Conditions: Venous Thromboembolism (VTE) Deep Vein Thrombosis (DVT) Pulmonary Embolism (PE) Cancer
Keywords: Active Cancer with Metastasis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1046
Healthy volunteers: no

Brief summary:
The primary objective is to demonstrate the non-inferiority of edoxaban (preceded by a short course of LMWH) compared with dalteparin for the prevention of the combined outcome of recurrent venous thromboembolism (VTE) or major bleeding in subjects with VTE associated with cancer during a 12-month study period. If non-inferiority is established, LMWH/edoxaban will be compared with dalteparin for superiority.

Detailed description:

Arms:
arm 1: After 5 days of low molecular weight heparin (LMWH), patients receive edoxaban treatment daily - tablet for oral use arm 2: Participants receive Dalteparin treatment daily -solution for subcutaneous injection

Interventions: intervention 1: Edoxaban intervention 2: Dalteparin intervention 3: Low molecular weight heparin
Intervention descriptions: intervention 1: After the 5 day treatment with LMWH, patients receive edoxaban 60 mg once daily (QD) as 2 × 30 mg tablets (or 1 x 30 mg tablet QD for patients requiring dose adjustment) for the remainder of the treatment period. intervention 2: Dalteparin was administered via subcutaneous injection at a dose of 200 IU/kg (maximum daily dose 18,000 IU) for 30 days, and at a dose of 150 IU/kg from Day 31 to the end of treatment. intervention 3: Therapeutic doses of subcutaneous LMWH were administered for at least 5 days (to patients in the edoxaban group); this 5-day period may have included the pre-randomization LMWH (if applicable). The choice of parenteral LMWH was up to the treating physician.

Protocol document:
Prot_SAP_000.pdf: 
Pr o prietar y  a n d C o nfi de ntial
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C LI NI C A L S T U D Y P R O T O C O L
A P H A S E 3 B, P R O S P E C T I 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 V A L U A T O R ( P R O B E) 
S T U D Y E V A L U A TI N G T H E E F FI C A C Y A N D 
S A F E T Y O F ( L M W) H E P A RI N/ E D O X A B A N 
V E R S U S D A L T E P A RI N I N V E N O U S 
T H R O M B O E M B O LI S M A S S O CI A T E D WI T H 
C A N C E R
D U 1 7 6 b- D- U 3 1 1
I N D/E U D R A C T N U M B E R 6 3, 2 6 6/ 2 0 1 4- 0 0 4 7 0 8 - 3 0
V E R SI O N 3. 0, 2 0 J A N 2 0 1 6
V E R SI O N 2. 0, 1 7 D E C 2 0 1 5
V E R SI O N 1. 0 , 1 5 D E C 2 0 1 4
D AII C HI S A N K Y O P H A R M A D E V E L O P M E N T
3 9 9 T H O R N A L L S T R E E T
E DI S O N, N J 0 8 8 3 7
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 is pr o prietar y t o Daiic hi Sa n k y o .  T he 
i nf or mati o n is pr o vi de d t o yo 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 ne d 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 me 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 ned i n it t o a n y  t hir d part y ( ot her 
t ha n t h ose i n yo 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 he 
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 per missi o n of a n 
a ut h orize d re prese ntati ve of Daiic hi Sa n k y o.




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P R O T O C O L S Y N O P SI S
E u dra C T /IN D N u m ber:  
2 0 1 4- 0 0 4 7 0 8- 3 0 / 6 3, 2 6 6
Pr ot oc ol N u m ber:
D U 1 7 6 b - D-U 3 1 1
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 d ie nt(s)/I N N:  
N -( 5-C hl or o p y ri di n- 2-yl )-N - [( 1S , 2R , 4 S)-4-( N ,N -
di met h y lcar ba m oyl )- 2-( 5-met h y l- 4, 5, 6, 7-
tetra hy 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 y l be nze nes ulf o nate) m o n o h ydrate
St u d y  Title:
A P hase 3 b, pr os pecti ve, ran d o mize d, o pe n -la bel, bli n d 
e val uat or ( P R O B E) st u d y e val uati n g t he efficac y a n d safety 
of ( L M W) he pari n/ e d o xa ba n vers us dalte pari n i n ve n o us 
t hr o m b oe m b olis m ass ociate d wit h ca ncer
S h ort Title:
E d o xa ba n i n Ve n o us T hr o m b oe m b olis m Ass ociate d wit h 
Ca ncer ( H o kusai V T E Ca ncer)
St u d y  P hase:
P hase 3 b trial
I n dicati o n U n der 
I n vesti gati o n:
Ve n o us t hr o m b oe m b olis m ass ociate d wit h ca ncer
St u d y  O bjecti ves:  
Pri mar y  O bjecti ves: T he pri mar y  o bjecti ve is t o 
de m o nstrate t he n o n- i nferi orit y of e d o xa ba n ( prece de d by a 
s h ort c o urse of L M W H) c o m pare d wit h dalte pari n f or t he 
pre ve nti o n of t he c o m bi ne d o utc o me of rec urre nt ve n o us 
t hr o m b oe m b olis m ( V T E) or maj or blee di n g i n s u bjects 
wit h V T E ass ociate d wit h ca ncer d uri n g a 1 2 -m o nt h st u d y  
peri o d .  If n o n-i nferi ority is esta blis he d , L M W H/ e d o xa ba n 
will be c o m pare d wit h dalte pari n f or s u peri orit y .
Sec o n dar y  O bjecti ves: T o c o m pare L M W H /e d o xa ba n wit h 
dalte pari n wit h re gar ds t o rates of:
1.
Rec urre nt V T E ;
2.
Maj or blee di n g ;
3.
Cli nicall y  rele va nt n o n-maj or ( C R N M) blee di n g ;
4.
Maj or + C R N M blee di n g ;
5.
All blee di n g;




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D alte p ari n gr o u p : After ra n d o mizati o n, d alte pari n will be 
a d mi nistere d at a d ose of 2 0 0 I U/ k g S C ( ma xi m u m dail y  
d ose 1 8, 0 0 0 I U) f or 3 0 da y s.  T he 3 0 da y  peri o d ma y  
i ncl u de t he pre-ra n d o mizati o n a ntic oa g ula nt treat me nt if 
dalte pari n was use d i n t hera pe utic d oses.  T hereafter 
(a p pr o xi matel y Da y 3 1 f or war d), dalte pari n will be 
a d mi nistere d at a d ose of 1 5 0 I U/ k g S C ( ~ 7 5 % - 8 3 % of 
t he i nitial d ose) f or t he re mai n der of t he treat me nt peri o d.
T he i nte n de d treat me nt d urati o n a n d f oll o w - up f or all 
s u bjects is 1 2 m o nt hs, e xce pt f or t he fi nal s u bject(s) 
ra n d o mize d t o t he st u d y.  O nce 1 0 0 0 s u bjects are 
ra n d o mize d, a gl o bal E n d- of- Treat me nt ( E O T) date will be 
esta blishe d t hat e ns ures a mi ni m u m of 6 m o nt hs of st u d y 
treat me nt a n d f oll o w-u p f or t he fi nal s u bject(s) ra n d o mize d.
All s u bjects will per ma ne ntl y disc o nti n ue st u d y  treat me nt 
o n or bef ore t he E O T date .
After ra n d o mizati o n s u bjects will be assesse d at M o nt h 1, 
M o n t h 3, a n d q uarterly t hereafter f or u p t o 1 2 m o nt hs u ntil 
t he y c o m plete t he st u d y.
S u bjects re q uiri n g a d diti o nal a nti -c oa g ulati o n t hera p y w h o 
c o m plete t heir treat me nt a n d f ull 1 2 -m o nt h p ost 
ra n d o mizati o n f oll o w-u p or w h ose treat me nt is tr u ncate d 
d ue t o t he gl o bal E n d of Treat me nt date will be ma na ge d 
acc or di n g t o l ocal practice.
G ui da nce f or s witc hi n g fr o m e d o xa ba n t o ot her 
a ntic oa g ula nts is pr o vi de d i n A p pe n di x 1 7. 2.
A d diti o nal g ui da nce f or l o n g -ter m ma na ge me nt of ca ncer 
s u bjects wit h V T E is pr o vi de d b y L yma n, et al.
1
St u d y  D urati o n:
T he e x pecte d st u d y d urati o n is a p pr o xi matel y 3 0 m o nt hs 
fr o m t he ti me t he first s u bject is e nr olle d (J ul y 2 0 1 5 ) t o t he 
ti me of t he last s u bject’s last f oll o w-u p visit .
St u d y  Sites a n d L ocati o n:  
A p pr o xi matel y  14 0 st u d y sites i n N ort h A merica, E ur o pe, 
a n d A ustralia/ N e w Zeala n d are pla n ne d t o e nr oll s u bjects i n 
t his st u d y.
Pla n ne d Sa m ple Size:  
Ass u mi n g a h azar d rati o of 1, a t otal of 1 9 1 o v erall pri mar y 
e ve nts is pr ojecte d t o accr ue i n t he m o difie d i nte nti o n- t o-
treat ( mI T T) a nalys is set w hic h will e ns ure at least 8 0 % 
p o wer f or t he pri mar y  a nal ysis at a n o n- i nferi orit y mar gi n 
f or t he hazar d rati o of 1. 5 a n d a T ype I err or of 0. 0 5 (t w o-
si de d).


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Ass u mi n g a pri mar y  c o m bi ne d o utc o me rate (rec urre nt 
V T E or maj or blee d) of 2 0. 0 %, a t otal of 1 0 0 0 s u bjects are 
e x pecte d t o be ra n d o mize d t o st u d y  treat me nt i n or der t o 
accr ue 1 9 1 o verall pri mar y e ve nts i n t he mI T T a nal ysis.
S u bject Eli gi bilit y  Criteria:
A d ult male or fe male s u bjects w h o prese nt wit h V T E 
ass ociate d wit h ca ncer ( ot her t ha n basal -cell or s q ua m o us -
cell carci n o ma of t he s ki n) f or w h o m l o n g -ter m treat me nt 
wit h L M W H is i n dicate d , are eli gi ble t o partici pate i n t his 
st u d y.
Ke y  eli gi bilit y criteria i ncl u de:
I ncl usi o n Criteria:
1.
Male or fe male s u bjects wit h a ge ≥ 1 8 ye ars or t he 
ot her wise le gal l o wer a ge acc or di n g t o t he c o u ntr y 
of resi de nce ;
2.
C o nfir me d s y m pt o matic or u ns us pecte d l o wer 
e xtre mit y pr o xi mal D V T (ie, p o pliteal, fe m oral, 
iliac or i nferi o r ve na ca va vei n t hr o m b osis), or 
c o nfir me d s y m pt o matic P E, or u ns us pecte d P E of a 
se g me ntal or lar ger p ul m o nar y arter y;
3.
Ca ncer, ot her t ha n basal -cell or s q ua m o us-cell 
carci n o ma of t he s ki n.  Ca ncer s h o ul d be acti ve (see 
Secti o n 6. 1 ) or dia g n ose d wit hi n 2 years pri or t o 
ra n d o mizati o n.  T he dia g n osis/ hist or y of ca ncer 
m ust be o bjecti vel y  d oc u me nte d ;
4.
I nte nti o n f or l o n g-ter m treat me nt (at least 6 m o nt hs) 
wit h pare nteral L M W H ;
5.
A ble t o pr o vi de writte n i nf or me d c o nse nt.
E xcl usi o n Criteria :
1.
T hr o m bect o m y, i nserti o n of a ca val filter, or use of 
a fi bri n ol ytic a ge nt t o treat t he c urre nt (i n de x) 
e pis o de of D V T a n d/ or P E;
2.
M ore t ha n 7 2 h o urs pre -treat me nt wit h t hera pe utic 
d osa ges of a ntic oa g ula nt treat me nt ( L M W H, 
u nfracti o nate d he pari n , a n d fo n da pari n u x per l ocal 
la beli n g), oral direct a ntic oa g ula nts or vita mi n K 
a nta g o nist (V K A ) pri or t o ra n d o mizati o n t o treat t he 
c urre nt (i n de x) e pis o de;
3.
Treat me nt wit h t hera pe utic d oses of a n 
a ntic oa g ula nt i ncl u di n g dalte pari n f or a n i n dicati o n


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ot her t ha n V T E pri or t o ra n d o mizati o n ;
4.
Acti ve blee di n g or a n y  c o ntrai n dicati o n f or
treat me nt wit h LM W H / dalte pari n or e d o xa ba n ;
5.
A n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) 
Perf or ma nce Stat us of 3 or 4 at t he ti me of 
ra n d o mizati o n (see A p pe n di x 1 7. 6 );
6.
Calc ulate d creati ni ne cleara nce (Cr C L )
< 3 0 m L / mi n;
7.
Hist or y  of he pari n ass ociate d t hr o m b oc yt o pe nia;
8.
Ac ute he patitis, c hr o nic acti ve he patitis, li ver 
cirr h osis;
9.
He pat ocell ular i nj ur y wit h c o nc urre nt tra nsa mi nase 
(ala ni ne tra nsa mi nase [A L T ]/as partate tra nsa mi nase
[A S T ] > 3 x u p per li mit of n or mal [ U L N ]) a n d 
bilir u bi n ( > 2 x U L N) ele vati o ns i n t he a bse nce of 
a cli nical e x pla nati o n;
1 0. Life e x pecta nc y  < 3 m o nt hs;
1 1. Platelet c o u nt < 5 0, 0 0 0/ m L ;
1 2. U nc o ntr olle d h y perte nsi o n as j u d ge d b y t he 
In vesti gat or ( e g, s yst olic bl o o d press ure > 
1 7 0 m m H g or diast olic bl o o d press ure > 1 0 0 m m H g 
des pite a nti h y perte nsi ve treat me nt);
1 3.
W o me n of c hil d beari n g p ote ntial wit h o ut pr o per 
c o ntrace pti ve meas ures, a n d w o me n w h o are 
pre g na nt or breast fee di n g;
1 4. C hr o nic treat me nt wit h 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 Ds) i ncl u di n g b ot h 
c ycl o o x yge nase -1 ( C O X -1) a n d c y cl o o x yge nase - 2 
( C O X-2) i n hi bit ors f or ≥4 da y s/ wee k a ntici pate d t o 
c o nti n ue d uri n g t he st u d y;
1 5. Treat me nt wit h as piri n i n a d osa g e of m ore t ha n 1 0 0 
m g/ per da y  or d ual a nti platelet t hera py (a ny 2
a nti platelet a ge nts i ncl u di n g as piri n pl us a n y ot her 
oral or i ntra ve n o us a nti platelet dr u g) a ntici pate d t o 
c o nti n ue d uri n g t he st u d y;
1 6. Treat me nt wit h t he P -g p i n hi bit ors rit o na vir, 
nelfi na vir , i n di na vir, or sa q ui na vir a ntici pate d t o 
c o nti n ue d uri n g t he st u d y;


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1 7. S y ste mic use of t he P-g p i n hi bit ors ket oc o naz ole, 
itrac o naz ole, er yt hr o myc i n, azit hr o m yci n or 
clarit hr o m yci n at t he ti me of ra n d o mizati o n; 
s u bse q ue nt use is per mitte d ( wit h a p pr o priate d ose 
re d ucti o n of e d o xa ba n see A p pe n di x 1 7. 3. 7 );
1 8. S u bjects wit h a n y  c o n diti o n t hat as j u d ge d by 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.
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 ( 3 0 m g) will be s u p plie d b y t he Sp o ns or as 
ye ll o w fil m-c oate d ta blets a n d a d mi nistere d per oral ( P O).
L M W H f or t he e d o xa ba n lea d- i n will be as prescri be d b y 
t he Pri nci pal I n vesti gat or (see St u d y Desi g n, a b o ve).
Dal te pari n will be s u p plie d b y t he Sp o ns or as si n gle-use
pre -fille d s yri n ges a n d a d mi nistere d b y S C i njecti o n.
St u d y  O utc o mes :
T he pri mar y  st u d y o utc o me is t he c o m p osite of rec urre nt 
V T E, a n d maj or blee di n g.
Rec urre nt V T E is eit her :

s ym pt o matic c o nfir me d ( n e w) D V T or ( ne w) P E;

u ns us pecte d ( ne w) pr o xi mal D V T of t he le gs or 
u ns us pecte d ( ne w) P E l ocate d i n se g me ntal or m ore 
pr o xi mal arteries :

U ns us pecte d D V T or P E are t hr o m bi t hat 
are detecte d d uri n g i ma gi n g testi n g 
perf or me d f or ot her reas o ns (e g, c o m p ute d 
t om o gra p h y ( C T) f or ca ncer sta gi n g) a n d n ot 
f or s us pici o n of D V T or P E.

fatal P E (i ncl u di n g u ne x plai ne d deat h f or w hic h P E 
ca n n ot be r ule d o ut ). 
Sec o n dar y  O utc o mes:

Rec urre nt V T E;

Maj or blee di n g;

C R N M blee di n g;

Maj or + C R N M blee di n g;

All blee di n g;

E ve nt -free s ur vi val, defi ne d as t he pr o p orti o n of 


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s u bjects o ver ti me free of rec urre nt V T E, maj or 
blee di n g e ve nts, a n d deat h;

V T E -relate d deat h;

M ortalit y  fr o m all ca uses; 

Rec urre nt D V T;

Rec urre nt P E;

Healt hcare res o urce utilizati o n f or p ote ntial 
rec urre nt V T E a nd blee d e ve nts .
Ot her o utc o mes i ncl u de:
Statistical A nal y ses:  
A nal y sis of t he Pri mar y St u d y  O utc o me
T he pri mar y  a nalys is will be base d o n t he mI T T A nal ysis 
Set ( w hic h i ncl u des all ra n d o mize d s u bjects w h o recei ve at 
least 1 d ose of st u dy dr u g) usi n g all pri mar y  o utc o me 
e ve nts (ie, rec urre nt V T E or maj or blee di n g) occ urri n g 
fr o m ra n d o mizati o n t hr o u g h t he e n d of t he 1 2 m o nt h st u d y 
peri o d or u p t o t he gl o bal E O T visit w he n t he st u d y has 
bee n st o p pe d, re gar dless of w het her t he s u bject is ta ki n g 
st ud y  dr u g. I n t his a nal ysis, t he ti me t o t he first e ve nt of 
t he c o m p osite o utc o me will be a nalyz e d usi n g a C o x’s 
pr o p orti o nal hazar ds m o del i ncl u di n g treat me nt a n d t he 
stratificati o n fact ors as c o variates.  T he L M W H/e d o xa ba n
t o c o m parat or hazar d rati o will be c o m p ute d al o n g wit h a 
9 5 % c o nfi de nce i nter val [ CI ] (t w o-si de d) base d o n t his 
m o del.  T he L M W H/e d o xa ba n will be c o nsi dere d n o n -
i nferi or t o t he c o m parat or if t he u p per li mit of t he CI is 
< 1. 5.
T he f oll o wi n g se nsiti vit y a nal ys es will be perf or me d f or t he 
Pri mar y  O utc o me :

O n -Treat me nt e ve nts base d o n t he per -pr ot oc ol 
(P P ) A nal y sis Set will be a nalyz e d usi n g t he 
c o u nti n g pr ocess a p pr oac h of t he C o x 
pr o p orti o nal hazar ds re gressi o n m o del i ncl u di n g 
treat me nt gr o u p, a n d t he stratificati o n fact ors as 


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c o variates.    A n O n - Treat me nt e ve nt is defi ne d 
as t he e ve nt occ urri n g d uri n g t he ti me peri o d t he 
s u bject is ta ki n g st u dy dr u g u p t o 3 da ys after 
t heir last d ose f or t hat ti me peri o d.  O nl y e ve nt s
occ urri n g pri or t o or o n Da y  3 6 5 will be 
i ncl u de d i nt o t his a nal ysis. S u bjects w h o d o n ot 
e x perie nce a n O n -Treat me nt e ve nt will be 
ce ns ore d at Da y 3 6 5, or t he ti me st u d y dr u g is 
per ma ne ntl y disc o nti n ue d pl us 3 da ys or o n t he 
last da y t he s u bject ha d a c o m plete assess me nt 
(i n-pers o n visit or b y tele p h o ne) f or st u d y 
o utc o mes, or t he da y  of gl o bal e n d of treat me nt, 
w hic he ver c o mes first .

E ve nts occ urri n g d uri n g t he first 6 m o nt hs 
( 1 8 0 da y s) base d o n t he mIT T A nal ys is Set will 
be a nal yz e d usi n g t he sa me statistical m o del as 
t he pri mar y a nal ysis of t he pri mar y o utc o me. 
T he ti me t o e ve nt is defi ne d as t he ti me ( da ys) 
fr o m t he ra n d o mizati o n t o t he first e ve nt d uri n g 
t he first 6 m o nt hs after ra n d o mizati o n.  S u bjects 
w h o d o n ot e x perie nce a n e ve nt u ntil Da y 1 8 0
will be ce ns ore d a t Da y 1 8 0, or t he ti me st u d y 
dr u g is per ma ne ntl y disc o n ti n ue d or o n t he last 
da y  t he s u bject ha d a c o m plete assess me nt (i n-
pers o n visit or b y  tele p h o ne) f or st u d y 
o utc o mes, w hic he ver c o mes first.


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 1
T A B L E O F C O N T E N T S
I NV 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 ................................................................................................................ 3
LI S T O F T A B L E S ......................................................................................................................... 1 7
LI S T O F FI G U R E S ....................................................................................................................... 1 8
LI S T O F A B B R E VI A TI O N S ........................................................................................................ 1 9
1.  
I NT R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N .................................. 2 2
1. 1.  
Data S u m mar y ............................................................................................................ 2 2
1. 1. 1.  
I n vesti gati o nal Pr o d uct(s)........................................................................................... 2 3
1. 1. 1. 1.  
Na me ........................................................................................................................... 2 3
1. 1. 1. 2.  
Descri pti o n ..................................................................................................................2 3
1. 1. 1. 3.    
N o ncli nical St u dies..................................................................................................... 2 3
1. 1. 1. 4.  
Cli nical E x perie nce..................................................................................................... 2 3
1. 2.  
St u d y  Rati o nale........................................................................................................... 2 4
1. 3.  
Ris ks a n d Be nefits f or St u d y  S u bjects........................................................................ 2 6
1. 4.  
P o p ulati o n, R o ute, D osa ge, D osa ge Re gi me n, Treat me nt Peri o d .............................. 2 7
1. 5.  
C o m plia nce State me nt, Et hics a n d Re g ulat or y  C o m plia nce...................................... 2 8
1. 5. 1.  
S u bject C o nfi de ntialit y ...............................................................................................2 8
1. 5. 2.  
I nf or me d C o nse nt Pr oce d ure ...................................................................................... 2 9
1. 5. 3.  
Re g ulat or y  C o m plia nce..............................................................................................3 0
2.  
S T U D Y O BJ E C TI V E S A N D H Y P O T H E S E S .......................................................... 3 1
2. 1.  
St u d y  O bjecti ves......................................................................................................... 3 1
2. 1. 1.  
Pri mar y  O bjecti ve....................................................................................................... 3 1
2. 1. 2.  
Sec o n dar y  O bjecti ves ................................................................................................. 3 1
2. 1. 3.  
E x pl orat or y  O bjecti ves...............................................................................................3 1
2. 2.  
St u d y  H yp ot hesis ........................................................................................................3 2
3.  
S T U D Y D E SI G N .......................................................................................................3 3
3. 1.  
O verall Pla n ................................................................................................................ 3 3
3. 1. 1.  
St u d y  T ype ..................................................................................................................3 3
3. 1. 2.  
Treat me nt Gr o u ps a n d D osi n g .................................................................................... 3 3
3. 1. 2. 1.  
Treat me nt D urati o n ..................................................................................................... 3 5
3. 1. 3.  
St u d y  G o ver na nce....................................................................................................... 3 6


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 2
3. 1. 3. 1.  
Steeri n g C o m mittees ................................................................................................... 3 6
3. 1. 3. 2.  
Data M o nit ori n g C o m mittee ....................................................................................... 3 6
3. 1. 3. 3.  
Cli nical E ve nts C o m mittee ......................................................................................... 3 6
3. 1. 4.  
St u d y  O utc o mes.......................................................................................................... 3 7
3. 1. 4. 1.  
Pri mar y  O utc o me........................................................................................................ 3 7
3. 1. 4. 2.  
Sec o n dar y  O utc o mes.................................................................................................. 3 7
3. 1. 4. 3.  
Ot her O utc o mes .......................................................................................................... 3 7
3. 2.  
Selecti o n of D oses ...................................................................................................... 3 8
3. 2. 1.  
E x peri me ntal Treat me nts ............................................................................................ 3 8
4.  
S T U D Y P O P U L A T I O N............................................................................................. 3 9
4. 1.  
E nr oll me nt .................................................................................................................. 3 9
4. 1. 1.  
I ncl usi o n Criteria ........................................................................................................ 3 9
4. 1. 2.  
E xcl usi o n Criteria ....................................................................................................... 3 9
4. 2.  
Re m o val of S u bjects Fr o m T hera p y ........................................................................... 4 0
4. 2. 1.  
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n ......................................................... 4 0
4. 2. 1. 1.  
Te m p ora r y Interr u pti o n ..............................................................................................4 1
4. 2. 1. 2.  
Wit h dra wal of C o nse nt fr o m St u d y  Partici pati o n ...................................................... 4 2
4. 2. 1. 3.  
S u bjects L ost t o F oll o w -U p ........................................................................................ 4 3
4. 2. 2.  
Wit h dra wal Pr oce d ures ...............................................................................................4 4
4. 2. 2. 1.  
F oll o w -U p of S u bjects wit h St u d y  Dr u g Disc o nti n uati o ns........................................ 4 4
5.  
T R E A T M E N T S A D MI NI S T E R E D ........................................................................... 4 6
5. 1.  
I n vesti gati o nal Pr o d ucts..............................................................................................4 6
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Tr eat me nts a n d Dis pe nsi n g of 
St u d y  Dr u g.................................................................................................................. 4 6
5. 1. 2.  
Met h o d of Assessi n g Treat me nt C o m plia nce............................................................. 4 7
5. 1. 3.  
La beli n g a n d Pac ka gi n g ..............................................................................................4 7
5. 1. 4.  
St ora ge ........................................................................................................................4 7
5. 1. 4. 1.  
E d o xa ba n .................................................................................................................... 4 7
5. 1. 4. 2.  
Dalte pari n ...................................................................................................................4 7
5. 1. 5.  
Dr u g Acc o u nta bilit y ...................................................................................................4 7
5. 2.   
C o nc o mita nt Me dicati o ns................................ ...........................................................4 8
5. 3.  
T h era pe utic Ma na ge me nt of S u bjects i n E mer ge nc y  Sit uati o ns................................4 8
5. 3. 1.   
Blee di n g................................ ......................................................................................4 8


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 3
5. 3. 2.  
E mer ge nc y  S ur ger y .................................................................................................... 4 9
5. 3. 3. 
S us pecte d Rec urre nt V T E........................................................................................... 4 9
5. 4.  
T hera pe utic Ma na ge me nt of S u bjects f or Pla n ne d I nter ve nti o ns............................... 4 9
5. 5.  
T hera pe utic Ma na ge me nt of S u bjects i n Ot her Critical Sit uati o ns ............................ 4 9
5. 6.  
T hera pe utic Ma na ge me nt of S u bjects Be y o n d M o nt h 1 2 a n d at 
Gl o bal E n d - of-Treat me nt ............................................................................................ 5 0
6. 
S T U D Y P R O C E D U R E S............................................................................................ 5 1
6. 1.  
St u d y  Q ualificati o n/ Pre-ra n d o mizati o n ...................................................................... 5 1
6. 2.  
Da y 1/ Ra n d o mizati o n ................................................................................................. 5 3
6. 3.  
Treat me nt Peri o d ........................................................................................................ 5 5
6. 3. 1.  
Da y  3 1 ( ± 3) Visit....................................................................................................... 5 5
6. 3. 2.  
M o nt hs 3, 6, a n d 9 ( ± 7 da y s) ..................................................................................... 5 5
6. 4.  
E n d of Treat me nt/ M o nt h 1 2 ( ± 7 da y s) ...................................................................... 5 6
6. 5.  
F oll o w -U p ................................................................................................................... 5 7
6. 6.  
Pr ot oc ol De viati o ns .................................................................................................... 5 7
7.  
O U T C O M E A S S E S S M E N T S .................................................................................... 5 8
7. 1.  
Pri mar y  O utc o me Varia ble(s)..................................................................................... 5 8
7. 2.  
Sec o n dar y  O utc o me Varia ble(s)................................................................................. 5 9
7. 3.  
Ot her O utc o me Varia ble(s) ......................................................................................... 5 9
8.  
P H A R M A C O KI N E TI C A S S E S S M E N T S ................................................................. 6 0
8. 1.  
P har mac o ki netic ( P K) Varia ble(s).............................................................................. 6 0
8. 2.  
P har mac o d y na mic ( P D) Varia bl e(s) ........................................................................... 6 0
8. 3.  
Bi o mar ker a n d E x pl orat or y  Varia ble(s) ..................................................................... 6 0
9.  
S A F E T Y A S S E S S M E N T S ........................................................................................ 6 1
9. 1.  
A d verse E ve nts ........................................................................................................... 6 1
9. 2.  
Safet y  O utc o mes.........................................................................................................6 2
9. 2. 1.  
Blee di n g O utc o mes .....................................................................................................6 2
9. 3.   
E ve nts of S pecial I nterest........................................................................................... 6 2
9. 3. 1.  
C o m bi ne d Ele vati o ns of A mi n otra nsferase a n d Bilir u bi n .......................................... 6 2
9. 4 .    
Defi niti o ns..................................................................................................................6 3
9. 4. 1.  
A d verse E ve nt ( A E) ....................................................................................................6 3
9. 4. 2.  
Seri o us A d verse E ve nt ( S A E) .................................................................................... 6 3
9. 4. 3.  
A d verse E ve nt Se verit y ..............................................................................................6 4


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 4
9. 4. 4.  
Ca usalit y  Assess me nt ................................................................................................. 6 4
9. 4. 5.  
Acti o n Ta ke n Re gar di n g t he St u d y  Pr o duct ...............................................................6 5
9. 4. 6.  
A d verse E ve nt O utc o me ............................................................................................. 6 5
9. 4. 7.  
Ot her Acti o n Ta ke n f or E ve nt .................................................................................... 6 5
9. 5.  
Seri o us A d verse E ve nt Re p orti n g – Pr oce d ure F or I n vesti gat ors................................ 6 5
9. 5. 1.  
N otif y i n g Re g ulat or y A ut h orities, In vesti gat ors, a n d I R B/I E C ................................. 6 6
9. 6.  
E x p os ure I n Uter o D uri n g Cli nical St u dies ................................................................ 6 6
9. 7.  
Cli nical L a b orat or y E val uati o ns................................................................................. 6 7
9. 8.  
Vital Si g ns .................................................................................................................. 6 7
9. 9.  
Electr ocar di o gra ms ..................................................................................................... 6 7
9. 1 0.  
P h y sical Fi n di n gs ........................................................................................................ 6 7
9. 1 1.  
Ot her Safet y Assess me nts ...........................................................................................6 7
1 0.  
O T H E R A S S E S S M E N T S .......................................................................................... 6 8
1 1.  
S T A TI S TI C A L M E T H O D S ....................................................................................... 6 9
1 1. 1.  
A nal y sis Sets............................................................................................................... 6 9
1 1. 1. 1.  
Ra n d o mize d A nal y sis Set ........................................................................................... 6 9
1 1. 1. 2.  
M o difie d I nte nti o n -t o-Treat A nal ys is Set................................................................... 6 9
1 1. 1. 3.  
Per- Pr ot oc ol A nal ys is Set........................................................................................... 6 9
1 1. 1. 4.  
Safet y  A nalys is Set..................................................................................................... 6 9
1 1. 2.  
Ge neral Statistical C o nsi derati o ns .............................................................................. 6 9
1 1. 3.  
St u d y  P o p ulati o n Data................................................................................................ 6 9
1 1. 4.  
O utc o me A nal ys es ...................................................................................................... 7 0
1 1. 4. 1.  
Pri mar y  O utc o me A nalys es ........................................................................................ 7 0
1 1. 4. 2.  
S u peri orit y  A nal ysis of t he Pri mar y O utc o me............................................................7 1
1 1. 4. 3.  
Sec o n dar y  Efficac y O utc o me A nalys es ......................................................................7 1
1 1. 5.  
P har mac o ki netic A nal y ses ..........................................................................................7 1
1 1. 6.  
Safet y  A nalys es ..........................................................................................................7 1
1 1. 6. 1.  
A nal y sis of t he Pri mar y Safet y O utc o me ................................................................... 7 1
1 1. 6. 2.  
A nal y sis of Sec o n dar y Safety O utc o mes ....................................................................7 2
1 1. 6. 3.  
E x pl orat or y  A nalys es f or Safet y O utc o mes ...............................................................7 2
1 1. 6. 4.  
A d verse E ve nt A nal ys es .............................................................................................7 3
1 1. 6. 5.  
Cli nical L a b orator y  E val uati o n A nal yses ...................................................................7 3
1 1. 6. 6.  
Vital Si g n A nal ys es ....................................................................................................7 3


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 5
1 1. 6. 7.  
P h y sical Fi n di n g A nalys es .......................................................................................... 7 3
1 1. 7.  
Ot her A nal ys es ............................................................................................................ 7 3
1 1. 8.  
I nteri m A nalys es ......................................................................................................... 7 3
1 1. 9.  
Data a n d Safet y M o nit ori n g B oar d ............................................................................. 7 4
1 1. 1 0.  
S u b gr o u p A nal y ses f or Efficac y a n d Safet y...............................................................7 4
1 1. 1 1.  
Sa m ple Size Deter mi nati o n ........................................................................................ 7 4
1 2.  
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 .............................................. 7 5
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns ........................................................................................ 7 5
1 2. 2.  
Data C ollecti o n ........................................................................................................... 7 6
1 2. 3.  
Data Ma na ge me nt ....................................................................................................... 7 6
1 2. 4.  
St u d y  D oc u me ntati o n a n d St ora ge ............................................................................. 7 7
1 2. 5.  
Rec or d Kee pi n g ..........................................................................................................7 7
1 3.  
FI N A N CI N G A N D I N S U R A N C E ............................................................................. 7 8
1 3. 1.  
Fi na nces ...................................................................................................................... 7 8
1 3. 2.  
Rei m b urse me nt, I n de m nit y , a n d I ns ura nce................................................................ 7 8
1 4.  
P U B LI C A TI O N P O LI C Y .......................................................................................... 7 9
1 5.  
S T U D Y A D MI NI S T R A TI V E I NF O R M A TI O N ....................................................... 8 0
1 5. 1.  
Pr ot oc ol A me n d me nts ................................................................................................ 8 0
1 5. 2.  
A d dress List ................................................................................................................ 8 0
1 5. 2. 1.  
S p o ns or ....................................................................................................................... 8 0
1 5. 2. 2.  
C R O ............................................................................................................................ 8 0
1 5. 2. 3.  
Aca de mic Researc h Or ga nizati o n ( A R O) .................................................................. 8 0
1 6.  
R E F E R E N C E S ...........................................................................................................8 1
1 7.  
A P P E N DI C E S ............................................................................................................8 3
1 7. 1.  
A d diti o nal I nf or mati o n o n I n vesti gati o nal Pr o d ucts ..................................................8 4
1 7. 1. 1.  
Fra g mi n Pac ka ge I nsert ..............................................................................................8 4
1 7. 2.  
Tra nsiti o n fr o m E d o xa ba n t o Ot her a ntic oa g ula nts .................................................... 8 4
1 7. 2. 1.   
E d o xa ba n t o V K A....................................................................................................... 8 4
1 7. 2. 2.  
E d o xa ba n t o n o n -V K A Oral A ntic oa g ula nts ..............................................................8 4
1 7. 2. 3.  
E d o xa ba n t o Pare nteral A ntic oa g ula nts ...................................................................... 8 4
1 7. 3.  
Pr o hi bite d C o nc o mita nt Me dicati o ns ......................................................................... 8 4
1 7. 3. 1.  
A nti platelet Dr u gs ....................................................................................................... 8 4
1 7. 3. 2.  
Oral A ntic oa g ula nts Ot her T ha n St u d y Dr u g ............................................................. 8 5


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 6
1 7. 3. 3. 
Pare nteral A ntic oa g ula nts........................................................................................... 8 5
1 7. 3. 4.  
I ntra ve n o us Fi bri n ol ytics............................................................................................ 8 5
1 7. 3. 5.  
N S AI Ds ( E xcl u di n g As piri n) ..................................................................................... 8 6
1 7. 3. 6.  
C O X -2 I n hi bit ors........................................................................................................ 8 6
1 7. 3. 7.  
P- g p I n hi bit ors ............................................................................................................ 8 7
1 7. 4.  
Preca uti o ns a n d D ose M o dificati o ns f or Dalte pari n................................................... 8 8
1 7. 5.  
Defi niti o ns of Car di o vasc ular a n d T hr o m b otic E ve nts .............................................. 8 9
1 7. 5. 1.  
S y ste mic E m b olic E ve nt ( S E E) .................................................................................. 8 9
1 7. 5. 2.  
T hr o m b otic E ve nts at Ot her L ocati o ns ....................................................................... 8 9
1 7. 6.  
Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us......................... 9 0
1 7. 7.  
Sc he d ule of E ve nts ..................................................................................................... 9 1


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 7
LI S T O F 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 ga ge A F-TI MI  4 8 St u dies.............................. 2 2
Ta ble 1. 2:
Q ua ntitati ve Be nefit Ris k ........................................................................................... 2 7
Ta ble 1 7. 1: Dalte pari n D ose Re d ucti o n f or Platelet C o u nts Bet wee n 5 0, 0 0 0 a n d 
1 0 0, 0 0 0/ m m 3 ............................................................................................................... 8 9
Ta ble 1 7. 2: Sc he d ule of E ve nts ..................................................................................................... 9 1


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 8
LI S T O F FI G U R E S
Fi g ure 3. 1: St u d y  Desi g n............................................................................................................... 3 4
Fi g ure 1 1. 1:
N o n -I nferi ority a n d S u peri orit y Testi n g of L M W H/ E d o xa ba n 
vers us Dalt e pari n ........................................................................................................ 7 2


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 9
LI S T O F A B B R E VI A TI O N S
A b bre vi ati o n  
Defi niti o n
A E
A d verse eve nt
A L P
Al kali ne p h os hatase
A L T
Ala ni ne tra nsa mi nase
A N A
A nti n uclear a nti b o d y
A R O
Aca de mic Researc h Or ga nizati o n
A S T
As partate tra nsa mi nase
B P
Bl o o d press ure
C E C
Cli nical E ve nts C o m mittee
C F R
C o de of Fe deral Re g ulati o ns
CI
C o nfi de nce i nter val
C M V
C yt o me gal o vir us 
C O X - 1
C ycl o o x y ge nase - 1
C O X - 2
C ycl o o x y ge nase - 2
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
C o m p uterize d t o m o gra p h y
C T P A
C o m p uterize d t o m o gra p hic p ul m o nar y a n gi o gra p h y
C U S
C o m pressi o n ultras o n o gra p h y
C V C
Ce ntral ve n o us cat het her
D M C
Data M o nit ori n g C o m mittee
D T E
Data -dri ve n Trial E xec uti o n
D O A C
Direct oral a ntic oa g ula nt
D T E
Data -dri ve n Trial E xec uti o n
D U - 1 7 6 b
E d o xa ba n t os ylate 
D V T
Dee p vei n t hr o m b osis
E B V
E pstei n Barr vir us
E C G
electr ocar di o gra m
E C O G
Easter n C o o perati ve O nc ol o g y Gr o u p


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 0
A b bre vi ati o n  
Defi niti o n
e C R F
Electr o nic Case Re p ort F or m
E D C
Electr o nic Data Ca pt ure
E E A
E ur o pea n Ec o n o mic Area
EI U
E x p os ure I n Uter o
E O T
E n d of trial
E U
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F Xa
Fact or Xa
G C P
G o o d Cli nical Practice (refers t o I C H a n d C F R)
GI
G astr oi ntesti nal
G M P
G o o d Ma n ufact uri n g Practice
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
H R
Hazar d Rati o
I C F
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I N R
I nter nati o nal N or malize d R ati o
I R B
I nstit uti o nal Re vie w B oar d
I TR E A S
I nter nati o nal Trial E x pertise A d vis or y a n d Ser vices
I V
I ntra ve n o us
I VC
I nferi or ve na ca va
I XR S
I nteracti ve we b/ voice res p o nse S yste m
L F T
Li ver f u ncti o n test
L M W H
L o w m olec ular wei g ht he pari n
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 nte nti o n -t o-treat
N S AI Ds
N o n -ster oi dal a nti-i nfla m mat or y dr u gs
N V A F
N o n -val v ular atrial fi brillati o n
P C C
Pr ot hr o m bi n c o m ple x c o nce ntrate
P D
P har mac o d y na mic
P E
P ul m o nar y e m b olis m


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 1
A b bre vi ati o n  
Defi niti o n
PI
Pri nci pal I n vesti gat or
P K
P har mac o ki netic
P O
Per oral
P P
Per- pr ot oc ol
P R O B E
Pr os pecti ve, ra n d o mize d, o pe n -la bel, bli n d-e val uat or (st u d y desi g n)
Q D
O nce dail y
Q O L
Q ualit y of life
S A E
Seri o us a d verse eve nt
S A P
Statistical A nal ysis Pla n
S A V E R
Seri o us A d verse E ve nt Re p ort
S C
S u bc uta ne o us
S D R
S o urce data re vie w
S D V
S o urce data verificati o n
S E E
S yste mic e m b olic e ve nt
S M C C
Steeri n g Ma na ge me nt C o or di nati n g C o m mittee
S O P
Sta n dar d o perati n g pr oce d ure
S U S A R
S us pecte d u ne x pecte d seri o us a d verse reacti o ns
S V T
S pla nc h nic vei n t hr o m b osis
T E A E
Tr eat me nt -e mer ge nt a d verse e ve nts
U F H
U nfracti o nate d he pari n
U L N
U p per li mit of n or mal
U S
U nite d States
V K A
Vita mi n K a nta g o nist
V T E
Ve n o us t hr o m b oe m b olis m
V/ Q sca n
Ve ntilati o n perf usi o n sca n
W B C
W hite bl o o d cell
W H O D R U G
W orl d Healt h Or ga nizati o n Dr u g Refere nce


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 2
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N
Ve n o us t hr o m b oe m b olis m ( V T E) is a c o m m o n a n d cli nicall y i m p orta nt disease i n ca ncer 
patie nts a n d c urre nt sta n dar d treat me nt c o nsists of l o n g -ter m l o w-m olec ular wei g ht 
he pari n ( L M W H).1 ,2 ,3 ,4 Alt h o u g h s u b c uta ne o us ( S C) i njecti o ns wit h LM W H are 
effecti ve t he y are ofte n diffic ult t o t olerate a n d i nc o n ve nie nt f or l o n g-ter m use b y ca ncer 
patie nts. T heref ore, if oral me dicati o ns, s uc h as t he c urre nt direct oral a ntic oa g ula nts 
( D O A Cs) are effecti ve a n d safe with o ut t he nee d f or S C p u nct ures, t he y  are p ote ntiall y 
a n attracti ve alter nati ve i n t his p o p ulati o n.  T he H o k usai V T E st u d y  has s h o w n t hat 
ed o xa ba n, a n oral direct Fact or Xa (F Xa ) i n hi bit or, was effecti ve a n d safe i n t he 
treat me nt of V T E. 5 I n a s u b gr o u p a nal ysis a m o n g 7 7 1 ca ncer patie nt ra n d o mize d t o t he 
H o k usai V T E st u d y, e d o xa ba n was n o n-i nferi or i n ter ms of efficac y a n d ass ociate d wit h a 
relati ve ris k re d ucti o n of 1 9 % i n cli nicall y rele va nt blee di n g c o m pare d t o warfari n.6  I n 
vie w of t hese res ults , a cli nical st u d y wit h e d o xa ba n vers us L M W H i n ca ncer -ass ociate d 
V T E is pr o p ose d.
1. 1.  
D at a S u m m ar y
T he efficac y  a n d safety of e d o xa ba n f or t he treat me nt of V T E, i ncl u di n g 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 (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 . A lar ge pi v otal P hase 3 st u d y  i n 
n o n- val v ular atrial fi brillati o n ( N V A F) ( E N G A G E A F-TI MI  4 8) has als o bee n c o m plete d 
a n d pr o vi des i m p orta nt i nf or mati o n re gar di n g t he safet y of l o n g -ter m e d o xa ba n 
treat me nt. 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 a i V T E a n d E n g a ge A F -TI MI 4 8 S t u dies
St u d y 
P o p ul ati o n
Tre at me nt 
Gr o u ps
N u m ber 
of 
S u bjects
Me di a n 
D ur ati o n of 
Tre at me nt
Pri m ar y 
Effic ac y 
E n d p oi nt
Pri m ar y 
Effic ac y 
O utc o me 
( E d o x a b a n 
vs W arf ari n
Pri m ar y 
S afet y 
E n d p oi nt 
Pri m ar y 
S afet y 
O utc o me
( 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)
E d o xa ba n 6 0 m g  
4 1 1 8  
0. 7 years  
Rec urre nt 
V T E
H R ( 9 5 % CI) 
0. 8 9 ( 0. 7 0 3, 
1. 1 2 8)
Maj or + 
C R N M 
Blee di n g
H R ( 9 5 % CI) 
0. 8 1 ( 0. 7 0 5, 
0. 9 3 6)
Warfari n
4 1 2 2
E N G A G E 
A F -TI MI 
4 8 ( N V A F)
E d o xa ba n 6 0 m g  
7 0 1 2  
2. 5 years  
Str o ke a n d 
S E E
H R ( 9 5 % CI)
0. 7 9 ( 0.6 3 , 
0. 9 9 )
Maj or 
Blee di n g
H R ( 9 5 % CI) 
0. 8 0 ( 0. 71 , 
0. 9 1 )
E d o xa ba n 3 0 m g  
7 0 0 2
Warfari n   
7 0 1 2
V T E – ve n o us t hr o m b oe m b olis m; H R – Hazar d Rati o; CI – c o nfi de nce i nter val; C R N M – cli nicall y rele va nt n o n- maj or; 
N V A F – n o n- val v ular atrial fi brillati o n; S E E – s yste mic e m b olic e ve nt
Ot her c o m plete d st u dies i ncl u de 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 V 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 e d o xa ba n pr o gra m, a c o m bi ne d t otal of 1 8,1 3 2 s u bjects were 


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 3
treate d wit h e d o xa ba n ( 7 0 0 2 wit h e d o xa ba n 3 0 m g a n d 1 1,1 3 0 wit h e d o xa ba n 6 0 m g) 
e nc o m passi n g o ver a t otal e x p os ure of > 3 4 ,0 4 8 s u bjects y ears f or e d o xa ba n.7
1. 1. 1.  
I n vesti g ati o n al Pr o d uct(s)
1. 1. 1. 1.  
N a me
Na me of I n vesti gati o nal Pr o d uct: E d o xa ba n t os y late ( D U- 1 7 6 b)
E d o xa ba n (I N N), a n h y dr o us free base ( D U - 1 7 6)
Acti ve I n gre die nt: N -( 5-C hl or o p y ri di n- 2-yl )-N - [( 1S , 2R , 4 S)-4-( N ,N -
di met h y lcar ba m oyl )- 2-( 5-met h y l- 4, 5, 6, 7-tetra hy d r 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
1. 1. 1. 2.  
Descri pti o n
E d o xa ba n t os y late is a n a ntit hr o m b otic a ge nt, a n orall y acti ve, selecti ve, direct, a n d 
re versi ble i n hi bit or of F Xa, ma n ufacture 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 pr ol 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.
E d o xa ba n refers t o t he a n h y dr o us free base of e d o xa ba n t os y late.  Su bjects are gi ve n 
e d o xa ba n t os ylate (a m o n o h ydrate 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 eit her or b ot h f or ms.
1. 1. 1. 3.  
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 a s a n a ntit hr o m b otic a ge nt.  
N o n cli nical data i n dicate n o e vi de nce of li ver f u ncti o n a b n or malities 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 are a vaila ble i n e d o xa ba n I n vesti gat ors’ 
Br oc h ure. 7
1. 1. 1. 4.  
Cli nic al E x perie nce
T he gl o bal cli nical e x perie nce wit h e d o xa ba n i ncl u des 4 3 c o m plete d P hase 1 st u dies, 
1 2 c o m plete d P hase 2 st u dies a n d 8 c o m plete d P hase 3 st u dies .
E d o xa ba n has bee n e va l uate d i n t he treat me nt of V T E i n a lar ge pi v otal P hase 3 st u d y, 
t he H o k usai V T E st u dy. 5 I n t his st u d y, 8 2 9 2 patie nts were e nr olle d: 4 9 2 1 wit h D V T a n d 
3 3 1 9 wit h P E.  Patie nts were ra n d o mize d t o a n i nitial c o urs e of L M W H f oll o we d b y 
e d o xa ba n or L M W H / warfari n f oll o we d by warfari n al o ne .  T he pri mar y efficac y a nalys is 
of n o n -i nferi orit y vers us t he c urre nt sta n dar d of care (ie, he pari n o verla p pe d wit h 
warfari n u ntil t he i nter nati o nal n or malize d rati o (I N R) reac hes ≥2. 0) was de m o nstrate d 
wit h a hi g h de gree of c o nfi de nce ( hazar d rati o [ H R ]: 0. 8 9; 9 5 % c o nfi de nce i nter val [ CI ]: 
0. 7 0 3, 1. 1 2 8; p < 0. 0 0 0 1).  T he efficac y  was c o nsiste nt acr oss a nal ys is p o p ulati o ns, 
i n di vi d ual c o m p o ne nts of t he pri mar y e n d p oi nt a n d s u b gr o u ps of s u bjects i ncl u di n g ol der 
i n di vi d uals, t h ose wit h re nal i m pair me nt a n d s u bjects wit h l o wer b o d y wei g ht.  F or t he 
pri mar y  safet y o utc o me (a dj u dicate d m aj or/cli nicall y rele va nt n o n-maj or ( C R N M )
blee di n g, Safet y A nal ys is Set, O n-Treat me nt St u d y  Peri o d), e d o xa ba n was s u peri or t o 


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 4
warfari n ( H R: 0. 8 1; 9 5 % CI : 0. 7 1, 0. 9 4; p = 0. 0 0 4 0) f or a relati ve ris k re d ucti o n of 1 9 %.  
T he be nefit was m ost a p pare nt f or m ore seri o us blee di n g i ncl u di n g i ntracere bral 
he m orr ha ge . T here was a n i ncrease i n gastr oi ntesti nal ( GI) blee di n g, i n li ne wit h ot her 
F Xa i n hi bit ors. 8  T here was als o a n i ncrease i n va gi nal blee di n g , w here t he maj orit y of 
cases were me nses -relate d, b ut fe w cases were seri o us or le d t o disc o nti n uati o n of 
treat me nt.  
It was c o ncl u de d t hat o nce dail y e d o xa ba n after he pari n was e q uall y efficaci o us a n d 
ca use d si g nifica ntl y less blee di n g c o m pare d wit h hi g h -q ualit y sta n dar d t hera p y wit h 
warfari n i n a br oa d s pectr u m of V T E patie nts, i ncl u di n g t h ose wit h se vere P E .
A d diti o nal details are a vaila ble i n t he e d o xa ba n I n vesti ga t ors’ Br oc h ure.7
1. 2.  
St u d y R ati o n ale
Ve n o us t hr o m b oe m b olis m (c o m prisi n g D V T a n d P E) is a seri o us a n d fre q ue ntl y 
occ urri n g c o m or bi dit y  i n ca ncer patie nts. It is t he sec o n d m ost c o m m o n ca use of deat h i n 
t hese patie nts9 a n d c o m pare d wit h healt h y pers o ns ca ncer patie nts ha ve a 4 - t o 7-f ol d 
i ncrease d ris k f or de vel o pi n g V T E.1 0 ,1 1 T he ass ociati o n bet wee n t hr o m b otic disease a n d 
ca ncer ca n be e x plai ne d b y  pat h o p hys i ol o gical mec ha nis ms, w hile c he m ot hera p y a n d 
ce ntral ve n o us cat heters ( C V Cs) ofte n use d i n t his p o p ulati o n f urt her i ncrease t he ris k of 
V T E. 
I n a d diti o n t o a hi g her ris k f or de vel o pi n g V T E, patie nts wit h a mali g na nc y w he n treate d 
wit h a ntic oa g ula nts als o ha ve a n i ncrease d ris k of blee di n g, wit h maj or blee di n g rate s t hat 
are i n t he sa me ra n ge as t he rate of rec urre nt V T E (ie, 8 % - 1 2 % per y ear as s h o w n i n 
c o nte m p orar y st u dies).1 2 ,1 3 ,1 4
Gi ve n t hese fi n di n gs, cli nical st u dies e val uati n g effecti ve a n d safe V T E treat me nt are 
c o nsi dere d a pri orit y f or ca ncer patie nts. Si nc e t he pri nci pal pr o ble m i n ca ncer patie nts 
wit h V T E is t he u n derl yi n g ca ncer, V T E ma na ge me nt s h o ul d prefera bl y n ot i nterfere 
wit h t he ca ncer t hera p y a n d ha ve mi ni mal i m pact o n t he patie nt’s alrea d y c o m pr o mise d 
q ualit y  of life ( Q O L). I n t his res pect, V T E treat me nt i n ca ncer patie nts is m ore 
c halle n gi n g a n d differe nt t ha n V T E treat me nt i n n o n-ca ncer patie nts. C urre nt sta n dar d 
t hera py f or ca ncer -ass ociate d V T E is dail y S C i njecte d L M W H -dalte pari n f or at least 
6 m o nt hs. 1, 2, 3, 4  Alt h o u g h S C i njecti o ns are effecti ve t he y  are ofte n diffic ult t o t olerate 
a n d i nc o n ve nie nt f or l o n g-ter m use b y ca ncer patie nts.  T heref ore, if oral me dicati o n s
s uc h as t he c urre nt direct oral a ntic oa g ula nts are effecti ve a n d safe wit h o ut t he nee d f or 
S C p u nct ures t he n t he y  are p ote ntiall y a n attracti ve alter nati ve f or patie nts wit h ca ncer 
a n d V T E. T he H o k usai V T E st u d y  has s h o w n t hat e d o xa ba n, a n oral direct F Xa i n hi bit or 
( D O A C), was effecti ve a n d safe i n treat me nt of ve n o us t hr o m b oe m b olis m. 5
A d diti o nall y , am o n g 7 7 1 patie nts wit h ca ncer ra n d o mize d i n t he st u d y, t he rec urre nce 
rate o ver t he 1 2-m o nt h st u d y  peri o d i n t he e d o xa ba n gr o u p was 3. 7 % c o m pare d wit h 
7. 1 % i n t he warfari n gr o u p ( H R : 0. 5 3; 9 5 % CI: 0. 2 8 , 1. 0 0). I n t hese sa me patie nts, t he 
cli nicall y si g nifica nt blee di n g rates were 1 2. 4 % vers us 1 8. 8 % (H R: 0. 6 4; 9 5 % CI : 0. 4 5, 
0. 9 2) i n t he e d o xa ba n a n d warfari n treat me nt gr o u ps, res pecti vel y .6 I nteresti n gl y, i n t he 
s u b gr o u p of patie nts classifie d b y t he treati n g p h ysicia n as ha vi n g ca ncer acti ve at e ntr y 
i n t he st u d y ( n = 20 8), t he ris k of V T E rec urre nce was 3. 7 % i n t he e d o xa ba n gr o u p a n d 
7. 1 % i n t he warfari n gr o u p ( H R, 0. 5 5; 9 5 % CI , 0. 1 6, 1. 8 5), s h o wi n g virt uall y  i de ntical 


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Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 5
res ults bet wee n patie nts wit h a hist or y of ca ncer a n d t he s u bset of t h ose c o nsi dere d b y t he 
p h y sicia n t o ha ve “acti ve” ca ncer. T his n o vel o bser vati o n ill ustrates t hat t he ris k wit h 
res pect t o rec urre nt V T E is m ore t he hist or y of ca ncer t ha n t he m ore narr o w defi niti o n of 
ca ncer t hat is “acti ve.” T his c o ncl usi o n was reac he d als o i n a n ot her rece nt st u d y  i n a 
s u b gr o u p of ca ncer patie nts wit h V T E .1 5
I n vie w of t hese res ults, a c o m parati ve cli nical st u d y bet wee n sta n dar d treat me nt 
c o nsisti n g of l o n g-ter m S C LM W H -dalte pari n a n d t he ne w oral direct F Xa i n hi bit or, 
e d o xa ba n, is pr o p ose d. 
I n a cli nical st u d y e val uati ng ne w a ntic oa g ula nt t hera p y i n t he ca ncer patie nt p o p ulati o n 
se veral desi g n as pects re q uire c o nsi derati o n. 

B ot h rec urre nt V T E a n d maj or blee di n g are p ote ntial life- t hreate ni n g 
c o m plicati o ns occ urri n g at a c o m para ble rate a n d wit h a si g nifica nt a n d 
si milar i m pact o n t he patie nt’s cli nical stat us. T he V T E -treat me nt s h o ul d 
t heref ore ai m t o pre ve nt b ot h rec urre nt V T E a n d maj or blee d a n d i n a st u d y 
e val uati n g a ne w treat me nt o pti o n a n d t he 2 o utc o mes will nee d t o be e q uall y  
c o nsi dere d. T heref ore, i n t his n o vel desi g n it is pr o p ose d t hat t he pri mar y 
o utc o me of t he st u d y will be a c o m bi ne d o utc o me c o nsisti n g of rec urre nt V T E 
a n d maj or blee di n g.

I n ca ncer patie nts, V T E -s ym pt o ms ofte n are n ot o b vi o us a n d err o ne o usl y  
attri b ute d t o t he ca ncer or its treat me nt.  T h is u ns us pecte d V T E occ urs 
fre q ue ntly 1 6 ,1 7 ,1 8 a n d t he pr o g n osis of t hese u ne x pecte d V T Es i n ter ms of 
rec urre nt V T E a n d m ortalit y are si milar t o t h ose wit h s ym pt o matic 
disease .1, 1 9 ,2 0 ,2 1 ,2 2 As a c o nse q ue nce, c urre nt g ui deli nes a d vise a si milar 
treat me nt strate g y f or u ns us pecte d P E a n d D V T as f or cli nicall y a p pare nt 
V T E .1 T heref ore, u ns us pecte d P E a n d D V T will be c o nsi dere d as a n 
i ncl usi o n criteri o n a n d als o as a c o m p o ne nt of t he pri mar y  o utc o me.

I n n o n-ca ncer patie nts t he d urati o n of V T E -treat me nt is at least 3 m o nt hs a n d 
pr ol o n ge d u p t o 1 2 m o nt hs or i n defi nitel y  de pe n di n g o n t he cli nical j u d g me nt 
bala nci n g ris k a n d be nefit.  I n ca ncer patie nts t he rec o m me n de d treat me nt 
d urati o n is at least 6 m o nt hs.  C o nsiste nt wit h g ui deli ne rec o m me n dati o ns 
pr ol o n gi n g treat me nt nee ds t o be str o n gl y c o nsi dere d es peciall y i n patie nts i n 
w h o m ca ncer is still prese nt. 1, 2, 3 H o we ver, after 6 m o nt hs p h y sicia ns are 
face d wit h a dile m ma si nce data fr o m st u dies be yo n d 6 m o nt hs are a bse nt.
1, 2, 3
I n e val uati n g a ne w a ntic oa g ula nt treat me nt it is desira ble t o d oc u me nt t he 
effects of treat me nt o ver a l o n ger peri o d of ti me.  T heref ore, t he i nte nt i n t he 
prese nt st u d y is t o treat all s u bjects f or 1 2 m o nt hs, a n d t o f oll o w all s u bjects 
f or 1 2 m o nt hs after ra n d o mizati o n w het her or n ot t he y c o m plete 1 2 m o nt hs of 
treat me nt.  T his is i m p orta nt beca use blee di n g, i ncl u di n g C R N M blee di n g 
e ve nts, ma y lea d t o disc o nti n uati o n or i nterr u pti o n of a ntic oa g ula nt t hera p y, 
w hic h t he n i ncreases t he ris k of s u bse q ue nt rec urre nt V T E e ve nts, wit h s uc h 
e ve nts n ot ca pt ure d usi n g tra diti o nal O n- T reat me nt a nal yses.


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1. 3.  
Ris k s a n d Be nefits f or St u d y S u bjects
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 p re dicta ble 
a ntit hr o m b otic pr o perties.  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 
Q D , 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 ble li ver e nz y me a n d bilir u bi n ele vati o ns.
I n t he e d o xa ba n pr o gra m, a c o m bi ne d t otal of 1 8 ,1 3 2 s u bjects were treate d wit h 
e d o xa ba n ( 7 0 0 2 wit h e d o xa ba n 3 0 m g a n d 1 1 , 1 3 0 wit h e d o xa ba n 6 0 m g) e nc o m passi n g 
o ver a t otal e x p os ure of > 3 4 ,0 4 8 s u bjects years f or e d o xa ba n .7 T hi s e xce pti o nall y lar ge 
data base all o we d t he o verall safet y of e d o xa ba n t o be a de q uatel y c haracterize d i n ter ms 
of a d verse reacti o ns wit h rare fre q ue nc y  a n d t h ose occ urri n g after a l o n g late nc y peri o d.  
T he pr o gra m als o c o n d ucte d a lar ge n u m ber of s pecific s t u dies t o all o w c haracterizati o n 
of t he p har mac o ki netic ( P K ) a n d safet y pr ofile of e d o xa ba n i n s u bjects wit h he patic 
d y sf u ncti o n, se vere re nal i m pair me nt, a n d c o nc o mita nt me dicati o ns.  T hese s pecific 
st u dies t o get her wit h t he lar ge cli nical data base all o wed f or t he safet y of e d o xa ba n t o be 
assesse d i n a lar ge n u m ber of s u bject s u b gr o u ps of i ntri nsic a n d e xtri nsic fact ors.  
E d o xa ba n de m o nstrate d a c o nsiste nt safet y pr ofile acr oss s u b gr o u ps.  A n effecti ve oral 
a n d pare nteral tra nsiti o n sc he me fr o m e d o xa ba n t o ot her a ntic oa g ula nts has als o bee n 
de m o nstrate d.
T he c o m plete d P hase 3 cli nical trials i n A F a n d V T E ha ve de m o nstrate d efficac y  a n d 
safety of e d o xa ba n 6 0 -m g d ose ( wit h a 3 0 -m g  d ose re d ucti o n i n s u bjects wit h 1 or m ore 
of t he f oll o wi n g : m o derate t o se vere re nal i m pair me nt, wei g ht ≤6 0 k g, or c o nc o mita nt 
use of s pecifie d P -g p i n hi bit ors) i n t he pre ve nti o n of str o ke a n d s ys te mic e m b olis m i n 
a d ult s u bjects wit h N V A F a n d i n 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 
pre ve nti o n of rec urre nt V T E.
F or V T E i n p artic ular, t he pri mar y efficac y a nal ysis of n o n -i nferi orit y vers us t he c urre nt 
sta n dar d of care (ie, he pari n o verla p pe d t o warfari n u ntil t he I N R reac hes ≥2. 0) was 
de m o nstrate d wit h a hi g h de gree of c o nfi de nce. I n t he pri mar y efficac y m o difie d 
i nte nti o n-t o-treat (mI T T ) o verall a nal ysis, t he e d o xa ba n re gi me n de m o nstrate d n o n-
i nferi orit y vers us warfari n ( H R: 0. 8 9; 9 5 % CI: 0. 7 0 3, 1. 1 2 8; p < 0. 0 0 0 1).  T he efficac y  was 
c o nsiste nt acr oss a nal ysis p o p ulati o ns, i n di vi d ual c o m p o ne nts of t he pri mar y e n d p oi nts 
a n d s u b gr o u ps of s u bjects i ncl u di n g ol der i n di vi d uals, t h ose wit h re nal i m pair me nt, a n d 
li g hter s u bjects. 
E d o xa ba n 6 0 m g s h o we d a clear be nefit i n ter ms of re d uce d blee di n g w he n c o m pare d 
wit h well -c o ntr olle d warfari n treat me nt.  I n t he H o k usai V T E st u d y, t he pri mar y safet y 
e n d p oi nt (a dj u dicate d maj or/C R N M blee di n g , Safet y A nal ysis Set, O n-Treat me nt St u d y 
Peri o d), e d o xa ba n was s u peri or t o warfari n ( H R: 0. 8 1; 9 5 % CI: 0. 7 1 , 0. 9 4; p = 0. 0 0 4 0) f or a 
relati ve ris k re d ucti o n of 1 9 %. T he be nefit was m ost a p pare nt f or m ore seri o us blee di n g 
i ncl u di n g I C H, a n d i ntra-artic ular a n d i ntra-oc ular blee ds.  T here was a n e d o xa ba n 
ass ociate d i ncrease i n GI  blee di n g, i n li ne wit h ot her F Xa i n hi bit ors. There was als o a n 
i ncrease i n va gi nal blee di n g, w here t he maj orit y of cases were me nses-relate d, b ut fe w 
cases were seri o us or le d t o disc o nti n uati o n of treat me nt.  


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Bri n gi n g t o get her q ua ntitati vel y  t he be nefits a n d ris ks as a net cli nical o utc o me, Ta ble 1. 2
s u m marizes t he be nefit-ris k o utc o mes.  For eac h i n dicati o n, t he net cli nical o utc o me 
c o vers t he pri nci pal efficac y  a n d safety o utc o mes, a n d i ncl u des all -ca use m ortalit y.
T a ble 1. 2:  
Q u a ntit ati ve Be nefit Ris k
C o m p osite E n d p oi nt
H R ( 9 5 % CI) f or E d o xa ba n 6 0 m g vers us 
Warfari n
N V A F: Net Cli nical O utc o me mI T T, O verall
0. 8 9 ( 0. 8 3 t o 0. 9 6)
V T E: Net Cli nical O utc o me P P, O n - Treat me nt
0. 8 7 ( 0. 7 0 t o 1. 1 0)
H R – Hazar d Rati o; CI – c o nfi de nce i nter val; N V A F – n o n- val v ular at rial fi brillati o n; mI T T – m o difie d 
i nte nti o n-t o-treat; V T E – ve n o us t hr o m b oe m b olis m; P P – per pr ot oc ol
F or N V A F, net cli nical o utc o me is a c o m p osite of str o ke, s yste mic e m b olic e ve nt, maj or blee di n g, a n d 
all-ca use m ortalit y. 
F or V T E, net cli nical o utc o me is a c o m p osite of s y m pt o matic rec urre nt dee p vei n t hr o m b osis , n o n -fatal 
s y m pt o matic rec urre nt p ul m o nar y e m b olis m, fatal p ul m o nar y e m b olis m, a n d maj or blee di n g, 
a n d all-ca use m ortalit y.
O verall, e d o xa ba n has a n a de q uatel y c haracterize d p ositi ve be nefit -risk rati o i n lar ge a n d 
re prese ntati ve p o p ulati o ns gl o ball y i n patie nts wit h N V A F a n d V T E, de m o nstrati n g 
efficac y i n t he o verall p o p ulati o ns a n d s u b gr o u ps ( wit h d ose re d ucti o n as re q uire d) i n 
c o nj u ncti o n wit h a fa v ora ble blee d pr ofile as well as de m o nstrati n g its effecti ve ness i n a 
d ose -de pe n de nt ma n ner f or V T E pre ve nti o n after ort h o pe dic s ur ger y  s uc h as hi p or k nee 
re place me nt.  A d diti o nal a d va nta ges of e d o xa ba n are its o nce dail y ( Q D) d osi n g, 
d ose -re d ucti o n strate gies t o mi ni mize t he ris k of blee di n g wit h preser ve d effica c y a n d n o 
necessit y f or c o nsta nt m o nit ori n g of t hera p y.
Dalte pari n is t he o nl y lice nse d a ntic oa g ula nt f or t he e xte n de d treat me nt a n d pre ve nti o n of 
rec urre nce of V T E i n ca ncer patie nts a n d t h us is c o nsi dere d t he “ g ol d” sta n dar d 
treat me nt.  Si x m o nt hs of dalte pari n was f o u n d t o be m ore effecti ve t ha n, a n d as safe as, 
vita mi n K a nta g o nists [ V K As ] (ie, warfari n/c o u mari n) f or patie nts wit h ca ncer a n d ac ute 
V T E, wit h o ut si g nifica ntl y  i ncreasi n g t he ris k of maj or blee di n g.  T he a ut h ors c o ncl u de d 
t hat “l o n ger ter m” dalte pa ri n is safe i n ca ncer patie nts. 2 3
Refere nces a n d i nf or mati o n o n d alte pari n (Fra g mi n ® ) is a vaila ble i n t he S u m mar y  of 
pr o d uct C haracteristics / Pr o d uct M o n o gra p h a n d t he pac ka ge i nserts.2 4
C o m plete prescri bi n g i nf or mati o n f or dalte pari n c a n be f o u n d i n A p pe n di x 1 7. 1. 1 .
1. 4.  
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d
A d ult s u bjects w h o prese nt wit h V T E ass ociate d wit h ca ncer ( ot her t ha n basal -cell or 
s q ua m o us-cell carci n o ma of t he s ki n) f or w h o m l o n g-ter m treat me nt wit h L M W H is
i nte n de d are eli gi ble t o partici pate i n t his st u d y . Secti o n 4 lists all eli gi bilit y 
re q uire me nts necessar y  t o q ualif y f or t he st u d y. 
Eli gi ble s u bjects will be stratif ie d b y 1) blee di n g ris k , a n d 2) t he nee d f or d ose 
a dj ust me nt, a n d t he n ra n d o mize d t o recei ve eit her L M W H/ e d o xa ba n or dalte pari n (see 
f ull details bel o w; Secti o n 3 pr o vi des c o m plete treat me nt details).  


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
E d o xa ba n gr o u p : T hera pe utic d oses of L M W H ( S C) f or at least 5 da ys will be 
a d mi nistere d; t his 5 da y peri o d ma y i ncl u de t he pre-ra n d o mizati o n L M W H
treat me nt (if a p plica ble). T he c h oice of pare nteral LM W H is u p t o t he 
treati n g p hys icia n.  T hereafter, e d o xa ba n will b e starte d orall y at 6 0 m g Q D ( 2 
× 3 0 m g ta blets ; 3 0 m g Q D f or s u bjects re q uiri n g d ose a dj ust me nt) f or t he 
re mai n der of t he treat me nt peri o d.

Dalte pari n gr o u p : After ra n d o mizati o n, d alte pari n will be a d mi nistere d at a 
d ose of 2 0 0 I U/ k g S C ( ma xi m u m dail y  d ose 1 8, 0 0 0 I U) f or 3 0 da ys.  T he 
3 0 da y  peri o d ma y i ncl u de t he pre-ra n d o mizati o n a ntic oa g ula nt treat me nt if 
dalte pari n was use d i n t hera pe utic d oses. T hereafter (a p pr o xi matel y  Da y 3 1 
f or war d), dalte pari n will be a d mi nistere d at a d ose of 1 5 0 I U/ k g S C ( ~ 7 5% -
8 3 % of t he i nitial d ose) f or t he re mai n der of t he treat me nt peri o d .
1. 5.  
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 nter nati o nal C o nfere nce o n 
Har m o ni sati o n (I C H) c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( G C P) 
( C P M P/IC 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 Directi ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1) a n d/ or

E ur o pea n C o m mi ssi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) a n d/ or

F o o d a n d Dr u g A d mi nistrati o n ( F D A ) G C P Re g ulati o ns: C o de of Fe deral 
Re g ulati o ns ( C F R) Title 2 1, P arts 1 1, 5 0, 5 4, 5 6 a n d 3 1 2 as a p pr o priate a n d/ or

Ot h er a p plica ble l ocal re g ulati o ns .
1. 5. 1.  
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 ntiality 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 a n d l ocal re g ulati o ns.
F or E ur o pea n U ni o n ( E U) sites, 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 otect i o n Directi ve 9 5/ 4 6/ E C o n 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 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 Case 
Re p ort F or ms ( C R Fs/electr o nic C R F [e C R F]) or ot her d oc u me nts s u b mitte d t o t he 
S p o ns or a n d/ or its desi g nate d re prese ntati ves , s u bjects s h o ul d be i de ntifie d b y a u ni q ue 
s u bject i de ntifier as desi g nate d by t he s p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o 
S p o ns or a n d/ or it’s desi g nate d re prese ntati ves (e g, si g ne d I nf or me d C o nse nt F or ms 
[IC F s]) 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 Fe deral re g ulati o ns/I C 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 he c o m pa n y, of t he 
re g ulat or y a ge nc y(s), a n d t he In de pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal 
Re vie w B oar d (I R B) direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or 
verificati o n of st u d y- relate d pr oce d ures a n d data.  T he In vesti gat or is o bli gate d t o i nf or m 


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t he s u bject t hat his/ her st u d y-relate d rec or ds will be re vie we d by t he a b o ve na me d 
re prese ntati ves wit h o ut vi olati n g t he c o nfi de ntialit y of t he s u bject.
1. 5. 2.  
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 s t 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 or le gall y acce pta ble 
re prese ntati ve after 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 ny 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 (see Secti o n 6. 1 St u d y  Q ualificati o n).  A le gall y 
acce pta ble re prese ntati ve is a n i n di vi d ual or ot her b o d y  a ut h orize d u n der a p plica ble la w 
t o c o nse nt, o n be half of a pr os pecti ve s u bject, t o t he s u bject’s partici pati o n i n t he cli nical 
st u d y.  T he writte n IC F s h o ul d be 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.
I n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt, t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o 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 c o nse nt f or m a n d a n y 
re visi o n(s) s h o ul d be a p pr o ve d by t he I E C or I RB pri or t o bei n g pr o vi de d t o p ote ntial 
s u bjects.
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or t o his/ her partici pati o n i n 
t he st u d y, a n d s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y 2 1 
C F R Part 3 1 2. 6 2.  T he I C F s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject or a 
le gall y acce pta ble re prese ntati ve, a n d by t he a p pr o priate q ualifie d pers o n w h o c o n d ucte d 
t he i nf or me d c o nse nt disc ussi o n ( n ot necessaril y t he I n vesti gat or b ut dele gate d b y  t he 
I n vesti gat or).  T he ori gi nal si g ne d I CF s h o ul d be retai ne d i n acc or da nce wit h i nstit uti o nal 
p olic y , a n d a c o p y of t he si g ne d c o nse nt f or m s h o ul d be pr o vi de d t o t he s u bject or le gal 
re prese ntati ve.  T he date t hat i nf or me d c o nse nt was gi ve n s h o ul d be rec or de d o n t he 
C R F .
If the s u bject or le gall y acce pta ble re prese ntati ve ca n n ot rea d, t he n acc or di n g t o I C H 
G C P G ui deli ne, Secti o n 4. 8. 9, a n i m partial wit ness s h o ul d be prese nt d uri n g t he e ntire 
i nf or me d c o nse nt disc ussi o n.  T his wit ness s h o ul d si g n t he I C F after t he s u bject or t he 
le gall y acce pta ble re prese ntati ve has orall y c o nse nte d t o t he s u bject’s partici pati o n a n d, if 
p ossi ble, si g ne d t he I C F.  B y  si g ni n g t he I CF, t he wit ness attests t hat t he i nf or mati o n i n 
t he IC F a n d a n y  ot her writte n i nf or mati o n was a de q uatel y e x plai ne d t o a n d a p pare ntl y 
u n derst o o d b y  t he s u bject or t he le gall y acce pta ble re prese ntati ve a n d t hat i nf or me d 
c o nse nt was freel y gi ve n b y  t he s u bject or t he le gall y acce pta ble re prese ntati ve.
S u g geste d m o del te xt f or t he I C F f or t he st u d y  a n d a n y a p plica ble s u b parts ( ge n o mic, 
p har mac o ki netic , etc) are pr o vi de d i n t he S p o ns or I CF te m plate f or t he I n vesti gat or t o 
pre pare t he d oc u me nts t o be use d at his or her site.  U p dates t o a p plica ble f or ms will be 
c o m m u nicate d via letter fr o m t he Cli nical St u d y  Ma na ger.
T his st u d y will be c o n d ucte d i n t he U nite d States ( U S ), t heref ore, a d diti o nal c o nse nt is 
re q uire d f or t he Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A).  


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1. 5. 3.  
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 or mati o n a n d c o nse nt f or m, t he I n vesti gat or 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 gi ve n t o t he s u bject, a vaila ble safety 
i nf or mati o n, s u bject recr uit me nt pr oce d ures (e g, a d vertise me nts), 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 or 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 de ntif y all d oc u me nts re vie we d by 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 Statistical A nal y sis Pla n ( S A P).
T he I n vesti gat or m ust s u b mit a n d, w here necessar y , o btai n a p pr o val fr o m t he I E C or I R B 
a n d/ or S p o ns or f or all s u bs e q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d 
c o nse nt d oc u me nt or c ha n ges of t he site, facilities or pers o n nel.  T he I n vesti gat or s h o ul d 
n otif y  t he I E C or I RB of de viati o ns fr o m t he pr ot oc ol or seri o us a d verse e ve nts occ urri n g 
at t he site a n d ot her a d verse e ve nt re p orts recei ve d fr o m S p o ns or /c o ntract researc h 
or ga nizati o n ( 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 will 
ens 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.




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2. 2.  
St u d y H y p ot hesis
E d o xa ba n will be n o n -i nferi or t o dalte pari n wit h res pect t o t he occ urre nce of rec urre nt 
V T E or maj or blee di n g i n t he treat me nt of V T E ass ociate d wit h ca ncer. 
T he st u d y  treat me nt (e d o xa ba n ) will be c o nsi dere d n o n- i nferi or t o t he sta n dar d t hera py 
( dalte pari n) if t he u p per li mit of t he t w o-si de d 9 5 % CI f or t he hazar d rati o 
(e d o xa ba n/sta n dar d t hera p y) is < 1. 5.


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3.  
S T U D Y D E SI G N
3. 1.  
O ver all Pl a n
3. 1. 1.  
St u d y T y pe
T his is a m ulti nati o nal, pr o s pecti ve, ra n d o mize d, o pe n-la bel, bli n d-e val uat or ( P R O B E), 
n o n- i nferi ority st u d y c o m pari n g e d o xa ba n wit h dalte pari n f or pre ve nti o n of t he c o m bi ne d 
o utc o me of rec urre nt V T E or maj or blee di n g i n patie nts wit h V T E ass ociate d wit h 
ca ncer. A d ult s u bjects wit h V T E ass ociate d wit h ca ncer (ot her t ha n basal -cell or 
s q ua m o us-cell carci n o ma of t he s ki n; ca ncer s h o ul d be acti ve (see Secti o n 6. 1 ) or 
dia g n ose d wit hi n t he pre vi o us 2 years), a n d w h o prese nt wit h c o nfir me d ac ute 
s ym pt o matic or u ns us pecte d l o wer e xtre mit y pr o xi mal D V T, c o nfir me d sy m pt o matic P E, 
or u ns us pecte d P E i n a se g me ntal or lar ger p ul m o nar y arter y f or w h o m l o n g-ter m 
treat me nt (at least 6 m o nt hs) wit h L M W H is i n dicate d are eli gi ble t o partici pate i n t his 
st u d y. O ne t h o usa n d s u bjects ( 1 0 0 0) will be e q uall y ra n d o mize d t o 1 of t he 2 treat me nt 
gr o u ps .  
After a s u bject’s eli gi bilit y  is c o nfir me d, t he s u bject will be stratifie d b y 1) blee di n g ris k ,
a n d 2) t he nee d f or d ose a dj ust me nt, a n d t he n ra n d o ml y assi g ne d via i nteracti ve 
v oice/ we b res p o nse s ys te m (I X R S) i n a 1: 1 rati o t o treat me nt wit h eit her 
L M W H/e d o xa ba n or dalte pari n (see Secti o n 5. 1. 1 f or c o m plete details).
After ra n d o mizati o n s u bjects will be assesse d at M o nt h 1 , M o nt h 3, a n d t he n q uarterl y 
t hereafter f or u p t o 1 2 m o nt hs u ntil t he y c o m plete t he st u d y.
A p pr o xi matel y  1 40 st u d y sites i n N ort h A merica, E ur o pe, a n d A ustralia/ N e w Z eala n d are
pla n ne d t o e nr oll s u bjects i n t his st u d y .
3. 1. 2.  
Tre at me nt Gr o u ps a n d D osi n g
Fi g ure 3. 1 de picts t he st u d y desi g n a n d treat me nt pla n.  T he detaile d Sc he d ule of E ve nts 
is pr o vi de d i n A p pe n di x 1 7. 7 a n d t he pr ot oc ol -re q uire d st u d y pr oce d ures are pr o vi de d i n 
S ecti o n 6 . 


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Fi g ure 3. 1:  
St u d y Desi g n
E li gi ble s u bjects will be stratifie d b y 1) blee di n g ris k, a n d 2 ) t he nee d f or d ose 
a dj ust me nt: 
1.
Blee di n g ris k (assesse d at ti me of ra n d o mizati o n)

s ur ger y wit hi n 2 wee ks pri or t o ra n d o mizati o n

use of a nti platelet a ge nts ( e g, as piri n ≤1 0 0 m g / da y) t hat will c o nti n ue d uri n g 
t he st u d y

brai n t u m or or brai n metastases prese nt at t he ti me of r a n d o mizati o n

metasta tic disease prese nt at t he ti me of ra n d o mizati o n

re gi o nall y a d va nce d ca ncer prese nt at t he ti me of ra n d o mizati o n

gastr oi ntesti nal ca ncer at ra n d o mizati o n or dia g n ose d wit hi n a 6 -m o nt h peri o d 
pri or t o ra n d o mizati o n

ur ot helial ca ncer at ra n d o mizati o n or dia g n ose d wit hi n a 6 -m o nt h peri o d pri or 
t o ra n d o mizati o n

A vasti n ( be vaciz u ma b) use at ra n d o mizati o n or gi ve n wit hi n t he 6- wee k 
peri o d pri or t o ra n d o mizati o n
2.
T he nee d f or d ose a dj ust me nt

b o d y  wei g ht ≤ 6 0 k g, or

creati ni ne cleara nce (Cr C L ) bet wee n 3 0 a n d 5 0 m L/ mi n i ncl usi ve

c o nc o mita nt use of P-g p i n hi bit ors
After stratificati o n, s u bjects will be assi g ne d ra n d o ml y  via IX R S i n a 1: 1 rati o t o 1 of t he 
2 f oll o wi n g treat me nt gr o u ps:

L M W H / Ed o x a b a n gr o u p : T hera pe utic d oses of L M W H ( S C) will be 
a d mi nistere d f or at least 5 da ys; t his 5-da y  peri o d ma y i ncl u de t he pre-
ra n d o mizati o n L M W H
(if a p plica ble). T he c h oice of t his pare nteral L M W H


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is u p t o t he treati n g p hys icia n. T hereafter, e d o xa ba n will b e starte d orall y at 
6 0 m g Q D ( 2 × 3 0 m g ta blets ; 3 0 m g Q D f or s u bjects re q uiri n g d ose 
a dj ust me nt) f or t he re mai n der of t he treat me nt peri o d .
T he first d ose of e d o xa ba n s h o ul d be ta ke n: 

1 2 ( ± 3) h o urs after t he last i njecti o n of t he i nitial L M W H if t his was a t wice 
dail y  re gi me n, 

2 4 ( ± 3) h o urs after t he last i njecti o n of t he i nitial L M W H if t his was a o nce 
dail y re gi me n.
T he e d o xa ba n dail y d ose s h o ul d be decrease d t o 3 0 m g Q D f or:

b o d y  wei g ht ≤ 6 0 k g; or

creati ni ne cleara nce [ Cr C L] bet wee n 3 0 a n d 5 0 m L/ min i ncl usi ve ;

c o nc o mita nt use of P-g p i n hi bit ors (eg, h or m o nal a ge nts: ta m o xife n, 
e nzal uta mi de, a birater o ne).
D ose re d ucti o n of e d o xa ba n t o 3 0 m g Q D is i nte n de d o nl y  d uri n g c o nc o mita nt use of 
P- g p i n hi bit ors.  W he n use of t hese i n hi bit ors is disc o nti n ue d/i n ter mitte nt (e g, bet wee n 
c he m ot hera p y c ycles) t he f ull 6 0 m g e d o xa ba n d ose s h o ul d be use d.
After ra n d o mizati o n, if t he s u bject’s Cr C L bec o mes ≤5 0 m L / mi n a n d ≥ 3 0 m L / mi n a n d 
t he decrease i n Cr C L is > 2 0 % fr o m t he s u bject’s baseli ne Cr C L val ue, re peat t he 
meas ure me nt prefera bl y wit hi n 1 wee k.
If t he re peat meas ure me nt c o nfir ms t his 
decrease, t he e d o xa ba n d osa ge re gi me n will be re d uce d per ma ne ntl y, e ve n if t he s u bject 
s u bse q ue ntl y e x perie nces i m pr o ve d Cr C L t o > 5 0 m L / mi n at a later meas ure me nt.
After ra n d o mizati o n, if t he s u bje ct’s b o d y wei g ht dr o ps t o ≤ 6 0 k g (c o nfir me d b y  re peat 
meas ure me nt at l east 1 wee k a part) a n d t he b o d y  wei g ht c ha n ge is > 1 0 % of t he s u bject’s 
baseli ne b o d y wei g ht, t he e d o xa ba n d osa ge re gi me n will be re d uce d per ma ne ntl y, e ve n if 
t he s u bject s u bse q ue ntly re-gai ns wei g ht t o > 6 0 k g.
M ore details are pr o vi de d i n A p pe n di x 1 7. 3. 7 .

D alte p ari n gr o u p : A fter ra n d o mizati o n, d alte pari n will be a d mi nistere d at a 
d ose of 2 0 0 I U/ k g S C ( ma xi m u m dail y  d ose 1 8, 0 0 0 I U) f or 3 0 da ys.  T he 
3 0 da y  peri o d ma y i ncl u de t he pre-ra n d o mizati o n a ntic oa g ula nt treat me nt if 
dalte pari n was use d i n t hera pe utic d oses. T hereafter (a p pr o xi matel y  Da y 3 1 
f or war d), dalte pari n will be a d mi nistere d at a d ose of 1 5 0 I U/ k g S C ( ~ 7 5 % -
8 3 % of t he i nitial d ose) f or t he re mai n der of t he treat me nt peri o d .  
Dalte pari n d oses b y we i g ht a n d preca uti o ns f or d ose m o dificati o ns are liste d i n 
A p pe n di x 1 7. 4 .
3. 1. 2. 1.  
Tre at me nt D ur ati o n
T he i nte nti o n is t o treat patie nts f or 1 2 m o nt hs wit h t he all ocate d st u d y treat me nt. 
C o nti n uati o n of a ntic oa g ula nt trea t me nt be yo n d 6 m o nt hs will be base d o n t he 
ris k-be nefit e val uati o n b y  t he treati n g p h ysicia n.  


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C o nti n ue a ntic oa g ulati o n treat me nt if t he be nefit of d oi n g s o o ut wei g hs t he ris k a n d/ or 
ca ncer is still “acti ve”.  I n t his case o n g oi n g a ntic oa g ulati o n wit h t he all ocate d treat me nt 
re gi me n is preferre d (if t his is c o nsi dere d a p pr o priate b y t he In vesti gat or).  If h o we ver t he 
I n vesti gat or deci des t o s witc h t o a n ot her treat me nt re gi me n (e g, i n t he dalte pari n ar m t he 
decisi o n ca n be ma de t o st o p t he pare nteral a d mi ni strati o n a n d s witc h t o oral t hera py), it 
is rec o m me n de d t o s witc h t o V K A a n d str o n gly disc o ura ge d t o s witc h t o a D O A C. 
N ote : All s u bjects, i ncl u di n g t h ose i n w h o m st u d y me dicati o n is st o p pe d or t h ose w h o 
s witc h t o V K A, will be f oll o we d u p t o 1 2 m o nt hs wit h t he f oll o wi n g e xce pti o n:
O nce 1 0 0 0 s u bjects are ra n d o mize d i n t he st u d y, a gl o bal e n d- of-treat me nt (E O T ) date 
will be esta blis he d t hat e ns ures a mi ni m u m of 6 m o nt hs of st u d y  treat me nt a n d f oll o w- u p 
f or t he fi nal s u bject(s) ra n d o mize d. All s u bjects will per ma ne ntl y  disc o nti n ue st u d y 
treat me nt o n or bef ore t he E O T date.
3. 1. 3.  
St u d y G o ver n a nce
3. 1. 3. 1.  
S teeri n g C o m mittee s
T he st u d y  o versi g ht will be ma na ge d b y a Steeri n g Ma na ge me nt C o or di nati n g 
C o m mittee ( S M C C) w h ose me m bers are c o u ntr y c o or di nat ors, as well as, n o n -v oti n g 
re prese ntati ves of t he S p o ns or a n d A ca de mic R esearc h O r ga nizati o n (A R O ). I n t his 
st u d y, I nter nati o nal Trial E x pertise A d vis or y a n d Ser vices (I T R E A S) will f u ncti o n as t he 
A R O.
A n E xec uti ve C o m mittee t o t he S M C C will ha ve a scie ntific a d vis or y  f u ncti o n a nd will 
n ot be i n v ol ve d i n o perati o nal matters.
O n g oi n g st u d y o versi g ht a n d ma na ge me nt will be t he res p o nsi bilit y of a j oi nt s u per vis or y 
c o m mittee.  T he me m bers of t his c o m mittee are t he c hair ma n a n d c o -c hair of t he S M C C 
a n d desi g nate d re prese ntati ves fr o m t he S p o ns or, C R O a n d A R O .  
3. 1. 3. 2.  
D at a M o nit ori n g C o m mittee
A n i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will m o nit or safet y  d uri n g t he st u d y 
a n d gi ve rec o m me n dati o ns t o t he E xec uti ve C o m mittee .  T he D M C will peri o dicall y 
re vie w a n d e xa mi ne t he safet y a n d effi cac y data (m ortalit y  a n d e ve nts, blee di n g e ve nts, 
seri o us a d verse e ve nts [S A Es ], s yste mic e m b olic e ve nt [S E E ]) a n d alert t he C hair ma n of 
t he E xec uti ve C o m mittee i n case of a ny cli nicall y c o ncer ni n g safet y iss ues.
3. 1. 3. 3.  
Cli nic al E ve nts C o m mittee
A n i n de pe n de nt Cl i nical E ve nts C o m mittee ( C E C) will be esta blis he d t o o bjecti vel y 
a dj u dicate a n d cate g orize t he prese nti n g i n de x dia g n osis, V T E o utc o mes, car di o vasc ular 
e ve nts, blee di n g e ve nts, selecte d he patic e ve nts, a n d deat h.  A dj u dicat ors will be bli n de d 
as t o s u bject treat me nt all ocati o n.  




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3. 2.  
Selecti o n of D oses
3. 2. 1.  
E x peri me nt al Tre at me nts
I n t he c urre nt g ui deli nes e xte n de d LM W H t hera p y  is t he first c h oice f or l o n g-ter m 
treat me nt of V T E i n ca ncer patie nts.1, 2, 3 Dalte pari n is t he o nl y a p pr o ve d a ntic oa g ula nt 
s pecifically i n dicate d f or t he e xte n de d treat me nt a n d pre ve nti o n of rec urre nt V T E i n 
ca ncer patie nts; t h us, it is c o nsi dere d t he sta n dar d of care.  T he dalte pari n re gi me n t o be 
use d i n t his st u d y  is base d o n t he C LO T st u d y  w hic h s h o we d t hat 6 m o nt hs of dalte pari n 
was m ore effecti ve t ha n a n d as safe as V K As (ie, warfari n/c o u mari n) f or patie nts wit h 
ca ncer a n d ac ute V T E, wit h o ut si g nifica ntl y  i ncreasi n g t he ris k of maj or blee di n g.2 3
T he e d o xa ba n re gi me n ( 6 0 m g Q D wit h d ose re d ucti o n f or s pecifi c ris k fact ors) was 
selecte d f or t his st u d y base d o n t he H o k usai V T E st u d y res ults.  I n t he H o k usai V T E 
st u d y, e d o xa ba n pr o d uce d a 4 7 % relati ve re d ucti o n i n ris k f or rec urre nt V T E i n s u bjects 
wit h a hist or y  of ca ncer c o m pare d wit h warfari n.  A d diti o nall y, e d o xa ba n res ulte d i n a 
3 6 % relati ve re d ucti o n f or ris k of cli nicall y si g nifica nt blee di n g i n t hese sa me s u bjects. 2 5


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4.  
S T U D Y P O P U L A TI O N
4. 1.  
E nr oll me nt
S u bjects m ust si g n a n d date t he I C F pr o vi de d b y t he site bef ore a n y st u d y -s pecific 
q ualificati o n pr oce d ures are p erf or me d, e xce pt as n ote d i n Secti o n 6. 1 St u d y 
Q ualificati o n / Pre-ra n d o mizati o n.  
4. 1. 1. 
I ncl usi o n Criteri a
A d ult s u bjects prese nti n g wit h V T E ass ociate d wit h ca ncer (ot her t ha n basal -cell or 
s q ua m o us-cell carci n o ma of t he s ki n) f or w h o m l o n g-ter m treat me nt wit h L M W H is 
i nte n de d are eli gi ble t o partici pate i n t he st u d y. 
S u bjects m ust satisf y  all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:
1.
Male or fe male s u bjects wit h a ge ≥ 1 8 ye ars or t he ot her wise le gal l o w er a ge 
acc or di n g t o t he c o u ntr y  of resi de nce;
2.
C o nfir me d s y m pt o matic or u ns us pecte d l o wer e xtre mit y pr o xi mal D V T (ie, 
p o pliteal, fe m oral, iliac or i nferi or ve na ca va (IV C) vei n t hr o m b osis) , or 
c o nfir me d s y m pt o matic P E , or u ns us pecte d P E of a se g me ntal or la r ger 
p ul m o nar y  arter y;
3.
Ca ncer (ot her t ha n basal -cell or s q ua m o us-cell carci n o ma of t he s ki n), eit her 
acti ve or dia g n ose d wit hi n 2 years pri or t o ra n d o mizati o n.   [ N ote: Dia g n osis of 
ca ncer m ust be o bjecti vel y d oc u me nte d] ;
4.
I nte nti o n f or l o n g-ter m treat me nt (at least 6 m o nt hs) wit h pare nteral L M W H ;
5.
A ble t o pr o vi de writte n i nf or me d c o nse nt.
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 are n ot eli gi ble f or e nr oll me nt:
1.
T hr o m bect o m y, i nserti o n of a ca val filter, or use of a fi bri n ol yt ic a ge nt t o treat t he 
c urre nt (i n de x) e pis o de of D V T a n d/ or P E;
2.
M ore t ha n 7 2 h o urs pre -treat me nt wit h t hera pe utic d osa ges of a ntic oa g ula nt 
treat me nt ( L M W H, u nfracti o nate d he pari n , a n d f o n da pari n u x per l ocal la beli n g), 
oral direct a ntic oa g ula nts or V K A pri or t o ra n d o mizati o n t o treat t he c urre nt 
(i n de x) e pis o de;
3.
Treat me nt wit h t hera pe utic d oses of a n a ntic oa g ula nt i ncl u di n g dalte pari n f or a n 
i n dicati o n ot her t ha n V T E pri or t o ra n d o mizati o n;
4.
Acti ve blee di n g or a n y c o ntrai n dicati o n f or treat me nt wit h L M W H / dalte pari n o r 
e d o xa ba n;
5.
A n Easter n C o o perati ve O nc ol o g y  Gr o u p ( E C O G) Perf or ma nce Stat us of 3 or 4 at 
t he ti me of ra n d o mizati o n (A p pe n di x 1 7. 6 );


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6.
Calc ulate d Cr C L  < 3 0 m L/ mi n;
7.
Hist or y  of he pari n ass ociate d t hr o m b oc yt o pe nia;
8.
Ac u te he patitis, c hr o nic acti ve he patitis, li ver cirr h osis;
9.
He pat ocel ullar i nj ur y  wit h c o nc urre nt tra nsa mi nase ( A L T/ A S T > 3 x U L N) a n d 
bilir u bi n ( > 2 x U L N) ele vati o ns i n t he a bse nce of a cli nical e x pla nati o n ;
1 0. Life e x pecta nc y  < 3 m o nt hs;
1 1. Platelet c o u nt < 5 0, 0 0 0/ m L ;
1 2. U nc o ntr olle d h y perte nsi o n as j u d ge d b y t he I n vesti gat or (e g, sys t olic bl o o d 
press ure ( B P) > 1 7 0 m m H g or diast olic bl o o d press ure > 1 0 0 m m H g des pite 
a nti h yperte nsi ve treat me nt);
1 3.
W o me n of c hil d beari n g p ote ntial wit h o ut pr o per c o ntrace pti ve meas ures, a n d 
w o me n w h o are pre g na nt or breast fee di n g;
N ote: C hil d beari n g p ote ntial wit h o ut pr o per c o ntrace pti ve meas ures (ie, a met h o d of 
c o ntrace pti o n wit h a fail ure rate < 1 % d uri n g t he c o urse of t he st u d y  i ncl u di n g t he 
o bser vati o nal peri o d).  T hese met h o ds of c o ntrace pti o n acc or di n g t o t he n ote f or 
g ui da nce o n n o ncli nical safet y st u dies f or t he c o n d uct of h u ma n trials f or p har mace uticals 
( C P M P/IC H/ 2 8 6/ 9 5, m o dificati o n) i ncl u de c o nsiste nt a n d c orrect use of h or m o ne 
c o ntai ni n g i m pla nts a n d i njecta bles, c o m bi ne d or al c o ntrace pti ves, h or m o ne c o ntai ni n g 
i ntra uteri ne de vices, s ur gical sterilizati o n, se x ual a bsti ne nce, a n d vasect o m y f or t he male 
part ner).
1 4. C hr o nic treat me nt wit h 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 Ds) i ncl u di n g b ot h c ycl o o x yge nase -1 ( C O X -1) a n d c y cl o o x yge nase - 2 
( C O X-2) i n hi bit ors f or ≥4 da y s/ wee k a ntici pate d t o c o nti n ue d uri n g t he st u d y;
1 5. Treat me nt wit h as piri n i n a d osa ge of m ore t ha n 1 0 0 m g/ per da y  or d ual 
a nti platelet t hera p y (a n y 2 a nti platelet a ge nts i ncl u di n g as piri n pl us a n y ot her oral 
or i ntra ve n o us [I V] a nti platelet dr u g) a nti ci pate d t o c o nti n ue d uri n g t he st u d y ;
1 6. Treat me nt wit h t he P - g p i n hi bit ors rit o na vir, nelfi na vir, i n di na vir, or sa q ui na vir 
a ntici pate d t o c o nti n ue d uri n g t he st u d y;
1 7. S y ste mic use of t he P-g p i n hi bit ors ket oc o naz ole, itrac o naz ole, er y t hr o m yci n, 
azit hr o m yci n or clarit hr o m yci n at t he ti me of ra n d o mizati o n; s u bse q ue nt use is 
per mitte d ( wit h a p pr o priate d ose re d ucti o n of e d o xa ba n see A p pe n di x 1 7. 3. 7 );
1 8. S u bjects wit h a n y  co n diti o n t hat as j u d ge d b y  t he In vesti gat or w o ul d p lace 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.
4. 2.  
Re m o v al of S u bjects Fr o m T her a p y
4. 2. 1.  
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n
A s u bject ma y  disc o nti n ue or i nterr u pt st u dy dr u g f or a n u m ber of reas o ns i ncl u di n g, b ut 
n ot li mit e d t o, t h ose liste d bel o w: 


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Per ma ne nt Earl y D isc o nti n uati o n

Deat h;

Wit h dra w of c o nse nt as defi ne d i n Secti o n 4. 2. 1. 2 ;

L ost t o f oll o w -u p as defi ne d i n Secti o n 4. 2. 1. 3 (ever y  atte m pt will be ma de b y 
t he In vesti gat or n ot t o ha ve s u bjects "l ost t o f oll o w -u p");

Cr C L  decrease t o < 3 0 m L / mi n, c o nfir me d by re peat testi n g at least 1 wee k 
later or nee d f or ki d ne y  dial ysis;  

I n vesti gat or j u d g me nt d ue t o:
o
S A E or ot her safet y c o ncer n e g ,

Maj or life -t hreate ni n g blee di n g 

O nset c li nical ja u n dice or ot her o vert si g ns of li ver t o xicit y 
o
U nfa v ora ble be nefit -t o-ris k e val uati o n f or c o nti n ui n g a ntic oa g ula nt 
treat me nt 

S u bject decisi o n (ref usal f or i nta ke or a d mi nistrati o n of st u d y  dr u gs). It is 
i m p orta nt t o disti n g uis h bet wee n wit h dra wal of c o nse nt wit h re gar ds t o 
c o nti n ui n g o n st u d y me dicati o n b ut c o nti n ui n g t o be f oll o we d o n st u d y ;

Ter mi nati o n of all or part of t he st u d y  b y t he S M C C acti n g i n c o ncert wit h t he 
S p o ns or.
4. 2. 1. 1.  
Te m p or ar y Interr u pti o n
Te m p orar y  i nterr u pti o ns of i nitial LM W H, e d o xa ba n a n d dalte pari n f or 4 or m ore 
c o nsec uti ve da ys will be rec or de d i n t he e C R F.  P ote ntial reas o ns ma y  i ncl u de:

S h ort -ter m use of pr o hi bite d c o nc o mita nt me dicati o ns;

S ur gical pr oce d ures;

A n y  me dical c o n diti on w here c o nti n ui n g st u d y  dr u g ma y e x p ose t he s u bject t o 
a n i ncrease d hazar d ;

Ne w o nset of ele vate d li ver e nz y mes i n t he a bse nce of a k n o w n ca use:
o
A L T > 8 × U L N or
o
A S T or A L T > 5 x U L N f or m ore t ha n t w o wee ks
o
A L T or A S T > 3 x U L N, b ut n ot reac hi n g t he li mit s i n t he a b o ve criteria, 
i n c o m bi nati o n wit h cli nical s y m pt o ms s u g gesti ve of he patitis 
o
A L T or A S T > 3 x U L N wit h T B L > 2 x U L N 
I nterr u pti o ns f or less t ha n 4 c o nsec uti ve da ys will n ot be rec or de d i n t he e C R F u nless t he 
me dicati o n was i nterr u pte d d ue t o a n a d verse e ve nt (ie, a n y i nterr u pti o n i n st u d y 
me dicati o n d ue t o a n A E m ust be rec or de d i n t he e C R F ).


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D uri n g a st u d y  dr u g i nterr u pti o n or after st u d y dr u g disc o nti n uati o n, a s u bject ca n be 
place d o n a ntit hr o m b otic t hera p y per l ocal g ui deli nes a n d t he I n vest i gat or's discreti o n. It 
is, h o we ver, disc o ura ge d t o s witc h t o a n ot her D O A C. G ui da nce f or s witc hi n g fr o m 
e d o xa ba n t o ot her a ntic oa g ula nts is pr o vi de d i n A p pe n di x 1 7. 2 .
P ost -ra n d o mizati o n c ha n ges ( ot her t ha n Cr C L decrease d t o < 3 0 m L / mi n or nee d f or 
ki d ne y  dialys is) i n healt h stat us relate d t o st u d y e xcl usi o n criteria s h o ul d n ot 
a ut o maticall y lea d t o st u d y dr u g i nterr u pti o n or disc o nti n uati o n u nless c o nti n ui n g st u d y 
dr u g places t he s u bject at u n d ue hazar d as deter mi ne d b y  t he I n vesti gat or. S uc h 
sit uati o ns s h o ul d be ha n dle d o n a case-b y -case basis.  It is str o n gl y rec o m me n de d t hat t he 
I n vesti gat or c o ns ults wit h IT R E A S ( Me dical S u p p ort L i ne:  + 3 2 4 9 5 5 4 7 4 5 1) if a 
s u bject has a p ost ra n d o mizati o n c ha n ge i n healt h stat us t hat is ass ociate d wit h a n 
e xcl usi o n criteri o n.
Als o, a decisi o n t o st o p pre mat urel y t he o verall recr uit me nt i n t he st u d y  a n d/ or i nta ke of 
st u d y dr u g ca n be ta ke n b y t he E xec uti ve C o m mittee / S p o ns or f oll o wi n g a d vice o n safet y 
as pects of t he st u d y b y t he D M C.  T he I E Cs/I R Bs will be i nf or me d of t his decisi o n. T he 
D M C st o p pi n g g ui deli nes will be defi ne d pri or t o t he start of t he st u d y .  T he S p o ns or has 
t he ri g ht t o cl ose t his st u d y a n d t he ri g ht t o cl ose a ce nter, at a n y ti me, alt h o u g h t his 
s h o ul d occ ur o nl y after c o ns ultati o n bet wee n i n v ol ve d parties a n d t he E x ec uti ve 
C o m mittee . T he I E C s/I R Bs m ust be i nf or me d.  S h o ul d t he site be cl ose d pre mat urel y, all 
st u d y materials (e xce pt d oc u me ntati o n t hat has t o re mai n st ore d at site) m ust be ret ur ne d 
t o t he S p ons or. T he I n vesti gat or will retai n all ot her d oc u me nts u ntil n otificati o n b y  
S p o ns or f or destr ucti o n
If t he s u bject is wit h dra w n d ue t o a n a d verse e ve nt, t he In vesti gat or will f oll o w t he 
s u bject u ntil t he a d verse e ve nt has res ol ve d or sta bilize d.
4. 2. 1. 2.  
Wit h dr a w al of C o nse nt fr o m St u d y P artici p 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 fr o m st u d y partici pati o n at a n y  ti me a n d f or a ny reas o n 
wit h o ut prej u dice t o his or her f ut u re me dical care b y t he p hys icia n or at t he i nstit uti o n.
H o we ver, it is i m p orta nt t o disti n g uis h bet wee n ref usal t o c o nti n ue o n st u d y  me dicati o n 
a n d c o nti n ui n g t o be f oll o we d o n st u d y  vers us wit h dra wal of c o nse nt wit h re gar ds t o 
c o ntin ui n g t he st u d y all t o g et her (ie, wit h dra wal of c o nse nt wit h re gar ds t o c o nti n ui n g o n 
st u d y me dicati o n a n d a n y f urt her st u d y f oll o w-u p) .
O nl y  s u bjects w h o ref use all 4 of t he f oll o wi n g met h o ds of f oll o w -u p will be c o nsi dere d 
t o ha ve wit h dra w n c o nse nt fr o m st u d y partici pati o n :

Pa rtici pati o n i n t he trial f oll o w- u p visits per pr ot oc ol, eit her i n cli nic or b y 
tele p h o ne;

C o ntact b y  trial pers o n nel e ve n if o nl y b y tele p h o ne ( q uarterly, bi -a n n uall y, 
a n n uall y, E n d of Treat me nt v isit o nl y);

Per missi o n f or trial pers o n nel t o c o ntact a n alt er nati ve pers o n (e g, fa mil y
me m ber , s p o use, part ner, le gal re prese ntati ve, p hysicia n , t he a ntic oa g ulati o n 
cli nic, or a n ot her healt hcare pr o vi der) e ve n if o nl y b y tele p h o ne;


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
Per missi o n f or trial pers o n nel t o access a n d re vie w t heir me dical i nf or mati o n 
fr o m alter nati ve s o urces (e g, d oct or’s n otes, h os pital rec or ds).
If t he s u bject ref uses all 4 of t he a b o ve met h o ds of f oll o w-u p, t he I n vesti gat or s h o ul d 
pers o nall y s pea k t o t he s u bject t o e ns ure t he s u bject u n dersta n ds all of t he p ote ntial 
met h o ds of f oll o w - u p.  If t he s u bject c o nti n ues t o ref use all p ote ntial met h o ds of 
f oll o w-u p, t he I n vesti gat or will d oc u me nt t his as a wit h dra wal of c o nse nt i n t he me dical 
rec or d.
All s u bjects s h o ul d be f oll o we d f or t he f ull d urati o n of t he trial usi n g a n y or all of t he 
a b o ve met h o ds, u nless t here is writte n d oc u me ntati o n b y  t he I n vesti gat or of t he s u bject's 
wit h dra wal of c o nse nt t o A L L of t he a b o ve met h o ds of f oll o w - u p.
If a s u bject is wit h dra w n e ntirel y fr o m t he st u d y, t he I X R S will be calle d b y t he site t o 
re gister t he s u bject as per ma ne ntl y disc o nti n ue d fr o m t he st u d y (a n d st u dy t reat me nt if 
n ot d o ne pre vi o usl y ).
T he site will c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hly as p ossi ble u p t o t he 
date of c o nse nt wit h dra wal a n d i ncl u di n g t he date of t he fi nal d ose of st u d y dr u g. T he 
reas o n(s) f or li mite d f oll o w-u p/ data c ollecti o n will be clearl y d oc u me nte d i n t he me dical 
recor d a n d e C R F.
P u blic data bases a n d s u bject fi n der ser vices ma y be use d t o deter mi ne s u bject stat us a n d 
t o l ocate p ote ntial l ost t o f oll o w-u p patie nt s.
4. 2. 1. 3.  
S u bjects L ost t o F oll o w -U p
T he I n vesti gat or will ma ke e ver y  eff ort n ot t o ha ve a n y s u bjects l ost t o f oll o w- u p.  If a 
s u bject is p ote ntiall y l ost t o f oll o w-u p (e g, misse d st u d y  visits, u na ble t o be c o ntacte d b y 
p h o ne), t he I n vesti gat or will ma ke e ver y  eff ort t o c o ntact t he s u bject bef ore t he s u bject is 
declare d l ost t o f oll o w - u p.  T hese eff orts ma y  i ncl u de b ut are n ot li mite d t o:

Call i n g all tele p h o ne n u m bers f or t he s u bject a n d t heir c o ntacts (i ncl u di n g 
d uri n g t he e ve ni n g a n d o n wee ke n ds);

Call i n g pri mar y  care p h ysicia n, referri n g s pecialist a n d/ or ot her liste d 
p h y sicia ns f or m ore rece nt l ocat or i nf or mati o n, date of last office visit, or t o 
deter mi ne m ortalit y  stat us;

Se n d i n g e mail a n d f oll o w wit h maili n g certifie d letters (ret ur n recei pt 
re q ueste d) t o all kn o w n s u bject a d dre sses a n d all liste d c o ntacts (eg, relati ves, 
frie n ds, nei g h b ors);

Re vie w i n g s u bject’s rec or ds a n d me dical n otes f or a n y details of a 
h os pitalizati o n, d oct or’s visit , or ot her pr oce d ure t hat ma y  i n dicate stat us of 
s u bject;

Us i n g t he I nter net t o searc h f or p ossi ble c o ntact i nf or mati o n f or s u bject

Tr y  re verse direct or y f or p h o ne n u m bers t o get p ossi ble a d dresses

Uti lize s ocial net w or ki n g sites (eg, Face b o o k); 


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
C hec k i n g l ocal, re gi o nal, a n d nati o nal p u blic rec or ds t o l ocate s u bject or 
searc h for m ortalit y stat us i n acc or da nce wit h l ocal la w;

P ossi ble h o me visit.
O nce t he site has e x ha uste d a n d d oc u me nte d t hese acti o ns, t he Cli nical Researc h 
Ass ociate or m o nit or s h o ul d be c o ntacte d f or a d diti o nal g ui da nce a n d alter nati ve o pti o ns.
P u blic data bas es a n d s u bject fi n der ser vices ma y  be use d t o deter mi ne s u bject stat us a n d 
t o l ocate p ote ntial l ost t o f oll o w-u p patie nt s.
4. 2. 2.    
Wit h dr a w al Pr oce d ures
4. 2. 2. 1.  
F oll o w -U p of S u bjects wit h St u d y Dr u g Disc o nti n u ati o ns
T he I n vesti gat or ma y  co ntact I T R E A S ( Me dical S u p p ort Li ne:  + 3 2 4 9 5 5 4 7 4 5 1 ) or
e mail) i n case of a n y q uesti o ns re gar di n g h o w t o ha n dle a st u d y dr u g disc o nti n uati o n or 
i nterr u pti o n.
All ra n d o mize d s u bjects, i ncl u di n g t h ose w h o te m p oraril y i nterr u pte d or disc o nti n ue d 
st u d y dr u g, will be f oll o we d f or a 1 2-m o nt h peri o d after ra n d o mizati o n, e xce pt w he n t he 
st u d y is tr u ncate d as n ote d i n Secti o n 3. 1. 2. 1 .
I n case of pre mat ure disc o nti n uati o n of treat me nt, st u d y o utc o mes ca n be c ollecte d b y 
tele p h o ne c o ntact u ntil 1 2 m o nt hs after t he first d ose of st u d y dr u g. If t he s u bject has a n 
o n- site visit at a n y ti me after st u d y dr u g disc o nti n uati o n, it is e x pecte d t hat a cli nical 
stat us will be o btai ne d al o n g wit h a ny la b orat or y  assess me nts dee me d a p pr o priate b y t he 
I n vesti gat or.
If the s u bject a n d I n vesti gat or a gree t hat st u dy dr u g ca n be res u me d wit h o ut i ncrease d 
hazar d t o t he s u bject, st u d y  me dicati o n ma y be res u me d at a n y ti me, re gar dless of t he 
d urati o n of st u d y  dr u g i nterr u pti o n.
A n y  s u bject w h o te m p oraril y i nterr u pts or disc o ntin ues st u d y  dr u g d ue t o c o nfir me d li ver 
e nz yme a b n or malities or ja u n dice i n t he a bse nce of a k n o w n ca use (e g, u n derl yi n g 
ca ncer), s h o ul d ha v e a n e val uati o n t o deter mi ne t he ca use of t he e ve nt. E val uati o n ma y  
i ncl u de t he f oll o wi n g de pe n di n g o n t he cli nical sit uati o n:

A b d o mi nal ultras o u n d;

He patitis A, B, C, a n d E scree ni n g (a nti -H A V I gM , H bs A g, a nti-H C V pl us 
viral titer, a n d e val uati o n f or He p E), A nti n uclear a nti b o d y  ( A N A) a n d a nti-
S m A b, C y t o me gal o vir us ( C M V), E pstei n Barr vir us ( E B V);

A d diti o nal e val uati o n s as dee me d a p pr o priate by t he I n vesti gat or t o e xcl u de 
ot her ca uses of li ver e nz y me a n d bilir u bi n ele vati o ns.
I n t he a bse nce of a k n o w n ca use, foll o w -u p of li ver e nz y mes a n d bilir u bi n (t otal a n d 
direct) s h o ul d be perf or me d o n a re g ular basis u ntil t he val u es are sta bilize d .
All la b orat or y  res ults, i ncl u di n g l ocal la b orat or y refere nce ra n ges are t o be rec or de d i n 
t he e C R F.


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If t he s u bject a n d I n vesti gat or a gree t hat st u dy dr u g ca n be res u me d wit h o ut i ncrease d
hazar d t o t he s u bject, st u d y  dr u g ma y be res u me d at a ny ti me, re gar dless of t he d urati o n 
of st u d y  dr u g i nterr u pti o n.
All cli nicall y  si g nifica nt he patic e nzy m e a b n or malities a n d/ or he patic e ve nts are t o be 
d oc u me nte d i n t he e C R F a n d pr o m pt s u b missi o n of t he a dj u dicati o n d ossier s h o ul d als o 
occ ur w he n i n dic ate d/directe d (see Secti o n 9. 3. 1 ).


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5.  
T R E A T M E N T S A D MI NI S T E R E D
5. 1.  
I n vesti g ati o n al Pr o d ucts
T he I n vesti gat or m ust e ns ure t hat t he i n vesti gati o nal pr o d uct s will be use d o nl y  i n 
acc or da nce wit h t he pr ot oc ol.

E d o xa ba n ( 3 0 m g) will be s u p plie d b y  t he s p o ns or as yell o w fil m-c oate d 
ta blets a n d a d mi nistere d oral l y (P O ).

L M W H f or t he e d o xa ba n lea d- i n will be as prescri be d b y t he Pri nci pal 
I n vesti gat or (PI ).

Dalte pari n will be s u p plie d b y  t he Sp o ns or as si n gle-use pre -fille d syr i n ges 
a n d a d mi nistere d b y S C i njecti o n.
T he I n vesti gat or or desi g nee will be res p o nsi ble f or dis pe nsi n g st u d y  dr u gs. 
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 s u bject n u m ber a n d date of dis pe nsi n g.  
S u bjects m ust be s u p plie d wit h s ufficie nt st u d y  dr u g t o last u ntil t he ne xt sc he d ule d 
dis pe nsi n g visit.  
S u bjects ma y  ta ke e d o xa ba n wit h or wit h or wit h o ut f o o d, i n t he A M or P M, b ut at 
a p pr o xi matel y t he sa me ti me e ver y da y.  Dalte pari n s h o ul d als o be c o nsiste ntl y 
a d mi nistere d at a p pr o xi matel y t he sa me ti me e ver y da y as well.
5. 1. 1.    
Met h o d of Assi g ni n g S u bjects t o Tre at me nts a n d Dis pe nsi n g of St u d y 
Dr u g
Eli gi ble s u bjects will be stratifie d b y  1) blee di n g ris k , a n d 2 ) t he nee d f or d ose 
a dj ust me nt.  After c o nfir mati o n of eli gi bilit y , t he In vesti gat or will pr o vi de t he I X R S wit h 
t he st u d y ce nter n u m ber, a p pr o priate de m o gra p hic i nf or mati o n c o nsiste nt wit h l ocal 
re g ulati o ns, blee di n g ris k pr ofile, Cr C L , bo d y  wei g ht cate g or y (≤ 6 0 k g or > 6 0 k g), a n d 
w het her t he s u bject’s c urre ntl y usi n g P- g p i n hi bit ors (see A p pe n di x 1 7. 3. 7 ).
T he I X R S will assi g n t he u ni q ue s u bject i de ntificati o n n u m ber, stratif y t he s u bject b y 
bl ee di n g ris k a n d nee d f or d ose a dj ust me nt, t he n all ocate t he treat me nt gr o u p assi g n me nt 
f or t he s u bject.  A fa x or email will be se nt b y  t he I X R S t o t he st u d y site n oti n g t he 
treat me nt gr o u p a n d d osa ge stre n gt h of t he assi g ne d me dicati o n.  T he fa x or e-mail will 
als o pr o vi de a cale n dar of s u bse q ue nt dis pe nsi n g dates .  St u d y  dr u g will be dis pe nse d at 
ra n d o mizati o n, a p pr o xi matel y Da y 3 1, M o nt h 2 t he n at least o nce e ver y 3 m o nt hs ( m ore 
fre q ue nt dis pe nsi n g of st u d y dr u g is all o we d if necessar y), t hereafter w hile t he s u bject 
re mai ns o n treat me nt.
T his st u d y  has a n o pe n-la bel, bli n d-e val uat or desi g n wit h L M W H /e d o xa ba n a n d 
dalte pari n.  T he s u bjects, In vesti gat ors, S p o ns or, C R O, a n d I TR E A S staff i n v ol ve d i n t he 
treat me nt or cli nical e val uati o n of t he s u bjects will be a ware of t he treat me nts recei ve d.  
T here will be a n i n de pe n de nt D M C t o m o nit or t he efficac y a n d safety data o n a peri o dic 
basis . All st u d y o utc o me e ve nts will be a dj u dicate d b y  t he C E C usi n g bli n de d e val uat ors.


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T he s pecificati o ns f or ge nerati o n of t he ra n d o mizati 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 C R O i n c har ge of t he I X R S.  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 t he ra n d o mizati o n n u m ber, 
ra n d o mizati o n bl oc k n u m ber, a n d treat me nt.
5. 1. 2.  
Met h o d of Assessi n g Tre at me nt C o m pli a nce
D osi n g c o m plia nce will be assesse d b y mea ns of e d o xa ba n ta blet a n d dalte pari n s yri n ge
c o u nts.  
5. 1. 3.  
L a beli n g a n d P ac k a gi n g
E d o xa ba n 3 0 m g ta blets f or oral use will be s u p plie d b y  t he S p o ns or i n P V C/f oil blister 
pac ks.  
D alte parin will be s u p plie d i n pre-fille d syri n ges.
Dr u g la beli n g will be acc or di n g t o nati o nal la w a n d G o o d Ma n ufact uri n g Practice ( G M P) 
r uli n g A n ne x 1 3. 1 9.
5. 1. 4.  
St or a ge
5. 1. 4. 1.  
E d o x a b a n 
E d o xa ba n m ust be st ore d b y  t he site at 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F) as meas ure d b y a 
t her mo meter 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.   Te m perat ure meas ure me nts will be rec or de d 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 y s.
E xc ursi o ns fr o m 1 5° C t o 3 0° C ( 5 9° F t o 8 6°F ) are per mitte d.  T he S p o nsor 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 t his ra n ge .
5. 1. 4. 2.  
D alte p ari n 
Dalte pari n m ust be st ore d at c o ntr olle d r o o m te m perat ure bel o w 2 5° C ( 7 7° F).
5. 1. 5.    
Dr u g Acc o u nt a bilit y
T he I X R S will c o ntai n a Dr u g Acc o u nta bilit y  M o d ule f or an y  me dicati o ns pr o vi de d by 
t he Sp o ns or (e g, e d o xa ba n, dalte pari n).  T he I n vesti gat or or desi g nee will e nter t he 
re q uire d i nf or mati o n (see I X R S user ma n ual) i n t he I X R S dr u g acc o u nta bilit y m o d ule. I n 
a d diti o n, t he In vesti gat or or desi g nee s hall c o ntact S p o ns or as s oo n as p ossi ble if t here is 
a pr o ble m wit h t he s hi p me nt.
A Dr u g Acc o u nta bilit y  Rec or d will be pr o vi de d f or t he in vesti gati o nal pr o d uct s.  T he 
rec or d m ust be ke pt c urre nt a n d s h o ul d c o ntai n, t he dates a n d q ua ntities of dr u g recei ve d, 
s u bject’s (i de ntificati on n u m ber a n d/ or i nitials or s u p pl y  n u m ber as a p plica ble), f or 
w h o m t he i n vesti gati o nal pr o d uct was dis pe nse d, t he date a n d q ua ntit y  of i n vesti gati o nal 
pr o d uct dis pe nse d a n d re mai ni n g, if fr o m i n di vi d ual s u bject dr u g u nits as well as t he 
i nitials of t he dispe nser.


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At t he e n d of t he st u d y, or as directe d, all m e dicati o ns s u p plie d b y t he Sp o ns or, i ncl u di n g 
a n y u n use d, partially use d, a n d e m pt y blisters a n d s y ri n ges will be destr o ye d at t he site 
acc or di n g t o 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 pe rati n g pr oce d ures 
( S O Ps).  A c o py of t hese S O Ps m ust be a vaila ble o nsite.  T he certificate of destr ucti o n 
m ust be pr o vi de d t o Daiic hi Sa n k y o d oc u me nti n g t he dr u g, t he q ua ntit y  (i n ta blets or 
s yri n ges), met h o d of destr ucti o n, a n d date of destr ucti o n. 
If sites are u na ble t o destr o y dr u g, t he m o nit or will ma ke arra n ge me nts t o ret ur n dr u g t o a 
desi g nate d de p ot f or destr ucti o n.  
Me dicati o ns pr o vi de d b y t he S p o ns or will be destr o y e d ( or 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 n i n ve nt or y  t o verif y t he q ua ntit y t o be destr oye d ( or ret ur ne d).  
T he destr ucti o n ( or ret ur n) of me dicati o ns pr o vi de d b y  t he s p o ns or m ust be d oc u me nte d 
a n d t he d oc u me ntati o n file d (a n d if ret ur ne d, i ncl u de d i n t he s hi p me nt) .
5. 2.  
C o nc o mit a nt Me dic ati o ns
Pre -s pecifie d me dicati o ns that t he s u bject has ta ke n wit hi n 3 0 da y s bef ore ra n d o mizati o n 
or d uri n g t he st u d y  will be rec or de d i n t he “tar gete d c o nc o mita nt me dicati o ns” e C R F.  
T hese pre -s pecifie d me dicati o ns ta ke n b y t he s u bjects u p o n e ntr y t o t he st u d y or at a n y 
ti me d uri n g t he st u dy are re gar de d as tar gete d c o nc o mita nt me dicati o ns 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 has a n e n d p oi nt e ve nt 
or a n S A E, t he n i nf or mati o n o n tar gete d a n d n o n -tar gete d c o nc o mita nt me dicati o ns ta ke n 
wit hi n t he past 3 0 da y s m ust be d oc u me nte d o n t he a p pr o priate e C R F pa ges.  
C o nc o mita nt t hera p y will be ca pt ure d u ntil t he s u bjects c o m pletes t he 1 2-m o nt h st u d y  
peri o d.
A list of s pecificall y e xcl u de d me dicati o ns is pr o vi de d i n A p pe n di x 1 7. 3 .  The list reflects 
t he list at t he be gi n ni n g of t he st u d y.  If t here are c ha n ges t o t his list d uri n g t he st u d y, t he 
c ha n ges will n ot be c o nsi dere d a pr ot oc ol a me n d me nt b ut u p date d i nf or mati o n.  I t is 
str o n gly e nc o ura ge d t o restrict t he d ose of a s piri n (if i n dicate d) t o ≤1 0 0 m g dail y , 
alt h o u g h hi g her d oses are per mitte d f or str o n g cli nical i n dicati o n (e g, de vel o p me nt o f a n 
ac ute MI ).
5. 3.  
T her a pe utic M a n a ge me nt of S u bjects i n E mer ge nc y Sit u ati o ns
5. 3. 1.  
Blee di n g
T here is n o s pecific a nti d ote t o re verse t he e ffect of e d o xa ba n.  T he f oll o wi n g ste ps are 
rec o m me n de d f or s u bjects wit h o n g oi n g life-t hreate ni n g blee di n g ( blee di n g res ulti n g i n 
he m o d y na mic c o m pr o mise re q uiri n g i nter ve nti o n or a n y  i ntracra nial he m orr ha ge):

Wit h h ol d st u d y  dr u g a n d all a nti platelets/a ntic oa g ula nts;

I nstit ute sta n dar d of care f or life-t hreate ni n g blee di n g (lar ge b ore I V or ce ntral 
ve n o us li ne, t y pe a n d cr oss matc h bl o o d, a d mit t o t he i nte nsi ve care u nit, 
pr o vi de he m o d y na mic a n d res pirat or y s u p p ort);

A d mi nister a nti d otes if a p plica bl e (eg, a d mi nister pr ota mi ne if t he s u bject ha d 
rece ntly recei ve d he pari n);


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
A d mi nister pac ke d re d bl o o d ce lls ( or w h ole bl o o d) as nee de d.
If life-t hreate ni n g blee di n g persists, it is rec o m me n de d t o c o ntact t he IT R E A S Me dical 
S u p p ort L i ne 
 t o disc uss s u bject ma na ge me nt.  Use of pr ot hr o m bi n 
c o m ple x c o nce ntrates ( P C Cs), rec o m bi na nt Fact or VIIa, ot her fact or pr oc oa g ula nts, or 
a ntifi bri n ol ytics ( de pe n di n g u p o n t he cli nical sit uati o n a n d l ocal a vaila bilit y) s h o ul d be 
c o nsi dere d i n c o ns ultati o n wit h a n e x pert a n d t he I T R E A S Me dical S u p p ort L i ne.
5. 3. 2.  
E mer ge nc y S ur ger y
If a n ur ge nt s ur gical i nter ve nti o n is nee de d, a ntic oa g ula nt t hera py s h o ul d be disc o nti n ue d 
a n d t he s ur ger y s h o ul d be deferre d, if p ossi ble, u ntil at least 1 2 ho urs a n d i deall y 2 4 ho urs
after t he l ast a d mi nistrati o n of a ntic oa g ula nt t hera p y . T here is n o re versal a ge nt f or 
e d o xa ba n. Pr ota mi ne ca n be use d t o ( partiall y ) re verse t he effect of L M W H . De pe n di n g 
u p o n t he cli nical sit uati o n a n d l ocal a vaila bilit y , t he use of fact or pr oc oa g ula nts or ot her
meas ures ca n be c o nsi dere d i n case of t he rece nt i nta ke of e d o xa ba n pri or t o t he s ur gical 
pr oce d ure. It is rec o m me n de d t o c o ns ult t he I T R E A S Me dical S u p p ort Li ne    
 
 i n case of ur ge nt s ur ger y.
5. 3. 3.  
S us pecte d R ec urre nt V T E
I n case of s us pecte d rec urre nt V T E, t he In vesti gat or ma y  deci de t o treat t he s u bject 
acc or di n g t o t he sta n dar d of care .
5. 4.  
T her a pe utic M a n a ge me nt of S u bjects f or Pl a n ne d 
I nter ve nti o ns
Gi ve n t he half -life of b ot h st u d y me dicati o ns a n d t he i nter val of d osi n g (ie, o nce a da y ) it 
is ad vise d t o wit h h ol d t he st u d y  me dicati o ns at least 2 4 h o urs pri or t o t he pla n ne d 
i nter ve nti o n. St u d y  dr u g ca n be res u me d u p o n c o m plete he m ostasis a n d after t he 
assess me nt of t he blee di n g ris k, ie, after 6 t o 2 4 h o urs f or m ost mi n or pr oce d ures a n d 
after 2- 3 d a y s f or m ost s ur gical pr oce d ures t hat carr y a blee di n g ris k. A ntit hr o m b otic 
t hera py ot her t ha n t he st u d y dr u g ca n be i nitiate d, e g, a ( pr o p h yl actic) d ose of LM W H, 
acc or di n g t o t he i nstit uti o nal best practice, u ntil re-i nitiati n g d osi n g of t he st u d y dr u g is 
c o nsi dere d t o be a p pr o priate .
It is rec o m me n de d t o c o ns ult t he IT R E A S Me dical S u p p ort L i ne 
 i n 
case of a n y f urt her q uesti o ns o n t he ma na ge me nt of s u bjects w h o nee d a pla n ne d 
i nter ve nti o n.
5. 5.  
T her a pe utic M a n a ge me nt of S u bjects i n Ot her C ritic al 
Sit u ati o ns
Ot her critical sit uati o ns c o ul d be a d missi o n t o h os pital f or ac ute me dical ill ness or acti ve 
peri o ds of c he m ot hera p y.   In t hese circ u msta nces gastr oi ntesti nal dis or ders mi g ht 
precl u de i nta ke of oral t hera p y wit h e d o xa ba n a n d bri d gi n g t o L M W H is all o we d 
acc or di n g t o t he g ui da nce i n A p pe n di x 1 7. 2 .  I n case of d o u bt it is rec o m me n de d t o 
c o ntact t he I T R E A S Me dical S u p p ort Li ne 


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5. 6.  
T her a pe utic M a n a ge me nt of S u bjects B e y o n d M o nt h 1 2 a n d at 
Gl o b al E n d -of -Tre at me nt
S u bjects re q uiri n g a d diti o nal a nti -c oa g ulati o n t hera p y w h o c o m plete t heir treat me nt a n d 
f ull 1 2-m o nt h p ost ra n d o mizati o n f oll o w -u p or w h ose treat me nt is tr u ncate d d ue t o t he 
gl o bal E n d of Treat me nt date will be ma na ge d acc or di n g t o l ocal practice.
G ui da nce f or s witc hi n g fr o m e d o xa ba n t o ot her a ntic oa g ula nts is pr o vi de d i n 
A p pe n di x 1 7. 2.
A d diti o nal g ui da nce f or l o n g -ter m ma na ge me nt of ca ncer s u bjects wit h V T E is pr o vi de d 
b y  L yma n, et al .1


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6.  
S T U D Y P R O C E D U R E S
T he Sc he d ule of St u d y Pr oce d ures f or t his st u d y is pr o vi de d i n A p pe n di x 1 7. 7 .
6. 1.  
St u d y Q u alific ati o n / Pre-r a n d o miz ati o n
It is e x pecte d t hat m ost s u bjects will ha ve ha d s o me or all of t he st u d y q ualificati o n 
pr oce d ures d o ne as part of r o uti ne care o utsi de t he a us pices of t his st u d y  (f or e xa m ple, 
dia g n ostic w or k -u p a n d ass ociate d care f or V T E).  If t hese pr oce d ures are d o ne pri or t o
ra n d o mizati o n, t he y ma y be use d t o ra n d o mize t he s u bject t o st u d y a n d be gi n c o m pleti o n 
of t he e C R F , o nce t he s u bject has si g ne d t he I C F.  T he s u bject d oes n ot nee d t o re peat 
rece ntly c o m plete d pr oce d ures/tests f or st u d y q ualificati o n.  F or s uc h s u bjects it ma y  be 
p ossi ble t o c o m bi ne t he st u d y  q ualificati o n a n d ra n d o mizati o n visits i nt o a si n gle visit.
A n y  pr ot oc ol-s pecifie d st u d y q ualificati o n pr oce d ures/tests n ot alrea d y d o ne as part of 
r o uti ne care will be c o n d ucte d o nl y after t he s u bject si g ns t he I C F a n d bef ore 
ra n d o mizati on.  Pri or t o si g ni n g t he I C F, p ote ntial s u bjects will ha ve t he st u d y ris ks a n d 
be nefits e x plai ne d t o t he m, t he ass ociate d I C F will be re vie we d, a n d all q uesti o ns 
a ns were d f or t he m.
T he f oll o wi n g st u d y q ualificati o n pr oce d ures m ust be c o m plete d t o e ns ure t h at t he 
s u bject is eli gi ble f or t he st u d y.

Si g n I C F ;

Re vie w i ncl usi o n/e xcl usi o n criteria , a n d e ns ure t hat t he s u bject q ualifies wit h 
re gar d t o t he cli nical la b orat or y tests f or e xcl usi o n criteria:

Calc ulate d Cr C L  < 3 0 m L/ mi n;

Platelet c o u nt < 5 0, 0 0 0/ m L

Re vi e w c o nc o mita nt me dicati o ns f or assess me nt of e xcl usi o n criteria;

E ns ure t hat t he s u bject has a dia g n osis of V T E c o nfir me d b y  a p pr o priate 
i ma gi n g met h o ds;
T he f oll o wi n g i ma gi n g met h o ds are t y picall y c o nsi dere d part of r o uti ne h os pital w or k - u p 
f or t he ma na geme nt of V T E a n d/ or ca ncer, a n d as s uc h, will n or mall y  be o btai ne d pri or 
t o i nf or me d c o nse nt as part of t he s u bject’s n or mal sta n dar d- of-care.
o
F or a s us pecte d s y m pt o matic D V T:  c o m pressi o n ultras o n o gra p h y ( C U S), 
ve n o gra p h y, or s pecific c o m p uterize d t o m o gra p h y  (C T ) ve n o gra p h y. 
o
F or u ns us pecte d D V T:  a t hr o m b us detecte d i n t he I V C or iliac vei ns o n a 
(sta gi n g) a b d o mi nal or pel vic C T will be c o nsi dere d dia g n ostic. Beca use 
of p ote ntial fl o w artifacts a n d la y eri n g of c o ntrast, a s us pecte d t hr o m b us 
detecte d i n t h e c o m m o n fe m oral vei n or m ore distal ca n o nl y be 
c o nsi dere d if c o nfir mat or y C U S or ( C T) c o ntrast ve n o gra p h y dia g n ostic 
criteria are als o met.


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o
F or s us pecte d s y m pt o matic P E: C o m p uterize d t o m o gra p hic p ul m o nar y  
a n gi o gra p h y ( C T P A; als o calle d s piral C T a n gi o gr a p h y [s piral C T] ), 
ve ntilati o n perf usi o n sca n ( V/ Q sca n; if perf usi o n sca n o nl y is d o ne a 
c o nfir mat or y test f or le g D V T is re q uire d), or cat heter p ul m o nar y 
a n gi o gra p h y. 
N ote : A perf usi o n sca n ( wit h o ut ve ntilati o n sca n) d oes n ot q ualif y  f or t he dia g n oses of 
P E, u nless c o nc o mita nt D V T is d oc u me nte d .
o
F or a n u ns us pecte d P E: f o u n d d uri n g a sta gi n g-C T a re peat test is n ot 
rec o m me n de d i n or der t o li mit ra diati o n a n d c o ntrast e x p os ure. T his 
i nci de ntal fi n di n g will o nl y be c o nsi dere d dia g n ostic if t he cl ot is i n a 
se g me ntal or greater arter y, w hereas cl ots i n s u b-se g me ntal or m ore 
peri p heral arteries will n ot be acce pte d d ue t o ris k of a false p ositi ve 
res ult.

Rec or d de m o gra p hic i nf or mati o n;

Rec or d me dical/s ur gical hist or y , i ncl u di n g c o-m or bi dities ;

Rec or d descri p ti o n of ca ncer (date of dia g n osis, t ype, (ie, hist ol o gicall y  or 
c yt ol o gicall y dia g n ose d s oli d t u m or), l ocati o n or he mat ol o gical mali g na nc y, 
sta ge (eg, earl y, re gi o nall y a d va nce d, metastatic), details o n t hera pe utic 
ma na ge me nt );

Base d o n data c o m plete d i n t he e C R F it will be assesse d w het her s u bject 
meets t he criteria f or acti ve ca ncer w hic h will be defi ne d as:

Dia g n ose d wit h ca ncer wit hi n t he past 6 m o nt hs; or

Rec urre nt, re gi o nall y a d va nce d or metastatic disease; 

C urre ntl y  recei vi n g treat me nt or ha ve recei ve d a n y treat me nt f or ca ncer 
d uri n g t he 6 m o nt hs pri or t o ra n d o mizati o n; or

A he mat ol o gic mali g na nc y  n ot i n c o m plete re missi o n
N ote :  S u bjects n ot meeti n g t hese criteria will be cate g orize d as hist or y  of ca ncer a n d 
t he n ca ncer s h o ul d ha ve bee n dia g n ose d wit hi n t he 2 ye ars prece di n g ra n d o mizati o n.

Perf or m p h ys ical e xa mi nati o n i ncl u di n g vital si g ns (sitti n g B P a n d heart rate) 
a n d rec or d hei g ht a n d b o d y wei g ht ( ma y be perf or me d b y a n I n vesti gat or or 
ot her healt hcare pr o vi der desi g nate d b y t he I n vesti gat or) ;

A ssess t he s u bject f or acti ve blee di n g, hi g h ris k f or blee di n g, a n d a ny ot her 
c o ntrai n dicati o ns f or treat me nt wit h L M W H
or e d o xa ba n.
Sa m ples o btai ne d as part of r o uti ne care o utsi de st u d y  a us pices ma y be a nal yze d b y l ocal 
la b orat ories a n d t he res ults use d t o q ualif y t he s u bject pr o vi de d t he tests were perf or me d 
wit hi n 7 da y s of ra n d o mizati o n.  
F ull d oc u me ntati o n f or t he a b o ve st u d y q ualificati o n pr oce d ures a n d relate d res ults are 
re q uire d, i ncl u di n g l ocal la b orat or y res ults use d t o q ualif y t he s u bject.  T heref ore, t he
e C R F m ust be c o m plete d f or e ver y  s u bject wit h a si g ne d I C F.


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A n i n de x e ve nt d ossier m ust be c o m pile d, w hic h i ncl u des c o pies of t he dia g n ostic tests 
d o ne t o c o nfir m t he i n de x V T E. T he d ossier will be re vie we d b y t he C E C. I nstr ucti o ns 
f or c o m pleti n g t he d ossier pac ka ge will be pr o vi de d i n t he o utc o me re p orti n g ma n ual. 
D ue t o l o gistical c o nstrai nts, a dj u dicati o n of i n de x e ve nts will be perf or me d after 
ra n d o mizati o n; he nce, t he a dj u dicate d res ult will n ot be use d t o q ualif y t he s u bject f or t he 
stu d y , b ut rat her t o s u bse q ue ntl y defi ne t he o utc o me a nalys es sets.
T he i n de x e ve nt pac ka ge m ust als o c o ntai n c o pies of test re p orts or h os pital letters 
c o nfir mi n g t he s u bject’s ca ncer dia g n osis.   T he i n vesti gati o nal site s h o ul d e ns ure t hat a n y 
pers o nal s u bj ect i de ntificati o n ot her t ha n s u bject n u m ber a n d i nitials are re m o ve d fr o m 
t he i n de x e ve nt d ossier.
Base d o n t he i ncl usi o n criteri o n t hat l o n g ter m treat me nt wit h L M W H is i nte n de d t o be 
gi ve n, it is e x pecte d t hat a lar ge pr o p orti o n of s u bjects will meet t h e criteria f or acti ve 
ca ncer.  Ne vert heless, t he perce nt of s u bjects wit h acti ve ca ncer will be m o nit ore d d uri n g 
t he st u d y b y a me dical m o nit or w h o will re p ort t o t he S M C C c hair.  If necessar y, t he 
S M C C will ta ke a p pr o priate acti o ns t o e ns ure t hat t he pr o p orti o n of s u bjects wit h acti ve 
ca ncer is s ufficie nt (ie, > 7 5 %) t o dra w vali d c o ncl usi o ns i n t he acti ve -ca ncer p o p ulati o n
6. 2.  
D a y 1/ R a n d o miz ati o n
Bef ore ra n d o mizati o n, t he I n vesti gat or will e ns ure t hat all pr ot oc ol -s pecifie d 
pre -ra n d o mizati o n re q uire me nts a n d pr oce d ures are met a n d/ or c o m plete d.  F or s u bjects 
w h o meet all t he i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria, t he f oll o wi n g will 
be perf or me d o n t he da y  of ra n d o mizati o n, pri or t o act ual ra n d o mizati o n .  

C o m plete t he I X R S Ra n d o mizati o n Visit w or ks heet i ncl u di n g re vie w of 
s u bject’s a ge, blee di n g ris k pr ofile, b o d y  wei g ht, calc ulate d Cr C L, a n d 
c o nc o mita nt me dicati o ns ;

Rec or d vital si g ns (sitti n g B P a n d heart rate) a n d wei g ht;

Assess a n d rec or d E C O G Perf or ma nce S tat us (see A p pe n di x 1 7. 6 f or t he 
E C O G perf or ma nce scale );

C ollect ser u m sa m ple f or arc hi vi n g b y  Q La bs f or later testi n g if necessar y.  
Use t he Q La bs pre -d ose Da y  1 kit a n d s hi p t he sa m ple t o Q La bs;

Rec or d t he f oll o wi n g l ocal la b orat or y  res ults i n t he e C R F:

Ser u m c he mistr y

T otal bilir u bi n ( direct a n d i n direct)

Ala ni ne tra nsa mi nase ( A L T)

As partate tra nsa mi nase ( A S T)

Al kali ne p h os p hatase ( A L P)

Ser u m creati ni ne

Cr C L


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
He mat ol o g y a n d platelet c o u nt

He mat ocrit

W hite bl o o d cell ( W B C) c o u nt 
wit h differe nti al

He m o gl o bi n

Platelet c o u nt
If all pr oce d ures a n d tests d o ne bef ore ra n d o mizati o n c o nfir m t he s u bject's eli gi bilit y f or 
t he st u d y, access t he I X RS, re gister t he s u bject f or st u d y  q ualificati o n, a n d o btai n t he 
s u bject i de ntificati o n n u m ber.  
T he f oll o wi n g acti vities a n d/ or assess me n ts will be perf or me d at/ d uri n g ra n d o mizati o n:

Rec or d A Es a n d treat me nts ( dr u g a n d n o n -dr u g) gi ve n f or A Es ;

Rec or d pri or tar gete d me dicati o ns ta ke n wit hi n 3 0 da ys bef ore ra n d o mizati o n;

Rec or d date a n d ti me f or Da y  1 d ose of st ud y  dr u g;

Dis pe nse st u d y  dr u g ( dalte pari n or e d o xa ba n) a n d rec or d a m o u nt ( n u m ber of 
ta blets a n d s yri n ges) dis pe nse d;

E x plai n t he st u d y  me dicati o ns a n d t he pr o per daily d osi n g t o t he s u bject a n d 
c o nfir m t hat t he s u bject u n dersta n ds t he pr o per dail y  d osi n g of st u d y 
me dicati o n, i ncl u di n g w he n t o st o p L M W H
a n d be gi n e d o xa ba n d osi n g ;

I nstr uct s u bject t o bri n g u n use d st u d y dr u gs t o eac h st u d y visit ;

Pr o vi de s u bjects wit h a patie nt i nf or mati o n b o o klet, w hic h will c o ntai n t he 
f oll o wi n g i nf or mati o n:

T he st u d y  o utline i n la y ma n’s ter ms;

T he l ocal me dical c o ntact pers o n a n d e mer ge nc y  tele p h o ne n u m ber;

T he visit sc he d ule pr o vi de d b y t he I X R S (fa x or e mail wit h dates of 
tele p h o ne a n d/ or h os pital visits);

H o w t o rec o g nize a n d re p ort si g ns a n d s y m pt o ms of p ossi ble rec urre nt 
s ym pt o matic P E/ D V T or blee di n g ;

I nstr ucti o ns t o kee p e m pt y me dicati o n pac ka ges;

H o w t o use t he st u d y  me dicati o n;

A s h ort list of pr o hi bite d me dicati o ns.

Pr o vi de s u bjects wit h a s u bject i de ntificati o n safet y car d .
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list of na mes of all 
t he s u bjects ra n d o mize d t o st u d y t o all o w 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.


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6. 3.  
Tre at me nt Peri o d
T he treat me nt peri o d be gi ns wit h t he first d ose of L M W H ( dalte pari n or ot her L M W H 
de pe n di n g o n ra n d o mize d treat me nt assi g n me nt) after ra n d o mizati o n a n d e n ds wit h t he 
last d ose of st u d y dr u g at t he ti me of per ma ne nt disc o nti n uati o n of st u d y  dr u g.  D uri n g 
t he treat me nt peri o d, t he s u bject will be i nstr ucte d t o bri n g all st u dy dr u g s u p plies t o eac h 
sc he d ule d (e ver y 3 m o nt hs) st u d y assess me nt.  O utc o me a n d ot her e ve nt re p orti n g (e g, 
V T E, blee di n g , A Es ) will be d o ne t hr o u g h o ut t he st u d y  as s o o n as site pers o n nel lear n of 
t he e ve nt.  Rec or di n g of A Es a n d treat me nts ( dr u g a n d n o n-dr u g) gi ve n f or A Es will be 
d o ne t hr o u g h o ut t he st u d y.
S u bjects w h o per ma ne ntl y disc o nti n ue st u d y dr u g will be f oll o we d f or efficac y a n d safet y 
o utc o mes a n d S A Es b y visit or tele p h o ne c o ntact at least o nce e ver y 3 m o nt hs u ntil 
M o nt h 1 2, e xce pt as n ote d i n Secti o n 3. 1. 2. 1 .  If t he s u bject has a n o n-site visit, o btai n 
vital si g ns a n d a n y la b orat or y  assess me nts dee me d a p pr o priate by t he I n vesti gat or.  
I deall y, a ll s u bjects s h o ul d ha ve t heir fi nal E O T p ost -ra n d o mizati o n visit c o m plete d i n 
pers o n eit her i n -cli nic or h o me visit.
6. 3. 1.  
D a y 3 1 ( ± 3) Visit
At Da y  3 1 f oll o wi n g ra n d o mizati o n, all s u bjects s h o ul d be see n by q ualifie d me dical 
pers o n nel f or t he f oll o wi n g pr oce d ures :

Assess f or A Es a n d o utc o me e ve nts;

Rec or d tar gete d c o nc o m ita nt me dicati o ns, a n y i nterr u pti o ns i n c he m ot hera p y 
treat me nt d ue t o a V T E or blee d e ve nt or me dicati o n gi ve n i n ass ociati o n wit h 
a n A E/ S A E;

Assess st u d y  dr u g d osi n g c o m plia nce;

Rec or d i nterr u pti o ns of e d o xa ba n or dalte pari n wit h t he date of last d ose a n d
t he date of t he first d ose of res u m pti o n of dr u g (see als o Secti o n 4. 2. 1. 1 );

Ca pt ure healt hcare res o urce utilizati o n as a p pr o priate;

Assess E C O G perf or ma nce stat us;

M o nit or a n d rec or d he m o gl o bi n / he mat ocrit, platelet c o u nts, wei g ht, ser u m 
creati ni ne, creati ni ne cleara nce , a n d P-g p i n hi bit or use a n d deter mi ne if a 
st u d y dr u g d ose a dj ust me nt is necessar y;

Dis pe nse st u d y  me dicati o ns a n d d o w n -titrate dalte pari n s u bjects t o 
mai nte na nce d ose .
6. 3. 2.  
M o nt hs 3, 6, a n d 9 ( ± 7 d a ys)
All s u bjects s h o ul d be see n b y  q ualifie d me dical pers o n nel f or t he f oll o wi n g pr oce d ures:

Assess f or A Es a n d o utc o me e ve nts;


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
Rec or d tar gete d c o nc o mita nt me dicati o ns, a n y i nterr u pti o ns i n c he m ot hera p y 
treat me nt d ue t o a V T E or blee d e ve nt or me dicati o n gi ve n i n ass ociati o n wit h 
a n A E/ S A E;

Assess st u d y  dr u g d osi n g c o m plia nce (if t he s u bject is still o n st u d y 
treat me nt);

Rec or d i nterr u pti o ns of e d o xa ba n or dalte pari n wit h t he date of last d ose a n d 
t he date of t he first d ose of res u m pti o n of dr u g (if t he s u bject is still o n st u d y 
treat me nt; see als o Secti o n 4. 2. 1. 1 );

Ca pt ure healt hcare res o urce utilizati o n as a p pr o priate;

Assess E C O G perf or ma nce stat us;

M o nit or a n d rec or d he m o gl o bi n/ he mat ocrit, platelet c o u nts, wei g h t, ser u m 
creati ni ne, creati ni ne cleara nce, a n d P -g p i n hi bit or use a n d deter m i ne if a 
st u d y dr u g d ose a dj ust me nt is necessar y (if t he s u bject is still o n st u d y 
treat me nt);

L i ver f u ncti o n test m o nit ori n g ( o nly at M o nt h 6 if t he s u bject is still o n st u d y 
treat me nt):

ie, rec or d ( or c ollect a ser u m sa m ple f or) tra nsa mi nase ( A L T/ A S T), 
al kali ne p h os p hatase, a n d bilir u bi n le vels

Dis pe nse st u d y  me dicati o ns (if t he s u bject is still o n st u d y treat me nt). 
6. 4.  
E n d of Tre at me nt / M o nt h 1 2 ( ± 7 d a ys)
All s u bjects s h o ul d be see n b y  q ualifie d me dical pers o n nel f or t he f oll o wi n g pr oce d ures
at M o nt h 1 2 or w he ne ver st u d y  treat me nt is per ma ne ntl y disc o nti n ue d.  S u bjects 
per ma ne ntl y disc o nti n ui n g st u d y treat me nt bef ore M o nt h 1 2 will still be f oll o we d u ntil 
M o nt h 1 2 or t he gl o bal E O T d ate w hic he ver occ urs first .

Assess f or A Es a n d o utc o me e ve nts;

Rec or d tar gete d c o nc o mita nt me dicati o ns , a n y i nterr u pti o ns i n c he m ot hera p y 
treat me nt d ue t o a V T E or blee d e ve nt or me dicati o n gi ve n i n ass ociati o n wit h 
a n A E/ S A E;

C ollect all u n use d st u d y  dr u g (if t he s u bject is still o n st u d y treat me nt)

Assess st u d y  dr u g d osi n g c o m plia nce (if t he s u bject is still o n st u d y 
treat me nt);

Rec or d i nterr u pti o ns of e d o xa ba n or dalte pari n wit h t he date of last d ose a n d 
t he date of t he first d ose of res u m pti o n of dr u g (if t he s u bject is still o n st u d y 
treat me nt; see als o Secti o n 4. 2. 1. 1 );

C o u nt u n use d e d o xa ba n ta blets a n d dalte pari n s y ri n ges a n d rec or d i n t he 
I X R S dr u g acc o u nta bilit y m o d ule (if t he s u bject is still o n st u d y treat me nt) ;

Ca pt ure healt hcare res o urce utilizati o n as a p pr o priate;


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
Assess E C O G Perf or ma nce Stat us ;

U p date ca ncer stat us/sta ge ;

Li ver F u ncti o n Test m o nit ori n g if t he s u bject is still o n st u d y treat me nt:

ie, rec or d ( or c ollect a ser u m sa m ple f or) tra nsa mi nase ( A L T/ A S T), 
al kali ne p h os p hatase a n d bilir u bi n .
6. 5.  
F oll o w - U p
N ot a p plica ble .
6. 6.  
Pr ot oc ol De vi ati o ns
T he In vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit 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 w hic h was gi ve n 
a p pr o val/fa v ora ble o pi ni o n b y  t he I RB/I E C.
A de viati o n t o a n y ke y pr ot oc ol pr oce d ures, or wai ver t o a n y state d eli gi bilit y criteria will 
n ot be all o we d e xce pt as n ote d bel o w a n d w here necessar y  t o eli mi nate i m me diate 
hazar d(s) t o t he s u bject.  
S u bjec ts f or w h o m e x peri me ntal a ntica ncer treat me nt is i nstit ute d after ra n d o mizati o n t o 
t he ca ncer V T E trial will re mai n i n t he st u d y  a n d f oll o we d f or 1 2 m o nt hs or t he gl o bal 
E O T date, w hic he ver occ urs first . T he decisi o n w het her t o disc o nti n ue t he V T E st u d y  
treat me nt will be at PI discreti o n acc or di n g t o l ocal re g ulati o ns .
S p o ns or m ust be n otifie d of a n y  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, misse d st u d y visits).
T he In vesti gat or, or pers o n desi g nate d b y  t he In vesti ga t 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.
If a s u bject was i neli gi ble or recei ve d t he i nc orrect d ose of i n vesti gati o nal treat me nt, a n d 
ha d at least 1 a d mi nistrati o n of i n vesti gati o nal pr o d uct, t he patie nt s h o ul d be f oll o we d
u ntil st u d y  disc o nti n uati o n.
T he I n vesti gat or s h o ul d n otif y  t he I E Cs/I RB s of de viati o ns fr o m t he pr ot oc ol i n 
acc or da nce wit h l ocal pr oce d ures.


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7.  
O U T C O M E A S S E S S M E N T S
S u bjects wit h s us pecte d rec urre nt P E/ D V T will u n der g o o bjecti ve testi n g t o assess t he 
rec urre nt e pis o de.  I n s u bjects wit h blee di n g a d diti o nal e xa mi nati o ns will be d o ne if 
dee me d necessar y  b y t he i n vesti gat or (e g, he mat ol o g y  bl o o d sa m ple, dia g n ostic 
i ma gi n g/sc o pi n g). I n s u bjects wit h ot her s us pecte d o utc o mes s uc h as deat h, 
car di o vasc ular e ve nts, or ot her t hr o m b otic e ve nts t he dia g n ostic w or k- u p will be 
c o n d ucte d acc or di n g t o t he h os pital r o uti ne .
F or all s us pecte d e ve nts a n a dj u dicati o n d ossier m ust be pre pare d f or s hi p me nt t o t he 
C E C. T his d ossier will c o ntai n t he f oll o wi n g d oc u me ntati o n:

co pie s of all dia g n ostic i ma gi n g (re p orts a n d/ or i ma ges);

cli nicall y rele va nt n otes/ h os pital letters/ la b orat or y re p orts/ me dical rec or ds.
Details re gar di n g t he defi niti o ns of t he st u d y  o utc o mes a n d h o w t he y will be assesse 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 testi n g a n d re p orti n g are pr o vi de d i n 
t he O utc o me Re p orti n g Ma n ual a n d will be pr o vi de d t o all sites.
7. 1.  
Pri m ar y O utc o me V ari a ble(s)
T he pri mar y  st u d y o utc o me is t he c o m p osite of rec urre nt V T E a n d maj or blee di n g.
Rec urre nt V T E is eit her: 

sy m pt o matic c o nfir me d ( ne w) D V T or ( ne w) P E ;

u ns us pecte d ( ne w) pr o xi mal D V T

U ns us pecte d D V T is a D V T c oi nci de ntall y detecte d d uri n g ot her 
i n vesti gati o ns (e g, a b d o mi nal or pel vic C T f or ca ncer sta gi n g) .  T his D V T 
will o nl y  be i ncl u de d as a n o utc o me if it c oncer ns a ( ne w) cl ot l ocate d i n 
t he p o pliteal or m ore pr o xi mal le g vei ns.  A t hr o m b us detecte d i n t he I V C 
or iliac vei ns o n a n a b d o mi nal or pel vic C T d oes n ot re q uire a d diti o nal 
c o nfir mati o n. A t hr o m b us detecte d i n t he c o m m o n fe m oral vei n or m ore 
distal ve i ns ca n o nl y be c o nfir me d if C U S ( or ve n o gra p hy) dia g n ostic 
criteria are als o met.

u ns us pecte d ( ne w) P E ;

u ns us pecte d P E is a n e m b olis m c oi nci de ntall y  detecte d d uri n g ot her 
i n vesti gati o ns (e g, C T f or ca ncer sta gi n g), t hat i n v ol ves se g me ntal or m ore 
pr o xi ma l p ul m o nar y arteries.

fatal P E (i ncl u di n g u ne x plai ne d deat h f or w hic h P E ca n n ot be r ule d o ut).
Maj or blee di n g is defi ne d as o vert blee di n g a n d:

ass ociate d wit h a decrease i n he m o gl o bi n of ≥ 2 g/ d L , or

lea di n g t o a tra nsf usi o n of ≥ 2 u nits of pac ke d re d bl o o d cells or w h ole bl o o d,
or 




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8.  
P H A R M A C O KI N E TI C A S S E S S M E N T S
8. 1.  
P h ar m ac o ki netic ( P K) V ari a ble(s)
N ot a p plica ble .
8. 2.  
P h ar m ac o d y n a mic ( P D) V ari a ble(s)
N ot a p plica ble.
8. 3.  
Bi o m ar k er a n d E x pl or at or y V ari a ble(s)
N ot a p plica ble.


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9.  
S A F E T Y A S S E S S M E N T S
9. 1.  
A d verse E ve nts
T his st u d y  will f oll o w a tar gete d a p pr oac h t o A E a n d S A E re p orti n g.  All AEs occ urri n g 
after t he s u bject si g ns t he I CF a n d t hr o u g h M o nt h 1 2 or t he gl o bal E O T date, w hic he ver 
occ urs first (see Secti o ns 4. 2. 2. 1 a n d Secti o n 6. 4 ), w het her o bser v e d b y t he In 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 Master E ve nt/ A E pa ge of t he C R F
if 
t he y f ulfill 1 o f t he f oll o wi n g criteria: 1) meet seri o us ness criteria (see Secti o n 9. 4. 2 ) or 
res ult in i nterr u pti o n or disc o nti n uati o n of st u d y  dr u g (e d o xa ba n or dalte pari n ) ) [ E ve nts 
t hat are assesse d b y t he i n vesti gat or t o be relate d t o t he u n derlyi n g ca ncer or treat me nt of 
t he u n derlyi n g ca ncer d o n ot meet criteria f or tar gete d A E re p orti n g, as defi ne d i n 
Secti o n 9. 4. 2 ]; 2) meet criteria as a st u d y o utc o me (see Secti o n 3. 1. 4 ); or 3 ) a n e ve nt of 
s pecial i nterest (see Secti o n 9. 3 ).
All la b orat or y a n d vital si g n val ues 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 a b n or mal la b orat or y res ults or vital s i g n fi n di n gs s h o ul d be 
re p orte d as A Es if t he y are cli nicall y si g nifica nt , a n d 1) meet serio us ness criteria (see 
Secti o n 9. 4. 2 ); or 2) res ult i n i nterr u pti o n or disc o nti n uati o n of st u d y  dr u g (e d o xa ba n or 
dalte pari n) u nless relate d t o u n derl y i n g ca ncer or ot her pre- e xisti n g c o n diti o n .  Cli nicall y 
si g nifica nt a b n or mal la b orat or y fi n di n gs ass ociate d wit h t he s u bject’s ca ncer or ot her pre-
e xisti n g c o n diti o ns will n ot be re p orte d as A Es or S A Es u nless j u d ge d b y t he I n vesti gat or 
as m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n a n d meet t he criteria f o r tar gete d 
A E a n d S A E re p orti n g.  La b orat or y  res ults t hat are defi ne d as a n A E of s pecial i nterest 
( A E SI) ie, c o m bin e d ele vati o ns of a mi n otra nsferase a n d bilir u bi n s h o ul d be re p orte d 
re gar dless of ca usalit y as descri be d i n Secti o n 9. 3. 1 .  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 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 inf or me d co nse nt 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 di ng t o t he pr oce d ures i n Secti o n 9. 5 S eri o us A d verse E ve nt Re p orti n g-
Pr oce d ure f or I n vesti gat ors .  
All S A Es occ urri n g after i nf or me d c o nse nt f or ge neral st u d y partici pati o n is o btai ne d 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 .  Al wa ys re p ort t he dia g n osis as 
a n 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 ym 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 ble.  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 
seri o us a d verse e ve nt ( dia g n osis or sy m pt o m re q uiri n g h os pitalizati 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.  A p re-
pla n ne d ( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) pr o ce d ure or treat me nt re q uiri n g 
h os pitalizati o n 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 s h o ul d n ot be 
re p orte d as S A Es (see Secti o n 9. 4. 2 f or Defi niti o ns).  F or deat hs, t he u n derl yi n g or 
i m me diate ca use of deat h s h o ul d al wa ys be re p orte d as a n S A E. W he n a s u bject dies 
fr o m disease pr o gressi o n of pre -e xisti n g ca ncer wit h n o ot her i m me diate ca uses, “ disease
pr o gressi o n” s h o ul d be re p orte d as a n S A E.   I n a d diti o n, a n y seri o us, u nt o war d e ve nt t hat 


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m a y occ ur s u bse 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 re p orte d a n d ma na ge d as a n S A E.
At eac h visit, t he I n vesti gat or or a p pr o priatel y q ualifie d desi g nee will deter mi ne 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 d verse e ve nts 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 p ecific s ym pt o ms.  T he 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 n 9. 4 . 
T he I n vesti gat or’s assess me nt m ust be clearl y d oc u me nt e 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 vesti gat or s h o ul d f oll o w s u bjects wit h A Es 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 ve d A Es i ncl u di n g si g nifica nt a b n or mal la b orat or y 
val u es at t he e n d of st u d y assess me nt, t hese e ve nts will be f oll 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. 2.  
S afet y O utc o me s
9. 2. 1.  
Blee di n g O utc o mes
All s us pecte d blee di n g e ve nts, irres pecti ve of t he cli nical rele va nce assesse d b y  t he 
In ve sti gat or, m ust be re p orte d a n d will be re vie we d a n d classifie d by t he C E C as maj or, 
cli nicall y rele va nt n o n maj or, n uisa nce or n o blee di n g e ve nt.  
Details re gar di n g t he classificati o n of blee di n g e ve nts a n d h o w t hese e ve nts will be 
assesse 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 re p orti n g blee di n g 
e ve nts are pr o vi de d i n t he O utc o me Re p orti n g Ma n ual a n d will be pr o vi de d t o all st u d y  
sites.  
9. 3.  
E ve nts of S peci al I nterest
9. 3. 1.  
C o m bi ne d Ele v ati o ns of A mi n otr a nsfer ase a n d Bilir u bi n
T here was n o cli nica ll 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 nce i n v ol vi n g o ver 3 4, 1 0 0 
e d o xa ba n s u bject-ye ars e x p os ure ( wit h me dia n dr u g e x p os ure of ~ 2. 5 ye ars 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  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 v i de nce of p ossi ble c h olestasis) a n d wit h o ut 
alter nati 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 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 b ut wit hi n 2 4 h o urs of 
a ware ness if t he y meet t he f oll o wi n g criteria (see 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 ):

T he e ve nt meets seri o us ness criteria;


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
T he e ve nt (seri o us or n o n -seri o us) res ults i n st u d y dr u g i nterr u pti o n or 
disc o nti n uati o n;

T he e ve nt is n o n -seri o us b ut t here is n o e vi de nce of c h olestasis ( A L P > 2 x 
U L N) a n d wit h o ut alter nati ve eti ol o g y  f or he pat ocell ular da ma ge.
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 nat ure a n d t he e xte nt of li ver i nj ur y is i de ntifie 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 are sta bilize d ( Please refer t o Secti o n
4. 2. 2. 1 ).
9. 4.  
Defi niti o ns
9. 4. 1.  
A d verse E ve nt ( A E)
A n y  u nt o war d me dical occ urre nce i n a s u bject or cli nical i n vesti gati o n 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 t o ha ve a 
ca usal relati o ns hi p wit h t hi s treat me nt.  A n A E ca n t heref ore be a n y  u nfa v ora 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 orat 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 pr o d uct, w het her or n ot 
c o nsi dere d relate d t o t he me dici nal pr o d uct (I C H E 2 A G ui deli ne.  Cli nical S afet y Data 
Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 9 9 4).
It is t he res p o nsi bilit y of I n vesti gat ors, base d o n t heir k n o wle d ge a n d e x perie nce, t o 
deter mi ne, t h ose circ u msta nces or a b n or mal la b orat or y fi n di n gs w hic h s h o ul d be 
c o nsidere d a d verse e ve nts.
9. 4. 2.  
Seri o us A d verse E ve nt ( S A E)
A n y  u nt o war d me dical occ urre nce t hat at a ny d ose:

Res ults i n deat h ;

Is life-t hreate ni n g;

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti 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 maly/ birt h defect ; or

Is a n i m p orta nt me dical e ve nt.
N ote : 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 deat h if it were m ore se vere (I C H E 2 A 
G ui deli ne.  Cli nical Safet y Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d 
Re p orti n g, Oct 1 9 9 4).
Me dical a n d scie ntific j u d g 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 me dical 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 dize 
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 


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defi niti o n a b o ve.  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 y scrasias or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
N ote :
T he f oll o wi n g are n ot c o nsi dere d A Es or S A Es i n t he c o nte xt of t his st u d y :

H os pitalizati o n f or a pre -pla n ne d pr oce d ure or dia g n ostic tests (i ncl u d i n g f or 
ca ncer sta gi n g, e g, C T sca n, M a g netic R es o na nce Ima gi n g , gastr osc o p y, 
c yst osc o p y, br o nc h osc o p y, etc) or treat me nt f or pre-e xisti n g c o n diti o ns (e g, 
c he m ot hera p y, r a diati o n t hera p y) s h o ul d N O T be re p orte d as S A Es;

H os pitalizati o n a n d/ or i nter ve nti o n f or dia g n ostic w or k-u p or treat me nt of 
w orse ni n g u n derl yi n g ca ncer or c o m plicati o ns of ca ncer treat me nt (e g, w or k -
u p f or fe brile ne utr o pe nia, tra nsf usi o n f or a ne mia, M U G A sca n t o r ule o ut 
car di o m y o pat h y) s h o ul d N O T be re p orte d as S A Es .
9. 4. 3.    
A d verse E ve nt Se verit y
T he f oll o wi n g defi niti o ns s h o ul d be use d t o assess i nte nsit y  of A Es per t he N CI  C T C A E 
criteria:

Gra de 1 Mil d A E

Gra de 2 M o derate A E

Gra de 3 Se vere A E

Gra de 4 Life -t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d

Gra de 5 Deat h relate d t o A E
9. 4. 4.  
C a us alit y Assess me nt
T he In vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n a d verse e ve nt a n d t he st u d y 
pr o d uct L M W H /e d o xa ba n 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 st u d y  dr u g 
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 
cli nical state or ot her fact 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 st u d y  dr u g 
a d mi nistrati o n, a n d is a k n o w n reac ti o n t o t he dr u g u n der st u d y or its 
c he mical gr o u p, or is pre dicte 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 st u d y  pr o d uct 
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 


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state or other fact 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. 4. 5. 
Acti o n T a ke n Re g ar di n g t he St u d y Pr o d uct

1 = D ose N ot C ha n ge d : N o c ha n ge i n st u d y dr u g d osa ge was ma de.

2 = Dr u g Wit h dra w n : T he st u d y pr o d uct was per ma ne ntl y st o p pe d.

3 = D ose Re d uce d: T he d osa ge of st u d y  pr o d uct was re d uce d.

4 = Dr u g I nterr u pte d: T he st u d y pr o d uct was te m p orarily st o p pe d.

5 = D ose I ncrease d: T he d osa ge of st u d y pr o d uct was i ncrease d.
9. 4. 6.  
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 ve re d fr o m t he a d verse e ve nt 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 he resi d ual effects of t he a d verse e ve nt 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 d verse e ve n t itself is still prese nt a n d o bser va ble.

4 = Fatal

5 = U n k n o w n
9. 4. 7.  
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 = 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 was re q uire d t o treat t he 
a d verse e ve nt.

3 = Ot her .
9. 5.  
S eri o us A d verse E ve nt Re p orti n g – Pr oce d ure F or I n vesti g at ors
All A Es, S A Es, A E SI s, a n d st u d y o utc o mes t hat meet t he criteria s pecifie d a b o ve will be 
ca pt ure d i n t he e C R F. 
St u d y  o utc o mes are cli nicall y a ntici pate d e ve nts a n d will be peri o dically re vie we d b y t he 
D M C 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. St u d y  
o utc o mes (s us pecte d rec urre nt D V T or P E, blee di n g, MI, str o ke, S E E [see A p pe n di x


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1 7. 5. 1 ], a n d t hr o m b otic e ve nts at ot her l ocati o ns [see A p pe n di x 1 7. 5. 2 ]) will be e xe m pte d 
fr o m e x pe dite d safety re p ort s of s us pecte d u ne x pecte d seri o us a d verse reacti o ns
( S U S A Rs) t o re g ulat or y a ut h orities, In vesti gat ors, IE Cs, a n d I RBs.   All S A Es res ul ti n g i n 
deat h, re gar dless of w het her t he y  are wai ve d e n d p oi nt e ve nts, will be ca pt ure d i n t he 
S p o ns or’s gl o bal safet y data base.
T he f oll o wi n g t y p es of e ve nts s h o ul d be re p orte d b y  t he I nvesti gat or i n e C R F wit hi n 
2 4 h o urs of a ware ness t o s u p p ort e x pe dite d s afet y re p orti n g:

S A Es (see Secti o n 9. 4. 2 f or defi niti o n)

Li ver e nz y me a b n or malities/li ver d y sf u ncti o n e ve nts [ A LT 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] meeti n g t he f oll o wi n g criteria:

T he e ve nt meets s eri o us ness criteria;

T he e ve nt (seri o us or n o n -seri o us) res ults i n st u d y dr u g i nterr u pti o n or 
disc o nti n uati o n;

T he e ve nt is n o n -seri o us b ut t here is n o e vi de nce of c h olestasis ( A L P 
> 2 x U L N) a n d wit h o ut alter nati ve eti ol o g y  f or he pat ocell ular da ma ge.
Call Q ui ntiles (tele p h o ne n u m ber will be pr o vi de d per c o u ntr y , per re gi o n; please refer t o 
St u d y  Ma n ual f or a n a p pr o priate p h o ne n u m ber) f or a n y q uesti o ns o n S A E re p orti n g. 
Ur ge nt safet y  q ueries m ust be f oll o we d u p a n d a d dresse d pr o m ptly.  F oll o w - u p 
i nf or mati on a n d res p o nse t o n o n- ur ge nt safet y  q ueries s h o ul d be c o m bi ne d f or re p orti n g 
t o pr o vi de t he m ost c o m plete data p ossi ble wit hi n eac h f oll o w- u p.
I n t he e ve nt t hat e C R F is u na vaila ble, re p ort S A Es b y fa xi n g t he pa per Daiic hi Sa n k yo 
Seri o us A d verse E ve nt Re p or t ( S A V E R) F or m t o Q ui ntiles usi n g t he pr o vi de d fa x c o ver 
s heet a n d t he a p pr o priate fa x n u m ber pr o vi de d f or yo ur c o u ntr y  ( please refer t o St u d y 
Ma n ual f or a n a p pr o priate fa x n u m ber).  O nce e C R F bec o mes a vaila ble, please e nter 
S A Es re p orte d o n t he S A V E R F or m i nt o e C R F as s o o n as p ossi ble.
9. 5. 1.  
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 R B/IE C
Daiic hi Sa n k y o a n d/ or Q ui ntiles will i nf or m I n vesti gat ors , I RBs (I nstit uti o nal Re vie w 
B oar d)/ 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 Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u d y  ce nters or ot her Daiic hi Sa n k yo 
st u dies of t he i n vesti gati o nal pr o d uct (e xcl u di n g wai ve d st u dy o utc o mes per Secti o n 9. 5 ), 
as a p pr o priate per l ocal re p orti n g re q uire me nts.
I n t he U S, u p o n recei pt of t he S p o ns or’s n otificati o n of S U S A Rs t hat occ urre d wit h t he 
in vesti gati o nal p r o d uct, u nless dele gate d t o t he S p o ns or, it is t he In vesti gat or’s 
res p o nsi bilit y t o i nf or m t he IR B per S p o ns or’s i nstr ucti o n.
I n t he E ur opea n Ec o n o mic Area ( E E A) states, 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 all E Cs.
9. 6.  
E x p os ure I n Uter o D uri n g Cli nic al St u dies
Daiic hi Sa n k y o m ust be n otifie d of a n y  s u bject w h o bec o mes pre g na nt w hile recei vi n g 
i n vesti gati o nal pr o d uct a n d t hr o ug h M o nt h 1 2 or t he gl o bal E O T date, w hic he ver occ urs 


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first, or, wit hi n 3 0 da y s of last d ose if it occ urre d less t ha n 3 0 da ys of t he gl o bal E O T 
date. 
Alt h o u g h pre g na nc y  is n ot tec h nicall y a n a d verse e ve nt, all pre g na ncies m ust be f oll o we d 
t o c o ncl usi o 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 
safety 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 ny pre g na nc y i n a fe male s u bject usi n g t he E x p os ure In Uter o ( EI U) Re p orti n g 
f or m.  Please c o ntact y o ur st u d y m o nit o r t o recei ve t he EI U Re p orti n g for m u p o n
lear ni n g of a pre g na nc y.  T he In vesti gat or s h o ul d ma ke e ver y  eff ort t o f oll o w t he s u bject 
u ntil c o m pleti o n of t he pre g na nc y .  If t he o utc o me of t he pre g na nc y meets t he criteria for 
i m me diate classificati o n as a S A E (ie, p ost-part u m c o m plicati o ns, s p o nta ne o us a b orti o n, 
still birt h, ne o natal deat h, or c o n ge nital a n o mal y, i ncl u di n g t hat 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 S A Es o utli ne d i n Secti o n 9. 5 .  
9. 7.  
Cli nic al L a b or at or y E v al u ati o ns
L ocal la b orat or y  res ults a n d refere nce ra n ges f or t he a nalyt es o utli ne d i n Secti o ns 6. 2 , 
6. 3. 1 , 6. 3. 2 , a n d 6. 4 will be rec or de d i n t he e C R F.
9. 8.  
Vit al Si g ns
Vital si g n data will c o nsist of heart rate, B P , a n d hei g ht .  Wei g ht will als o be rec or de d i n
or der t o ma ke deter mi nati o ns re gar di n g st u dy dr u g d ose a dj ust me nts .
9. 9.  
Electr oc ar di o gr a ms
R o uti ne E C Gs are n ot re q uire d b ut will be rec or de d i n t he e C R F w he n a p pr o priate .
9. 1 0.  
P h ysic al Fi n di n gs
A p h y sical e xa mi nati o n, c o n d ucte d pri or t o or at t he ti me of ra n d o mizati o n b y  the 
I n vesti gat or or ot her q ualifie d healt h care pr o vi der desi g nate d b y t he I n vesti gat or, will 
c o nsist of assess me nt of eac h of t h e rele va nt maj or b o d y sys te ms.
9. 1 1.  
Ot her S afet y Assess me nts
Ot her safet y  assess me nts will be c o n d ucte d as necessar y.


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1 0.  
O T H E R A S S E S S M E N T S
N ot a p plica ble.


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1 1.  
S T A TI S TI C A L M E T H O D S
1 1. 1.  
A n al ysis Sets
1 1. 1. 1. 
R a n d o mize d A n al ysis Set
T he r a n d o mize d a nal ys is set i ncl u des all s u bjects ra n d o mize d t o treat me nt.
1 1. 1. 2.  
M o difie d I nte nt i o n-t o- Tre at A n al ysis Set
T he mI T T A nal ys is Set i ncl u des all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of 
st u d y dr u g1.
1 1. 1. 3.  
Per -Pr ot oc ol A n al ysis Set
T he Per -Pr ot oc ol ( P P) A nal y sis Set i ncl u des all ra n d o mize d s u bjects w h o recei ve at least 
1 d ose of st u d y  dr u g, w h o ha ve n ot e x perie nce d treat me nt misall ocati o n, a n d f or w h o m 
t he i n dex D V T or P E e ve nt at baseli ne was c o nfir me d b y  t he C E C.  Treat me nt 
misall ocati o n is defi ne d as a s u bject ta ki n g i nc orrect treat me nt d uri n g t he e ntire st u d y  
peri o d.
1 1. 1. 4.  
S afet y A n al ysis Set
T he Safet y A nal ysis Set i ncl u des all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of 
ra n d o mize d st u d y dr u g.  A nal yses will be base d o n t he ra n d o mize d treat me nt, u nless a 
s u bject i na d verte ntly recei ves t he i nc orrect dr u g d uri n g t he e ntire 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.
1 1. 2.  
Ge ner al St atistic al C o nsi der ati o ns
T he efficac y a nal ys es will be base d o n t he mI T T a n d P P A nal ysis sets.
T he safet y a nal ys es will be base d o n t he Safety A nal ysis Set.
T he data a nal ys is will be perf or me d by a C R O u n der t he g ui da nce of t he st u d y  
bi o statisticia n.  Data a nal yses will be perf or me d usi n g s oft ware S A S Versi o n 8. 0 or 
hi g her.
1 1. 3.  
St u d y P o p ul ati o n D at a
T he n u m ber of s u bjects i n eac h a nal ys is set will be prese nte d b y treat me nt gr o u p.  
S u bjects e xcl u de d fr o m t he a nal ys is sets will be liste d a n d s um marize d b y  treat me nt 
gr o u p a n d reas o n f or e xcl usi o n.  T he n u m ber a n d perce nta ge of ra n d o mize d s u bjects w h o 
disc o nti n ue d treat me nt pre mat urel y will be ta b ulate d b y mai n reas o n f or disc o nti n uati o n 
a n d treat me nt gr o u p.  De m o gra p hic a n d baseli ne c haracteristi cs (i ncl u di n g ris k fact ors) 
will be s u m marize d b y  treat me nt gr o u p usi n g descri pti ve statistics.  N o statistical tests 
will be perf or me d.
                                                
1 St u d y dr u gs i ncl u de t he L M W H prescri be d b y t he PI as t he e d o xa ba n lea d -i n, e d o xa ba n, a n d dalte pari n.


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1 1. 4.  
O utc o me A n al yses
1 1. 4. 1.  
Pri m ar y O utc o me A n al yses
T he pri mar y  o utc o me a nal ysis will be base d o n t he mI T T A nal ys is S et.  I n t his a nal ysis,
t he ti me t o t he first e ve nt of t he c o m p osite pri mar y  o utc o me (rec urre nt V T E
[s ym pt o matic rec urre nt D V T, n o n -fatal s ym pt o matic rec urre nt P E, u ns us pecte d P E, fatal -
P E ] or maj or blee d ) will be a nalyz e d usi n g a C o x’s pr o p orti o nal hazar d m o del i ncl u d i n g 
treat me nt gr o u p , a n d t he stratificati o n fact ors as c ovariates.  T he ti me t o first e ve nt is 
defi ne d as t he ti me ( da y s) fr o m t he da y of ra n d o mizati o n t o t he first e ve nt e x perie nce d b y 
a s u bject d uri n g t he 1 2-m o nt h st u d y  peri o d.  S u bjects w h o d o n ot ha ve a pri mar y 
o utc o me d uri n g t he 1 2-m o nt h st u d y  peri o d will be ce ns ore d at Da y 3 6 5, or t he last da y 
t he s u bject ha d a c o m plete assess me nt f or st u dy o utc o mes, or t he gl o bal E O T date, 
w hic he ver c o mes first.  S u bjects l ost t o f oll o w - u p, s u bjects w h o die d beca use of reas o ns 
ot her t ha n D V T/ P E , or s u bjects w h o wit h dre w i nf or me d c o nse nt bef ore t he e n d of t he 1 2-
m o nt h treat me nt peri o d a n d w h o di d n ot ha ve a pri mar y  o utc o me, will be ce ns ore d at t he 
last da y t he s u bject ha d a c o m plete assess me nt f or st u d y o utc o mes.  T he 
L M W H /e d o xa ba n-t o-c o m parat or H azar d R ati o will be c o m p ute d wit h 9 5 % CI (t w o-si de d 
testi n g), base d o n t his m o del.  L M W H /e d o xa ba n will be c o nsi dere d n o n-i nferi or t o 
c o m parat or if t he u p per li mit of t he CI  is < 1. 5.
T he ass u m pti o n of pr o p orti o nal hazar ds will be c hec ke d usi n g gra p hical met h o ds as l o g
(l o g)-pl ots a n d pl ots of scale d Sc h oe nfel d resi d uals f or t he pri mar y a nalys is.  If t he 
ass u m pti o n is seri o usl y vi olate d, t he n a l o gistic m o del i ncl u di n g treat me nt gr o u p a n d t he 
stratificati o n fact ors as c o variates will be use d.  T he i m pact of selecte d baseli ne 
c o variates o n t he pri mar y o utc o me will be descri be d b y  calc ulati n g a dj uste d Hazar d 
Rati os a n d c orres p o n di n g 9 5 % CI  of t he treat me nt effect.  
T he fre q ue ncies of t he eac h c o m p o ne nts c o ntri b uti n g t o t he pri mar y  o utc o me will be 
descri be d.
T he f oll o wi n g se nsiti vit y a nal ys es will be perf or me d f or t he Pri mar y  O utc o me :

O n -Treat me nt e ve nts base d o n t he P P A nal y sis Set will be a nal yze d usi n g t he 
c o u nti n g pr ocess a p pr oac h of t he C o x pr o p orti o nal hazar ds re gressi o n m o del 
i ncl u di n g treat me nt gr o u p, a n d t he stratificati o n fact ors as c o variates.    A n 
O n -Treat me nt e ve nt is defi ne d as t he e ve nt occ urri n g d uri n g t he ti me peri o d 
t he s u bject is ta ki n g st u d y dr u g u p t o 3 da ys after t heir last d ose f or t hat ti me 
peri o d.   O nl y e ve nt s occ urri n g pri or t o or o n Da y  3 6 5 will be i ncl u de d i nt o 
t his a nal ysis. S u bjects w h o d o n ot e x perie nce a n O n -Treat me nt e ve nt will be 
ce ns ore d at Da y 3 6 5, or t he ti me st u d y dr u g is per ma ne ntl y disc o nti n ue d pl us 
3 da y s or o n t he last da y t he s u bject ha d a co m plete assess me nt (i n -pers o n 
visit or b y  tele p h o ne) f or st u d y o utc o mes, or t he da y of gl o bal e n d of 
treat me nt, w hic he ver c o mes first. 

E ve nts occ urri n g d uri n g t he first 6 m o nt hs ( 1 8 0 da ys) base d o n t he mI T T
A nal y sis Set will be a nal yze d usi n g t he sa me statistical m o del as t he pri mar y 
a nal ys is of t he pri mar y o utc o me . T he ti me t o e ve nt is defi ne d as t he ti me 
( da ys) fr o m t he ra n d o mizati o n t o t he first e ve nt d uri n g t he first 6 m o nt hs after 


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ra n d o mizati o n.  S u bjects w h o d o n ot e x perie nce a n e ve nt u ntil Da y 1 8 0 will 
be ce ns ore d a t Da y 1 8 0, or t he ti me st u d y dr u g is per ma ne ntly disc o nti n ue d or 
o n t he last da y  t he s u bject ha d a c o m plete assess me nt (i n-pers o n visit or b y 
tele p h o ne) f or st u d y o utc o mes, w hic he ver c o mes first.
1 1. 4. 2.  
S u peri orit y A n al ysis of t he Pri m ar y O utc o m e
If n o n-i nferi orit y i n t he pri mar y o utc o me is esta blis he d, L M W H /e d o xa ba n will be 
c o m pare d t o dalte pari n f or s u peri orit y ( α = 0. 0 5, t w o-si de d) wit h re gar d t o t he ti me t o a n 
e ve nt i n t he c o m p osite cli nical o utc o me of rec urre nt V T E (s ym pt o matic rec urre nt D V T, 
n o n- fatal sy m pt o matic rec urre nt P E, u ns us pecte d P E, a n d fatal -P E ) or maj or blee d d uri n g 
t he 1 2-m o nt h st u d y  peri o d.  T his a nal ysis will be base d o n t he m I T T A nal ysis S et usi n g 
t he sa me pr o p orti o nal hazar d m o del as f or t he pri mar y o utc o me .
1 1. 4. 3.  
Sec o n d ar y Effic ac y O utc o me A n al yses
S u m mar y  statistics will be pr o vi de d f or f oll o wi n g efficac y o utc o mes :

rec urre nt V T E;

e ve nt-free s ur vi val, t he pr o p orti o n of s u bjects o ver ti me free of rec urre nt 
V T E, maj or blee di n g e ve nts, a n d deat h;

V T E -relate d deat h;

rec urre nt D V T;

rec urre nt P E.  
T he i m pact of ca ncer stat us o n t he pri mar y  o utc o me will als o be assesse d.
A descri pti o n of all pla n ne d a nal ys es will be i nc or p orate d i nt o t he S A P .
1 1. 5.  
P h ar m ac o k i netic A n al yses
N ot a p plica ble .
1 1. 6.  
S afet y A n al yses
All safet y a nal ys es will be perf or me d o n t he Safet y  A nal ysis Set.
1 1. 6. 1.  
A n al ysis of t he Pri m ar y S afet y O utc o me
T he pri mar y  a nalys is of t he pri mar y safety o utc o me is base d o n a n “ O n -T reat me nt” 
a p pr oac h.  T he “ o n-treat me nt” maj or blee di n g e ve nts will be c o m pare d bet wee n 
treat me nt gr o u ps f or s u peri orit y ( α = 0. 0 5, t w o-si de d) f or s u bjects i n t he Safet y P o p ulati o n, 
usi n g t he c o u nti n g pr ocess a p pr oac h of t he C o x pr o p orti o nal hazar ds re gressi o n m o del 
i ncl u di n g treat me nt gr o u p, a n d t he stratificati o n fact ors as c o variates.  H o we ver, s u bjects 
will be ce ns ore d 3 d a y s after t he da y of per ma ne nt st u d y me dicati o n disc o nti n uati o n.
T o c o ntr ol st u d y -wise t y pe I err or, t he testi n g f or n o n -i nferi ority a n d s u peri orit y  will 
f oll o w t he pla n as descri be d i n Fi g ure 1 1. 1 .  All tests will be t w o -si de d.




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1 1. 6. 4. 
A d verse E ve nt A n al yses
A d verse e ve nts will be c o de d acc or di n g t o t he Me dical Dicti o nar y  f or Re g ulat or y 
Acti vities ( Me d D R A).
A n y  A E t hat occ urs d uri n g t he st u d y is a st u d y A E.  Treat me nt-e mer ge nt a d verse e ve nts 
( T E A Es) are defi ne d as a n e ve nt t hat e mer ges d uri n g treat me nt ha vi n g bee n a bse nt 
pre -treat me nt, or w orse ns relati ve t o t he pre-treat me nt state.  T he i nci de nce of T E A Es 
will be prese nte d f or t he Safet y  A nalys is Set b y treat me nt gr ou p, b y  relati o ns hi p t o t he 
st u d y dr u g, a n d by s e verit y.  Fre q ue nt T E A Es (re p orte d b y at least 5 % of s u bjects i n a n y 
treat me nt gr o u p) will be s u m marize d b y treat me nt gr o u p.  A d verse e ve nts t hat start or 
w orse n after t he t hir d da y f oll o wi n g t he cale n dar date of a n y “last d ose” a n d bef ore t he 
date of t he ne xt “first d ose” are defi ne d as p ost -treat me nt A Es.  Beca use a s u bject ca n 
ha ve st u d y dr u g i nterr u pti o ns, it will be p ossi ble t o ha ve a p ost -treat me nt A E t hat occ urs 
at a n earlier cale n dar date t ha n a T E A E.
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 disc o nti n uati o n of 
st u d y dr u g will be s u m marize d b y  treat me nt gr o u p.  All A Es 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 1. 6. 5.  
Cli nic a l 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 at eac h sc he d ule d visit 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 Safet y A nal ys is Set b y treat me nt gr o u p.  S hift ta bles (l o w, 
n or mal, a n d hi g h) will be pr o vi de d f or eac h tre at me nt gr o u p f or selecte d cli nical
la b orat or y para meters.  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 cli nical 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 me nt gr o u p f or selecte d cli nical la b orat or y p ara meters.  All a b n or mal cli nical
la b orat or y val ues will be prese nte d i n a listi n g.  
1 1. 6. 6.  
Vit al Si g n 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 Safety A nal ys is Set b y treat me nt gr o u p.  T he n u m ber a n d perce nta ges of s u bjects 
wit h a b n or mal vital si g ns w hile o n st u d y  dr u g will be s u m marize d b y treat me nt gr o u p.
1 1. 6. 7.   
P h ysic al Fi n di n g A n al yses
A b n or malities i n p h y sical e xa mi nati o ns b y b o d y s yste m will be liste d.
1 1. 7.  
Ot her A n al yses
1 1. 8.  
I nteri m A n al yses
N o f or mal i nteri m a n al ys is is pla n ne d.  Ris k-be nefit will be e val uate d b y t he D M C, 
w hic h will gi ve rec o m me n dati o ns o n a re g ular basis t o t he E xec uti ve C o m mittee.  Access 
t o i nteri m ta b ular ris k-be nefit data will be restricte d.  T he pr oce d ures of t he D M C will be 
descri be d i n i ts c harter.




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1 2.  
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, 
IE C /IR B re vie w a n d re g ulat or y i ns pecti o ns b y pr o vi di n g direct access t o s o urce 
data/ d oc u me nts.  Direct access i ncl u des per miss i o n t o e xa mi ne, a nal yze, verif y, a n d 
re pr o d uce a ny rec or ds a n d re p orts t hat are i m p orta nt t o t he e val uati o n of a cli nical st u d y .
T his st u d y  will utilize Q ui ntiles Data -dri ve n Trial E xec uti o n ( D T E), w hic h is Q ui ntiles 
m o del f or ris k -base d m o nit ori n g. 
Q ui nt iles’ D T E a n d Daiic hi Sa n k yo will be gi n wit h a ris k assess me nt t o e val uate t he 
scie ntific a n d o perati o nal ris ks of t he st u d y. D uri n g t his ris k assess me nt ke y  data p oi nts 
f or t he st u dy will be i de ntifie d a n d t he o pti m u m met h o d f or m o nit ori n g (e g, re m ote, 
o n- site, a n d/ or ce ntralize d m o nit ori n g pr ocesses) eac h ke y data p oi nt will be deter mi ne d.  
Ke y  data p oi nts are data ite ms t hat are critical t o st u d y a nalys is, i n dicate if t he o bjecti ves 
of t he st u d y  ha ve bee n met, s u p p ort patie nt safety,  a n d/ or are dee me d as a pri orit y f or 
m o nit ori n g .
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns
T he Q ui ntiles m o nit or a n d re g ulat or y  a ut h ority 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 he p ur p ose of i ns pecti n g t he facilities 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 dy (e g, eC R F s, 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 c o n d ucti n g b ot h o nsite a n d re m ote m o nit ori n g visits 
t hr o u g h o ut t he st u dy 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 C H 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 fre q ue nc y  of m o nit ori n g visits will be de pe n de nt o n t he 
acti vities at t he site. At a mi ni m u m t he m o nit or will visit acti ve sites o n a n a n n ual ba sis. 
T he m o nit or is res p o nsi ble f or i ns pecti n g t he eC R F s 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 is res p o nsi ble f or i ns pecti n g t he eC 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 a ccess 
t o s u bject me dical rec or ds a n d ot her st u dy- relate d rec or ds nee de d t o verif y t he e ntries o n 
t he eC R F s.
Tra nscri pti o n -Base d s o urce data verificati o n ( S D V) is a strate gic m o nit ori n g tas k t hat 
will be use d t o detect tra nscri pti o n err ors bet wee n t he s o urc e d oc u me nts a n d t he e C R F. 
S D V will be perf or me d o n 1 0 0 % of data f or a sa m ple of e nr olle d s u bjects at eac h site. 
T he sa m ple size ma y be i ncrease d w here iss ues are i de ntifie d. 
S o urce data r e vie w ( S D R) is a n o n- site m o nit ori n g pr ocess i n w hic h s o urce 
d oc u me n tati o n is re vie we d t o e ns ure t hat t he site’s pr ocess f or d oc u me nti n g s o urce n otes 
is a p pr o priate a n d t hat t he site is a d heri n g t o t he re q uire me nts of t he pr ot oc ol. T he S D R 
will be perf or me d o n t he sa me s u bjects as S D V. T he S D R ma y  be perf or me d o n 
a d diti onal s u bjects w here iss ues are i de ntifie d .


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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 perate 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.
M o nit ori n g tri g gers c o nsisti n g of esse ntial o perati o nal data ele me nts will be use d t o 
assess site perf or ma nce, data q ualit y, a n d patie nt safet y. M o nit ori n g tri g gers ma y  
i n de pe n de ntly tri g ger a site c o ntact or m o nit ori n g visit.
I n acc or da nce wit h I C 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 by 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, I C H G C P, a n d 
a p plicable re g ulat or y  re q uire me nts.
1 2. 2.  
D at a C ollecti o n
T he e C R F c o m pleti o n a n d q uer y res ol uti o n s h o ul d be ke pt c urre nt t o e na ble 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 dy a n d t o e na ble re vie w of 
t he data by Cli nical Data Ma na ge me n t.
1 2. 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 de ntifier as defi ne d b y 
t he s p o ns or.
T o e ns ure t he q ualit y  of cli nical data acr oss all s u bjects a n d sites, t w o le vels of re vie w 
will be perf or me d :
T he first le vel re view will c o m prise of tra diti o nal data ma na ge me nt re vie w. T he sec o n d 
le vel re vie w is a ma n ual c hec k f or cli nical c o n gr ue nc y of t he data.
B ot h t he first a n d sec o n d le vels of t he 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 p ecificati o ns a gree d b y S p o ns or a n d C R O.  Data 
will be vette d b ot h electr o nicall y a n d ma n uall y;  e C R Fs data will be electr o nicall y vette d 
b y  pr o gra m me d data r ules wit hi n t he Electr o nic Data Ca pt ure ( E D C ).  Q ueries ge nerate d 
b y  r ules a n d raise d b y re vie wers will be ge nerate d a n d res ol ve d wit hi n t he E D C 
a p plicati o n.  D uri n g t hese re vie ws, 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.  T o res ol ve a n y  q uesti o ns arisi n g fr o m t he
Cli nical/ Data Ma na ge me nt re vie w pr ocess, e C R Fs q ueries will be raise d a n d res ol ve d 
wit hi n t he E D C a p plicati o n . 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la borat ories will be rec o ncile d t o t he 
cli nical data base.
Seri o us A E s i n t he cli nical data base will be rec o ncile d wit h t he safety data b ase.
All A d verse E ve nts a n d me dical hist or y e ntries will be c o de d usi n g Me d D R A. 
C o nc o mita nt me dicati o ns, w he n necessar y , will be c o de d usi n g t he W orl d Healt h 
Or ga nizati o n Dr u g Refere nce ( W H O D R U G) List .  


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1 2. 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 wil l mai ntai n a Si g nat ure List of a p pr o priately 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 pers o ns a ut h orize d t o ma ke e ntries a n d/ or 
c orrecti o ns o n eC R F s 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, d ata, a n d rec or ds fr o m w hic h t he s u bject’s 
eC 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 ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s ys te 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 t he 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 c o m plete d e C R F s, i nf or me d c o nse nts, a n d s u p p orti n g 
c o pies of s o urce d oc u me ntati o n (if ke pt).

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, In vesti gat or’s 
Br oc h ure, c o pies of re le 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 t he S p o ns or.

Rec or ds relate d t o t he I n vesti gati o nal Pr o d uct(s) 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 rec o nciliati o n a n d a p plica 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 eC R F s m ust be 
mai ntai ne d a n d be rea dil y  a vaila ble.
1 2. 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, dat a c orrecti o n f or ms, 
eC 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 RB/ E C 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 nf or me d c o nse nt f or ms, 
I n vesti gat or’s A gree me nt, cli nical s u p plies recei pts, distri b uti o n a nd 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 orts a n d rec or ds neces sar 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 site 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.


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1 3.  
FI N A N CI N G A N D I N S U R A N C E
1 3. 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 gat 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 Q ui ntiles. 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 3. 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 by t he parties.


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1 4.  
P U B LI C A TI O N P O LI C Y
A 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 1 year after t he st u d y has e n de d, w hic he ver 
occ urs first.  T heref ore, t he site will ha ve t he o p p ort u nit y t o p u blis h t he res ults of t he 
st u d y, pr o vi de d t hat Daiic hi Sa n k yo 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 site’s pr o p ose d p u blicati o n pri or t o its bei n g s u b mitte d f or p u blicati o n wit h t he pri or 
a d vice of D aiic hi S a n k y o Le gal Affairs (i ntellect ual pr o pert y c o u ncil) a n d wit h pr o p er 
re gar d t o t he pr otecti o n of s u bjects’ i de ntities.


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1 5.  
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 5. 1.  
Pr ot oc ol A me n d me nts
A n y  a me n d me nts t o t he st u d y pr ot oc ol t hat see m t o be a p pr o priate as t he st u d y 
pr o gresses will be c o m m u nicate d t o t he In vesti gat or b y  t he S p o ns or.  All pr ot oc ol 
a me n d me nts will u n der g o t he sa me re vie w a n d a p pr o val pr ocess as t he ori gi nal pr ot oc ol.  
A pr ot oc ol a me n d me nt ma y  be i m ple me nte d after it has bee n a p pr o ve d b y t he IR B/ E C, 
u nless i m me diate i m ple me ntati o n of t he c ha n ge is necessar y  f or s u bject safety.  I n t his 
case, t he sit uati o n m ust be d oc u me nte d a n d re p orte d t o t he I R B/ E C wit hi n 5 w or ki n g 
da y s.  T he Sp o ns or will e ns ure t he ti mel y s u b missi o n of a me n d me nts t o re g ulat or y 
a ut h orities.
1 5. 2.  
A d dress List
1 5. 2. 1.  
S p o ns or
Daiic hi Sa n k y o P har ma De vel o p me nt
3 9 9 T h or nall Street
E dis o n, NJ 0 8 8 3 7
1 5. 2. 2.  
C R O
Q ui ntiles, I nc.
4 8 2 0 E m per or Bl v d
D ur ha m, N C 2 7 7 0 3
1 5. 2. 3.  
Ac a de mic Rese arc h Or g a niz ati o n ( A R O )
I T R E A S
W g -Plei n 1 8 8
A mster da m 1 0 5 4 S C
T he Net herla n ds


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1 6.  
R E F E R E N C E S
                                                
1 L y ma n G H, K h ora na A A, K u derer N M, et al. Ve n o us t hr o m b oe m b olis m pr o p h yla xis a n d treat me nt i n 
patie nts wit h ca ncer. A mer ica n S ociet y of Cli nical O nc ol o g y Cli nical Practice G ui deli ne U p date. J Cli n 
O nc ol 2 0 1 3; 3 1( 1 7): 2 1 8 9 -2 0 4.
2 Kear o n C, A kl E A, C o mer ota AJ, et al. A ntit hr o m b otic t hera p y f or V T E disease: A ntit hr o m b otic T hera p y 
a n d Pre ve nti o n of T hr o m b osis, 9 t h e d: A merica n Colle ge of C hest P h ysicia ns E vi de nce -Base d Cli nical 
Practice G ui deli nes. C hest 2 0 1 2; 1 4 1( 2 S u p pl):e 4 1 9 S -4 9 6 S.
3 Ma n dalà M, Fala n ga A, R oila F. Ma na ge me nt of ve n o us t hr o m b oe m b olis m ( V T E) i n ca ncer patie nts: 
E S M O Cli nical Practice G ui deli nes . A n n O nc ol 2 0 1 1; 2 2 S u p pl 6: vi 8 5 -9 2.
4 Far ge D, De b o ur dea u P, Bec kers M, et al. I nter nati o nal cli nical practice g ui deli nes f or t he treat me nt a n d 
pr o p h yla xis of ve n o us t hr o m b oe m b olis m i n patie nts wit h ca ncer. J T hr o m b Hae m ost 2 0 1 3; 1 1( 1): 5 6 -7 0.
5 B ü ller H R, Déc o us us H, Gr oss o M A , et al. E d o xa ba n vers us warfari 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 5.
6 Ras k o b G, B uller H, A n gc hais u ksiri P , et al. E d o xa ba n f or l o n g-ter m treat me nt of ve n o us 
t hr o m b oe m b olis m i n ca ncer patie nts. 2 01 3; oral a bstract at 5 5 t h A merica n S ociet y of He mat ol o g y A n n ual 
Meeti n g a n d E x p ositi o n.
7 E d o xa ba n I n vesti gat or’s Br oc h ure, v 1 4, 3 0 J u n 2 0 1 4.
8 H olster I L, Val k h off V E, K ui pers EJ, et al. Ne w oral a ntic oa g ula nts i ncrease ris k f or gastr oi ntesti nal 
blee di n g: a s yste matic re vie w a n d meta -a nal ysis. Ga str oe nter ol o g y 2 0 1 3; 1 4 5( 1): 1 0 5-1 2.
9 K h ora na A A, Fra ncis W C, C ula k o va E, et al . T hr o m b oe m b olis m is a lea di n g ca use of deat h i n ca ncer 
patie nts recei vi n g o ut patie nt c he m ot hera p y. J T hr o m Hae m ost 2 0 0 7; 5( 3): 6 3 2-4.
1 0 T i m p J F, Brae k ka n S K, Verstee g H H, et al. E pi de mi ol o g y of ca ncer-ass ociate d ve n o us t hr o m b osis. 
Bl o o d 2 0 1 3; 1 2 2( 1 0): 1 7 1 2 -2 3.
1 1 L y ma n G H, Ec kert L, Wa n g Y, et al. Ve n o us t hr o m b oe m b olis m ris k i n patie nts wit h ca ncer recei vi n g 
c he m ot hera p y; a real -w o rl d a nal ysis. O nc ol o gist 2 0 1 3; 1 8( 1 2): 1 3 2 1-2 9.
1 2 Ka k kar A K. L o n g -ter m f oll o w-u p of ca ncer patie nts. 2 0 1 4.
1 3 Far ge D, M o nreal M. Fatal e ve nts i n ca ncer patie nts recei vi n g a ntic oa g ula nt t hera p y f or ve n o us 
t hr o m b oe m b olis m. 2 0 1 4.
1 4 Pra n d o ni P, Le nsi n g A W, Picci oli A, et al . Rec urre nt ve n o us t hr o m b oe m b olis m a n d blee di n g 
c o m plicati o ns d uri n g a ntic oa g ula nt treat me nt i n patie nts wit h ca ncer a n d ve n o us t hr o m b osis. Bl o o d 
2 0 0 2 ; 1 0 0( 1 0): 3 4 8 4-8 8.
1 5 Sc h ul ma n S, Eri k ks o n H, G ol d ha ber H Z, et al.  I nfl ue nce of acti ve ca ncer o n t he effica c y a n d safet y of 
da bi gatra n vers us warfari n f or t he treat me nt of ac ute ve n o us t hr o m b oe m b olis m:  a p o ole d a nal ysis fr o m 
R E -C o ver a n d R E -C o ver II 2 0 1 3.
1 6 Di Nisi o M, Ferra nte N, De T ursi M, et al.  I nci de ntal ve n o us t hr o m b oe m b olis m i n a m b ulat or y ca ncer 
patie nts recei vi n g c he m ot hera p y. T hr o m b Hae m ost 2 0 1 0; 1 0 4( 5): 1 0 4 9 -5 4.
1 7 De ntali F, A ge n o W, Becatti ni C, et al.  Pre vale nce a n d cli nical hist or y of i nci de ntal, as y m pt o matic 
p ul m o nar y e m b olis m: a meta -a nal ysis.  T hr o m b Res 2 0 1 0; 1 2 5( 6): 5 1 8 -2 2.
1 8 La u w  M N, va n D o or maal F F, Mi d dle d or p S, et al. Ca ncer a n d ve n o ust hr o m b osis: c urre nt 
c o m pre he nsi o ns a n d f ut ure pers pecti ves. Se mi n T hr o m b He m ost 2 0 1 3 ; 3 9( 5): 5 0 7 -1 4.
1 9 O’ C o n nell C L, Raza vi P A, Lie b ma n H A. S y m pt o ms a d versel y i m pact s ur vi val a m o n g patie nts wit h 
ca ncer a n d u ns us pecte d p ul m o nar y e m b olis m. J Cli n O nc ol 2 0 1 1; 2 9( 3 1): 4 2 0 8 -9.
2 0 C o n n oll y G C, Me na pace I, Safa dj o u S, et al. Pre vale nce a n d cli nical si g nifica nce of i nci de ntal a n d 
cli nicall y s us pecte d ve n o us t hr o m b oe m b olis m i n l u n g ca ncer patie nts. Cli n L u n g Ca ncer 2 0 1 3; 1 4( 6): 
7 1 3 -8.
2 1 Sa h ut D’Izar n M, Ca u m o nt P A, Pla n q uette B, et al. Ris k fact ors a n d cli nical o utc o me of u ns us pecte d 
p ul m o nar y e m b olis m i n ca ncer patie nts: a case -c o ntr ol st u d y. J T hr o m b Hae m ost 2 0 1 2; 1 0( 1 0): 2 0 3 2 -8.
2 2 S hi na gare A B, O kaji ma Y, O x nar d G R et al . U ns us pecte d p ul m o nar y e m b olis m i n l u n g ca ncer patie nts: 
c o m paris o n of cli nical c haracteristics a n d o utc o me wit h s us pecte d p ul m o nar y e m b olis m. L u n g Ca ncer 
2 0 1 2; 7 8( 2): 1 6 1 -6.


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2 3 Lee A Y, Le vi ne M N, Ba ker RI, et al. L o w -m olec ular wei g ht he pari n vers us a c o u ma ri n f or t he 
pre ve nti o n of rec urre nt ve n o us t hr o m b oe m b olis m i n patie nts wit h ca ncer . N E n gl J Me d; 
2 0 0 3; 3 4 9( 2): 1 4 6 -5 3.
2 4 Pfizer L. Fra g mi n e xte n de d treat me nt i n O nc ol o g y; S u m mar y of Pr o d uct C haracteristics ( S P C). 
2 0 1 1/ 0 9/ 3 0 [cite d] . A vaila ble fr o m: htt p:// w w w. me dici nes. or g. u k/e mc/searc h .
2 5A P hase 3, Ra n d o mize d, D o u ble -Bli n d, D o u ble -D u m m y, Parallel -Gr o u p, M ulti -Ce nter, M ulti -Nati o nal 
St u d y f or t he E val uati o n of Efficac y a n d Safet y of ( L M W) He pari n/ E d o xa ba n vers us ( L M W) 
He pari n/ Warfari n i n S u bjects wit h S y m pt o m atic Dee p -Vei n T hr o m b osis a n d/ or P ul m o nar y E m b olis m : 
Daiic hi Sa n k y o Cli nical St u d y Re p ort 1 9 Ma y 2 0 1 4; St u d y N u m ber D U 1 7 6 B- D- U 3 0 5 ( H o k usai).


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1 7.  
A P P E N DI C E S


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1 7. 1.  
A d diti o n al I nf or m ati o n o n I n vesti g ati o n al Pr o d ucts
1 7. 1. 1.  
Fr a g mi n P ac k a ge I nsert
T he Fra g mi n ( dalte pari n) pac ka ge i nsert ca n be accesse d at t he f oll o wi n g li n k: 
htt p:// w w w. me dici nes. or g. u k/e mc , t he n t ypi n g Fra g mi n i n t he searc h fiel d.
1 7. 2.  
Tr a nsiti o n fr o m E d o x a b a n t o Ot her a ntic o a g ul a nts
1 7. 2. 1.  
E d o x a b a n t o V K A
Disc o nti n ue e d o xa ba n a n d a d mi nister a pare nteral a ntic oa g ula nt a n d V K A at t he ti me of 
t he ne xt sc he d ule d e d o xa ba n d ose.  O nce a sta ble I N R ≥ 2. 0 is ac hie ve d, t he pare nteral 
a ntic oa g ula nt m ust be disc o nti n ue d a n d t he V K A c o nti n ue d.
1 7. 2. 2.  
E d o x a b a n t o n o n -V K A Or al A ntic o a g ul a nts
Disc o nti n ue e d o xa ba n a n d start t he n o n- V K A a ntic oa g ula nt at t he ti me of t he ne xt 
sc he d ule d d ose of e d o xa ba n.
1 7. 2. 3.  
E d o x a b a n t o P are nter al A ntic o a g ul a nts
Disc o nti n ue e d o xa ba n a n d start t he pare nteral a ntic oa g ula nt at t he ti me of t he ne xt 
sc he d ule d d ose of e d o xa ba n.
1 7. 3.  
P r o hi bite d C o nc o mit a nt Me dic ati o ns
S pecificall y e xcl u de d c o nc o mita nt me dicati o ns a n d ca uti o ns re gar di n g ot her c o nc o mita nt 
me dicati o ns are pr o vi de d bel o w .  T he list i n t his a p pe n di x reflects e xcl usi o nar y 
c o nc o mita nt me dicati o ns at t he be gi n ni n g of t he st u d y.  If t here are c ha n ges t o t his list 
d uri n g t he st u d y, t he c ha n ges will be pr o vi de d as a n u p date t o t his a p pe n di x, b ut will n ot 
be c o nsi dere d a pr ot oc ol a me n d me nt.
1 7. 3. 1.  
A nti pl atelet Dr u gs
D ual a nti platelet t hera p y (a ny 2 a nti platelet a ge nts i ncl u di n g as piri n pl u s a n y ot her oral or 
I V a nti platelet dr u g) is pr o hi bite d w hile o n st u d y dr u g.  If a cli nical i n dicati o n f or d ual 
a nti platelet t hera p y arises after ra n d o mizati o n (e g, place me nt of a n i ntrac or o nar y  ste nt), 
st u d y dr u g s h o ul d be i nterr u pte d a n d use of o pe n-la bel L M W H/ V K A is per mitte d at t he 
p h y sicia n’s discreti o n.
Use of a n y a nti platelet me dicati o n, i ncl u di n g as piri n, as si n gle a ge nt a nti platelet t hera p y 
is all o we d w hile o n st u d y dr u g.
It is str o n gly e nc o ura ge d t o restrict t he d ose of as piri n (if i n dicate d) t o ≤1 0 0 m g dail y, 
alt h o u g h hi g her d oses are per mitte d f or a str o n g cli nical i n dicati o n (e g, de vel o p me nt of 
a n ac ute M I).
E xa m ples of n o n -as piri n oral a nti platelet a ge nts i ncl u de t he f oll o wi n g: 

T hie n o p y ri di nes: cl o pi d o grel ( Pla vi x ® ), ticl o pi di ne ( Ticli d® ), pras u grel 
( Effie nt™) 


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 5

Di p y ri da m ole: Persa nti ne® , A g gre n o x®

Pe nt o xif y lli ne ( Tre ntal® ) 

S ulfi n p y raz o ne ( A nt ura ne® ) 

Tica grel or ( Brili nta ® ) 

Cil ostaz ol ( Pletal ® ) 
I V a nti platelet a ge nts i ncl u de t he f oll o wi n g: 

Gl y c o pr otei n II b/IIIa i n hi bit ors: A bci xi ma b ( Re o Pr o ™), E ptifi bati de 
(I nte grili n® ), Tir ofi ba n ( A g grastat® ) 

P G Y 1 2 I n hi bit or: Ca n grel or 

De xtra n 
1 7. 3. 2.  
Or al A ntic o a g ul a nts Ot her T h a n St u d y Dr u g
Oral a ntic oa g ula nts i ncl u di n g vita mi n K a nta g o nists (e g, warfari n), Fact or IIa i n hi bit ors 
(e g, da bi gatra n), a n d F Xa i n hibit ors (e g, ri var o xa ba n, a pi xa ba n) after ra n d o mizati o n are 
pr o hi bite d ( u nless use d t o bri d ge a te m p orar y st u d y dr u g i nterr u pti o n). T he o nl y all o we d 
oral a ntit hr o m b otics are t he st u d y  dr u gs.
1 7. 3. 3.   
P are nter al A ntic o a g ul a nts
Pare nteral a ntic oa g ula nts s uc h as he pari n, L M W Hs , direct t hr o m bi n i n hi bit ors, a n d F Xa 
i n hi bit ors are pr o hi bite d e xce pt as s pecificall y o utli ne d i n t he pr ot oc ol. F or i nsta nce, 
L M W Hs are all o we d as lea d -i n t hera p y pri or t o e d o xa ba n a d mi nistrati o n.
E xa m ples of 
pr o hi bite d pare nteral a ntic oa g ula nt me dicati o ns , w he n use d c o ntrar y t o pr ot oc ol 
s pecificati o ns, i ncl u de t he f oll o wi n g: 

L o w m olec ular wei g ht he pari ns: dalte pari n ( Fra g mi n ® ), ti nza pari n (I n n o he p® , 
L o gi pari n ® ), re vi pari n ( Cli vari n® ), na dr o pari n ( Fra xi pari ne® ), ar de pari n 
( N or mifl o® ), cert o pari n ( Sa n d o pari n® ), par na pari n ( Fl u x u m® ) 

Direct t hr o m bi n i n hi bit ors: bi valir u di n ( A n gi o ma x ® ), ar gatr o ba n ( Ac o va® ), 
desir u di n (I pra vas k ® ), le pir u di n ( Refl u da n® )

F Xa i n hi bit ors: f o n da pari n u x ( Ari xtra ® )
1 7. 3. 4.  
I ntr a ve n o us Fi bri n ol ytics
E xa m ples of fi bri n ol y tics i ncl u de t he f oll o wi n g:

Tiss ue plas mi n o ge n acti vat or ( alte plase, Acti vase ® ) 

T N K (te necte plase, T N Kase ® ) 

r P A (rete plase, Reta vase® ) 

Stre pt o ki nase ( Stre ptase ® ) 

A nistre plase ( E mi nase ® )


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 6
If a s u bject re q uires treat me nt wit h a fi bri n ol ytic a ge nt, t he n st u dy dr u g m us t be 
i nterr u pte d w hile t he s u bject is ta ki n g t he fi bri n ol ytic dr u g a n d at least 2 4 h o urs after 
a d mi nistrati o n of a fi bri n ol ytic a ge nt.
1 7. 3. 5. 
N S AI Ds ( E xcl u di n g As piri n) 
W hile o n st u d y  dr u g, N S AI Ds ca n n ot be ta ke n f or 4 da y s per wee k.  Less fre q ue nt use 
of N S AI Ds is per mitte d w hile o n st u d y dr u g.  H o we ver, t he In vesti gat or s h o ul d wei g h t he 
be nefit/ris k of N S AI D use i n c o m bi nati o n wit h a n oral a ntic oa g ula nt f or t he i n di vi d ual 
s u bject.  E xa m ples of N S AI Ds i ncl u de t he f oll o wi n g:
Acecl ofe nac
Ace metaci n
Alcl ofi nac
A mt ol meti n
A xa pr o paz o ne
Be n o xa pr ofe n
Br o mfe nac
B ufe xa mac
Car pr ofe n
Cl o ni xi n
De xi b u pr ofe n
De x ket o pr ofe n
Dicl ofe nac
Dicl ofe nac/ H yal ur o nic Aci d  
Difl u nisal
Di p yr o ne
Dr o xica m
Et o d olac
Et ofe na mate
Fel bi nac
Fel b ufe n
Fe n o pr ofe n
Fe ntiazac
Fl octafe ni ne
Fl ufe na mic Aci d
Fl ur bi pr ofe n or 
fl uri b u pr ofe n
H y dr oc o d o ne/I b u pr ofe n
I b u pr ofe n
I n d o met haci n
I n d o pr ofe n
Is o xica m
Ket o pr ofe n
Ket or olac
La ns o praz ole/ Na pr o xe n  
L or n o xica m
L o x o pr ofe n
Mecl ofe na mate
Mefa na mic Aci d
Mel o xica m
M or nifl u mate
Na b u met o ne
Na pr o xe n
Nifl u mic Aci d
Ni mes uli de
O xa pr ozi n
O x yc o d o ne/I b u pr ofe n  
P he n yl b utaz o ne
Pi ket o pr ofe n
Piraz olac
Pir o xica m
Pir o pr ofe n
Pr o p he naz o ne
Pr o q uaz o ne
S uli n dac
S u pr ofe n
Te ni da p
Te n o xica m
Tia pr ofe nac A ci d
T ol meti n
Z o me pirac
1 7. 3. 6.    
C O X- 2 I n hi bit ors 
W hile o n st u d y  dr u g, C O X-2 i n hi bit ors ca n n ot be ta ke n f or 4 da y s per wee k.  Less 
fre q ue nt use of C O X-2 i n hi bit ors is per mitte d w hil e o n st u d y dr u g.  H o we ver, t he 
In vesti gat or s h o ul d wei g h t he be nefit/ris k of C O X -2 i n hi bit or use i n c o m bi nati o n wit h a n 
oral a ntic oa g ula nt f or t he i n di vi d ual s u bject.  E xa m ples of C O X - 2 i n hi bit ors i ncl u de t he 
f oll o wi n g:


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 7
Celec o xi b
Parec o xi b
Artil o g
D y nastat
Celec o x
R ofec o xi b
Cele bra
Ar ofe x
Cele bre x
Ce o x x
S ole xa
C o x xil
Et oric o xi b
D olc o x x
Arc o xia
Mira x x
L u mirac o xi b
Vi o x x
L u mirela x
Vi o x xalt
L u mrela x ( F M)
Val dec o xi b
L u mire m
Be xtra
1 7. 3. 7.  
P- g p I n hi bit ors
C o nc o mita nt use of pr otease i n hi bit ors (s uc h as rit o na vir, nelfi na vir, i n di na vir, a n d
sa q ui na vir) a ntici pate d t o c o nti n ue d uri n g t he c o urse of t he st u dy is pr o hi bite d.  
C o nc o mita nt use of c ertai n macr oli de a n ti bi otics (er yt hr o m yci n, azit hr o m yci n , a n d 
clarit hr o m yci n) a n d az ole a ntif u n gals ( ket oc o naz ole a n d itrac o naz ole) are als o pr o hi bite d 
at t he ti me of ra n d o mizati o n, b ut s u bse q ue nt use of t hese a ge nts is per mitte d after 
ra n d o mizati o n wit h a p pr o priate d ose re ducti o n of e d o xa ba n t o 3 0 m g Q D .  O nce 
treat me nt wit h t hese P-g p i n hi bit ors is c o m plete, t he f ull 6 0 m g e d o xa ba n d ose s h o ul d be 
res u me d.  
T he f oll o wi n g c o m m o n P -g p i n hi bit ors t hat mi g ht be a d mi nistere d t o st u d y s u bjects 
re q uire a re d ucti o n i n t he e d o xa ba n d ose t o 3 0 m g Q D:

T y r osi ne ki nase i n hi bit ors: i mati ni b, nil oti ni b, la pati ni b, s u niti ni b, cri oziti ni b,
va n deta ni b

H or m o nal a ge nts: ta m o xife n, e nzal uta mi de, a birater o ne,

I m m u n o-m o d ulati n g a ge nts: c y cl os p ori ne, trac oli m us
O nce treat me nt wit h t hese P- g p i n hi bi t ors is c o m plete, t he f ull 6 0 m g e d o xa ba n d ose 
s h o ul d be res u me d.
N ote :  Ot her a ge nts i n t hese classes ma y be a d mi nistere d c o nc urre ntly wit h o ut re d uci n g 
t he e d o xa ba n d ose.


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 8
1 7. 4.  
Prec a uti o ns a n d D ose M o dific ati o ns f or D alte p ari n 
M o nt h 1 – D alte p ari n D oses b y Wei g ht
B o d y Wei g ht 
( k g)
Sc he d ule d D alte p ari n 
D ose (I U)
≤ 4 6
7 5 0 0
4 7 t o 5 6
1 0 0 0 0
5 7 t o 6 8
1 2 5 0 0
6 9 t o 8 2
1 5 0 0 0
≥8 3
1 8 0 0 0
M o nt h s 2- 1 2 – D alte p ari n D oses b y Wei g ht
B o d y Wei g ht 
( k g)
Sc he d ule d D alte p ari n 
D ose (I U)
≤ 5 6
7 5 0 0
5 7 t o 6 8
1 0 0 0 0
6 9 t o 8 2
1 2 5 0 0
8 3 t o 9 8
1 5 0 0 0
≥9 9
1 8 0 0 0
Prec a uti o ns a n d D ose M o dific ati o ns
M o nt h 1 : 
I n t he case of c he m ot hera p y-i n d uce d t hr o m b oc yt o pe nia, t he dalte pari n d ose s h o ul d be 
a dapte d as f oll o ws: 

I n s u bjects recei vi n g dalte pari n w h o e x perie nce platelet c o u nts bet wee n 
5 0, 0 0 0 a n d 1 0 0, 0 0 0/ m m 3, t he dail y d ose of dalte pari n s h o ul d be re d uce d b y 
2, 5 0 0 I U u ntil t he platelet c o u nt rec o vers t o ≥1 0 0, 0 0 0/ m m 3. 

I n s u bjects recei vi n g dalte pari n w h o e x perie nce platelet c o u nts < 5 0, 0 0 0/ m m 3, 
dalte pari n s h o ul d be disc o nti n ue d u ntil t he pla telet c o u nt rec o vers a b o ve 
5 0, 0 0 0/ m m 3. 


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 9
M o nt hs 2 - 1 2: 
I n t he case of c he m ot hera p y-i n d uce d t hr o m b oc yt o pe nia, t he dalte pari n d ose s h o ul d be 
a dapte d as f oll o ws: 

Wit h platelet c o u nts <
5 0, 0 0 0/ m m 3, dalte pari n d osi n g s h o ul d be i nterr u pte d 
u ntil t he platelet c o u nt rec o vers a b o ve 5 0, 0 0 0/ m m 3. 

F or platelet c o u nts bet wee n 5 0, 0 0 0 a n d 1 0 0, 0 0 0/ m m 3, dalte pari n s h o ul d be 
re d uce d as ill ustrate d i n t he ta ble bel o w i n acc or da nce wit h t he s u bject's 
wei g ht.  O nce t he platelet c o u nt has rec o vere d t o > 1 0 0, 0 0 0/ m m 3, dalte pari n 
sh o ul d be re -i nstit ute d at f ull d ose.
T a ble 1 7. 1: 
D alte p ari n D ose Re d ucti o n f or Pl atelet C o u nts B et wee n 5 0, 0 0 0 a n d 
1 0 0, 0 0 0/ m m 3
B o d y Wei g ht 
( k g)
Sc he d ule d 
D alte p ari n D ose
(I U)
Re d uce d D alte p ari n 
D ose (I U)
≤5 6
7 5 0 0
5 0 0 0
5 7 t o 6 8  
1 0 0 0 0
7 5 0 0
6 9 t o 8 2  
1 2 5 0 0
1 0 0 0 0
8 3 t o 9 8  
1 5 0 0 0
1 2 5 0 0
≥9 9
1 8 0 0 0
1 5 0 0 0
1 7. 5.  
Defi niti o ns of C ar di o v asc ul ar a n d T hr o m b otic E ve nts
1 7. 5. 1.   
S yste mic E m b olic E ve nt ( S E E)
A s y ste mic e m b olic e ve nt is defi ne d as 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 gic e vi de nce of arterial occl usi 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).  Arterial e m b olic e ve nts 
i n v ol vi n g t he C N S (i ncl u di n g t he e ye), c or o nar y, a n d p ul m o nar y arterial circ ulati o n are 
n ot c o nsi dere d S E Es, b ut will be classifie d res pecti vel y  as str o ke/ TI A, my o car dial 
i nfarcti o n, a n d p ul m o nar y e m b olis m.  I n t he prese nce of at her oscler otic peri p heral 
vasc ular disease, dia g n osis of e m b olis m t o t he l o wer e xtre mities re q uires ar teri o gra p hic 
de m o nstrati o n of a br u pt arterial occl usi o ns.
1 7. 5. 2.  
T hr o m b otic E ve nts at Ot her L oc ati o ns
T hese i ncl u de:

Cat heter -ass ociate d t hr o m b osis

Cere bral ve n o us a n d si n us t hr o m b osis

Reti nal vei n occl usi o n

U p per e xtre mit y ve n o us t hr o m b osis


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 9 0

a xillar y, s u bcla vai n a n d brac hial vei n t hr o m b osis

J u g ular vei n t hr o m b osis

S u peri or ca val vei n t hr o m b osis

A b d o mi nal vei n t hr o m b osis

S pla nc h nic vei n t hr o m b osis 

P ortal vei n t hr o m b osis

Mese nteric vei n t hr o m b osis

S ple nic vei n t hr o m b osis

He patic vei n t hr o m b osis

Ge nit o -uri nar y  ve n ous t hr o m b osis

Re nal vei n t hr o m b osis

O varia n vei n t hr o m b osis

Pe nile vei n t hr o m b osis

S u perficial vei n t hr o m b osis of t he l o wer or u p per li m b
1 7. 6.  
E aster n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) Perf or m a nce 
St at us
T hese scales a n d criteria are use d b y d oct ors a n d researc hers t o assess h o w a patie nt's 
disease is pr o gressi n g, assess h o w t he disease affects t he dail y  li vi n g a bilities of t he 
patie nt, a n d deter mi ne a p pr o priate treat me nt a n d pr o g n osis. T he y  are i ncl u de d here f or 
healt h care pr ofessi o nals t o access.
E C O G P E R F O R M A N C E S T A T U S *
Gr a de
E C O G
0  
F ull y acti ve, a ble t o carr y o n all pre -disease perf or ma nce wit h o ut restricti o n
1  
Restricte d i n p h ysicall y stre n u o us acti vit y b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht 
or se de ntar y nat ure, e. g., li g ht h o use w or k, offi ce wor k
2  
A m b ulat or y a n d ca pa ble of all selfcare b ut u na ble t o carr y o ut a n y w or k acti vities. U p a n d 
a b o ut m ore t ha n 5 0 % of wa ki n g h o urs
3  
Ca pa ble of o nl y li mite d selfcare, c o nfi ne d t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs
4  
C o m pletel y disa ble d. Ca n n ot carr y o n a n y selfcare. T otall y c o nfi ne d t o be d or c hair
5  
Dea d
* As p u blis he d i n A m. J. Cli n. O nc ol.: 
O ke n, M. M., Creec h, R. H., T or me y, D. C., H ort o n, J., Da vis, T. E., Mc Fa d de n , E. T., Car b o ne, P. P.: T o xicit y 
A n d Res p o nse Criteria Of T he Easter n C o o p erati ve O nc ol o g y Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 9 1
1 7. 7.  
Sc he d ule of E ve nts
T a ble 1 7. 2: 
Sc he d ule of E ve nts
Tre at m e nt Peri o d
Pre -r a n d o miz ati o n  
D a y 1
R a n d o miz ati o n
D a y 3 1
± 3 d a ys
M o nt h 3
± 7 d a ys
M o nt h 6
± 7 d a ys
M o nt h 9
± 7 d a ys
M o nt h 1 2
± 7 d a ys
E O T g
± 7 d a ys
I nf or me d C o nse nt
X
Dia g n osis of V T E
X
I ncl usi o n/ E xcl usi o n Criteria
X a
De m o gra p hic I nf or mati o n
X
Me dical/ S ur gical Hist or y
X
P h ysical E xa mi nati o n b
X
Vital Si g ns/ Wei g ht
X
X
Ca ncer Stat us/ Sta ge
X
X    
X
Cli nical Assess me nts a n d E C O G 
Perf or ma nce Stat us
X
X    
X    
X    
X    
X    
X
I X R S Ra n d o mizati o n
X
L F T M o nit ori n g c
X
X
X h
Ser u m C reati ni ne/ Cr CL
X
X    
X    
X    
X
He mat ol o g y a n d Platelet C o u nt 
X
X    
X    
X    
X
Arc hi ve Ser u m Sa m ple d
X c
Pri or a n d C o nc o mita nt Me dicati o n
X
X
X    
X    
X    
X    
X    
X
A E Re p orti n g e
X
X    
X    
X    
X    
X    
X
O utc o me E ve nts Re p orti n g e
X
X    
X    
X    
X    
X    
X
Healt hcare Res o urce Utilizati o n
X    
X    
X    
X    
X    
X
St u d y Dr u g D is pe nsi n gf
X
X    
X    
X    
X


Pr ot oc ol D U 1 7 6 b - D-U 3 1 1
Versi o n 3. 0, 2 0 Ja n 2 0 1 6 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 9 2
Tre at m e nt Peri o d
Pre -r a n d o miz ati o n  
D a y 1
R a n d o miz ati o n
D a y 3 1
± 3 d a ys
M o nt h 3
± 7 d a ys
M o nt h 6
± 7 d a ys
M o nt h 9
± 7 d a ys
M o nt h 1 2
± 7 d a ys
E O T g
± 7 d a ys
St u d y Dr u g C o m plia nce
X    
X    
X    
X    
X    
X
C o ntact I X R S f or st u d y dr u g 
assi g n me nt or t o e nter s u bject stat us 
c ha n ges g
X
X    
X    
X    
X
L F T -li ver f u ncti o n test; V T E -ve n o us t hr o m b oe m b olis m; A E -a d verse e ve nt(s); I X R S -I nteracti ve web/ v oice res p o nse s yste m ; Cr C L-creati ni ne cleara nce; 
A L T -ala ni ne tra nsferase; A S T -as partate tra nsferase; E O T -e n d-of -treat me nt; E C O G-Easter n C o o perati ve O nc ol o g y Gr o u p.
a Re vie w i ncl usi o n/e xcl usi o n criteria a n d e ns ure t hat t he s u bject q ualifies wit h re gar d t o t he la b orat or y tests f or e xcl usi o n criteria ( Cr Cl , 3 0 m L/ mi n; 
Platelet c o u nt < 5 0, 0 0 0/ m m 3.
b P h y sical e xa mi nati o n at pre-ra n d o mizati o n ma y be perf or me d b y a n I n vesti gat or or ot her healt hcare pr o vi der desi g nate d b y t he I n vesti gat or.  T he 
p h ysical e xa mi na ti o n i ncl u des vital si g ns (sitti n g bl o o d press ure a n d heart rate), rec or d hei g ht, a n d rec or d b o d y wei g ht.
c A L T/ A S T, t otal bilir u bi n, a n d al kali ne p h os p hatase at ra n d o mizati o n a n d s u bse q ue nt assess me nts .
d O ne ser u m sa m ple will be c ollecte d at ra n d o mizati o n f or arc hi vi n g.
e A E re p orti n g a n d O utc o me E ve nts 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 ; ca pt ure healt hcare res o urce 
utilizati o n data f or p ote ntial rec urre nt V T E a n d blee d e ve nts.
f St u d y dr u g assi g ne d b y t he I X R S will be dis pe nse d as a 3-m o nt h s u p pl y.
g All s u bjects s h o ul d be see n b y q ualifie d me dical pers o n nel f or t he f oll o wi n g pr oce d ures at M o nt h 1 2 or whe ne ver st u d y treat me nt is per ma ne ntl y 
disc o nti n ue d.  S u bjects w h o disc o nti n ue st u d y treat me nt bef ore M o n t h 1 2 will still be f oll o we d u ntil M o nt h 1 2, or u ntil t he gl o bal E O T date, w hic he ver 
c o mes first.
h If t he s u bject is still o n st u d y treat me nt.