o mf ort s ufficie nt t o re d uce or affect n or mal dail y acti vit y. 
Se vere:    
I na bilit y t o w or k or  perf or m n or mal dail y acti vit y. 
9. 3. 2.  
C a us alit y Assess me nt  
T he I n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n A E a n d t h e assi g ne d a ntic oa g ula nt-
base d re gi me n (i.e., e d o xa ba n- base d or V K A- base d) o n t he basis or his/ her cli nical j u d g me nt a n d 
t he f oll o wi n g defi niti o ns.  T he ca usalit y assess me nt s h o ul d be ma de base d o n t he a vaila ble 
i nf or mati o n a n d ca n be u p date d as ne w i nf or mati o n bec o mes a vaila ble. 
 1 = Relate d: 
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, a n d ca n n ot be  reas o na bl y e x plai ne d b y t he s u bject’s 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 0 of 1 0 9 
 
cli nical state or ot her fa ct ors (e. g., disease u n der st u d y, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns). 
T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, a n d is a k n o w n reacti o n t o a n y of t he st u d y 
me dicati o ns (i.e. t he c o m p o ne nts of eac h st u d y re gi me n) u n der st u d y or its 
c he mical gr o u p, or is pre d icte d b y k n o w n p har mac ol o g y. 
 2 = N ot Relate d: 
T he A E d oes n ot f oll o w a reas o na ble se q ue nce fr o m t he assi g ne d a ntic oa g ula nt-
base d re gi me n a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s 
cli nical state or ot her fa ct ors (e. g., disease u n der st u d y, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns). 
9. 3. 3.  
Acti o n T a ke n Re g ar di n g t he Assi g ne d A ntit hr o m b otic Re gi me n 
F or eac h st u d y treat me nt, t he acti o n ta ke n after a n A E m ust be rec or de d i n t he e C R F as deli neate d 
bel o w: 
1 = D ose N ot C ha n ge d: N o c ha n ge i n d osa ge was ma de. 
2 = Dr u g Wit h dra w n: Per ma ne ntl y st o p pe d. 
3 = D ose Re d uce d: T he d osa ge was re d uce d. 
4 = Dr u g I nterr u pte d: Te m p oraril y st o p pe d. 
5 = D ose I ncrease d: T he d osa ge was i ncrease d. 
9. 3. 4.  
Ot her Acti o n T a ke n f or E ve nt 
1 = N o ne: N o treat me nt was re q uire d. 
2 = C o nc o mita nt me dicati o n re q uire d: Prescri pti o n a n d/ or o ver-t he-c o u nter 
me dicati o n were re q uire d t o treat t he A E. 
3 = C o nc o mita nt me dicati o n per ma ne ntl y disc o nti n ue d: Prescri pti o n a n d/ or o ver-
t he-c o u nter me dicati o n ot her t ha n t he assi g ne d a ntic oa g ula nt- base d re gi me n 
was per ma ne ntl y disc o nti n ue d d ue t o t he A E.  
4 = C o nc o mita nt me dicati o n te m p oraril y i n terr u pte d: Prescri pti o n a n d/ or o ver-t he-
c o u nter me dicati o n ot her t ha n t he assi g ne d a ntic oa g ula nt- base d re gi me n was 
te m p oraril y i nterr u pte d d ue t o t he A E.  
5 = Ot her. 
9. 3. 5.  
A d verse E ve nt O utc o me 
1 = Rec o vere d/ Res ol ve d: T he s u bject f ull y rec o vere d fr o m t he A E wit h n o 
resi d ual effect o bser ve d. 
2 = Rec o vere d/ Res ol ve d wit h Se q uelae: T h e resi d ual effects of t he A E are still 
prese nt a n d o bser va ble. I ncl u de  se q uelae/resi d ual effects. 
3 = N ot Rec o vere d/ N ot Res ol ve d: T he A E itself is still prese nt a n d o bser va ble. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 1 of 1 0 9 
 
4 = Fatal 
5 = U n k n o w n 
T he I n vesti gat or s h o ul d f oll o w s u bjects wit h A E s u ntil t he e ve nt has res ol ve d or t he c o n diti o n has 
sta bilize d.  I n case of u nres ol ved A Es i ncl u di n g si g nifica nt a b n or mal la b orat or y val ues at t he e n d 
of st u d y assess me nt, t hese e ve nts will be f o ll o we d u p u ntil res ol uti o n or u ntil t he y bec o me 
cli nicall y n ot rele va nt. 
 
9. 4.  
Ti mi n g of A d verse E ve nt Re p orti n g 
All  A Es  m ust  be  rec or de d  a n d  re p orte d  fr o m  t h e  state d  starti n g  p oi nt  of  t he  cli nical  trial  
(i m me diatel y after si g ni n g I C) i ncl u di n g A Es ta ki n g place d uri n g t he a d mi nistrati o n of ot her 
dr u gs. E ve n if t he s u bject has n ot yet recei ve d t he i n vesti gati o nal treat me nt, u nt o war d me dical 
occ urre nces ha ve t o be treate d as A Es. 
T he peri o d of A E re p orti n g is defi ne d as f oll o ws: 
A Es t hat occ ur wit hi n 3 0 da ys after t he last  d ose of t he assi g ne d st u d y treat me nt, w hic h are 
re p orte d t o t he I n vesti gat or (re gar dless of t he date of a f oll o w- u p visit) m ust be rec or de d i n t he 
e C R F. 
 
9. 5.  
Re p orti n g S A Es/ A Es 
9. 5. 1.  
D oc u me nt ati o n 
T o effecti vel y e val uate t he safet y pr ofile of t he st u d y treat me nts, t his st u d y will re p ort all ( S) A Es 
occ urri n g after t he s u bject si g ns t he I C a n d u p t o 3 0 da ys after t he last d ose of t he assi g ne d 
treat me nt, w het her o bser ve d b y t he I n vesti gator or re p orte d b y t he s u bject. All A Es will be 
rec or de d o n t he A E/ O utc o me e C R F pa ge(s) a n d i ncl u de: 
 A n y c o m p o ne nts of t he st u d y e n d p o i nt assess me nts (see Secti o n 7 ); 
 A E t hat meet seri o us ness criteria (see Secti o n 9. 2. 4 );  
 A E t hat res ult i n i nterr u p ti o n or disc o nti n uati o n of t he assi g ne d st u d y treat me nt; 
 A E t hat meet t he criteria f or A E SI (see Secti o n 9. 2. 5 );  
 A n y ot her A E. 
All la b orat or y res ults a n d vital si g ns s h o ul d be e val uate d b y t he I n vesti gat or re gar di n g cli nical 
si g nifica nce.  Is olate d ab n or mal la b orat or y res ults or vital si g n fi n di n gs t hat are n ot part of a 
dia g n osis  s h o ul d  be  re p orte d  as  A Es  or  S A Es .  Me dical  c o n diti o ns  (i ncl u di n g  la b orat or y  
val ues/ vital si g ns t hat ar e o ut of ra n ge) t hat were dia g n ose d or  k n o w n t o e xist pri or t o I C will be 
rec or de d as part of me dical hist or y. 
All S A Es are t o be re p orte d acc or d i n g t o t he pr oce d ures i n Secti o n 9. 5. 2 .  Al wa ys re p ort t he 
dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is u na vaila ble, re p ort t he pri mar y si g n or 
s y m pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he narrati ve u ntil t he 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 2 of 1 0 9 
 
dia g n osis bec o mes a vaila ble.  If t he si g ns a n d s y m pt o ms are disti nct an d d o n ot s u g gest a c o m m o n 
dia g n osis, re p ort t he m as i n di vi d ua l e ntries of A E or S A E.  F or e ve nts t hat are seri o us d ue t o 
h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust  be re p orte d as t he S A E ( dia g n osis or s y m pt o m 
re q uiri n g h os pitalizati o n). 
A Es ma y be directl y o bser ve d, re p orte d s p o nta ne o usl y b y t he s u bjec t or b y q uesti o ni n g t he s u bject 
at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g a b o ut t he 
occ urre nce  of  a n y  s pecific  s y m pt o ms.   T he  I n ve sti gat or  m ust  assess  all  A Es  t o  deter mi ne  
seri o us ness, se verit y, a n d ca usalit y, i n acc or da nce wit h t he defi niti o ns i n Secti o ns 9. 2  a n d 9. 3 .  
T he I n vesti gat or’s assess me nt m ust be clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n wit h 
t he I n vesti gat or’s si g nat ure. 
I n case of a n occ urre nce of a n ( S) A E, t he I n vesti gat or a p plies t he f oll o wi n g r ules: 
 E ns ure a p pr o priate me dical treat me nt a n d deci de w het her t o disc o nti n ue or i nterr u pt a n y 
of t he st u d y me dicati o ns. 
 C o m plete t he i nitial A E/ O utc o me e C R F pa ge u p o n e ve nt a ware ness. 
 Rec or d t he e ve nt, its ma na ge me nt, a n d o utc o me i n t he  e C R F pa ge. 
 F or S A Es, re p ort i n t he e C R F wit hi n 2 4 h o urs of recei vi n g k n o wle d ge of t he occ urre nce. 
I n t he e ve nt t hat all t he re q uire d i nf or mati o n is n ot a vaila ble, t he i nf or mati o n w hic h is 
a vaila ble is t o be se nt wit h o ut dela y ( wit hi n  2 4 h o urs), a n d t he o utsta n di n g data rela ye d as 
s o o n as a vaila ble t hereafter. A ns wer a n y q ueries relate d t o t he re p o rte d S A E as s o o n as 
p ossi ble. 
 F or A E SIs, re p ort wit hi n 2 4 h o urs  of recei vi n g k n o wle d ge of t he occ urre nce as defi ne d f or 
S A Es a b o ve. 
 F or A Es, o btai n all data re q uire d i ncl. a n y i nf or mati o n w hic h, is o nl y a vaila ble after 
c o nsi dera ble  dela y  (i.e.  h os pital  re p or ts,  o utc o mes,  res ol uti o n  e n d  dates),  as  s o o n  as 
a v ail a ble  
 C o m p o ne nts of t he st u d y e n d p oi nt assess me nts w hic h res ult i n deat h m ust be re p orte d as 
S A Es wit hi n 2 4 h o urs  of t he I n vesti gat or’s a ware ness. 
9. 5. 2.  
N otif yi n g  Re g ul at or y  A ut h orities,  I n vesti g at ors  a n d  I nstit uti o n al  Re vie w 
B o ar d/I n de pe n de nt Et hics C o m mittee 
Detaile d S A E pr ocessi n g, distri b uti o n a n d re p orti n g will be lai d o ut i n s p o ns or’s S A E Fl o w Pla n. 
S p o ns or a n d/ or C o ntract Resear c h Or ga nizati o n ( C R O) will i nf or m  I n vesti gat ors, I nstit uti o nal 
Re vie w B oar ds (I R Bs)/I n de pe n de nt Et hics C o m mitt ees (I E Cs), a n d re g ulat or y a ut h orities of a n y 
S us pecte d U ne x pecte d Seri o us A d verse E ve nt R eacti o ns ( S U S A Rs) occ urri n g i n t he st u d y or 
ot her  s p o ns or  st u dies  of  t he  i n vesti gati o nal  pr o d uct,  as  a p pr o priate  per  l ocal  re p orti n g  
re q uire me nts. 
I n t he E U c o u ntries, it is t he S p o ns or’s res p o nsi bilit y t o re p ort S U S A Rs t o re g ulat or y a ut h orities 
a n d I E Cs. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 3 of 1 0 9 
 
St u d y e n d p oi nts are cli nicall y a ntici pate d e ve nts i n A F s u bjects recei vi n g a ntit hr o m b otic t hera p y 
a n d  will  be  peri o dicall y  re vi e we d  b y  t he  D S M B  i n  a  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 safet y iss ues. 
 
9. 6.  
Re p orti n g of Pre g n a nc y/ E x p os ure i n Uter o 
T he s p o ns or or desi g nee m ust be n otifie d of a n y s u bject t hat bec o mes pre g na nt w hile partici pati n g 
i n a cli nical st u d y. All pre g na ncies m ust be f oll o we d t o c o ncl usio n t o deter mi ne t heir o utc o me. 
T his  i nf or mati o n  is  i m p orta nt  f or  b ot h  dr u g  sa fet y  a n d  p u blic  healt h  c o ncer ns.  It  is  t he  
res p o nsi bilit y of t he I n vesti gat or, or desi g nee, t o re p ort a n y preg na nc y i n a s u bject, w hic h occ urs 
d uri n g t he st u d y. 
If a n y st u d y s u bject bec o mes, or is f o u n d t o be, pre g na nt w hile recei vi n g, or wit hi n 3 0 da ys of 
disc o nti n ui n g t he i n vesti gati o nal pr o d uct, t he I n ve sti gat or s h o ul d c o ntact t he Me dical M o nit or t o 
disc uss s u bject ma na ge me nt a n d recei ve f urt her i nf or mati o n. N otificati o n of t he pre g na nc y s h o ul d 
be  s u b mitte d  i n  t he  e C R F  ( A E SIs)  wit hi n  2 4  h o urs  a n d  re p orte d  usi n g  E x p os ure  i n  Uter o  
Re p orti n g f or m ( pa per f or m).  
If it is t he part ner, rat her t ha n t he s u bject, w h o is f o u n d t o be  pre g na nt, t he E x p os ure i n Uter o 
Re p orti n g F or m s h o ul d be c o m plete d wit h t he s u bj ects’ I D n u m ber, a n d year of birt h. Details 
re gar di n g t he part ner s h o ul d be e ntere d i n t he narrati ve Secti o n of t he E x p os ure i n Uter o Re p orti n g 
f or m if a c o nse nt of t he trial s u bject’s part ner has bee n o btai ne d b y t he I n vesti gat or. 
If t he pre g na nc y is t o be ter mi nate d, t he a ntici pate d date of ter mi nati o n sh o ul d be pr o vi de d. If t he 
pre g na nc y e n ds f or a n y reas o n bef ore t he a nti ci pate d date, t he I n vest i gat or s h o ul d n otif y t he 
S p o ns or. If t he o utc o me of t he pre g na nc y meets t he criteri a f or i m me di ate cl assific ati o n as a 
S A E  (i.e.  p ost- p art u m  c o m plic ati o ns,  s p o nt a ne o u s  a b orti o n,  still birt h,  ne o n at al  de at h,  or 
c o n ge nit al  a n o m al y,  i ncl u di n g t h at  i n  a n  a b orte d  fet us), t he I n vesti gat or s h o ul d f oll o w t he 
pr oce d ures f or re p orti n g a n S A E.  At t he c o m pleti o n of t he pre g na nc y, t he I n vesti gat or will 
d oc u me nt t he o utc o me of t he pre g na nc y i n a f oll o w- u p E x p os ure i n Uter o Re p orti n g F or m. 
 
9. 7.  
Cli nic al L a b or at or y E v al u ati o ns 
Refer t o t he La b orat or y Ma n ual f or detaile d i nst r ucti o ns of sa m ple c ollecti o n, st ora ge, a n d 
s hi p me nt. T he res ults will be re vie we d a n d c o m pare d t o t he ce ntral la b ora t or y’s n or mal ra n ges. 
T he visits at w hic h t hese sa m ples will be c ollec te d are s h o w n i n t he sc he d ule of assess me nts 
( Secti o n 1 6. 9 ). 
T he f oll o wi n g safet y la b orat or y e val uati o ns ar e perf or me d i n i n di vi d ual bl o o d sa m ples.  
 Li ver F u ncti o n Pa nel 
o  T B L (c o nj u gate d/ u nc o nj u gate d perf or me d w he n t otal ser u m bilir u bi n ≥2 m g/ d L) 
o  A L T 
o  A S T 
o  A L P 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 4 of 1 0 9 
 
 Ser u m C he mistr y Pa nel 
o  Creati ni ne 
 He mat ol o g y Pa nel i ncl u di n g 
o  W B C c o u nt wit h differe ntial if ele vate d 
o  Re d Bl o o d Cell c o u nts a n d stat us (e. g., he m o gl o bi n, he mat ocrit) 
o  Platelet c o u nt 
 I N R ( o nl y i n s u bjects ra n d o mize d t o V K A) 
I n w o me n of c hil d beari n g p ote ntial, a uri ne test f or pre g na nc y will be perf or me d at scree ni n g, at 
baseli ne, a n d at Da y 3 0. F urt her m or e, pre g na nc y te sts are carrie d o ut w he ne ver t here are cli nical 
i n dicati o ns f or t he e xiste nce of a pre g na nc y. 
All ot her assess me nts are c ollecte d fr o m l ocal la b orat or y res ults f or tests d o ne as part of r o uti ne 
care. L ocal la b orat or y assess me nts are use d t o verif y eli gi bilit y a n d f or para meters t hat re q uire 
m o nit ori n g acc or di n g t o l ocal r o uti ne. 
 
9. 8.  
Vit al Si g ns 
T he f oll o wi n g para meters are rec or de d f or vital si g ns: 
 Heart Rate (at all visits p ost scree ni n g) 
 B P, sitti n g diast olic a n d s yst olic B P (at all visits) 
 Wei g ht (at all visits) 
 Hei g ht ( o nl y at ra n d o mizati o n) 
 
9. 9.  
Electr oc ar di o gr a ms 
T wel ve-lea d  E C Gs  are  c ollecte d  acc or di n g  t o  t he  sc he d ule  of  assess me nts  ( Secti o n  1 6. 9 ).  
I n vesti gati o nal sites will utilize l ocal E C G e q uip me nt a n d rec or d perti ne nt i nf or mati o n i n t he 
e C R F w hile preser vi n g all rec or de d E C G traci n gs as s u bject s o urce d oc u me ntati o n.  
 
9. 1 0.  
P h ysic al E x a mi n ati o n Fi n di n gs 
T he I n vesti gat or or a lice nse d te a m me m ber perf or ms tar gete d p h ys ical e xa mi nati o n at Scree ni n g. 
T his p h ysical e xa mi nati o n c o nsists of assess me nt of eac h of t he rele va nt (i ncl u di n g b ut n ot li mite d 
t o car diac, ne ur ol o gic, p ul m o nar y, GI) maj or b o d y s yste ms. A n y cli nicall y si g nifica nt fi n di n gs 
m ust be rec or de d i n t he e C R F u n der me dical hist or y. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 5 of 1 0 9 
 
9. 1 1.  
M a g netic Res o n a nce I m a gi n g: Diff usi o n- Wei g hte d I m a gi n g 
Pr oce d ure-ass ociate d str o ke, as t h e m ost se vere disa blin g c o m plicati o n, is rare a n d occ urs i n less 
t ha n 1 % of s u bjects u n derg oi n g a blati o n. Ma g netic res o na n ce i ma gi n g ( M RI) i de ntifie d ne w 
e m b olic lesi o ns i n 4 0- 5 0 % of cases. P ositi ve M RI fi n di n gs ma y occ ur i n patie nts wit h o ut a p pare nt 
ne ur ol o gical deficit a n d are t heref ore classifie d as “as y m pt o matic” or “sile nt”. Sile nt cere bral 
e ve nts  ( S C E)  are  n ot  u ni q ue  t o  A F  a blati o n  b ut  ha ve  bee n  i de ntifie d  after  nearl y  a n y  C V  
i nter ve nti o ns, i ncl u di n g c or o nar y a n gi o gra p h y i n 1 5 %, val ve s ur ger y i n 4 2 %, a n d b ot h o n-a n d 
off- p u m p C A B G i n 2 2 %. As a c o nse q ue nce, S C E or sile nt cere bral le si o ns ( S C L) ha ve bee n 
ter me d t he “e m b olic fi n ger pri nt” of a s pecific C V i nter ve nti o n (2 9 ). 
I n c o m parati ve st u dies, S C E ( D WI- M RI p ositi ve o nl y) a p pear t o be a p pr o xi matel y 3 ti mes m ore 
c o m m o n c o m pare d t o usi n g a defi niti o n of sile nt  cere bral lesi o ns ( S C L; wit h o ut fl ui d atte n uate d 
i n verse rec o ver y se q ue nce [ F L AI R] p ositi vit y). W hereas t he F L AI R se q ue nce ma y t ur n p ositi ve 
wit hi n da ys after t he isc he mic e ve nt, S C E de fi niti o n is hi g hl y se nsitive f or earl y p hases of 
isc he mic brai n da ma ge. 
D W- M RI will be perf or me d i n a s u bset of st u d y s ites i n or der t o assess t he i nci de nce of S C E/ S C L 
u n der t he N O A C e d o xa ba n as c o m pare d t o c urre nt st a n dar d of care ma na ge me nt of u ni nterr u pte d 
V K A i n patie nts u n der g oi n g a n a blati o n pr oce d ure. 
T he M RI o utc o mes of i nterest i ncl u de b ut are n ot li mite d t o: ac ute D WI i nfarct prese nt or n ot, 
n u m ber of ac ute D WI i nfarcts prese nt, v ol u me of  eac h ac ute D WI i nfarct, t otal ac ute D WI i nfarct 
v ol u me, w hite matter lesi o n v ol u me o n T 2/ F L AI R, gre y matter ( G M) lesi o n v ol u me (ac ute a n d 
c hr o nic i nfarcts) o n T 2/ F L AI R. 
T he M RI pr ot oc ol will be pr o vi de d i n its e ntire t y i n t he Trial Site I ma gi n g Ma n ual a n d will be 
a da pte d acc or di n g t o t he M RI ve n d or a n d s pecificati o ns. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 6 of 1 0 9 
 
1 0.  
S T A TI S TI C A L M E T H O D S 
A ge neral descri pti o n of t he statis tical met h o ds use d is o utli ne d bel ow. A m ore detaile d statistical 
a nal ysis pla n ( S A P) will be pr o vi de d i n a se parate d oc u me nt. T he S A P will als o acc o m m o date 
pr ot oc ol a me n d me nts or u ne x pecte d iss ues i n st u d y e xec uti o n or data t hat affect pla n ne d a nal yses, 
a n d will pr o vi de m ore details o n t he a nal ytic a p pr oac hes, c o di n g g ui deli nes, ce ns ori n g of ti me-
t o-e ve nt varia bles, a n d o ut p ut ta bles a n d fi g ures. T o preser ve t he i ntegrit y of t he statistical a nal ysis 
a n d cli nical st u d y c o ncl usi o ns, t he S A P will be fi nalize d pri or t o data base l oc k. 
 
1 0. 1.  
A n al ysis Sets 
1 0. 1. 1.  
I nte nt-t o- Tre at A n al ysis Set 
T he I nte nt-t o-treat (I T T) a nal ysis set c o nsists of  all ra n d o mize d s u bjects irres pecti ve w het her t he y 
recei ve d a si n gle d ose of t he ra n d o mize d st u d y re gi me n or n ot. 
A nal yses will be base d o n t he ra n d o mize d treat me nt re gi me n e ve n if a s u bject i na d verte ntl y 
recei ves  t he  i nc orrect  dr u g(s)  or  d osa ge  or  has  his/ her  e d o xa ba n  d ose  a dj uste d  ( decrease d/  
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of r a n d o mizati o n. 
1 0. 1. 2.  
M o difie d I nte nt-t o- Tre at A n al ysis Set 
T he m o difie d I nte nt-t o- Treat ( mI T T) a nal ysis set c o nsists of all ra n d o mize d s u bjects w h o recei ve d 
at least o ne d ose of st u d y e d o xa ba n or st u d y V K A acc or di n g t o I X R S assi g n me nt.  
A nal yses will be base d o n t he ra n d o mize d treat me nt re gi me n e ve n if a s u bject i na d verte ntl y 
recei ves  t he  i nc orrect  dr u g(s)  or  d osa ge  or  has  his/ her  e d o xa ba n  d ose  a dj uste d  ( decrease d/  
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of first i ntake of st u d y e d o xa ba n or st u d y V K A. 
1 0. 1. 3.  
Per Pr ot oc ol A n al ysis Set 
T he Per Pr ot oc ol ( P P) a nal ysis se t c o nsists of all ra n d o mize d s u bjects w h o recei ve d at least o ne 
d ose of t he st u d y re gi me n a n d d o n ot ha ve a n y of  t he f oll o wi n g maj or pr ot oc ol vi olati o ns: 
 N ot u n der g oi n g a cat heter a blati o n  
 N o A F 
 K n o w n c o ntrai n dicati o n f or O A C 
 A maj or vi olati o n of t he i ncl usi o n criteria 
 A maj or vi olati o n of t he e xcl usi o n criteria 
T he f ull list of maj or vi olati o ns wi ll be descri be d i n t he S A P a n d finalize d bef ore data base l oc k.  
T he list a n d t he e xcl usi o ns will be c o nfir me d i n a bli n de d wa y, i.e. wit h o ut k n o wle d ge of t he 
ra n d o mize d st u d y re gi me n a n d of t he cli nical o utc o mes. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 7 of 1 0 9 
 
A nal yses will be base d o n t he ra n d o mize d treat m e nt re gi me n, e ve n if a s u bject i na d verte ntl y 
recei ves t he i nc orrect dr u g(s) or d osa ge or has his/ her e d o xa ba n d osa ge a dj uste d ( decrease d/ 
i ncrease d) o ne or m ore ti mes d uri n g t he st u d y. T he refere nce date f or c o nsi derati o n of e n d p oi nts 
is t he date a n d ti me of first i ntake of st u d y e d o xa ba n or st u d y V K A. 
1 0. 1. 4.  
S afet y A n al ysis Set 
T he Safet y ( S A F) a nal ysis set c o nsists of all ra n d o mize d s u bjects w h o rece i ve d at least o ne d ose 
of t he st u d y e d o xa ba n or st u d y V K A acc or di n g t o I X R S assi g n me nt. 
A nal yses will be base d o n t he ra n d o mize d trea t me nt re gi me n, e ve n if t he s u bject’s e d o xa ba n 
d osa ge  is  a dj uste d  after  ra n d o mizati o n,  u nless  a  s u bject  i na d verte ntl y  recei ves  t he  i nc orrect  
dr u g(s) or d osa ge d uri n g t he e nti re st u d y, i n w hic h case t he s u bject will be gr o u pe d acc or di n g t o 
t he treat me nt act uall y recei ve d. T he refere nce date f or c o nsi deratio n of e n d p oi nts is t he date of 
first st u d y me dicati o n i nta ke. 
N ote: T his S A F a nal ysis set will be use d f or t he safet y para meters (e. g. A Es, vital si g ns, la b orat or y 
para meters, etc.) as descri be d u n der Secti o n 9 . 
 
1 0. 2.  
Ge ner al St atistic al C o nsi der ati o ns 
Acc or di n g t o t he o bjecti ves of t his st u d y, t he statistical a nal ysis s h o ul d be i nter prete d i n a p urel y 
e x pl orat or y- descri pti ve wa y. N o  f or mal c o nfir mat or y statistical testi n g is pla n ne d. 
All a nal yses will be perf or me d o n o bser ve d data  o nl y. N o missi n g data will be i m p ute d. Data o n 
s u bjects w h o d o n ot reac h a s pecific e n d p oi nt will be ce ns ore d i n t he c orres p o n di n g statistical 
a nal yses. 
Ra w data will be prese nte d wit h t he e xact precis i o n ( deci mal p oi nts) wit h w hic h it was c ollecte d. 
T he p- val ues will be prese nte d i n t he e n d- of-te xt ta bles e xactl y as t he y are i n s u p p orti n g statistical 
d oc u me nts ( 4 deci mal p oi nts). T he te xt a n d i n-te xt ta bles will dis pla y p- val ues wit h t hree deci mal 
places, as l o n g as, t he decisi o n f o r statistical si g nifica nce will n ot be c ha n ge d b y r o u n di n g.  
T he n u m ber of deci mal places t o dis pla y f or calc ul ate d data will be deter mi ne d b y t he scale of 
meas ure me nt. N o deci mal places will be dis p la ye d if t he s mallest calc ulate d val ue is ≥1 0 0; O ne 
( 1) deci mal place will be dis pla ye d w he n all calc ulate d val ues are wit hi n t he i nter val ( 1 0, 1 0 0), 
wit h 1 0 bei n g i ncl usi ve; T w o ( 2) deci mal places w ill be dis pla ye d w he n all calc ulate d val ues are 
wit hi n  ( 1,  1 0),  wit h  1  bei n g  i ncl usi ve;  a n d  s o  o n  f or  e ve n  s maller  scales  of  meas ure me nt.  
Perce nta ges will be re p orte d wit h  e xactl y o ne deci mal place.  
F or c o nti n u o us varia bles, statistical s u m mar ies will i ncl u de n ( n u m ber of s u bjects wit h n o n-
missi n g data), mea n, me dia n, sta n dar d de viati o n, mi ni m u m a n d ma xi m u m. Mea ns a n d me dia ns 
will be dis pla ye d t o o ne m ore deci mal places t ha n t he ra w or calc ulate d data; sta n dar d de viati o n 
a n d ot her dis persi o n statistics will ha ve t wo m ore deci mal places; a n d mi ni m u m a n d ma xi m u m 
val ues will be dis pla ye d t o t he sa me n u m ber of  deci mal places as t he ra w or calc ulate d data. 
F or cate g orical varia bles, statistical s u m maries will i ncl u de c o u nts a n d perce nta ges. Perce nta ges 
will be re p orte d wit h e xactl y o ne deci mal place. I n ge neral, perce nta ges are base d o n t he t otal 
n u m ber of s u bjects wit h i nf or mati o n a vaila ble (ie n o n- missi n g data). F or A E a n d i nci de nce base d 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 8 of 1 0 9 
 
a nal yses, perce nta ges will be base d o n t he t otal n u m b er of s u bjects i n t he a nal ysis set of i nterest 
a n d i n t hat treat me nt re gi me n. 
T he  statistical  data  a nal ysis  will  be  perf or me d  b y  a  C R O  u n der  t he  g ui da nce  of  t he  st u d y  
bi ostatisticia n usi n g S A S Versi o n 9. 3 or hi g her. 
 
Defi niti o n of ter ms: 
‘Over all St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m t he refere nce date ( date a n d ti me 
of ra n d o mizati o n or date a n d ti me of firs t d ose of st u d y me dicati o n) t o Da y 9 0/ E O T. 
‘Over all St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me fr o m t he refere nce date 
( date a n d ti me of ra n d o mizati o n or date a n d ti me of first d ose of st u d y me dicati o n) t o Da y 9 0/ E O T 
+ 3 0 da ys. 
‘P ost- a bl ati o n St u dy Peri o d ’:   T his peri o d is defi ne d as t he ti me fr o m t he e n d of t he cat heter 
a blati o n pr oce d ure t o Da y 9 0/ E O T. 
‘P ost- a bl ati o n St u dy Peri o d + 3 0 d ays ’:   T his peri o d is defi ne d as t he ti me fr o m t he e n d of t he 
cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T + 3 0 da ys. 
 
F oll o w- u p is ce ns ore d at t he last  date of k n o w n f oll o w- u p stat us i n s u bjects wit h i nc o m plete 
f oll o w- u p. I n vesti gat ors are i nstr ucte d t o c o m plete f oll o w- u p as m uc h as p ossi ble irres pecti ve of 
c ha n ges or disc o nti n uati o n of st u d y me dicati o n. 
All a dj u dicate d e n d p oi nts are a nal yze d as ti me t o first occ urre nce of a n y of its c o m p o ne nts. 
F or all s pecific e n d p oi nts bli n dl y a dj u dicate d b y t he C E C, t he C E C’ s i nter pretati o n pre vails a n d 
is use d i n t he statistical a nal yses. 
T he a nal ysis set a n d a nal ysis peri o d t o be use d f or t he mai n a nal ysis of t he vari o us a dj u dicate d 
e n d p oi nts is prese nte d bel o w: 
E n d p oi nt(s) 
Pri m ar y a n al ysis set   
Pri m ar y a n al ysis peri o d 
Pri mar y  
P P 
p ost-a blati o n peri o d 
Pri mar y safet y  
mI T T 
o verall st u d y peri o d 
Sec o n dar y efficac y  
P P 
p ost-a blati o n peri o d 
Sec o n dar y safet y  
mI T T 
o verall st u d y peri o d 
 
H o we ver, i n s u p ple me ntal a nal yses, ot her c o m bi nati o ns of a nal ysis sets a n d a nal ysis peri o ds ma y 
be c o nsi dere d t o e val uate t he r o b ust ness of t he mai n a nal yses o n a dj u dicate d efficac y a n d/ or safet y 
e n d p oi nts. Details o n t hese a nal yses  will be descri be d i n t he S A P. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 7 9 of 1 0 9 
 
1 0. 3.  
St u d y P o p ul ati o n D at a 
S u bject dis p ositi o n will be s u m marize d f or eac h  ra n d o mize d treat me nt a n d i n t otal f or t he I T T 
a nal ysis set. T he n u m ber of s u bjects f or eac h de fi ne d a nal ysis set b y treat me nt gr o u p will als o be 
ta b ulate d. 
T he  de m o gra p hic  a n d  baseli ne  c haracteristics  i ncl u di n g  baseli ne  disease  stat us  will  be  
s u m marize d descri pti vel y b y treat me nt gr o u p f or t he I T T, mI T T, P P a n d S A F a nal ysis sets. 
E x p os ure  t o  st u d y  me dicati o n  (e d o xa ba n  a n d  V K A)  will  be  s um marize d  usi n g  descri pti ve  
statistics b y treat me nt gr o u p f or t he mI T T, P P a n d S A F a nal ysis sets. I nterr u pti o ns a n d per ma ne nt 
disc o nti n uati o ns (see Secti o n 5. 2. 3 ) will be s u m marize d b y treat me nt gr o u p f or t he sa me a nal ysis 
sets. 
T he ti me i n t hera pe utic ra n ge ( T T R) (I N R: 2. 0- 3. 0, i ncl usi ve) will be esti mate d f or eac h s u bject 
ra n d o mize d t o t he V K A ar m usi n g t he i nter p olati o n met h o d of R ose n daal (3 0 ). 
1 0. 4.  
St atistic al A n al ysis 
1 0. 4. 1.  
A n al ysis of A dj u dic ate d Effic ac y E n d p oi nts 
T he f oll o wi n g e n d p oi nts are c o nsi dere d as efficac y e n d p oi nts: 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d Maj or 
Blee di n g [I S T H defi niti o n] ( pri m ary effic acy e n d p oi nt ) 
 C o m p osite of all-ca use deat h, str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d, acc or di n g 
t o alter nati ve defi niti o n (1 ); see Secti o n 7. 4. 2 . f or details) a n d Maj or Blee di n g (I S T H 
defi niti o n) 
 C o m p osite of str o ke (isc he mic, he m orr ha gic , or u n deter mi ne d) S E E, a n d C V m ortalit y  
 C o m p osite of str o ke (isc he mic, he m orr ha g ic, or u n deter mi ne d) S E E, a n d all-ca use 
m ortalit y 
 C o m p osite of str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) a n d TI A 
 Str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 Str o ke (isc he mic) 
 Str o ke ( he m orr ha gic) 
 Str o ke ( u n deter mi ne d) 
 S E E 
 TI A 
 Fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n-fatal str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d)  
 Disa bli n g str o ke (isc he mic, he m orr ha gic, or u n deter mi ne d) 
 N o n- disa bli n g str o ke (isc he mic,  he m orr ha gic, or u n deter mi ne d) 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 0 of 1 0 9 
 
 
F or all e n d p oi nts bli n dl y a dj u dica te d b y t he C E C, t he C E C’s i nter pretati o n pre vails a n d is use d i n 
t he statistical a nal ysis. 
F or eac h of t he pri mar y a n d sec o n dar y efficac y e n d p oi nts, a p pr o priate s u m mar y statistics (e. g. 
e ve nt rate) i ncl u di n g 9 5 % c o nfi de nce i nter val ( CI) will be pr o vi de d.  
F or eac h of t he e n d p oi nts, t he ti me fr o m refere nce da te t o t he first occ urre nce of a n e ve nt ( base d 
o n C E C a dj u dicati o n) is a nal yze d usi n g a C o x pr o p orti o nal hazar d m o del wit h treat me nt re gi me n 
as a fact or, t o pr o vi de p oi nt esti mates a n d 9 5 %  CI f or t he hazar d rati o ( H R). De pe n di n g o n t he 
a nal ysis peri o d use d i n t he statistical a nal ysis, s u bjects wit h o ut a n occ urre nce of a n e ve nt will be 
ce ns ore d at t he last date of t he a nal ysis peri o d or at t he last date of k n o w n o utc o mes stat us. T he 
latter is deter mi ne d a n i n di vi d ual basis f or s u bjects wit h i nc o m plete f oll o w- u p. 
T he para meter esti mate β  ( = l n ( H R), its sta n dar d err or, p- val ue, a n d 9 5 % c o nfi de nce li mits are 
calc ulate d  acc or di n g  t o  t he  ma xi m u m  partia l  li keli h o o d  met h o d  ( M L),  wit h  Bresl o w’s  
a p pr o xi mati o n f or ties ( S A S P H R E G pr oce d ure). 
F or ti me t o first e ve nt a nal yses base d o n t he ‘ o verall st u d y peri o d’, ‘ o verall st u d y peri o d + 
3 0 da ys’, ‘ p ost-a blati o n st u d y peri o d’ a n d p ost-a blati o n st u d y peri o d + 3 0 da ys’, c u m ulati ve e ve nt 
rates o ver ti me are s u m marize d usi n g t he Ka pla n- Meier met h o d. 
1 0. 4. 2.  
A n al ysis of A dj u dic ate d S afet y E n d p oi nts 
T he f oll o wi n g e n d p oi nts are c o nsi dere d as safet y e n d p oi nts: 
 Maj or Blee di n g [I S T H defi niti o n] ( pri m ary s afety e n d p oi nt ) 
 Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 Maj or or C R N M blee di n g [I S T H defi niti o n] 
 C R N M blee di n g [I S T H defi niti o n] 
 Mi n or blee di n g [I S T H defi niti o n] 
 A n y blee di n g 
 I C H 
 Life-t hreate ni n g blee di n g 
 Fatal Maj or Blee di n g [I S T H defi niti o n] 
 N o n-fatal Maj or Blee di n g [I S T H defi niti o n] 
 Fatal Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 N o n-fatal Maj or Blee di n g [ defi ne d b y TI MI, B A R C ( 2 or hi g her)] 
 
All t hese e n d p oi nts will be a nal yze d usi n g t he sa me me t h o d ol o g y as descri be d i n Secti o n 1 0. 4. 1 . 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 1 of 1 0 9 
 
1 0. 4. 3.  
A n al ysis of Ot her P ar a meters 
All para meters me nti o ne d i n Secti o n 7. 3. 1  will be s u m marize d descri pti vel y b y treat me nt 
re gi me n f or t he I T T, mI T T, a n d P P a nal ysis sets. 
 
1 0. 4. 4.  
S afet y A n al yses 
1 0. 4. 4. 1.  A d verse E ve nt A n al yses 
A d verse e ve nts meeti n g t he criteria defi ne d i n Secti o n  9. 1 will be rec or de d i n t he e C R F a n d c o de d 
b y s yste m or ga n class a n d preferre d ter m usi n g t he Me dical Dic ti o nar y f or Re g ulat or y Acti vities 
( Me d D R A), versi o n 1 9. 1 or ne wer. 
Treat me nt-e mer ge nt a d verse e ve nts ( T E A Es) are defi ne d as e ve nts w hic h star t o n or after a n y first 
d ose of t he assi g ne d st u d y me dicati o n re gi me n or starte d pri or t o b ut  t he n w orse ne d after a n y first 
d ose of t he assi g ne d st u d y me dicati o n re gi me n. A n A E t hat occ urs m ore t ha n 3 0 da ys after t he date 
of t he last d ose of t he assi g ne d st u d y me dicati o n re gi me n will  n ot be c o u nte d as a T E A E. 
T he A E a nal ysis will be base d o n t he S A F a nal ys is set. T E A Es will be s u m marize d b y treat me nt 
gr o u p. T he i nci de nce of T E A Es will be prese n te d b y treat me nt gr o u p, b y relati o ns hi p t o t he 
assi g ne d st u d y re gi me n, a n d b y se verit y.  If m ore t ha n o ne A E is c o de d t o t he sa me preferre d ter m 
f or t he sa me s u bject, t he s u bject will be c o u nte d o nl y o nce f or t hat preferre d ter m usi n g t he greatest 
se verit y a n d strictest ca usalit y f or t he s u m marizati o n b y se verit y a n d ca usal relati o ns hi p. Fre q ue nt 
T E A Es (re p orte d b y at least 5 % re s p. 1 % of s u bjects i n a n y treat ment gr o u p) will be s u m marize d 
b y re gi me n gr o u p. 
T he i nci de nce of deat h, S A Es, dr u g-relate d S A Es, a n d A Es lea di n g t o per ma ne nt disc o nti n uati o n 
of t he assi g ne d st u d y re gi me n will be s u m marize d.  All A Es rec or de d will be i ncl u de d i n a data 
listi n g a n d a listi n g t o dis pla y t he c o di n g of A Es will be pre pare d as well. 
1 0. 4. 4. 2.  Cli nic al L a b or at or y E v al u ati o n A n al yses 
T he cli nical la b orat or y e val uati o ns  f or eac h sc he d ule d test a n d t he c ha n ge fr o m baseli ne will be 
s u m marize d f or t he S A F a nal ysis set b y treat me nt gr o u p. S hift ta bles (i n cate g ories of l o w, n or mal, 
a n d hi g h) will be pr o vi de d f or eac h treat me nt re gi me n f or selecte d la b orat or y para meters. Als o, 
t he n u m ber a n d perce nta ge of s u bjects wit h cli nicall y rele va nt a b n or mal la b orat or y val ues w hile 
o n st u d y dr u g will be calc ulate d f or eac h treat m e nt re gi me n f or selecte d la b orat or y para meters. 
All a b n or mal la b orat or y val u es will be prese nte d i n a listi n g. M ore details w ill be pr o vi de d i n t he 
S A P. 
1 0. 4. 4. 3.  Vit al Si g ns A n al yses 
Vital si g ns at eac h e val uati o n p oi nt a n d t he c ha n ge  fr o m baseli ne will be s u m marize d f or t he S A F 
a nal ysis set b y treat me nt gr o u p. M ore de tails will be pr o vi de d i n t he S A P. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 2 of 1 0 9 
 
1 0. 4. 4. 4.  Electr oc ar di o gr a m A n al yses 
T he E C G e val uati o ns at ra n d o mizati o n, car diac a blati o n visit, h os pital disc ha r ge, Da y 3 0 a n d Da y 
9 0 will be s u m marize d b y treat me nt gr o u p base d o n S A F a nal ysis set. M ore details o n t he E C G 
a nal ysis will be pr o vi de d i n t he S A P. 
1 0. 4. 4. 5.  P h ysic al E x a mi n ati o n A n al yses 
A p h ysical e xa mi nati o n will o nl y be pe rf or me d at t he Scree ni n g visit. 
C o u nts  a n d  perce nta ges  of  p h ysical  e xa mi nati o n  fi n di n gs  will  be  s u m marize d  b y  treat me nt  
re gi me n base d o n S A F a nal ysis set. 
1 0. 4. 5.  
Ot her A n al yses 
Details o n a n y ot her a nal yses, if a p pl ica ble, will be gi ve n i n t he S A P. 
 
1 0. 5.  
I nteri m A n al yses 
N ot a p plica ble. 
 
1 0. 6.  
D at a a n d S afet y M o nit ori n g B o ar d  
T here will be a n i n de pe n de nt D S M B t o pr otect t he ri g hts, safet y  a n d well- bei n g of s u bjects 
partici pati n g i n t his st u d y. T he D S M B will be i n v ol ve d i n t he ma na ge me nt of t his cli nical st u d y 
ser vi n g as t he safet y m o nit ori n g a d vis or y gr o u p f or t he st u d y. T he pri mar y r ole of t he D S M B will 
be t o e xa mi ne t he safet y data (i nci de nce of Maj or Blee di n gs, C R N M bl ee di n g, or ot her safet y 
e n d p oi nts,  or  s us pecte d  relate d  ( S) A Es)  o n  a n  o n g oi n g  ma n ner  a n d  t o  alert  t he  E xec uti ve  
C o m mittee i n case of a n y cli nicall y c o ncer ni n g safet y iss ues. 
T he fre q ue nc y a n d e xte nt of t he data re vie ws b y t he D S M B, details a b o ut t he re vie ws a n d st o p pi n g 
r ules  or  criteria  f or  e val uati n g  nee d  f or  st u d y  pr ot oc ol  m o dificati o ns  will  be  descri be d  a n d  
s pecifie d i n t he D S M B c harter.  
 
1 0. 7.  
S a m ple Size Deter mi n ati o n 
T he pri mar y efficac y e n d p oi nt is t he i nci de nce of a c o m p osite of all-ca use deat h, str o ke (isc he mic, 
he m orr ha gic or u n deter mi ne d), a n d Maj or Blee di n g e ve nts (I S T H defi niti o n) d uri n g t he peri o d 
fr o m t he e n d of t he cat heter a blati o n pr oce d ure t o Da y 9 0/ E O T.  
A rate of u p t o 3 % of  t he c o m bi ne d pri mar y e n d p oi nt ca n be e x pecte d i n t he V K A ar m as o bser ve d 
fr o m  p u blis he d  st u dies  a n d  retr os pecti ve  a nalyses.  Base d  o n  a  ver y  rece nt  st u d y  i n v ol vi n g  
u ni nterr u pte d a ntic oa g ulati o n wit h V K A, a sli g htl y  l o wer rate of t he c o m bi ne d e n d p oi nt of a b o ut 
2 % ca n be a ntici pate d ( V E N T U R E A F [ 5 ]).  
I n a lar ge retr os pecti ve case series, fatal o utc o me i n cat heter a blati o n of A F has bee n f o u n d t o 
occ ur i n 0. 1 % ( 3 1 ). Ne ur ol o gical c o m plicati o ns ( p ost o perati ve str o ke/ TI A) were re p orte d i n 1. 0 % 
of patie nts u n der g oi n g a blati o n i n o ne lar ge s ur ve y ( 3 2 ). I n a n ot her s ur ve y, str o ke ( 0. 2 3 %) a n d 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 3 of 1 0 9 
 
TI A ( 0. 7 1 %) ha ve bee n re p orte d se paratel y ( 9 ). I n t he C O M P A R E st u d y, patie nts u n der c o nti n ue d 
a ntic oa g ulati o n wit h warfari n e x perie nce d 0. 2 5 % str o kes ( 1 4 ). I n a m ore rece nt st u d y i n v ol vi n g 
N O A Cs, a rate 2. 1 % of str o kes has bee n f o u n d u n der V K A ( 1 0 ). Maj or Blee di n g c o m plicati o ns 
ha ve occ urre d wit h i nci de nces of 3. 3 8 % ( p ost o p he m orr ha ge) a n d 0. 5 8 % ( p ost o p he m orr ha ge 
re q uiri n g tra nsf usi o n) i n a lar ge s ur ve y (3 2 ). A n i nci de nce of 0. 3 8 % of Maj or Blee di n g e ve nts has 
bee n re p orte d i n t he C O M P A R E st u d y u n der c o nti n ue d a d mi nistra ti o n of warfari n (1 4 ). U n der 
i nterr u pte d V K A, t he i nci de nce of Maj or Blee di n g was 4. 2 % i n a n ot her rece nt st u d y ( 1 0 ). I n a 
f urt her rece nt st u d y i n vesti gati n g t w o re gi me ns of u ni nterr u pte d a ntic oa g ulati o n, 2. 2 % of Maj or 
Blee di n g e ve nts occ urre d i n t he warfari n gr o u p ( 1 1 ). I n a meta-a nal ysis c o veri n g a br oa der ra n ge 
of patie nts u n der g oi n g de vice i m pla ntati o n, 2. 8 % of patie nts were  s ufferi n g fr o m Maj or Blee di n g 
e ve nts u n der c o nti n ue d oral a ntic oa g ulati o n ( 3 3 ). 
Base d u p o n t his pre dicte d rate, a f or mal sa m ple  size deter mi nati o n base d o n n o n-i nferi orit y or 
s u peri orit y of e d o xa ba n vers us V K A is n ot feasi ble. T he st u d y size is pla n ne d base d u p o n t he 
pri mar y c o m p osite e n d p oi nt t o i n cl u de a n a de q uate n u m ber of s u bjects t hat wi ll pr o vi de t he 
e x pecte d i nci de nce rates o n t he pr i mar y e n d p oi nt. T heref ore, t he pla n is t o i ncl u de 4 5 0 s u bjects 
i n t he P P st u d y p o p ulati on (s u bjects w h o ha ve u n der g o ne t he a blati o n pr oce d ure a n d c o m pleti n g 
t he st u d y). I n or der t o ac hie ve t his, a p pr o xi matel y 5 6 0 s u bjects will nee d t o be e nr olle d i n t he 
st u d y. T he st u d y will be st o p pe d o nce t he n u m ber of 4 5 0 s u bjects bel o n gi n g t o t he P P a nal ysis set 
is reac he d. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 4 of 1 0 9 
 
1 1.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E 
T he I n vesti gat or/i n vesti gati o nal site will per mit st u d y-relate d m o nit ori n g, a u dits, I E C re vie w a n d 
re g ulat or y  i ns pecti o ns  b y  pr o vi din g  direct  access  t o  s o urce  data/ d oc u me nts.   Direct  access  
i ncl u des per missi o n t o e xa mi ne, a nal yze, verif y a n d re pr o d uce a n y rec or ds a n d re p orts t hat are 
i m p orta nt t o t he e val uatio n of a cli nical st u d y. 
 
1 1. 1.  
M o nit ori n g a n d I ns pecti o ns 
T he S p o ns or, site m o nit ors, a n d re g ulat or y a ut h orit y i ns pect ors are res p o nsi ble f or c o ntacti n g a n d 
visiti n g t he I n vesti gat or f or t h e p ur p ose of i ns pecti n g t he faci lities a n d, u p o n re q uest, i ns pecti n g 
t he vari o us rec or ds of t he st u d y (e. g., e C R Fs, s o urce data, a n d ot her perti ne nt d oc u me nts). 
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals (as detaile d i n t he M o nit ori n g 
Pla n) t hr o u g h o ut t he st u d y t o verif y a d here nce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d 
c o nsiste nc y of t he data; a n d a d here nce t o I nter nati o nal C o nfere nce o n Har m o nizati o n G o o d 
Cli nical Practice ( G C P) a n d l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is 
res p o nsi ble f or i ns pecti n g t he e C R Fs a n d e ns uri n g c o m plete ness of t he st u d y esse ntial d oc u me nts.  
T he m o nit or s h o ul d ha ve access t o s u bject me dical rec or ds a n d ot her st u d y-relate d rec or ds nee de d 
t o verif y t he e ntries o n t he e C R Fs. 
T he  m o nit or  will  c o m m u nicate  de viati o ns  fr o m  t he  pr ot oc ol,  S O Ps,  G C P  a n d  a p plica ble  
re g ulati o ns  t o  t he  I n vesti gat or  a n d  will  e ns ure t hat  a p pr o priate  acti o n  desi g ne d  t o  pre ve nt  
rec urre nce of t he detecte d de viati o ns is ta ke n a n d d oc u me nte d. 
T he I n vesti gat or a grees t o c o o pera te wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms detecte d i n t he 
c o urse of t hese m o nit ori n g visits  are a d dresse d a n d d oc u me nte d. 
I n acc or da nce wit h G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y ma y be selecte d f or a u dit b y 
re prese ntati ves fr o m s p o ns or.  I ns pecti o n of site facilities (e. g., p har mac y, dr u g st ora ge areas, 
la b orat ories, etc.) a n d re vie w of st u d y relate d rec or ds will occ ur i n or der t o e val uate t he st u d y 
c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, G C P,  a n d a p plica ble re g ulat or y re q uire me nts. 
I n t he e ve nt t hat a re g ulat or y a ut h orit y i nf or ms t he I n vesti gat or  t hat it i nte n ds t o c o n d uct a n 
i ns pecti o n, s p o ns or s hall be n otifie d i m me diatel y. 
 
1 1. 2.  
D at a C ollecti o n 
T he e C R F c o m pleti o n s h o ul d be ke pt c urre nt t o e na b le t he m o nit or t o re vie w t he s u bject’s stat us 
t hr o u g h o ut t he c o urse of t he st u d y.  T he e C R F is c o m plete d b y t he I n vesti gat or or q ualifie d 
desi g nee.   C o m plete d  e C R Fs  are  re vie we d  a n d  e-si g ne d  b y  t he  I n ves ti gat or  ( or  b y  a  s u b-
I n vesti gat or, wit h per missi o n of t he S p o ns or). 
 
1 1. 3.  
D at a M a n a ge me nt 
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject I D n u m ber as defi ne d b y t he 
s p o ns or. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 5 of 1 0 9 
 
T o e ns ure t he q ualit y of cli nical data acr oss al l s u bjects a n d sites, a Cli nical Data Ma na ge me nt 
re vie w will be perf or me d o n s u bject data acc or di n g t o s pecificati o ns gi ve n t o t he C R O.  Data i n 
t he e C R F is vette d electr o nicall y b y pr o gra m me d data r ules wit hi n t he a p plicati o n. Q ueries 
ge nerate d b y r ules a n d raise d b y re vie wers will be ge nerate d wit hi n t he electr o nic data ca pt ure 
( E D C) a p plicati o n.  D uri n g t his re vie w, s u bject data will be c hec ke d f or c o nsiste nc y, o missi o ns, 
a n d a n y a p pare nt discre pa ncies. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la bs will be rec o ncile d t o t he cli nical data base. 
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safet y data base. 
 
1 1. 4.  
St u d y D oc u me nt ati o n a n d St or a ge 
T he I n vesti gat or will mai ntai n a Si g nat ure List of  a p pr o priatel y q ualifie d pers o ns t o w h o m he/s he 
has dele gate d st u d y d uties.  All pe rs o ns a ut h orize d t o ma ke e ntries a n d/ or c orrecti o ns o n e C R Fs 
will be i ncl u de d o n t he Si g nat ure List. 
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds fr o m w hic h t he s u bject’s e C R F data 
are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o  h os pital rec or ds, cli nical a n d office c harts, 
la b orat or y a n d p har mac y rec or ds, diaries, micr ofic hes, X-ra ys, a n d c orres p o n de nce. 
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai n i n g a c o m pre he nsi ve a n d ce ntralize d 
fili n g  s yste m  ( Trial  Master  File)  of  all  st u d y-relate d  (esse ntial)  d oc u me ntati o n,  s uita ble  f or  
i ns pecti o n at a n y ti me b y re prese ntati ves fr o m s p o ns or a n d/ or a p plica ble re g ulat or y a ut h orities. 
Esse ntial d oc u me nts i ncl u de: 
 S u bject files c o ntai ni n g I Cs, a n d s u p p orti n g c o pies of s o ur ce d oc u me ntati o n as use d f or 
e C R Fs c o m pleti o n. I n a d diti o n, all ori gi nal  s o urce d oc u me nts s u p p orti n g e ntries i n t he 
e C R Fs m ust be mai ntai ne d a n d be rea dil y a vaila ble. 
 St u d y files c o ntai ni n g t he pr ot oc ol  wit h all a me n d me nts, I B, co pies of rele va nt esse ntial 
d oc u me nts re q uire d pri or t o c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d 
fr o m t he I E C/I R B a n d S p o ns or. 
 Rec or ds relate d t o t he st u d y me dicati o ns deli vere d i ncl u di n g ac k n o wle d g me nt of recei pt at 
site, acc o u nta bilit y rec or ds a n d fi nal reco nciliati o n a n d a p plic a ble c orres p o n de nce. 
I n a d diti o n, all ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he e C R Fs m ust be mai ntai ne d 
a n d be rea dil y a vaila ble. 
Esse ntial cli nical trial d oc u me nt s (i ncl u di n g case re p ort f or ms) other t ha n s u bject's me dical files 
m ust be ke pt f or at least 1 5 y ears after c o m pleti o n or disc o nti n uati o n of t he trial. S u bject's me dical 
files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gisl ati o n a n d i n acc or da nce wit h t he 
ma xi m u m  peri o d  of  ti me  per mitte d  b y  t he  h os pital,  i nstit uti o n  or  pri vate  practice.  It  is  t he  
res p o nsi bilit y of t he s p o ns or t o i nf or m t he I n vesti gat or/i nstit uti o n as t o w he n t he cli nical trial 
d oc u me nts n o l o n ger nee d t o be retai ne d.  
N o st u d y d oc u me nt s h o ul d be destr o ye d wit h o ut pr i or writte n a gree me nt bet wee n s p o ns or a n d t he 
I n vesti gat or.  S h o ul d t he I n vesti gat or wis h t o assi g n t he st u d y rec or ds t o a n ot her part y or m o ve 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 6 of 1 0 9 
 
t he m t o a n ot her l ocati o n, he/s he m ust n otif y D SE i n writi n g of t he ne w res p o nsi ble pers o n a n d/ or 
t he ne w l ocati o n. 
 
1 1. 5.  
Rec or d Kee pi n g 
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, data c orrecti o n f or ms, e C R Fs, 
i n ve nt or y of st u d y pr o d uct, re g ulat or y d oc u me nts (e. g., pr ot oc ol a n d a me n d me nts, I E C/I R B 
c orres p o n de nce  a n d  a p pr o vals,  a p pr o ve d  a n d  si g ne d  I Cs,  I n vesti gat or’s  A gree me nt,  cli nical  
s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her s p o ns or c orres p o n de nce pertai ni n g t o 
t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he site.  S o urce d oc u me nts i ncl u de all 
rec or di n gs a n d o bser vati o ns or n otati o ns of cli nical acti vities a n d all re p or ts a n d rec or ds necessar y 
f or t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hese rec or ds will be retai ne d i n a 
sec ure file f or t he peri o d re q uire d b y t he i nstit uti o n or s ite p olic y.  Pri or t o tra nsfer or destr ucti o n 
of t hese rec or ds, t he S p o ns or m ust be n otifie d i n writi n g a n d be gi ve n t he o p p ort u nit y t o f urt her 
st ore s uc h rec or ds. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 7 of 1 0 9 
 
1 2.  
FI N A N CI N G A N D I N S U R A N C E 
1 2. 1.  
Fi n a nces 
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti g at or a n d/ or i nstit uti o n will si g n a cli nical st u d y 
a gree me nt wit h t he s p o ns or or wit h a n a ut h orize d  re prese ntati ve of s p o ns or.  T his a gree me nt will 
i ncl u de t he fi na ncial i nf or mati o n a gree d u p o n b y t he parties. 
 
1 2. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce 
Rei m b urse me nt, i n de m nit y a n d i ns ura nce s hall be  a d dresse d i n a se parate a gree me nt o n ter ms 
a gree d u p o n b y t he parties. 
T he S p o ns or pr o vi des i ns ura nce f or st u d y s u bjects t o ma ke a vaila ble c o m pe nsati o n i n case of 
st u d y-relate d i nj ur y. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 8 of 1 0 9 
 
1 3.  
P U B LI C A TI O N P O LI C Y 
A st u d y site ma y n ot p u blis h res ults of a st u d y u ntil after a c o or di nate d m ultice nter p u blicati o n 
has bee n s u b mitte d f or p u blicati o n or u ntil o ne y ear after t he st u d y has en de d, w hic he ver occ urs 
first.  T heref ore, t he st u d y site will ha ve t he o p p ort u nit y t o p u blis h t h e res ults of t he st u d y, 
pr o vi de d  t hat  s p o ns or  a n d  t he  e xec uti ve  c o m mittee  has  ha d  t he  o p p ort u nit y  t o  re vie w  a n d  
c o m me nt o n t he st u d y site’s pr o p ose d p u blicati o n pri o r t o its bei n g s u b mitte d f or p u blicati o n wit h 
t he a d vice of c o m pa n y pate nt c o u ncil a n d i n acc or d wit h nee ds f o r s u bject pr otecti o n. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 8 9 of 1 0 9 
 
1 4.  
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N 
1 4. 1.  
C o m pli a nce St ate me nt, Et hics  a n d Re g ul at or y C o m pli a nce 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat ha ve t heir 
ori gi n  i n  t he  Declarati o n  of  Helsi n ki,  t he  I C H  c o ns oli date d  G ui deli ne  E 6  f or  G C P  
( C P M P/I C H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y re q uire me nt(s): 
 E ur o pea n C o m missi o n Dir ecti ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1); 
 E ur o pea n C o m missi o n Dir ecti ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5); 
 E ur o pea n Data Pr otecti o n Directi ve 9 5/ 4 6/ E C; 
 Ot her a p plica ble l ocal re g ulati o ns. 
 
1 4. 2.  
S u bject C o nfi de nti alit y 
T he I n vesti gat ors a n d t he S p o ns or will preser ve t he c o nfi de ntialit y of all s u bjects ta ki n g part i n 
t he st u d y, i n acc or da nce wit h G C P, t he r ules lai d d o w n f or t he pr otecti o n of i n di vi d uals wit h 
re gar d t o t he pr ocessi n g of pers o nal data a n d t he free m o ve ment of s uc h data  a n d ot her l ocal 
re g ulati o ns. 
F or  E U  st u d y  ce nters,  t he  S p o ns or  will  o bser ve  t he  r ules  lai d  d o w n  i n  t he  E ur o pea n  Data  
Pr otecti o n Directi ve 9 5/ 4 6/ E C o n t h e pr otecti o n of i n di vi d uals wit h  re gar d t o t he pr ocessi n g of 
pers o nal data a n d t he free m o ve me nt of s uc h data. 
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y is mai ntai ne d.  O n t he e C R Fs or ot her 
d oc u me nts s u b mitte d t o t he S p o ns or, s u bjects s h o u l d be i de ntifie d b y a u ni q ue s u bject I D n u m ber 
as desi g nate d b y t he s p o ns or. T he I n vesti gat or m ust o bliterate a n y pri vate i nf or mati o n c o ntai ne d 
o n d oc u me nts (e. g. na me or a d dress) pri or t o pass i n g t he m o n t o t he s p o nsor or C R O.  D oc u me nts 
t hat are n ot f or s u b missi o n t o eit her S p o ns or or C R O (e. g., si g ne d I C) s h o ul d be ke pt i n strict 
c o nfi de nce b y t he I n vesti gat or. 
I n c o m plia nce wit h G C P G ui deli nes, it is re q uire d t hat t he I n vesti gat or a n d i nstit uti o n per mit 
a ut h orize d re prese ntati ves of t h e c o m pa n y, of t he re g ulat or y a ge n c y(s), a n d t he I E C/I R B direct 
access t o re vie w t he s u bject’s ori gi nal me dical re c or ds f or verificati o n of st u d y-relate d pr oce d ures 
a n d data.   
 
1 4. 3.  
I nf or me d C o nse nt Pr oce d ure 
Bef ore a s u bject’s partici pati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o o btai n freel y 
gi ve n c o nse nt, i n writi n g, fr o m t he s u bject afte r a de q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial  hazar ds of t he st u d y a n d bef ore a n y pr ot oc ol-s pecific scree ni n g 
pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  S u bjects m ust  ha ve t he o p p ort u nit y t o as k 
q uesti o ns a n d recei ve satisfact or y a ns wers t o t hei r i n q uiries, a n d m ust ha ve a de q uate ti me t o 
deci de w het her or n ot t o partici pate i n t he st u d y.  T he writte n I C F is pre pare d i n t he l ocal 
la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 0 of 1 0 9 
 
 
1 4. 4.  
Re g ul at or y C o m pli a nce 
T he  st u d y  pr ot oc ol,  s u bject  i nf o r mati o n  a n d  c o nse nt  f or m,  t he  I n vesti gat or’s  Br oc h ure,  a n y  
s u bject diar y car d or writte n i nstr ucti o ns t o be give n t o t he s u bject, a vaila ble safet y i nf or mati o n, 
s u bject recr uit me nt pr oce d ures, i nf or mati o n a b o ut pa y me nts a n d c o m pe nsati o n a vaila ble t o t he 
s u bjects a n d d oc u me ntati o n e vi de nci n g t he I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o 
t he I E C/I R B f or et hical re vie w a n d a p pr o val acc or di n g t o l ocal re g ulati o ns, pri or t o t he st u d y start.  
T he writte n a p pr o val s h o ul d i d e ntif y all d oc u me nts re vie we d b y na me a n d versi o n. 
C ha n ges i n t he c o n d uct of t he st u d y or pla n ne d a nal ysis will be d oc u me nte d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P. 
All s u bse q ue nt s u bsta ntial pr ot oc ol a me n d me nts a n d c ha n ges t o t he I C F will be s u b mitte d t o t he 
I E C/I R B f or a p pr o val. T he I n vesti gat or s h o ul d n otif y t he I E C/I R B of de viati o ns fr o m t he pr ot oc ol 
or S A Es occ urri n g at t he site a n d ot her a d vers e e ve nt re p orts recei ve d fr o m S p o ns or/ C R O, i n 
acc or da nce wit h l ocal pr oce d ures. 
As re q uire d b y l ocal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y Affairs gr o u p or dele gate will 
i ns ure all le gal as pects are c o vere d, a n d a p pr o val of t he a p pr o priate re g ulat or y b o dies o btai ne d, 
pri or t o st u d y i nitiati o n, a n d t hat i m ple me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d ot her 
rele va nt st u d y d oc u me nts ha p pe n o nl y after t he a p pr o priate n otificati o n of or a p pr o val b y t he 
rele va nt re g ulat or y b o dies. 
 
1 4. 5.  
Pr ot oc ol De vi ati o ns 
T he I n vesti gat or c o n d ucts t he st u d y i n c o m plia nce w it h t he pr ot oc ol a gree d t o b y s p o ns or a n d, if 
re q uire d, b y t he re g ulat or y a ut h orit y(ies) a n d b y t he E C. 
Acti o ns ta ke n t o eli mi nate i m me di ate s u bject hazar d(s) t hat de viat e fr o m a n y pr ot oc ol pr oce d ures 
are mar ke d / fla g ge d as a de viati o n. T he s p o ns or a n d site m o nit or m ust be n otifie d of all i nte n de d 
or u ni nte n de d de viati o ns t o t he pr ot oc ol (e. g., i ncl usi o n/e xcl usi o n criteria, d osi n g) o n a n e x pe dite d 
basis. T he I n vesti gat or, or pe rs o n desi g nate d b y t he I n vesti gat or, s h o ul d d oc u me nt a n d e x plai n 
a n y  de viati o n  fr o m  t he  a p pr o ve d  pr ot oc ol  a n d  n o tif y  t he  E C  of  a n y  pr ot oc ol  de viati o ns  i n  
acc or da nce wit h l ocal pr oce d ures. 
E ve n  if  a  s u bject  was  i neli gi ble  or  i na d verte ntl y  recei ve d  t he  i nc orrect  dr u g  or  d osa ge,  
disc o nti n ue d or i nterr u pte d t he assi g ne d treat me n t re gi me n, or ref use d t o f urt her u n der g o o n-site 
visits, cli nical f oll o w- u p data s h o ul d still be c ollecte d u p t o Da y 9 0 after cat heter a blati o n (i.e., 
E O T). 
 
1 4. 6.  
S u p pl y of Ne w I nf or m ati o n Affect i n g t he C o n d uct of t he St u d y 
W he n ne w i nf or mati o n bec o mes a vaila ble t hat ma y a d versel y affect t he safet y of s u bjects or t he 
c o n d uct of t he st u d y, t he S p o ns or w ill i nf or m all I n vesti gat ors in v ol ve d i n t he cli nical st u d y, 
E Cs/I R Bs, a n d re g ulat or y a ut h orities of s uc h i nf or mati o n, a n d w he n nee de d, will a me n d t he 
pr ot oc ol a n d/ or s u bject i nf or mati o n. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 4 of 1 0 9 
 
1 5.  
R E F E R E N C E S 
1.  
Gi u glia n o R P, R uff C T, Bra u n wal d E, M u r p h y S A, Wi vi ott S D, Hal peri n J L, et 
al. E d o xa ba n vers us warfari n i n patie nts wit h atrial fi brillati o n. N E n gl J Me d. 
2 0 1 3; 3 6 9( 2 2): 2 0 9 3- 2 1 0 4. 
2.  
Kirc h h of P, Be n ussi S, K otec ha D, A hlss o n A, Atar D, Casa dei B, et al. 2 0 1 6 E S C 
G ui deli nes f or t he ma na ge me nt of atrial  fi brillati o n de vel o pe d i n c olla b orati o n 
wit h E A C T S: T he Tas k F orce f or t he ma na ge me nt of atrial fi brillati o n of t he 
E ur o pea n S ociet y of Car di ol o g y ( E S C) De ve l o pe d wit h t he s pecial c o ntri b uti o n of 
t he E ur o pea n Heart R h yt h m Ass ociatio n ( E H R A) of t he E S C E n d orse d b y t he 
E ur o pea n Str o ke Or ga nisati o n ( E S O). E ur o pace 2 0 1 6 A u g 2 7 e p u b 
3.  
Cra wf or d T, Oral H. C urre nt stat us a n d o utc o mes of cat heter a blati o n f or atrial 
fi brillati o n. Heart R h yth m 2 0 0 9; 6( 1 2 S u p pl): S 1 2- 1 7. 
4.  
H ussei n A A, Marti n D O, Sali ba W, Patel D, Kari m S, Batal O, et al. 
Ra di ofre q ue nc y a blati o n of atrial fi brill ati o n u n der t hera pe utic i nter nati o nal 
n or malize d rati o: a safe a n d efficaci o us peri pr oce d ural a ntic oa g ulati o n strate g y. 
Heart R h yt h m 2 0 0 9; 6( 1 0): 1 4 2 5- 1 4 2 9. 
5.  
Ca p pat o R, Marc hli ns ki F E, H o h nl oser S H , Naccarelli G V, Xia n g J, Wil ber DJ, et 
al. U ni nterr u pte d ri var o xa ba n vs. u ni nterr u pte d vita mi n K a nta g o nists f or cat heter 
a blati o n i n n o n- val v ular atrial fi brillati o n. E ur Heart J. 2 0 1 5 ; 2 1; 3 6( 2 8): 1 8 0 5-
1 8 1 1.  
6.  
C he n J, T o d d D M, H oci ni M, Larse n T B, B o n gi or ni M G, Bl o mstr ö m- L u n d q vist 
C.; Scie ntific I nitiati ve C o m mittee, E ur o p ea n Heart R h yt h m Ass ociati o n. C urre nt 
peri pr oce d ural ma na ge me nt of a blati o n f or atrial fi brillati o n i n E ur o pe: res ults of 
t he E ur o pea n Heart R h yt h m Ass ociatio n s ur ve y. E ur o pace  2 0 1 4; 1 6( 3): 3 7 8 – 3 8 1.  
7.  
E d o xa ba n I B, versi o n 1 6. 0, J U N 2 0 1 6. 
8.  
H o k usai V T E I n vesti gat ors, B uller H R, Dec o us us H, Gr oss o M A, Merc uri M, 
Mi d del d or p S, et al. E d o xa ba n vers us wa rfari n f or t he treat me nt of s y m pt o matic 
ve n o us t hr o m b oe m b olis m. N E n gl J Me d. 2 0 1 3; 3 6 9( 1 5): 1 4 0 6- 1 4 1 5. 
9.  
Ca p pat o R, Cal ki ns H, C he n S A, Da vies W, Iesa ka Y, Kal ma n J, et al. U p date d 
w orl d wi de s ur ve y o n t he met h o ds, efficac y, a n d safet y of cat heter a blati o n f or 
h u ma n atrial fi brillati o n. Circ Arr h yt h m  Electr o p h ysi ol. 2 0 1 0 Fe b; 3( 1): 3 2- 3 8.  
1 0.  
Pr o vi de ncia R, Marij o n E, Al be n q ue J P, et al. Ri var o xa ba n a n d da bi gatra n i n 
patie nts u n der g oi n g cat heter a blati o n of atrial fi brillati o n. E ur o pace 
2 0 1 4; 1 6: 1 1 3 7 – 1 1 4 4. 
1 1.  
La k kire d d y D, Re d d y Y M, Di Biase L, et  al. Feasi bilit y a n d Safet y of 
U ni nterr u pte d Ri var o xa ba n f or Peri pr o ce d ural A ntic oa g ulati o n i n Patie nts 
U n der g oi n g Ra di ofre q ue nc y A blati o n f or At rial Fi brillati o n. J A m C oll Car di ol 
2 0 1 4; 6 3: 9 8 2 – 8. 
1 2.  
Ar yal M R, U kai g we A, Pa n dit A, Kar mac har ya P, Pra d ha n R, Mai nali N R, et al. 
Meta-a nal ysis of efficac y a n d safet y of ri var o xa ba n c o m pare d wit h warfari n or 
da bi gatra n i n patie nts u n der g oi n g cat heter  a blati o n f or atrial fi brillati o n. A m J 
Car di ol. 2 0 1 4; 1 1 4( 4): 5 7 7- 8 2.  

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 5 of 1 0 9 
 
1 3.  
P ha n K, Wa n g N, Pis o n L, K u mar N, H it os K, T h o mas S P. Ri var o xa ba n vers us 
warfari n or da bi gatra n i n patie nts u n der g oi n g cat heter a blati o n f or atrial 
fi brillati o n: A meta-a nal ysis. I nt J Car di ol. 2 0 1 5; 1 8 5: 2 0 9- 1 3.  
1 4.  
Di Biase L, B ur k har dt J D, Sa nta n geli P, et  al. Peri pr oce d ural Str o ke a n d Blee di n g 
C o m plicati o ns i n Patie nts U n der g oi n g Ca t heter A blati o n of Atrial Fi brillati o n 
Wit h Differe nt A ntic oa g ulati o n Ma na ge me nt. Circ ulati o n. 2 0 1 4; 1 2 9( 2 5): 2 6 3 8-
2 6 4 4. 
1 5.  
Cal ki ns H, K uc k K H, Ca p pat o R, Br u ga da J, Ca m m AJ, C he n S A, et al. 2 0 1 2 
H R S/ E H R A/ E C A S e x pert c o nse ns us state me nt o n cat heter a n d s ur gical a blati o n 
of atrial fi brillati o n: rec o m me n dati o ns f or patie nt selec ti o n, pr oce d ural tec h ni q ues, 
patie nt ma na ge me nt a n d f oll o w- u p, defi n iti o ns, e n d p oi nts, a n d researc h trial 
desi g n. E ur o pace 2 0 1 2; 1 4( 4): 5 2 8- 6 0 6. 
1 6.  
Patel M R, Ma haffe y K W, Gar g J, Pa n G, Si n ger D E, Hac ke W et al. Ri var o xa ba n 
vers us Warfari n i n N o n val v ular At rial Fi brillati o n. N E n gl J Me d. 
2 0 1 1; 3 6 5( 1 0): 8 8 3- 8 9 1 
1 7.  
Stic herli n g C, Mari n F, Bir nie D, B o ria ni G, Cal ki ns H, Da n G A, et al. 
A ntit hr o m b otic ma na ge me nt i n patie nts u n der g oi n g electr o p h ysi ol o gical 
pr oce d ures: a E ur o pea n Heart R h yt h m Ass ociati o n ( E H R A) p ositi o n d oc u me nt 
e n d orse d b y t he E S C W or ki n g Gr o u p T hr o m b osis, Heart R h yt h m S ociet y ( H R S), 
a n d Asia Pacific Heart R h yt h m S ociet y ( A P H R S). E ur o pace. 2 0 1 5; 1 7( 8): 1 1 9 7- 2 1 4 
1 8.  
Me hra n R, Ra o S V, B hatt D L, Gi bs o n C M , Cai xeta A, Ei kel b o o m J, et al. 
Sta n dar dize d blee di n g defi niti o ns f or car di o vasc ular cli nical trials: a c o nse ns us 
re p ort fr o m t he Blee di n g Aca de mic Researc h C o ns orti u m. Circ ulati o n. 
2 0 1 1; 1 2 3( 2 3): 2 7 3 6- 2 7 4 7. 
1 9.  
Sc h ul ma n S, Kear o n C. Defi niti o n of Maj or Blee di n g i n cli nical i n vesti gati o ns of 
a nti he m ostatic me dici nal pr o d ucts i n n o n-s u r gical patie nts. J T hr o m b Hae m ost. 
2 0 0 5; 3( 4): 6 9 2- 6 9 4. 
2 0.  
Kaatz S, A h ma d D, S p yr o p o ul os A C, Sc h ul ma n S, S u bc o m mittee o n C o ntr ol of 
A ntic oa g ulati o n. Defi niti o n of cli nicall y re le va nt n o n- Maj or Blee di n g i n st u dies of 
a ntic oa 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 olic disease i n n o n-
s ur gical patie nts: c o m m u nicati 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. 
2 0 1 5; 1 3( 1 1): 2 1 1 9- 2 1 2 6. 
2 1.  
B hatt D L, Cr yer B L, C o nta nt C F, C o he n M, La nas A, Sc h nitzer TJ, et al. 
Cl o pi d o grel wit h or wit h o ut o me praz ole i n c or o nar y arter y disease. N E n gl J Me d. 
2 0 1 0; 3 6 3( 2 0): 1 9 0 9- 1 7. 
2 2.  
Wi vi ott S D, Bra u n wal d E, Mc Ca be C H, M o nt alesc ot G, R uz yll o W, G ottlie b S, et 
al. Pras u grel vers us cl o pi d o grel  i n patie nts wit h ac ute c or o nar y s y n dr o mes. N E n gl 
J Me d. 2 0 0 7; 3 5 7( 2 0): 2 0 0 1- 1 5. 
2 3.  
B o vill E G, Terri n M L, St u m p D C, Ber ke A D, Fre deric k M, C olle n D, et al. 
He m orr ha gic e ve nts d uri n g t hera p y wit h  rec o m bi na nt tiss ue-t y pe plas mi n o ge n 
acti vat or, he pari n, a n d as piri n f or ac ute m y ocar dial i nfarcti o n. Res ults of t he 
T hr o m b ol ysis i n M y ocar dial I nfarcti o n ( TI MI), P hase II Trial. A n n I nter n Me d. 
1 9 9 1; 1 1 5( 4): 2 5 6- 6 5. 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 6 of 1 0 9 
 
2 4.  
Tzi kas A, H ol mes Jr D R, Gaf o or S, et al. Perc uta ne o us left atrial a p pe n da ge 
occl usi o n: t he M u nic h c o nse ns us d oc u me nt o n defi niti o ns, e n d p oi nts a n d data 
c ollecti o n re q uire me nts f or cli nical st u dies. E ur oI nter ve nti o n 2 0 1 6; 1 2( 1): 1 0 3- 1 1 1. 
2 5.  
Ka p petei n A P, Hea d SJ, Gé nére u x P, et  al. U p date d sta n dar dize d e n d p oi nt 
defi niti o ns f or tra nscat heter a ortic va l ve i m pla ntati o n: t he Val ve Aca de mic 
Researc h C o ns orti u m- 2 c o nse ns us d oc u me nt. E ur Heart J. 2 0 1 2; 3 3( 1 9): 2 4 0 3-
2 4 1 8. 
2 6.  
Hic ks K A, Tc he n g J E, B oz k urt B, et al . 2 0 1 4 A C C/ A H A Ke y Data Ele me nts a n d 
Defi niti o ns f or Car di o vasc ular E n d p oi nt E v e nts i n Cli nical Trials: A Re p ort of t he 
A merica n C olle ge of Car di ol o g y/ A merica n Heart Ass ociati o n Tas k F orce o n 
Cli nical Data Sta n dar ds ( Writi n g C o m mitt ee t o De vel o p Car di o vasc ular E n d p oi nts 
Data Sta n dar ds). Circ ul ati o n. 2 0 1 5; 1 3 2( 4): 3 0 2- 6 1. 
2 7.  
C utli p D E, Wi n dec ker S, Me hra n R, B oa m A, C o he n DJ, va n Es G A, et al. 
Cli nical e n d p oi nts i n c or o nar y ste nt tria ls: a case f or sta n dar dize d defi niti o ns. 
Circ ulati o n. 2 0 0 7; 1 1 5( 1 7): 2 3 4 4- 5 1. 
2 8.  
Hijazi Z, Li n d bäc k J, Ale xa n der J H, et  al. T he A B C (a ge, bi o mar kers, cli nical 
hist or y) str o ke ris k sc ore: a bi o mar ker- b ase d ris k sc ore f or pre dicti n g str o ke i n 
atrial fi brillati o n. E ur He art J. 2 0 1 6; 3 7( 2 0): 1 5 8 2- 1 5 9 0. 
2 9.  
De ne ke T, Jais P, Sca gli o ne M, et al. S ile nt Cere bral E ve nts/ Lesi o ns Relate d t o 
Atrial Fi brillati o n A blati o n: A Cli nical  Re vie w. J Car di o vasc Electr o p h ysi ol. 
2 0 1 5; 2 6( 4): 4 5 5- 4 6 3. 
3 0.  
R ose n daal F R, Ca n ne gieter S C, va n der Me er FJ, Briet E. A met h o d t o deter mi ne 
t he o pti mal i nte nsit y of oral a ntic oag ula nt t hera p y. T hr o m b os hae m ost. 
1 9 9 3; 6 9( 3): 2 3 6- 9. 
3 1.  
Ca p pat o R, Cal ki ns H, C he n S A et al. Pre vale nce a n d ca uses of fatal o utc o me i n 
cat heter a blati o n of atrial  fi brillati o n. J A m C oll Car di ol. Ma y 1 2 2 0 0 9; 5 3( 1 9): 
1 7 9 8 – 1 8 0 3. 
3 2.  
Des h m u k h A, Patel NJ, Pa nt S, et al. I n - h os pital c o m plicati o ns ass ociate d wit h 
cat heter a blati o n of atrial fi brillati o n i n t he U nite d States bet wee n 2 0 0 0 a n d 2 0 1 0: 
a nal ysis of 9 3 8 0 1 pr oce d ures. Circ ulati o n 2 0 1 3;  1 2 8( 1 9): 2 1 0 4- 1 2. 
3 3.  
Ber nar d M L, S h ot well M, Nietert PJ, et al. Meta- A nal ysis of Blee di n g 
C o m plicati o ns Ass ociate d Wit h Car d iac R h yt h m De vice I m pla ntati o n. Circ 
Arr h yt h m Electr o p h ysi ol. 2 0 1 2; 5( 3): 4 6 8- 4 7 4. 
3 4.  
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m 
creati ni ne. Ne p hr o n. 1 9 7 6; 1 6( 1): 3 1- 4 1. 
3 5.  
Le ve y, A S, Ste ve ns L A, Sc h mi d C H, et al. f or t he C K D- E PI C hr o nic Ki d ne y 
Disease E pi de mi ol o g y C olla b orati o n): A Ne w E q uati o n t o esti mate Gl o mer ular 
Filtzrati o n Rate. A n n I nter n Me d 2 0 0 9; 1 5 0: 6 0 7- 6 1 2. 
3 6.  
Ver ma A, Cair ns J A, Mitc hell L B, et al. 2 0 1 4 F oc use d U p date of t he Ca na dia n 
Car di o vasc ular S ociet y G ui deli nes f or t h e Ma na ge me nt of Atrial Fi brillati o n. Ca n 
J Car di ol. 2 0 1 4; 3 0( 1 2): 1 1 1 4- 1 1 3 0. 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 7 of 1 0 9 
 
1 6.  
A P P E N DI C E S 
1 6. 1.  
St u d y Or g a ni z ati o n 
1 6. 1. 1.  
D at a a n d S afet y M o nit ori n g B o ar d  
T here will be a n i n de pe n de nt D S M B t o pr otect t he ri g hts, safet y a n d well- bei n g of s u bjects 
partici pati n g i n t he st u d y. T he D S M B c o nsists of  q ualifie d scie ntists, w h o are n ot I n vesti gat ors 
i n t he st u d y a n d n ot ot her wise directl y ass ociate d wit h t he s p o ns or, a n d has t he pri mar y r ole 
i n e xa mi ni n g t he safet y data a n d ot her perti ne nt data. T he D S M B m o n it ors st u d y data i n a n 
u n- bli n de d, o n g oi n g ma n ner a n d alerts t he E xec u ti ve C o m mittee i n case of a n y cli nicall y 
c o ncer ni n g safet y iss ues. 
T he fre q ue nc y a n d e xte nt of t he data re vie w s b y t he D S M B, details a b o ut t he re vie ws a n d 
st o p pi n g r ules or criteria f or e val uati n g nee d f or st u d y pr ot oc ol m o dificati o ns will be descri be d 
a n d s pecifie d i n t he D S M B c harter. T he D S M B ca n rec o m me n d m o dificati o n of t he st u d y 
pr ot oc ol, or st u d y, or treat me nt re gi me n t o t he E xec uti ve C o m mittee base d o n pre-s pecifie d 
r ules descri be d i n t he D S M B c harter. 
All  acti vities  of  t he  D S M B  will  be  d oc u me nte d.   T his  d oc u me ntati o n  will  i ncl u de  data  
s u m maries a n d a nal yses (see Secti o n 1 0. 6 ) pr o vi de d t o t he D S M B as well as mi n utes of t he 
meeti n gs.  T he d oc u me ntati o n will re mai n c o nfi de ntial wit hi n t he D S M B u ntil t he st u d y is 
c o m plete d. A n i n de pe n de nt statisticia n w h o is n ot  ot her wise i n v ol ve d i n t he st u d y will pre pare 
t he re q uire d data o ut p uts a n d pr o vi de t he o ut p uts t o t he D S M B  as per t he D S M B c harter. 
1 6. 1. 2.  
Cli nic al E ve nts C o m mittee  
A n i n de pe n de nt C E C re vie ws a n d a dj u dicates t h e f oll o wi n g e ve nts i n a bli n de d ma n ner a n d 
wit h o ut a n y k n o wle d ge of t he s u bjec t’s assi g ne d treat me nt re gi me n: 
 Maj or Blee di n g; 
 C R N M blee di n g; 
 Mi n or blee di n g; 
 Deat h fr o m a n y ca use; 
 S us pecte d str o ke; 
 S us pecte d S E E; 
 S us pecte d MI; 
 S us pecte d TI A; 
Details a b o ut t he defi niti o ns  of t he e n d p oi nts ( Secti o n 7. 4 ), e n d p oi nt s u b-cate g ories a n d ot her 
C E C pr ocesses are descri be d i n t he C E C c harter. 
T he si n gle c o m p o ne nts of t he c o m p osite pri m ar y (a n d sec o n dar y e n d p oi nts me nti o ne d a b o ve 
are  e x pl ore d,  as  well  as  s pec ific  s u bcate g ories  (e. g.,  I C H,  isc he mic  str o ke)  a n d  e ve nt  
classificati o ns acc or di n g t o ot her defi niti o ns (e. g., B A R C, TI MI). 
1 6. 1. 3.  
E xec uti ve C o m mittee 
T he E xec uti ve C o m mittee will be res p o nsi ble f o r t he o verall desi g n, c o n d uct, a n d s u per visi o n 
of  t he  st u d y,  i ncl u di n g  t he  de vel o p me nt  of  a n y  pr ot oc ol  a me n d me nts.   T he  E xec uti ve  
C o m mittee will als o re vie w t he pr o gress of t he st u d y at re g ular i nter vals t o e ns ure s u bject 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 9 8 of 1 0 9 
 
safet y  a n d  st u d y  i nte grit y.   T he  E xec uti ve  C om mittee  will  be  c o m prise d  of  desi g nate d  
re prese ntati ves fr o m t he st u d y in vesti gat ors, C R O, a n d S p o ns or. 
1 6. 1. 4.  
O per ati o ns C o m mittee 
T he O perati o ns C o m mittee will be res p o nsi ble f or t he o n g oi n g m o nit ori n g of t he st u d y data 
a n d i m ple me ntati o n of ste ps t o i m pr o ve t he q ualit y of t he st u d y c o n d uct. T he O perati o nal 
C o m mittee will be c o m prise d of desi g nate d re pr ese ntati ves of C R Os a n d S p o ns or a n d will 
re p ort at re g ular i nter vals t o t he E xec uti ve C o m mittee o n t he pr o gress of t he st u d y. 
 
1 6. 2.  
S u b-st u d y 
S u bjects  i n  t his  st u d y  ma y  partici pate  i n  o ne  s u b-st u d y.  De dicate d  sites  are  i n vite d  f or  
partici pati o n acc or di n g t o sites ca pa bilities t o meet s pecific s u b-st u d y re q uire me nts a n d o n t he 
re q uire d n u m ber of o bser vati o ns. C urre ntl y, o ne s u b-st u d y is bei n g c o nsi dere d i n v ol vi n g D W-
M RI.  
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 2 of 1 0 9 
 
1 6. 4.  
Defi niti o n of ter ms 
 
A b n or m al liver f u ncti o n  is defi ne d as c hr o nic he patic disease (e. g., cirr h osis) or 
bi oc he mical e vi de nce of si g nifica nt he pati c dera n ge me nt (e. g., bilir u bi n > 2 ti mes 
t he U L N, i n ass ociati o n wit h as partate tra nsa mi nase/ala ni ne tra nsa mi nase/al kali ne 
p h os p hatase > 3 ti mes t he U L N, a n d s o f ort h). 
A b n or m al re n al f u ncti o n  is defi ne d as c hr o nic dial ysis, re nal tra ns pla ntati o n, or 
ser u m creati ni ne ≥2 0 0 m ol/ L ( ≥2. 2 6 m g/ d L). 
C o n gestive he art f ail ure  is defi ne d as t he c urre nt prese nce or pri or hist or y of 
cli nical c o n gesti ve heart re q uiri n g me di cal atte nti o n a n d me dical t hera p y or 
d oc u me nte d ejecti o n fracti o n ≤3 5 % (left ve ntric ular s yst olic d ysf u ncti o n). 
Di a betes mellit us  i ncl u des dia betes re q uiri n g treat me nt wit h diet o nl y or wit h 
p har mac ol o gic t hera p y (i ns uli n, oral h y p o gl yce mic a ge nts). 
D oc u me nte d cli nic al nee d  is defi ne d as a k n o w n rec or d i n a n y f or m (i ncl. writte n, 
electr o nic or ver bal) rec or di n g perti ne nt s u bject data wit h re gar d t o t he cli nical 
reas o n f or t he c h oice of a n alter nati ve medicati o n. T his reas o n  m ust be ca pt ure d 
a n d pre- declare d bef ore s u bject ra n d o mizati o n. 
L a bile I N Rs  is defi ne d as u nsta ble or hi g h I N Rs or p o or ti me i n t hera pe utic ra n ge 
(e. g., < 6 0 %) w hile o n a vita mi n K a nta g o nist. 
Hy perte nsi o n  is defi ne d as h y perte nsi o n re q uiri n g p har mac ol o gic t hera p y t o 
mai ntai n a B P < 1 4 0/ 8 5 m m H g or u ntreate d h y perte nsi o n d oc u me nte d b y B P > 1 4 0 
m m H g s yst olic or > 9 0 m m H g diast olic o n t w o se parate occasi o ns. 
S E E:   A n a br u pt e pis o de of arterial i ns ufficie nc y ass ociate d wit h cli nical or 
ra di ol o gical e vi de nce of arterial occlusi o n i n t he a bse nce of ot her li kel y 
mec ha nis ms (e. g., at her oscler osis, i nstr u me ntati o n)  
Str oke:   A str o ke is defi ne d b y a n ac ute e piso de of f ocal or gl o bal ne ur ol o gical 
d ysf u ncti o n ca use d b y brai n, s pi nal c or d, or reti nal vasc ular i nj ur y as a res ult of 
he m orr ha ge or i nfarcti o n. T he e ve nt classifi es as a str o ke rat her t ha n a TI A base d 
o n a n y of t he f oll o wi n g: 
- 
D urati o n of ne ur ol o gical d ysf u ncti o n > 2 4 hrs. 
- 
D urati o n of ne ur ol o gical d ysf u ncti o n < 2 4 hrs i n case of i ma gi n g-
d oc u me nte d ne w he m orr ha ge or i nfarcti o n. 
- 
A ne ur ol o gical d ysf u ncti o n res ulti n g i n deat h ( 2 4 )     
TI A :   TI A is defi ne d b y a n y ne ur ol o gical d ysf u ncti o n n ot sa tisf yi n g t he a b o ve 
criteria f or str o ke, s pecificall y if last i n g < 2 4 h wit h o ut i ma gi n g- d oc u me nte d ac ute 
brai n i nfarcti o n.  
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 3 of 1 0 9 
 
1 6. 5.  
C o m p o ne nts of t he C H A D S 2, C H A2D S 2- V A Sc Sc ore a n d H A S- B L E D Sc ore 
 
T a ble 1 6. 4: C o m p o ne nts of t he C H A D S 2 Sc ore 
C H A D S 2- V A Sc 
Sc ore 
C o n gesti ve heart fail ure 
1 
H y perte nsi o n (s yst olic > 1 6 0 m m H g) 
1 
A ge > 7 5 y ears 
1 
Dia betes mellit us 
1 
Pri or cere bral isc he mia 
2 
M a xi m u m sc ore 
6 
 
T a ble 1 6. 5: C o m p o ne nts of t he C H A 2D S 2- V A Sc S c ore 
C H A 2D S 2- V A Sc 
Sc ore 
C o n gesti ve heart fail ure 
1 
H y perte nsi o n  
1 
A ge ≥7 5 y ears 
2 
Dia betes mellit us 
1 
Str o ke/ tra nsie nt isc he mic attac k ( TI A)/t hr o m b o-e m b olis m ( T E) 
2 
Vasc ular disease ( pri or m y ocar dial i nfarcti o n [ MI], peri p heral arter y 
disease [ P A D], or a ortic pla q ue) 
1 
A ge d 6 5 t o 7 4 y ears 
1 
Se x cate g or y (i.e., fe male se x) 
1 
M a xi m u m sc ore
1 0 
 
T a ble 1 6. 6: C o m p o ne nts of t he H A S- B L E D Sc ore 
H A S- B L E D  
Sc ore 
H y perte nsi o n hist or y (s yst olic bl o o d press ure > 1 6 0 m m H g s yst olic)  
1 
A b n or mal re nal f u ncti o n ( dial ysis, tra ns pla nt, ser u m creati ni ne 
> 2. 6 m g/ d L or > 2 0 0 m ol/ L) 
1 
A b n or mal li v er f u ncti o n (cirr h osis or bilir u bi n > 2 x U L N [ u p per li mit of 
n or mal] wit h as partate tra nsa mi nase [ A S T]/ala ni ne tra nsa mi nase [ A L T]/ 
al kali ne p h os p hatase [ A L P] > 3 x U L N) 
1 
Pre vi o us hist or y of str o ke  
1 
Pri or Maj or Blee di n g or pre dis p ositi o n t o blee di n g (e. g., a ne mia) 
1 
La bile I N Rs ( u nsta ble/ hi g h i nter nati o nal n or malize d rati o [I N Rs], ti me i n 
t hera pe utic ra n ge [ T T R] < 6 0 %) 
1 
El derl y (a ge > 6 5 y ears) 
1 
Dr u g usa ge (i.e., a nti platelet a ge nts, n o n -ster oi dal a nti-i nfla m mat or y dr u gs 
[ N S AI Ds]) 
1 
E xcessi ve alc o h ol use ( ≥8 dri n ks/ wee k) 
1 
M a xi m u m sc ore
9 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 4 of 1 0 9 
 
1 6. 6.  
Esti m ati o n of Cre ati ni ne Cle ar a nce ( Cr C L) 
 
Cre ati ni ne Cle ar a nce Usi n g C oc kcr oft- G a ult F or m ul a (3 4 ) 
T he C oc kcr oft- Ga ult f or m ula f or t he calc ulati o n of Cr C L will be use d i n t his st u d y. 
Creati ni ne Cleara nce f or Males:  
Cr C L = [ 1 4 0 – a ge ( years)] x [ b o d y wei g ht ( k g)] / [ 7 2 x ser u m creati ni ne ( m g/ d L)]  
 
Creati ni ne Cleara nce f or Fe males:  
Cr C L = 0. 8 5 x [ 1 4 0 – a ge ( years)] x [ b o d y wei g ht ( k g)] / [ 7 2 x ser u m creati ni ne 
( m g/ d L)] 
 
 
T he C hr o ni c Ki d ne y Dise ase E pi de mi ol o g y E q u ati o n ( C K D- E PI) t o esti m ate t he 
gl o mer ul ar filtr ati o n r ate ( G F R)   
 
T he ta ble is ta ke n o ut of t he p u blicati o n i n  A n nals of I nter nal me dici ne 2 0 0 9 ( 3 5). 
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 5 of 1 0 9 
 
 
1 6. 7.  
M o difie d R a n ki n Sc ale 
 
T a ble 1 6. 7: M o difie d R a n ki n Sc ale 
 
Sc ore   
Descri pti o n 
0  
N o s y m pt o ms at all 
1  
N o si g nifica nt disa bilit y des pite s y m pt o ms ; a ble t o carr y o ut all us ual d uties 
a n d acti vities 
2  
Sli g ht disa bilit y; u na ble t o carr y o ut all pre vi o us acti vities, b ut a ble t o l o o k 
after o w n affairs wit h o ut assista nce 
3  
M o derate disa bilit y; re q uiri n g s o me hel p, b ut a ble t o wal k wit h o ut 
assista nce 
4  
M o deratel y se vere disa bilit y; u na ble t o wal k wit h o ut assista nce a n d u na ble 
t o atte n d t o o w n b o dil y nee ds wit h o ut assista nce 
5  
Se vere disa bilit y; be dri d de n, i nc o nti ne nt, a n d re q uiri n g c o nsta nt n ursi n g 
care a n d atte nti o n 
6
 Dea d
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 6 of 1 0 9 
 
 
1 6. 8.  
Re gi o n al G ui deli ne Rec o m me n d ati o ns f or I N R 
 
T a ble 1 6. 8: Re gi o n al G ui deli ne Rec o m me n d ati o ns f or I N R 
G ui deli ne 
Ref.  
T ar get I N R R a n ge  
 
E ur o pe a n d Asia 
(1 5 ) 
2. 0 – 3. 0 
 
Ca na da
 ( 3 6 ) 
2. 0 – 3. 0 
 
 
 

Pr ot oc ol D S E- E D O- 0 1- 1 6- E U 
Versi o n 3. 0, 2 7 J U L Y 2 0 1 7 
 
C o nfi de ntial 
Pa ge 1 0 9 of 1 0 9 
 
d As a n alter nati ve t o t he T A, a pers o nal visit is o pti o nal f or t h os e patie nts w h o d o n ot ha ve t he o pti o n of I N R meas ure me nt b y t heir ge neral practiti o ner.  
e S u bjects are tra nsiti o ne d t o a n a vaila ble mar kete d O A C of t he I n vesti gat or’s c h oice. T he I n ve sti gat or will f oll o w t he tra nsiti on strate g y i n t he a p pr o ve d pr o d uc t la bel. S u bjects w h o pre mat urel y 
disc o nti n ue st u d y O A C are re q ueste d t o c o nti n ue cli nical f oll o w- u p wit h st u d y visits acc or di n g t o t his sc he d ule.  
f All ra n d o mize d s u bjects  w h o are o n st u d y me dicati o n (st u d y e d o xa ba n or V K A) at 9 0 da ys, will ha ve a ma n dat or y p ost-treat me nt c o ntact at 3 0- 3 5 da ys after t he E O T visit t o c ollect data o n 
c o nc o mita nt me dicati o ns, seri o us A Es, a nd ot her safet y e ve nts of i nterest.  
g S u bjects eli gi ble t o partici pate i n t he st u d y pr o vi de writte n I C bef ore ra n d o mizati o n or a n y st u d y-s pecific pr oce d ures. O nce writte n I C is o btai ne d, s u bjects s h o ul d be ra n d o mize d wit h o ut dela y. 
h F or s u bjects ra n d o mize d t o e d o xa ba n: If s u bject is o n: (a) V K A, disc o nti n ue t he V K A, t he first d ose of e d o xa ba n ca n be starte d w he n I N R ≤2. 5; ( b) N O A C, disc o n ti n ue N O A C a n d start 
e d o xa ba n at t he ti me of t he ne xt sc he d ule d  N O A C d ose. F or s u bjects ra n d o mize d t o V K A: If s u bject is o n: (a) V K A, c o nti n ue wit h me dicati o n as pr o vi de d b y I X R S w he n I N R ≤2. 5; ( b) N O A C, 
disc o nti n ue t he N O A C a n d start V K A at t he ti me of t he ne xt sc hed ule d N O A C d ose. See Secti o ns 5. 2. 1 a n d 5. 2. 2  f or m ore detaile d i nf or mati o n 
i A p plica ble o nl y w he n a vaila ble rece nt l ocal la b orat or y res ults are of s ufficie nt acc urac y t o verif y t he patie nt’s eli gi bilit y a n d s u p p ort ra n d o mizati o n i n t he j u d ge me nt of t he i n vesti gat or a n d if 
Scree ni n g a n d Ra n d o mizati o n visits are c o m bi ne d. C hec k t he m ost rece nt res ults fr o m l ocal la b orat or y tests d o ne: He m o gl o bi n, pl atelet c o u nt, W B C ( wit h differe nt ial if ele vate d), A L T, A S T, 
t otal bilir u bi n (if ele vate d, deter mi ne c o nj u gate d/ u nc o nj u gate d bilir u bi n fracti o n), Creati ni ne, a n d Cr C L as esti mate d b y t he Coc kcr oft- Ga ult f or m ula.  
j Bl o o d dra w f or ce ntral la b orat or y a nal ysis as descri be d i n Secti o ns 6. 2  a n d 9. 7 .  Cr C L will be pr o vi de d as esti mate d b y t he C oc kcr oft- Ga ult f or m ula. I n di vi d ual bl o o d sa m ples are c ollecte d, 
st ore d a n d s hi p pe d acc or di n g t o t he La b orat or y Ma n ual.  
k W o me n of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne test f or pre g na nc y ( o bli gat or y at Visits 0, 3, a n d 6) a n d be willi ng a n d a ble t o a d here t o t he pr o hi biti o ns a n d restricti o ns s pecifie d i n 
t he pr ot oc ol. F urt her m ore, pre g na nc y tests are carrie d o ut w he ne ver t here are cli nical i n dicati o ns f or t he e xiste nce of a pre g na nc y.  
l S p o ns or s u p plies st u d y s u bjects wit h e d o xa ba n a n d V K A acc or di n g t o assi g ne d re gi me n at ra n d o mizati o n. Me dicati o n kits are assig ne d t hr o u g h t he I X R S. A cc o u nta bilit y f or me dicati o ns 
pr o vi de d is perf or me d at dis pe nsi n g visits a n d t he E O T visit  
m V K A s u bjects o nl y: I N R val ues a n d V K A d ose are c ollecte d a n d e ntere d i nt o t he e C R F eit her d uri n g t he o n-site visits or b y l ocal la b orat or y deter mi nati o n. I N R val ues a n d V K A d oses c ollecte d 
t hr o u g h t he ge neral practiti o ner or l ocal a ntic oa g ulati o n cli nic m ust als o be c o nsi dere d a n d c ollecte d b ut t his d oes n ot c o nsti t ute a wai ver f or s u bjects’ pla n ned T A or I N R deter mi nati o n d uri n g 
o n-site visits. I n a n y case t he st u d y p h ysicia n is res p o nsi ble  f or c hec ki n g t he I N R val ue a n d a da pti n g t he V K A d ose acc or di n gl y. 
n V K A s u bjects o nl y: Fre q ue nt I N R deter mi nati o ns u p o n i nitiati o n s h o ul d be o bt ai ne d u ntil s u bject’s I N R is  sta ble i n t he t hera pe utic ra n ge. It is e x pecte d t hat m ore fre q ue nt visits will be pla n ne d 
f or ‘ de n o v o’ s u bjects o n V K A t o a dj ust t he d ose wit h t he g oal of reac hi n g I N R 2. 0- 3. 0 wit hi n 6- 8 da ys after e nr ol me nt. O btai n s u bse q ue nt I N R deter mi nati o ns as per rec o m me n dati o ns a n d 
g ui deli nes pr o vi de d i n  t he l ocal a p pr o ve d la bel fr o m t he res pecti ve V K A man ufact urer (see Secti o n 6. 2 ). 
o Vital si g ns i ncl u de heart rate, sitti n g bl o o d press ure, b o d y wei g ht a n d hei g ht. Hei g ht o nl y nee ds t o be rec o r de d at ra n d o mizatio n.  
p T E E or i ntracar diac ec h ocar di o gra m will be perf or me d d uri n g t he h os pital sta y relate d t o t he pr oce d ure directl y bef ore cat heter  a blati o n or t he da y bef ore ( u p t o 2 4 h bef ore a blati o n). 
q D W- M RI will be perf or me d i n a s u bset of st u d y sites 4 da ys ± 2 da ys p ost cat heter a blati o n.  
r A ntit hr o m b otic re gi me n c o m plia nce is ac hie ve d b y assessi n g s u bjec t c o m plia nce at eac h visit ( b ot h b y pill c o u nt, self-re p orti n g/ p h ysicia n-re p orti n g a n d b y I N R val ues f or V K A s u bjects o nl y). 
I n case of a s us pecte d st u d y e n d p oi nt, a n a d diti o nal assess me nt f or s u bject c o m plia nce t o t he assi g ne d re gi me n m ust be perf or med.  
s ( S) A Es, e n d p oi nt e ve nts, a n d e ve nts of s pecial i nterest s h o ul d be re p orte d as s o o n as  site pers o n nel lear n of t he e ve nt. E n d p oi nt e ve nt a n d A E re p orti n g s h o ul d occ ur t hr o u g h o ut t he st u d y a n d 
n ot be restricte d t o s pecific visits. If A L T or A S T > 3 x U L N wit h si m ulta ne o us T B L > 2 x U L N is o bs er ve d, t he n A L P s h o ul d be deter mi n e d. Re p ort o n g oi n g all e n d p oi nts a n d all A Es i ncl u di n g 
a b n or mal la b orat or y fi n di n gs. A n y la b orat or y meas ure me nts perf or me d d uri n g u nsc he d ule d visits  are c ollecte d.