Clinical trial NCT02923115
Conditions: Pulmonary Embolism Thrombotic Disease
Keywords: Venous thromboembolism (VTE) Pulmonary embolism (PE) Acute Submassive Pulmonary Embolism
Sponsor: Daiichi Sankyo
Start date: 2016-06-23; Completion date: 2019-08-05
Enrollment: 134 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 1b, double-blind (participants and Investigators), placebo-controlled, randomized, single-ascending dose, multi-center study to assess the safety, efficacy, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040b in participants with acute submassive pulmonary embolism.

Detailed description:

Arms: arm 1: Participants who are randomized to receive DS-1040b as a single, continuous intravenous infusion (initial loading dose 3-6 mg). All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion. arm 2: Participants who are randomized to receive placebo as a single, continuous intravenous infusion. All participants will also receive standard of care anticoagulation enoxaparin therapy during the study drug infusion.
Interventions: intervention 1: DS-1040b intervention 2: Placebo intervention 3: Enoxaparin
Intervention descriptions: intervention 1: Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort) intervention 2: Single, continuous intravenous infusion of 0.9% sodium chloride over 12 to 24 hours intervention 3: Subcutaneous injection 1 mg/kg twice daily

Protocol documents:
Prot_SAP_000.pdf: 
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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 1 B, R A N D O MI Z E D, D O U B L E -B LI N D, 
P L A C E B O -C O N T R O L L E D, M U L TI -C E N T E R, 
SI N G L E A S C E N DI N G D O S E S T U D Y T O A S S E S S 
T H E S A F E T Y, E F FI C A C Y , P H A R M A C O KI N E TI C S, 
A N D P H A R M A C O D Y N A MI C S O F D S -1 0 4 0 B W H E N 
A D D E D T O S T A N D A R D O F C A R E 
A N TI C O A G U L A TI O N T H E R A P Y I N S U B J E C T S 
WI T H A C U T E S U B M A S SI V E P U L M O N A R Y 
E M B O LI S M
D S 1 0 4 0 - B-U 1 0 7
I N D/E u dr a C T N U M B E R: 1 2 8 3 8 0/ 2 0 1 5- 0 0 5 2 1 1- 3 2
V E R SI O N 1. 0 , 2 1 J A N 2 0 1 6
D AII C HI S A N K Y O I N C
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 , U S A
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 I nc.  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 op y  of it or re veal a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her 
t ha n t h ose i n 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 I nc.
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P R O T O C O L S Y N O P SI S
E u dra C T:
2 0 1 5- 0 0 5 2 1 1 - 3 2
I ND N u m ber :
1 2 8 3 8 0
Pr ot oc ol N u m ber:
D S 1 0 4 0 - B-U 1 0 7
I n vesti gati o nal Pr o d uct: 
D S - 10 4 0 b
Acti ve I n gre die nt(s)/I N N: 
D S - 1 0 4 0b
St u d y  Title:
A P hase 1 b, Ra n d o mize d, D o u ble- Bli n d, Place b o -
C o ntr olle d, M ulti -Ce nter, Si n gle Asce n di n g D ose St u d y  t o 
Assess t he Safet y, Efficac y, P har mac o ki netics, a n d 
P har mac o d y na mics of D S -1 0 4 0 b w he n A d de d t o Sta n dar d 
of Care A ntic oa g ulati o n T hera p y i n S u bjects wit h Ac ute 
S u b massi ve P ul m o nar y  E m b olis m
St u d y  P hase:
P hase 1 b/ Pr o of -of C o nce pt
I n dicati o n U n der 
I n vesti gati o n:
P ul m o nar y  E m b olis m (P E )
St u d y  O bjecti ves:
Pri mar y  O bjecti ve:  To assess t he s afet y a n d t olera bilit y of 
asce n di n g d oses of D S -1 0 4 0 b gi ve n as a si n gle 
i ntra ve n o us (I V) i nf usi o n o ver 1 2, 2 4, 4 8 a n d 7 2 h o urs ( h), 
res pecti vely, w he n a d de d t o sta n dar d of care ( S O C) 
a ntic oa g ulati o n t hera py c om pare d t o place b o b y  
e val uati n g t he rate of a dj u dicate d cli nicall y rele va nt 
blee di n g (I nter nati o nal S ociet y of T hr o m b osis a n d 
Hae m ostasis (I S T H) maj or or cli nicall y rele va nt n o n -
maj or ( C R N M) blee di n g ).
Sec o n dar y  O bjecti ves: 
T o assess t he f oll o wi n g efficac y e n d p oi nts as e val uati o n of 
pr o of - of-c o nce pt:
1.
R elati ve red ucti o n ( % re d ucti o n) i n t otal t hr o m b us 
v ol u me fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -
1 0 4 0 b i nf usi o n, assesse d b y  c o m p ute d t o m o gra p hy
a n gi o gra p h y ( C T A) i n se g me ntal or lar ger 
p ul m o nar y  arteries;
2.
P r o p ortio n of s u bjects w h o ac hie ve a ≥ 2 0 % 
greater relati ve re d ucti o n i n t otal t hr o m b us v ol u me
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of 
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D S - 1 0 4 0 b i nf usi o n a n d c o m pare d t o place b o;
3.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % 
greater relati ve re d ucti o n i n t otal t hr o m b us v ol u me 
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -
1 0 4 0 b i nf usi o n a n d c o m pare d t o p lace b o;
4.
Rec urre nce of a dj u dicate d ve n o us 
t hr o m b oe m b olis m [V T E ] ( C o m p osite of rec urre nt 
P E, ne w or rec urre nt dee p vei n t hr o m b osis ( D V T ), 
V T E -relate d deat h; as well as t he i n di vi d ual 
c o m p o ne nts) u p t o h os pital d isc har ge a n d u p t o
Da y  3 0 Visit after d osi n g ;
5.
Deat h, maj or car di o vasc ular e ve nts ( M A C E : 
defi ne d as a c o m p osite of car di o vasc ular deat h or 
n o n- fatal my ocar dial i nfarcti o n, str o ke, or s ys te mic 
e m b olic e ve nts [ S E E]), he m o d y na mic 
dec o m pe nsati o n, treat me nt escalati o n ( defi ne d as 
catec h ola mi ne i nf usi o n, sec o n dar y t hr o m b ol ysis, 
e n d otrac heal i nt u bati o n, car di o p ul m o n ar y 
res uscitati o n, or e mer ge nc y s ur gical e m b olect o m y 
or t hr o m b us fra g me ntati o n b y  cat heter) u p t o
h os pital d isc har ge a n d u p t o Da y  3 0 Visit after 
d osi n g ;
6.
O verall safet y e val uati o n ( seri o us a d verse e ve nts 
[S A Es ], treat me nt-e mer ge nt a d verse e ve nts 
[T E A Es ], cli nical la b orat or y para meters) ;
7.
P har mac o ki netics ( P K) of D S -1 0 4 0 b i n s u bjects 
wit h P E.
8.
Assess t he p har mac o d y n a mic ( P D) effect of 
D S - 1 0 4 0 b o n thr o m bi n -acti vata ble fi bri n olys is 
in hi bit or (T A FIa ) acti vit y, T A FI a nti ge n a n d D-
di mer fi bri n ol ysis bi o mar kers, i n s u bjects wit h P E.
E x pl orat or y  O bjecti ve:
Assess t he effect of D S - 1 0 4 0 b o n cl ot l ysis as a bi o mar ker 
f or T A FIa acti vit y i n s u bjects wit h P E. 
St u d y  Desi g n:
T his will be a r a n d o mize d, d o u ble - bli n d, p lace b o-
c o ntr olle d, m ulti -ce nter, si n gle asce n di n g d ose st u d y i n 
s u bjects wit h ac ute P E c haracterize d as l o w -ris k or 
i nter me diate-ris k or s u b massi ve P E.  
T his st u d y  will f oll o w a n a da pti ve desi g n a n d i ncl u de u p 
t o si x se q ue ntial, asce n di n g-d ose/c o nti n u o us i nf usi o n ti me 
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c o h orts, or ga nize d i n t hree pairs ( 1 - 2, 3-4, a n d 5 -6) a n d u p 
t o t w o d ose o pti mizati o n e val uati o ns pla n ne d i n bet wee n 
t he first a n d sec o n d pair of c o h orts. 
All s u bjects partici pati n g i n t his st u d y  will recei ve S O C 
a ntic oa g ulati o n t hera p y as per t he c urre nt treat me nt 
g ui deli nes f or patie nts wit h ac ute P E, t o e ns ure a n 
effecti ve t hera pe utic bac k gr o u n d.  D ue t o t he earl y  sta ge 
of de vel o p me nt a n d i n or der t o mi ni mize varia bilit y , t he 
bac k gr o u n d a ntic oa g ulati o n re gi me n f or t his st u d y will be 
sta n dar dize d f or all s u bjects t o e n o xa pari n 1 m g/ k g, 
s u bc uta neo us, e ver y  1 2 h o urs f oll o we d b y e d o xa ba n 6 0 
m g ( 3 0 m g f or s u bjects re q uiri n g d ose a dj ust me nt) per 
oral, o nce dail y  t hr o u g h t he fi nal e val uati o n at Da y 3 0.  
F oll o wi n g t he e n d of t he st u d y , Sa va ysa ® / Li xia na®
(e d o xa ba n, per oral, o nce dail y) will be ma de a vaila ble at 
n o c ost t o t he patie nts f or at least 9 0 da y s, at t he 
In vesti gat or’s discreti o n per t he c urre nt treat me nt
g ui deli nes 1. At t he ti me of ra n d o mizati o n, eli gi ble 
s u bjects m ust i nitiate or be tra nsiti o ne d t o t he st u d y-
s pecifie d e n o xa pari n re gi me n.  T he e n o xa pari n 
a d mi nistrati o n will c o nti n ue f or 5 da ys ( 6 da ys for C o h ort 
6) t o c o ver t he i nf usi o n wit h bli n de d st u d y  dr u g a n d a n 
a d diti o nal 7 2 h o urs f oll o wi n g t he e n d of t he st u dy dr u g 
i nf usi o n nee de d t o e ns ure a n a de q uate was h o ut a n d 
c o m plete t he sa m ple c ollecti o n f or P K/ P D a n d bi o mar ker 
meas ure me nts , bef ore t he s u bjects ma y be s witc he d t o 
e d o xa ba n. Ra n d o mize d s u bjects will recei ve a n I V 
i nf usi o n wit h st u d y dr u g (eit her D S-1 0 4 0 b or p lace b o) 
o ver a peri o d of ti me ra n gi n g fr o m 1 2 h t o 7 2 h de pe n di n g 
o n t he c o h ort.  All s u bjects wit hi n a c o h ort will recei ve t he 
sa me d ose of st u d y dr u g a d mi nistere d via I V i nf usi o n of 
t he sa me d urati o n. T he assi g n me nt t o eit her acti ve dr u g or 
place b o will be bli n de d t o t he s u bjects a n d st u d y  site staff 
w h o ma y  c o me i n direct c o ntact wit h t he s u bjects as well 
as t o t he S p o ns or a n d Me d pace
st ud y  tea m.  T he st u d y  
ma y  be st o p pe d at a n y ti me f or safety reas o ns.
A n i n de pe n de nt, u n bli n de d, Data M o nit ori n g C o m mittee 
( D M C) will re vie w ke y safety para meters f or eac h c o h ort 
a n d pr o vi de its e n d orse me nt f or t he c o nti n uati o n of t he 
st u d y a n d t he d ose escalati o n decisi o ns. A bli n de d 
Cli nical E ve nts C o m mittee ( C E C) will be esta blis he d t o 
a dj u dicate blee di n g e ve nts. 
St u d y  e nr oll me nt will be d o ne i n pairs of c o h orts, 
be gi n ni n g wit h C o h orts 1 a n d 2, f oll o we d b y C o h orts 3 
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a n d 4, t he n 5 a n d 6. Wit hi n eac h pair of c o h orts, s u bject 
e nr oll me nt will be sta g gere d f or safet y.   E nr oll me nt i n 
C o h ort s 2, 4, a n d 6 will be gi n after t he first 1 0 s u bjects i n 
C o h ort s 1, 3, a n d 5, res pecti vel y ha ve s uccessf ully 
c o m plete d st u d y dr u g a d mi nistrati o n a n d ha ve reac he d 7 2 
h o urs p ost t he e n d of st u d y dr u g i nf usi o n ( w he n t he 
sa m ple c ollecti o n f or P K/ P D meas ure me nts e n ds) wit h o ut 
a n y i ncrease i n t he pri mar y safety e n d p oi nt ( cli nicall y 
rele va nt blee di n g) or ot her rele va nt safet y c o ncer ns 
e mer gi n g, as assesse d b y t he i n de pe n de nt, u n bli n ded 
D M C .
I n C o h orts 1 a n d 2 eli gi ble s u bjects will be ra n d o mize d i n 
a 2: 1 rati o t o eit her D S-1 0 4 0 b or place b o . Be gi n ni n g wit h 
C o h ort 3 t he ra n d o mizati o n rati o will c ha n ge t o 3: 1.   
A d ose o pti mizati o n e val uati o n is pla n ne d after all 
s u bjects i n C o h orts 1- 2 reac h 7 2 h p ost e n d of i nf usi o n,
w hic h will i ncl u de i ma gi n g ( t otal t hr o m b us v ol u me 
re d ucti o n fr o m baseli ne t o ≤1 2 h o urs p ost e n d of st u d y  
dr u g i nf usi o n), p har mac o ki netic, a n d select bi o mar ker 
data. T he o pti mize d d ose(s) a n d d osi n g re gi me ns will be 
t he n use d f or t he s u bse q ue nt c o h orts. If necessar y, a 
sec o n d d ose o pti mizati o n e val uati o n ma y be carrie d o ut 
after C o h orts 3 -4 are c o m plete d, t o f urt her o pti mize t he 
d ose(s) a n d d osi n g re gi me ns f or C o h orts 5 - 6. 
T he d ose o pti mizati o n e val uati o n(s) will be carrie d o ut i n 
a n u n bli n de d fas hi o n b y a se parate, desi g nate d tea m wit h 
t he a p pr o priate fire walls i n place t o pre ve nt acci de ntal 
u n bli n di n g of t he st u d y tea m. T he st u d y ma y e n d after 
C o h orts 3 - 4 are c o m plete d, s h o ul d t he o pti mize d d ose(s) 
a n d d osi n g re gi me ns teste d yiel d a cli nically mea ni n gf ul 
re d ucti o n i n t hr o m b us size/ v ol u me a n d ha ve acce pta ble 
safety a n d t olera bilit y .
St u d y  D urati o n:
D urati o n of s u bject partici pati o n will be a p pr o xi matel y  3 0
da y s fr o m st u d y q ualificati o n t hr o u g h fi nal f oll o w- u p.
D urati o n of s u bject treat me nt wit h t he bli n de d st u d y dr u g, 
a d mi nistere d as a c o nti n u o us IV i nf usi o n , will be eit her 
1 2, 2 4, 4 8, or 7 2 h o urs, de pe n di n g o n t he c o h ort. T he 
d urati o n of t he c o nti n u o us I V i nf usi o n wit h st u d y  dr u g 
will be t he sa me f or all s u bje cts i n t he sa me c o h ort.
T his st u d y  will e n d o nce t he last s u bject i n t he last c o h ort 
has c o m plete d t he e val uati o n at t he Da y  3 0 Visit.
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St u d y  Ce nter s a n d L ocati o n:
A p pr o xi matel y  4 2 sites i n N ort h A merica a n d E ur o pe .
S u bject Eli gi bilit y  Criteria: 
I ncl usi o n Criteria:
1.
Male or fe male s u bjects, a ge 1 8 t o 7 5 years a n d 
b o d y  wei g ht bet wee n 5 0 a n d 1 2 0 k g, i ncl usi ve;
2.
S u bjects a d mitte d t o h os pital wit h a cli nical 
dia g n osis of ac ute P E cate g ori ze d as l o w ris k or 
i nter me diate-ris k or s u b massi ve P E a n d f or w h o m
cat heter -base d t hera p y is n ot pla n ne d ;
a.
S u bjects m ust ha ve a C T A sca n c o nfir mi n g 
t he P E dia g n osis a n d wit h at least o ne 
meas ura ble i n de x lesi o n i n a se g me ntal or 
lar ger p ul m o nar y arter y pri or t o 
ra n d o mizati o n;
b.
S u bjects s h o ul d be i n ot her wise satisfact or y 
healt h i n t he o pi ni o n of t he I n vesti gat or;
c.
S u bjects ma y  ha ve c o nc urre nt D V T a n d 
ha ve a n i nferi or ve na ca va ( I V C) filter
place d pri or t o ra n d o mizati o n;   
d.
S u bjects ma y  alrea dy be o n S O C l o w 
m olec ular wei g ht ( He pari n) [ LM W
( He pari n)] at t he ti me of ra n d o miz ati o n b ut 
f or n o l o n ger t ha n 3 6 h o urs.
3.
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.
S u bjects wit h ac ute P E cate g orize d as hi g h- ris k or 
massi ve, or w h o are he m o d y na micall y  u nsta ble, 
e vi de nce d b y a heart rate > 1 2 0 / mi n a n d a s yst olic 
bl o o d press ure ( S B P) of < 9 0 m m H g f or m ore t ha n 
1 5 c o nsec uti ve mi n utes or a dr o p i n S B P of > 4 0 
m m H g si nce prese ntati o n ;
2.
S u bjects f or w h o m use of a t hr o m b ol y tic, eit her 
s yste mic or via cat heter, is pla n ne d;
3.
S u bjects wit h P E lesi o ns o nl y  i n t he s u b-se g me ntal 
or s maller arteries, w hic h d ue t o li mitati o ns of t he 
i ma gi n g met h o d ma y n ot be c o nsiste ntl y i de ntifie d 
a n d meas ure d ;
4.
S u bjects u na ble or u n willi n g t o ta ke t he 
st u d y-s o urce d S O C a ntic oa g ulati o n t hera p y ;
5.
S u bjects recei vi n g a n y vita mi n K a nta g o nists 
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(V K As ) pri or t o ra n d o mizati o n or recei vi n g m ore 
t ha n 3 6 h o urs treat me nt wit h LM W( He pari n) i n 
t hera pe utic d oses pri or t o ra n d o mizati o n;
6.
S u bjects w h o ha d pri or i ntracra nial he m orr ha ge, 
k n o w n arteri o ve n o us malf or mati o n or a ne ur y s m, 
or e vi de nce of acti ve blee di n g;
7.
S u bjects wit h a p latelet c o u nt 1 0 0, 0 0 0, 
i nter nati o nal n or malize d rati o (I N R) 1. 7, or a n 
ele vate d partial t hr o m b o plasti n ti me ;
8.
S u bjects w h o wit hi n 4 8 h o urs of ra n d o mizati o n 
ha ve use d a n a nti -Fact or IIa a ge nt s uc h as 
da bi gatra n or a n a nti -F Xa a ge nt s uc h as 
ri var o xa ba n, a pi xa ba n, or e d o xa ba n;
9.
S u bjects wit h hist or y  of e n d ocar ditis;
1 0. S u bjects wit h < 6 m o nt h hist or y  of ac ute c or o nar y 
s yn dr o me ( A C S) w het her or n ot t he y  ha ve 
u n der g o ne perc uta ne o us c or o nar y  i nter ve nti o n 
( P CI);
1 1. S u bjects w h o re q uire o n g oi n g d ual a nti platelet 
t hera py or treat me nt wit h as piri n al o ne i n a d osa ge 
of m ore t ha n 1 0 0 m g/ per da y ;
1 2. 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 3. S u bjects wit h u nc o ntr olle d h y perte nsi o n at 
ra n d o mizati o n, e vi de nce d b y S B P 1 8 0 m m H g or 
diast olic bl o o d press ure > 1 2 0 m m H g, or w h o 
re q uire pare nteral me dicati o n t o mai ntai n bl o o d 
press ure bel o w t hese li mits ;
1 4. S u bjects w h o wit hi n 3 m o nt hs pri or t o 
ra n d o mizati o n ha ve ha d i ntracra nial s ur ger y , 
cli nicall y si g nifica nt hea d tra u ma (i n t he o pi ni o n of 
t he Pri nci pal I n vesti gat or), a str o ke, or ha ve 
recei ve d t hr o m b ol ytic treat me nt;
1 5. S u bjects wit h E C G e vi de nce of 2 n d de gree or 
hi g her atri o ve ntric ular ( A V ) bl oc k or wit h Q Tc B 
or Q Tc F > 4 5 0 ms;
1 6. S u bjects w h o wit hi n 2 1 da y s pri or t o 
ra n d o mizati o n ha ve ha d gastr oi ntesti nal or 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 9
ge nit o uri nar y  blee di n g;
1 7. S u bjects w h o wit hi n 1 4 da y s pri or t o 
ra n d o mizati o n ha ve ha d maj or s ur ger y or a l u m bar 
p u nct ure ( or e pi d ural ster oi d i njecti o n) ;
1 8. S u bjects wit h he m o gl o bi n < 1 0 g/ d L ;
1 9. S u bjects wit h a n esti mate d gl o mer ular filtrati o n 
rate ( usi n g M o dificati o n of Diet i n Re nal Disease 
e q uati o n) 6 0 m L / mi n/ 1. 7 3 m2;
2 0. S u bjects wit h dia g n ose d acti ve li ver disease or 
wit h ele vati o n of li ver e nz y mes/ bilir u bi n: 
a.
Ala ni ne tra nsa mi nase ( A L T) or as partate 
tra nsa mi nase ( A S T) ≥ 2 ti mes u p per li mit 
of n or mal ( U L N)
b.
T otal bilir u bi n ( T B L) ≥1. 5 ti mes U L N 
(e xce pt d ue t o c o nfir me d Gil bert’s 
s yn dr o me)  
2 1. S u bjects wit h k n o w n h ist or y of testi n g p ositi ve f or 
He patitis B a nti ge n or He patitis C a nti b o d y  bef ore 
ra n d o mizati o n;
2 2. S u bjects wit h k n o w n hist or y  of testi n g p ositi ve f or 
t he h u ma n i m m u n o deficie nc y vir us ( HI V);
2 3. S u bjects wit h acti ve mali g na nc y  ( dia g n ose d withi n 
5 y ears) e xce pt f or a de q uatel y treate d n o n-
mela n o ma s ki n ca ncer or ot her n o n -i n vasi ve or i n-
sit u ne o plas m (e g, cer vical ca ncer i n sit u);
2 4. S u bjects u n der g oi n g c he m ot hera p y or ra diati o n 
t hera py i n t he 3 0 da ys pri or t o ra n d o mizati o n or 
e x pecte d t o i nitiate s uc h t hera py d uri n g st u d y 
partici pati o n ;
2 5. S u bjects wit h c o n gesti ve heart fail ure ;
2 6. S u bjects wit h c hr o nic o bstr ucti ve p ul m o nar y  
disease ;
2 7. Fe male s u bjects of c hil d beari n g p ote ntial wit h a 
p ositi ve pre g na nc y  test or w h o are lactati n g, or 
u n willi n g t o use reli a ble mea ns of c o ntrace pti o n
( p h ysical barrier, patie nt or part ner) i n c o nj u ncti o n 
wit h a s per mici dal pr o d uct, c o ntra ce pti ve ( pill, 
patc h, i njecta ble) , or i ntra uteri ne de vices (I U Ds)
f oll o wi n g treat me nt peri o d a n d t hr o u g h t he Da y  3 0 
fi nal f oll o w-u p visit ;
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 0
2 8. S u bjects c urre ntl y partici pati n g i n a n ot her 
i n vesti gati o nal st u dy or w h o ha ve partici pate d i n 
a n i n vesti gati o nal dr u g st u d y  wit hi n 3 0 da ys or 
pri or t o ra n d o mizati o n;
2 9. S u bjects u nli kel y  t o c o m pl y wit h t he pr ot oc ol (e g, 
u nc o o perati ve attit u de, i na bilit y  t o ret ur n f or 
s u bse q ue nt visits, a n d/ or ot her wise c o nsi dere d by 
t he i n vesti gat or t o be u nli kel y t o c o m plete t he 
st u d y);
3 0. S u bjects wit h a n y  c o n diti o n (i ncl u di n g la b orat or y 
a b n or malities) t hat, i n t he o pi ni o n of t he 
I n vesti gat or, w o ul d p ote ntiall y place t he s u bject at 
i ncrease d ris k of har m t hr o u g h partici pati o n i n t his 
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: D S -1 0 4 0 b I njecti o n 1 0 m g/ 1 0 m L vial will be tra nsferre d 
i nt o IV i nf usi o n s ol uti o n ( 0. 9 % S o di u m C hl ori de 
I njecti o n, U S P).  T he place b o f or D S -1 0 4 0 b will be 0. 9 % 
S o di u m C hl ori de I njecti o n, U S P.  
T he bli n de d s ol uti o n c o ntai ni n g eit her D S -1 0 4 0 b or 
p lace b o will be a d mi nistere d as a si n gle, c o nti n u o us I V 
i nf usi o n. T he I V i nf usi o n will c o nsist of a n i nitial l oa di n g 
d ose of 3- 6 m g ( de pe n di n g o n t he c o h ort) a d mi nistere d as 
a 0. 5 h o ur i nf usi o n f oll o we d b y a mai nte na nce d ose wit h 
t he bala nce of t he t otal d ose a d mi nistere d o ver t he 
re mai ni n g ti me f or t he res pecti ve c o h ort ( 1 1. 5 h f or C o h ort 
1, 2 3. 5 h f or C o h orts 2 a n d 3, u p t o 4 7. 5 h f or C o h orts 4 a n d 
5, a n d u p t o 7 1. 5 h f or C o h ort 6). 
T he D S -1 0 4 0 b t otal d oses f or C o h orts 1 a n d 2 are 2 0 m g 
o ver 1 2 h a n d 4 0 m g o ver 2 4 h, res pecti vel y. T hese d oses 
ha ve bee n s h o w n i n healt h y  v ol u nteers t o be safe a n d well 
t olerate d a n d t o pr o vi de a n al m ost c o m plete i n hi biti o n of
T A FI acti vit y . U p t o t w o d ose o pti mizati o n e val uati o n s 
are pla n ne d usi n g i ma gi n g, P K/ P D, a n d bi o mar ker data 
fr o m C o h orts 1- 2 a n d 1 -4, res pecti vel y, t o o pti mize t he 
t otal d ose of D S- 1 0 4 0 b a n d i nf usi o n d urati o n f or t he 
re mai ni n g c o h orts.
Bac k gr o u n d a ntic oa g ulati o n t hera p y per t he c urre nt S O C 
will be sta n dar dize d acr oss all st u d y  sites a n d s u bjects t o 
e n o xa pari n 1 m g/ k g, s u bc uta ne o us, e ver y 1 2 h f or 5 da y s ( 6 
da y s f or C o h ort 6) f oll o we d b y e d o xa ba n 6 0 m g ( 3 0 m g 
f or s u bjects re q uiri n g d ose a dj ust me nt) per oral, o nce dail y
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 1
t hr o u g h t he e n d of st u dy visit, at Da y  3 0.  B ot h e n o xa pari n 
a n d e d o xa ba n will be pr o vi de d as o pe n la bel a n d use d i n 
acc or da nce t o t heir a p pr o ve d la bels.  F oll o wi n g t he e n d of 
t he st u d y, Sa va y s a® / Li xia na® (e d o xa ba n, per oral, o nce 
dail y ) will be ma de a vaila ble at n o c ost t o t he patie nts f or 
at least 9 0 da y s, at t he i n vesti gat or’s discreti o n per t he 
c urre nt treat me nt g ui deli nes 1 .
St u d y  E n d p oi nts:
Efficac y  E n d p oi nts:
1.
R elati ve re d ucti o n ( % re d ucti o n) i n t otal t hr o m b us 
v ol u me fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -
1 0 4 0 b i nf usi o n assesse d b y C TA ) i n se g me ntal or 
lar ger p ul m o nar y arteries;
2.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % 
greater relati ve re d ucti o n i n t otal t hr o m b us v ol u me 
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of 
D S -1 0 4 0 b i nf usi o n ;
3.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % 
great er relati ve re d ucti o n i n t otal t hr o m b us v ol u me 
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of 
D S -1 0 4 0 b i nf usi o n ;
4.
Deat h, he m o d y na mic dec o m pe nsati o n, or 
treat me nt escalati o n u p t o h os pital disc har ge a n d 
u p t o Da y 3 0 Visit .  Treat me nt escalati o n is 
defi ne d as catec h ola mi ne i nf usi o n, sec o n dar y  
t hr o m b ol ysis, e n d otrac heal i nt u bati o n, 
car di o p ul m o nar y res uscitati o n, or e mer ge nc y 
s ur gical e m b olect o my or t hr o m b us fra g me ntati o n 
b y  cat heter;
5.
Rec urre nce of V T E (co m p osite of rec urre nt P E, 
ne w or rec urre nt D V T, V T E -relate d deat h; as well 
as t he i n di vi d ual c o m p o ne nts) u p t o h os pital 
disc har ge a n d u p t o Da y  3 0 Visit;
6.
M A C E
(defi ne d as a c o m p osite of car di o vasc ular 
deat h , n o n-fatal m yocar dial i nfarcti o n, str o ke, or 
s yste mic e m b olic e ve nts) u p t o h os pital disc har ge 
a n d u p t o Da y 3 0 Visit.
Safet y  E n d p oi nts:
1.
Cli nicall y  rele va nt blee di n g (I ST H maj or or 
C R N M blee di n g );
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 2
2.
Seri o us a d verse e ve nts a n d T E A Es .
P K/ P D E n d p oi nts :
1.
Plas ma c o nce ntrati o ns of D S - 1 0 4 0a:
a.
Area u n der c o nce ntrati o n-vers us -ti me 
c ur ve, fr o m ti me 0 t o t he last q ua ntifia ble 
c o nce ntrati o n sa m pli n g p oi nt ( A U C last);
b.
Area u n der c o nce ntrati o n-vers us -ti me 
c ur ve, fr o m ti me 0 e xtra p olate d t o i nfi nit y 
(A U C 0- i nf), if data all o ws
c.
ma xi m u m ( pea k) o bser ve d plas ma 
c o nce ntrati o n ( C ma x );
d.
ti me of ma xi m u m o bser ve d c o nce ntrati o n 
( Tma x );
e.
Plas ma c o nce ntrati o n i m me diatel y  pri or t o 
t he e n d of c o nti n u o us i nf usi o n;
f.
Eli mi nati o n half -life (T 1/ 2), if data all o ws
g.
T otal cleara nce ( C L), if data all o ws
2.
P har mac o d y na mic e n d p oi nts i ncl u di n g:
a.
t otal T A FIa acti vit y;
b.
D- di mer ;
c.
T A FI a nti ge n;
E x pl orat or y  E n d p oi nts:
1.
E val uati o n of cl ot l y sis as a bi o mar ker f or T A FIa 
acti vit y.
Pla n ne d Sa m ple Size: 
A p pr o xi matel y 2 2 s u bjects will be e nr olle d per c o h ort, t o 
yi el d at least 1 8 e val ua ble s u bjects f or C o h orts 1- 2 a n d at 
least 2 0 f or C o h orts 3 - 6 f or a t otal of 11 8 e val ua ble 
s u bjects.  T he ra n d o mizati o n rati os of D S - 1 0 4 0 b t o 
place b o are 2: 1 f or C o h orts 1 - 2 a n d 3: 1 f or C o h orts 3 - 6.  
A s u bject will be dee me d e val ua ble if he/s he has vali d 
C T A i ma gi n g e val uati o ns at b ot h baseli ne a n d at t he ≤1 2 h 
p ost -e n d of i nf usi o n a n d has s uccessf ull y  c o m plete d 
a d mi nistrati o n of t he bli n de d st u d y  dr u g i nf usi o n. 
Ra n d o mize d s u bjects w h o d o n ot c o m plete t he bli n d e d 
st u d y dr u g a d mi nistrati o n (ie, su bjects w h o st o p t he I V 
i nf usi o n early d ue t o A Es) will still be f oll o we d f or safet y 
t hr o u g h Da y 3 0.
T he pla n n e d sa m ple size is base d o n t he t w o sa m ple t -test 
wit h a n al p ha le vel of 0. 1 0 ( o ne -si de d), p o wer of o ver 
0. 8 5, 3 0 % t o 5 0 % hi g her re d ucti o n of D S - 1 0 4 0 b
c o m pare d t o place b o i n t otal t hr o m b us v ol u me, a n d 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 3
sta n dar d de viati o n of 4 0 %, i n or der t o detect at least 5 0 % 
hi g her re d ucti o n at C o h o rt 1, 4 0 % at C o h ort 2, 3 5 % at 
C o h ort 3 t o 5, a n d 3 0 % at C o h ort 6.
Statistical A nal y ses: 
Efficac y  A nalys es:  T he f oll o wi n g ke y efficac y e n d p oi nts 
will be s u m marize d a n d c o m pare d bet wee n t he i n di vi d ual 
D S - 1 0 4 0 b ar ms a n d p o ole d place b o ar m:
1.
R elati ve re d ucti o n ( % re d ucti o n) i n t otal t hr o m b us 
v ol u me fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -
1 0 4 0 b i nf u si o n assesse d b y C T A) i n se g me ntal or 
lar ger p ul m o nar y arteries;
2.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % 
greater relati ve re d ucti o n i n t otal t hr o m b us v ol u me 
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of 
D S- 1 0 4 0 b i nf usi o n ;
3.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % 
greater relati ve re d ucti o n i n t otal t hr o m b us v ol u me 
assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y 
arteries, fr o m baseli ne t o ≤ 1 2 h fr o m e n d of 
D S -1 0 4 0 b i nf usi o n ;
T he relati ve re d ucti o n ( % re d ucti o n fr o m baseli ne t o ≤ 1 2 h 
fr o m e n d of i nf usi o n) i n t otal t hr o m b us v ol u me of eac h 
D S - 1 0 4 0b d ose will be c o m pare d wit h p o ole d place b o ar m
usi n g t w o sa m ple t -test statistics a n d p-val ue wit h n o 
m ulti ple c o m paris o ns a dj ust me nt . T he pr o p orti o ns of 
s u bjects w h o ac hie ve 2 0 % a n d 5 0 % relati ve re d ucti o n i n 
t otal t hr o m b us v ol u me of eac h D S - 1 0 4 0b d ose will be 
c o m pare d wit h p o ole d place b o ar m usi n g c hi -s q uare 
statistics a n d p-val ue wit h n o m ulti ple c o m paris o ns 
a dj ust me nt.
T he f oll o wi n g sec o n dar y efficac y e n d p oi nts will be 
s u m marize d a n d c o m pare d bet wee n D S - 1 0 4 0b ar ms a n d 
p o ole d place b o ar m :
1.
Rec urre nce of V T E ( C o m p osite of rec urre nt P E, 
ne w or rec urre nt D V T, V T E -relate d deat h; as well 
as t he i n di vi d ual c o m p o ne nts) u p t o h os pital 
disc har ge a n d u p t o Da y 3 0 Visit;
2.
Deat h, he m o d y na mic dec o m pe nsati o n, or 
treat me nt escalati o n u p t o h os pital disc har ge a n d 
u p t o Da y  3 0 Visit;
3.
Rec urre nce of P E u p t o h os pital disc har ge a n d u p 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 4
t o Da y 3 0 Visit;
4.
M A C E u p t o h os pital disc har ge a n d u p t o Da y  3 0 
Visit.
Ti me t o e ve nt data fr o m ra n d o mizati o n will be 
s u m marize d b y  Ka pla n -Meier
met h o ds.
Safet y  A nalys es:  Safet y a nalys es i n ge neral will be 
descri pti ve a n d will be prese nte d i n ta b ular f or mat wit h 
t he a p pr o priate s u m mar y statistics.  Asi de fr o m T E A Es 
a n d S A Es, s afet y meas ure me nts will i ncl u de: p h ysical 
e xa mi nati o n fi n di n gs, vital si g n meas ure me nts, sta n dar d 
cli nical la b orat or y para meters (i ncl u di n g ser u m c he mistr y, 
he mat ol o g y , uri nal y sis, car diac bi o mar kers [ pr o B N P a n d 
tr o p o ni n], c oa g ulati o n para meters), a n d electr ocar di o gra m 
( E C G) para meters.
Val ues f or safet y assess me nts will be s u m marize d b y 
treat me nt gr o u p.  Res ults fr o m place b o-treate d s u bjects 
will be p o ole d acr oss c o h orts.
Blee di n g e ve nts will be s u m marize d as I S T H maj or or
C R N M blee di n g b y  treat me nt.  Res ults fr o m place b o -
treate d s u bjects will be p o ole d acr oss c o h orts w he n 
c o m pari n g wit h D S -1 0 4 0 b treate d s u bjects.
P K/ P D A nal y ses:  Descri pti ve statistics (sa m ple size [ N], 
n u m ber missi n g [ N missi n g], arit h metic mea n, sta n dar d 
de viati o n, c oefficie nt of var iati o n [ % C V], mi ni m u m, 
ma xi m u m, a n d me dia n) of D S- 1 0 4 0a plas ma 
c o nce ntrati o ns at eac h sa m pli n g ti me p oi nt a n d all P K 
para meters will be prese nte d b y  treat me nt.  I n a d diti o n, t he 
ge o metric mea n a n d % C V f or ge o metric mea n will als o be 
calc ulate d f or t he P K para meters A U C 0- i nf, A U Clast, Cma x , 
a n d plas ma c o nce ntrati o n pri or t o e n d of c o nti n u o us 
i nf usi o n. 
Mea n a n d me dia n plas ma c o nce ntrati o n vers us ti me data 
will be prese nte d gra p hicall y  f or all treat me nts usi n g 
ori gi nal a n d se mi -l o g scales.
Act ual sa m pli n g ti m es t hat differ fr o m t he sc he d ule d 
sa m pli n g ti mes b y m ore t ha n 5 mi n utes wit hi n t he first 
h o ur, or b y m ore t ha n 3 0 mi n utes wit hi n t he first 1 2 h o urs, 
or b y  m ore t ha n 1 h o ur t hereafter, will be liste d b ut 
e xcl u de d fr o m s u m mar y statistics a n d mea n a n d me dia n 
gra p hs.
T he relati o ns hi p bet wee n d ose a n d e x p os ure para meters 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 5
( A U Clast a n d A U C 0-i nf) will be e xa mi ne d gra p hicall y .
Ra w val ues f or t otal T A FIa acti vit y, T A FI a nti ge n, cl ot 
l ysis ti me, a n d D-di mer will be prese nte d gra p hicall y  b y 
s u bject, a n d will als o be s um marize d b y  ti me p oi nt a n d 
treat me nt.  C ha n ge fr o m baseli ne val ues (a bs ol ute val ue 
a n d perce nta ge) will als o be s u m marize d.  P o ole d place b o 
data of all c o h orts will be s u m marize d.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 6
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
T A B L E O F C O N T E N T S ............................................................................................................... 1 6
LI S T O F T A B L E S ......................................................................................................................... 2 1
LI S T O F FI G U R E S ....................................................................................................................... 2 2
LI S T O F A B B R E VI A TI O N S ........................................................................................................ 2 3
1. 
I NT R O D U C TI O N ...................................................................................................... 2 5
1. 1. 
Bac k gr o u n d ................................................................................................................. 2 5
1. 1. 1. 
Data S u m mar y ............................................................................................................ 2 5
1. 1. 1. 1. 
N o n cli nical St u dies ..................................................................................................... 2 5
1. 1. 1. 2. 
Cli nical E x perie nce..................................................................................................... 2 6
1. 2. 
St u d y  Rati o nale........................................................................................................... 2 8
1. 3. 
Ris ks a n d Be nefits f or St u d y  S u bjects........................................................................ 2 8
2. 
S T U D Y O BJ E C TI V E S A N D H Y P O T H E SI S ........................................................... 2 9
2. 1. 
St u d y  O bjecti ves......................................................................................................... 2 9
2. 1. 1. 
Pri mar y  O bjecti ves ..................................................................................................... 2 9
2. 1. 2. 
Sec o n dar y  O bjecti ves ................................................................................................. 2 9
2. 1. 3. 
E x pl orat or y  O bjecti ves...............................................................................................3 0
2. 2. 
St u d y  H yp ot hesis ........................................................................................................3 0
3. 
S T U D Y D E SI G N ....................................................................................................... 3 1
3. 1. 
O ver all Desi g n ............................................................................................................ 3 1
3. 2. 
Disc ussi o n of St u d y  Desi g n........................................................................................ 3 1
3. 3. 
St o p pi n g R ules................................ ............................................................................3 5
4. 
S T U D Y P O P U L A T I O N.............................................................................................3 6
4. 1. 
I ncl usi o n Criteria................................ ........................................................................3 6
4. 2. 
E xc l usi o n Criteria.......................................................................................................3 6
5. 
S T U D Y T R E A T M E N T( S) ......................................................................................... 3 9
5. 1. 
Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g ......................................................... 3 9
5. 1. 1. 
Treat me nt Gr o u p(s) ....................................................................................................3 9
5. 1. 2. 
Met h o d of Treat me nt All ocati o n ................................................................................ 3 9
5. 1. 3. 
Bli n di n g................................ ......................................................................................4 0
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 7
5. 1. 4. 
E mer ge nc y  U n bli n di n g Pr oce d ure .............................................................................. 4 0
5. 2. 
St u d y  Dr u g(s).............................................................................................................. 4 0
5. 2. 1. 
Descri pti o n .................................................................................................................. 4 0
5. 2. 2. 
La beli n g a n d Pac ka gi n g.............................................................................................. 4 1
5. 2. 3. 
Pre parati o n .................................................................................................................. 4 1
5. 2. 4. 
A d mi nistrati o n ............................................................................................................ 4 1
5. 2. 5. 
St o ra ge ........................................................................................................................ 4 2
5. 2. 6. 
Dr u g Acc o u nta bilit y ................................................................................................... 4 2
5. 3. 
C o ntr ol Treat me nt ....................................................................................................... 4 3
5. 4. 
D ose I nterr u pti o ns a n d Re d ucti o ns............................................................................. 4 3
5. 5. 
Met h o d of Assessi n g Treat me nt C o m plia nce............................................................. 4 3
5. 6. 
Pri or a n d C o nc o mita nt Me dicati o ns ........................................................................... 4 4
5. 7. 
S u bject Wit h dra wal/ Disc o nti n uati o n ..........................................................................4 4
5. 7. 1. 
Reas o ns f or Wit h dra wal ............................................................................................. 4 4
5. 7. 2. 
Wit h dra wal Pr oce d ures ...............................................................................................4 5
5. 7. 3. 
S u bjects L ost t o F oll o w -u p......................................................................................... 4 5
6. 
S T U D Y P R O C E D U R E S............................................................................................ 4 6
6. 1. 
St u d y  Q ualificati o n/ Pre-Ra n d o mizati o n ..................................................................... 4 6
6. 2. 
Da y  0: Baseli ne Visit.................................................................................................. 4 7
6. 3. 
Da y  1-3: D o u ble -Bli n d Treat me nt Peri o d .................................................................. 4 7
6. 4. 
Da y  4- 6: 7 2 h o ur After E n d of I nf usi o n F oll o w- u p.................................................... 4 8
6. 5. 
Da y  3 0 ± 3 da ys:  L o n g ter m F oll o w-u p Peri o d ......................................................... 4 8
7. 
E F FI C A C Y A S S E S S M E N T S .................................................................................... 4 9
7. 1. 
Pri mar y  Efficac y E n d p oi nt (s) .....................................................................................4 9
7. 2. 
Sec o n dar y  Efficac y E n d p oi nt (s) .................................................................................4 9
7. 3. 
E x pl orat or y  Efficac y E n d p oi nt(s)...............................................................................4 9
7. 4. 
A p pr o priate ness of Selecte d Efficac y  E n d p oi nt(s).....................................................4 9
8. 
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S ...................... 5 0
8. 1. 
P har mac o ki netic ( P K) E n d p oi nt (s).............................................................................5 0
8. 2. 
P har mac o d y na mic ( P D) E n d p oi nt (s).......................................................................... 5 1
8. 3. 
Bi o mar ker E n d p oi nt(s) ...............................................................................................5 1
8. 4. 
I m m u n o ge nicity ..........................................................................................................5 1
8. 5. 
P har mac o ge n o mic A nal ysis ........................................................................................5 1
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 8
9.  
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G ......................................................... 5 3
9. 1. 
A d verse E ve nt C ollecti o n a n d Re p orti n g ................................................................... 5 3
9. 2. 
Safet y  E n d p oi nt E ve nt(s)............................................................................................ 5 4
9. 2. 1. 
Blee di n g...................................................................................................................... 5 4
9. 3. 
E ve nts of S pecial I nterest ........................................................................................... 5 4
9. 4. 
A d verse E ve nt ............................................................................................................. 5 5
9. 4. 1. 
Defi niti o n of A d verse E ve nt....................................................................................... 5 5
9. 4. 2. 
Seri o us A d verse E ve nt ................................................................................................ 5 5
9. 4. 3. 
Se verit y  Assess me nt...................................................................................................5 6
9. 4. 4. 
Ca usalit y  Assess me nt ................................................................................................. 5 6
9. 4. 5. 
Acti o n Ta ke n Re gar di n g St u d y  Dr u g(s) ..................................................................... 5 6
9. 4. 6. 
Ot her Acti o n Ta ke n f or E ve nt .................................................................................... 5 7
9. 4. 7. 
A d verse E ve nt O utc o me ............................................................................................. 5 7
9. 5. 
Seri o us A d verse E ve nts Re p orti n g – Pr oce d ure f or I n vesti gat ors ................................ 5 7
9. 6. 
N otif y i n g Re g ulat or y A ut h orities, In vesti gat ors, a n d Instit uti o nal 
R e vie w B oar d / Et hics C o m mittee ............................................................................... 5 8
9. 7. 
E x p os ure I n Uter o D uri n g Cli nical St u dies ................................................................ 5 8
9. 8. 
Cli nical L a b orat or y E val uati o ns................................................................................. 5 9
9. 9. 
Vital Si g ns .................................................................................................................. 5 9
9. 1 0. 
Electr ocar di o gra ms ..................................................................................................... 6 0
9. 1 1. 
P h y sical E xa mi nati o ns ................................................................................................ 6 0
9. 1 2. 
Ot her E xa mi nati o ns ....................................................................................................6 0
1 0. 
O T H E R A S S E S S M E N T S .......................................................................................... 6 1
1 1. 
S T A TI S TI C A L M E T H O D S ....................................................................................... 6 2
1 1. 1. 
A nal y sis Sets............................................................................................................... 6 2
1 1. 2. 
Ge neral Statistical C o nsi derati o ns .............................................................................. 6 2
1 1. 3. 
St u d y  P o p ulati o n Data................................................................................................6 2
1 1. 4. 
Statistical A nal y sis...................................................................................................... 6 3
1 1. 4. 1. 
Efficac y  A nalys es .......................................................................................................6 3
1 1. 4. 1. 1. 
Pri mar y  Efficac y A nalys es .........................................................................................6 3
1 1. 4. 1. 2. 
Sec o n dar y  Efficac y A nal yses .....................................................................................6 3
1 1. 4. 1. 3. 
E x pl orat or y  Efficac y A nal yses ...................................................................................6 4
1 1. 4. 2. 
P har mac o ki netic/ P har mac o d y na mic A nal ys es ........................................................... 6 4
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 9
1 1. 4. 2. 1. 
P har mac o ki netic A nal y ses .......................................................................................... 6 4
1 1. 4. 2. 2. 
P har mac o d y na mic A nal yses ....................................................................................... 6 4
1 1. 4. 2. 3. 
Bi o mar ker A nal ys es .................................................................................................... 6 5
1 1. 4. 2. 4. 
P har mac o ge n o mic A nal yses ....................................................................................... 6 5
1 1. 4. 3. 
Safet y  A nalys es .......................................................................................................... 6 5
1 1. 4. 3. 1. 
A d verse E ve nt A nal ys es ............................................................................................. 6 5
1 1. 4. 3. 2. 
Cli nical L a b orat or y E val uati o n A nal yses ................................................................... 6 5
1 1. 4. 3. 3. 
Vital Si g n A nal ys es .................................................................................................... 6 5
1 1. 4. 3. 4. 
Electr ocar di o gra m A nal yses ....................................................................................... 6 6
1 1. 4. 3. 5. 
P h y sical E xa mi nati o n A nal yses.................................................................................. 6 6
1 1. 4. 3. 6. 
Blee di n g E ve nts A nal ys es .......................................................................................... 6 6
1 1. 4. 4. 
Ot her A nal ys is ............................................................................................................ 6 6
1 1. 5. 
I nteri m A nalys es ......................................................................................................... 6 6
1 1. 6. 
Sa m p le Size Deter mi nati o n ........................................................................................ 6 6
1 1. 7. 
Statistical A nal y sis Pr ocess ........................................................................................ 6 7
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 .............................................. 6 8
1 2. 1. 
M o nit ori n g a n d I ns pecti o ns ........................................................................................ 6 8
1 2. 2. 
Data C ollecti o n ........................................................................................................... 6 8
1 2. 3. 
Data Ma na ge me nt ....................................................................................................... 6 9
1 2. 4. 
St u d y  D oc u me ntati o n a n d St ora ge ............................................................................. 6 9
1 2. 5. 
Rec or d Kee pi n g .......................................................................................................... 7 0
1 3. 
FI N A N CI N G A N D I N S U R A N C E ............................................................................. 7 2
1 3. 1. 
Fi na nces ...................................................................................................................... 7 2
1 3. 2. 
Rei m b urse me nt, I n de m nit y , a n d I ns ura nce................................................................7 2
1 4. 
P U B LI C A TI O N P O LI C Y .......................................................................................... 7 3
1 5. 
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I NF O R M A TI O N .............................. 7 4
1 5. 1. 
C o m plia nce State me nt, Et hics a n d Re g ulat or y  C o m plia nce......................................7 4
1 5. 2. 
S u bject C o nfi de ntialit y ...............................................................................................7 4
1 5. 3. 
I nf or me d C o nse nt .......................................................................................................7 4
1 5. 4. 
Re g ulat or y  C o m plia nce..............................................................................................7 5
1 5. 5. 
Pr ot oc ol De viati o ns ....................................................................................................7 6
1 5. 6. 
S u p pl y  of Ne w I nf or mati o n Affecti n g t he C o n d uct of t he St u dy............................... 7 6
1 5. 7. 
Pr ot oc ol A me n d me nts ................................................................................................ 7 7
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 0
1 5. 8. 
St u d y  Ter mi nati o n...................................................................................................... 7 7
1 5. 9. 
Data a n d Safet y M o nit ori n g B oar d ............................................................................. 7 7
1 5. 1 0. 
A d dress List ................................................................................................................ 7 8
1 5. 1 0. 1. 
S p o ns or ....................................................................................................................... 7 8
1 5. 1 0. 1. 1.
S p o ns or Me dical M o nit or........................................................................................... 7 8
1 5. 1 0. 1. 2.
S p o ns or Cli nical St u d y  Lea der................................................................................... 7 8
1 5. 1 0. 1. 3.
S p o ns or Cli nical O perati o ns Deli ver y  Lea d ...............................................................7 9
1 5. 1 0. 2. 
I T R E A S ...................................................................................................................... 7 9
1 5. 1 0. 3. 
C R O s........................................................................................................................... 7 9
1 5. 1 0. 4. 
Dr u g Safe t y................................................................................................................. 8 0
1 5. 1 0. 4. 1.
Me d pace:  D S P D Seri o us A d verse E ve nt Re p orti n g F or m Ge neral 
C o ntact ........................................................................................................................ 8 0
1 5. 1 0. 5. 
Data Ma na ge me nt ....................................................................................................... 8 0
1 5. 1 0. 6. 
Ce ntral La b orat or y ...................................................................................................... 8 0
1 5. 1 0. 7. 
I ma gi n g/ C ore La b Ve n d or .......................................................................................... 8 0
1 5. 1 0. 8. 
I xR S Ve n d or ............................................................................................................... 8 1
1 6. 
R E F E R E N C E S ........................................................................................................... 8 2
1 7. 
A P P E N DI C E S ............................................................................................................ 8 3
1 7. 1. 
Sc he d ule of E ve nts ..................................................................................................... 8 4
1 7. 2. 
Listi n g of La b orat or y  Assa ys...................................................................................... 8 6
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 1
LI S T O F T A B L E S
Ta ble 3. 1:
D osi n g Ra n ges a n d I nf usi o n D urati o n b y  C o h ort....................................................... 3 4
Ta ble 3. 2:
Si m ulate d P K Pr ofiles f or C o h orts 1 a n d 2 ................................................................ 3 4
Ta ble 1 7. 1: Sc he d ule of E ve nts ..................................................................................................... 8 4
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 2
LI S T O F FI G U R E S
Fi g ure 3. 1: St u d y  Desi g n............................................................................................................... 3 1
Fi g ure 3. 2:
C o h ort D osi n g a n d D ose O pti mizati o n S c he me ........................................................ 3 3
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 3
LI S T O F A B B R E VI A TI O N S
A B B R E VI A TI O N 
D E FI NI TI O N
A C S
Ac ute C or o nar y S y n dr o me
A E
A d verse E ve nt
AI S
Ac ute Isc he mic Str o ke
A L T
Ala ni ne Tra nsa mi nase
A L P
Al kali ne P h os p hatase
a P T T
Acti vate d Partial T hr o m b o plasti n Ti me
A S T
As partate Tra nsa mi nase
A V
Atri o ve ntric ular 
B MI
B o d y Mass I n de x
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
C R F
Case Re p ort F or m
Cr C L
Creati ni ne Cleara nce
e C R F
Electr o nic 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 S P V
Cli nical Safet y a n d P har mac o vi gila nce
C T A
C o m p ute d T o m o gra p h y A n gi o gra p h y
D M C
Data M o nit ori n g C o m mittee
D V T
Dee p Vei n T hr o m b osis
E C
Et hics C o m mittee
E C G
Electr ocar di o gra m
E D C
Electr o nic Data Ca pt ure
F D A
F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice 
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 N N
I nter nati o nal N o n-pr o prietar y Na me
I R B
I nstit uti o nal Re vie w B oar d
I S T H
I nter nati o nal S ociet y of T hr o m b osis a n d Hae m ostasis
I TT
Inte nt -t o-treat
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 4
A B B R E VI A TI O N 
D E FI NI TI O N
I V
I ntra ve n o us 
I xR S
I nteracti ve We b/ V oice Res p o nse S yste m
L M W
L o w M olec ular Wei g ht
M A C E
Maj or Car di o vasc ular E ve nts
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
mI T T
M o difie d I T T
N O A E L
N o O bser ve d A d verse E ffect L e vel
P D
P har mac o d y na mic
P E
P ul m o nar y e m b olis m
P K
P har mac o ki netic
P P S
Per- Pr ot oc ol Set
T E A E
Treat me nt -e mer ge nt A d verse E ve nt
S A E
Seri o us A d verse E ve nt
S A P
Statistical A nal ysis Pla n
S O C
Sta n dar d of Care
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n
T A FI
T hr o m bi n -Acti vata ble Fi bri n ol ysis I n hi bit or
T A FIa
Acti vate d f or m of T A FI
T E A E
Treat me nt -E m er ge nt A d verse E ve nt
t-P A
T iss ue plas mi n o ge n acti vat or
U L N
U p per Li mit of N or mal
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
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 5
1. 
I N T R O D U C TI O N
1. 1. 
B ac k gr o u n d
T hr o m bi n-a cti vata ble fi bri n ol ysis in hi bit or ( T A FI) is a plas ma pr ocar b o x y pe pti dase t hat, 
u p o n acti vati o n b y  t hr o m bi n, t hr o m bi nt hr o m b o m o d uli n c o m ple x or plas mi n, t ur ns i nt o a n 
a ntifi bri n ol ytic e nzy m e ter me d acti vate d f or m of T A FI (T A FIa ). I n a t hr o m b us, T A FIa 
re m o ves lys i ne resi d ues at t he car b o xy t er mi nal of fi bri n de gra dati o n pr o d ucts, w hic h 
pre ve nts effecti ve bi n di n g of plas mi n o ge n a n d tiss ue plas mi n o ge n acti vat or (t- P A), 
res ulti n g i n i m paire d t hr o m b ol ysis 2. 
1. 1. 1. 
D at a S u m m ar y
1. 1. 1. 1. 
N o ncli nic al St u dies
I n vitr o effects of D S-1 0 4 0 b o n t he h u ma n- , rat-, a n d m o n ke y acti vate d f or m of T A FI 
( T A FIa) were e val uate d usi n g plas ma fr o m eac h s pecies.  D S - 1 0 4 0 b i n hi bite d h u ma n, rat, 
a n d m o n ke y T A FIa acti vit y wit h t he half ma xi mal i n hi bit or y c o nce ntrati o n (IC 5 0) val ues 
( 9 5 % c o nfi de nce i nter val [ CI] val ues) of 5. 9 2 n m ol/ L  ( 5. 3 5 n m ol/ L t o 6. 5 5 n m ol/ L), 
8. 0 1 n m ol/ L  ( 6. 4 0 n m ol/ L t o 1 0. 0 n m ol/ L), a n d 4. 4 8 n m ol/ L ( 3. 5 3 n m ol/ L t o 
5. 7 0 n m ol/ L), res pecti vel y.
T he i n vi v o effect of D S -1 0 4 0 b o n e n d o ge n o us fi bri n ol y tic acti vit y was e val uate d i n a 
tiss ue fact or-i n d uce d rat ve n o us t hr o m b oe m b olis m ( V T E ) m o del.  D S -1 0 4 0 b i ncrease d 
plas ma D -di mer le vels i n a d ose -de pe n de nt ma n ner, a n d t he i ncrease was si g nifica nt at a 
d ose of 0. 0 6 3 m g/ k g or m ore.  T he i n vitr o effect of D S- 1 0 4 0 b o n h u ma n platelet 
a g gre gati o n was e val uate d i n h u ma n platelet -ric h plas ma.  Platelet a g gre gati o n i n hi biti o n 
u p t o t he hi g hest D S -1 0 4 0 b c o nce ntrati o n use d ( 1 0 0 μ m ol/ L ) was less t ha n 5 0 % f or all 
a g o nists use d.  M ore o ver, base d o n a d diti o nal i n vitr o st u dies, D S - 1 0 4 0 b di d n ot affect 
c oa g ulati o n as meas ured b y  pr ot hr o m bi n ti me ( P T) a n d acti vate d partial t hr o m b o plasti n 
ti me (a P T T).  Als o blee di n g ti me was n ot i m pacte d b y D S-1 0 4 0 b a d mi nistrati o n i n a n i n 
vi v o rat tail blee di n g ti me m o del w here n o ne of t he D S- 1 0 4 0 b d oses i n vesti gate d ( 3, 1 0, 
a n d 3 0 m g/ k g) res u lte d i n blee di n g ti me pr ol o n gati o n, w hile rec o m bi na nt tiss ue 
plas mi n o ge n acti vat or (rt -P A) 5. 2 m g/ k g si g nifica ntl y  pr ol o n ge d blee di n g ti me ± S E M 
fr o m 3 0 0 ± 5 5 sec t o 1 3 5 0 ± 1 2 1 sec.
I n si n gle-d ose t o xicit y  st u dies i n rats a n d c yn o m ol g us m o n ke y s D S-1 0 4 0 b i n d uce d ac ute 
t o xicities (a ni mal deat h) at hi g h d oses b y b ol us i njecti o n ( 3 0 0 m g/ k g i n rats a n d 
1 0 0 0 m g/ k g i n c y n o m ol g us m o n ke ys).  D S - 1 0 4 0 b di d n ot i n d uce detecta ble or ga n 
t o xicit y, ge n ot o xicit y, l ocal irritati o n, or he m olys is i n t o xicit y e val uati o n.  T he obser ve d 
t o xicities i n t he b ol us i njecti o n st u dies are belie ve d t o be relate d t o t he ac ute i ncrease i n 
e x p os ure after b ol us i njecti o ns.  T he n o o bser ve d a d verse effect le vel ( N O A E L) was 2 2 0 
m g/ k g f or rats a n d 6 6 m g/ k g f or c y n o m ol o g us m o n ke y s, wit h n o difference bet wee n 
se xes.  T he N O A E L i n t he 1 4 -d a y s re peate d-d ose i ntra ve n o us (I V) b ol us i njecti o n st u dies 
was 3 0 m g/ k g/ da y  f or b ot h rats a n d c yn o m ol g us m o n ke y s, wit h n o differe nces bet wee n 
se xes.  N o deat hs or test article relate d t o xicities were o bser ve d i n a n y of t he gr o u ps.   I n 
t he e xte n de d si n gle-d ose ( 0. 5 h o ur s h ort -ter m i nf usi o n f oll o we d b y 2 4 h o ur c o nti n u o us 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 6
i nf usi o n) t o xicit y st u dies t he N O A E L was 2 2 0 m g/ k g f or rats a n d 6 6 m g/ k g f or 
c yn o m ol g us m o n ke y s, wit h n o differe nce bet wee n se xes.
A 4 -d a y  c o nti n u o us i nf usi o n t o xicit y st u d y of D S-1 0 4 0 b was c o n d ucte d i n male a n d 
fe male F 3 4 4/ D u Crl Crlj rats.  The N O A E L after a 4 -da y  c o nti n u o us i ntra ve n o us i nf usi o n 
of D S -1 0 4 0 b i n rats was c o nsi dere d t o be 2 0 0 m g / k g/ da y f or b ot h males a n d fe males. 
T here was n o test article-relate d deat h or m ori b u n dit y  a n d n o test article -relate d c ha n ges 
i n cli nical si g ns, b o dy wei g ht, f o o d c o ns u m pti o n, he mat ol o g y , bl o o d c he mistr y, 
necr o ps y, or ga n wei g ht, or hist o pat h ol o g y  i n a ny gr o u p .
A d diti o nal i nf or mati o n o n n o ncli nical st u dies is a vaila ble i n t he I n vesti gat or’s Br oc h ure .2
1. 1. 1. 2. 
Cli nic al E x perie nce
T hree cli nical st u dies ha ve bee n c o m plete d i n h u ma ns wit h D S - 1 0 4 0 b (D S 1 0 4 0 - A-U 1 0 1 ,
D S 1 0 4 0 - A- E 1 0 2, a n d D S 1 0 4 0 - A-U 1 0 4 ) a n d t he res ults are s u m marize d bel o w. 
A d diti o nal details are a vaila ble i n t he I n vesti gat ors Br oc h ure 2.  
T he first -i n-h u ma n st u d y ( D S 1 0 4 0 -A- U 1 0 1) was a P hase 1, si n gle -bli n d 
place b o -c o ntr olle d, ra n d o mize d, 3 -part, si n gle -asce n di n g d ose st u d y t o assess t he safety, 
t olera bilit y, P K, a n d P D of D S-1 0 4 0 b i n healt h y y o u n g ( 1 8 t o 4 5 ye ars of a ge, i ncl usi ve) 
a n d el derl y ( 6 5 t o 7 5 ye ars of a ge, i ncl usi ve) s u bjects.  A t otal of 1 0 3 s u bjects were 
e nr olle d i n this st u d y  w hic h e val uate d 2 d osi n g re gi me ns:  a 0. 5-h o ur i ntra ve n o us (I V)
i nf usi o n ( Part 1 a n d Part 2) a n d a 0. 5 h o ur l oa di n g i nf usi o n f oll o we d b y a 2 3. 5-h o ur 
c o nti n u o us i nf usi o n ( Part 3).  I n Part 1 of t he st u d y, a t otal of 6 4 y o u n g s u bjects were 
e nr olle d i n 8 d ose c o h orts of 8 s u bjects eac h ( 6 acti ve a n d 2 place b o i n eac h c o h ort).  T he 
d oses of D S -1 0 4 0 b e val uate d were 0. 1, 0. 2, 0. 4, 0. 8, 1. 6, 3, 6, or 1 2 m g a d mi nistere d as 
0. 5- h o ur I V i nf usi o n.  I n Part 2 of t he st u d y , a t otal of 1 5 el derly s u bjects were e nr olle d i n 
2 d ose c o h orts:  7 s u bjects ( 6 acti ve a n d 1 place b o) i n a 3 m g d ose c o h ort a n d 8 s u bjects 
( 6 acti ve a n d 2 place b os) i n a 6 m g d ose c o h ort.  T he d oses of D S-1 0 4 0 b e val uate d, 3 m g 
a n d 6 m g, were a d mi nistere d as a 0. 5 -h o ur I V i nf usi o n.  In Part 3 of t he st u d y , a t otal of 
2 4 y o u n g s u bjects were e nr olle d i n 3 d ose c o h orts of 8 s u bjects eac h ( 6 acti ve a n d 2 
place b o i n eac h c o h ort).  T he d oses of D S -1 0 4 0 b e val uate d were 1 0, 2 0, or 4 0 m g 
a d mi nistere d as a l oa di n g i nf usi o n of 1 0 % of t he t otal d ose i n 0. 5 h o urs f oll o we d b y a 
2 3. 5- h o ur c o nti n u o us i nf usi o n.
T he c ha n ge i n c oa g ulati o n para meters P T, i nter na ti o nal n or malize d rati o (I N R), a P T T, 
a n d fi bri n o ge n fr o m baseli ne were mi n or a n d n ot cli nicall y  si g nifica nt; n o clear d ose 
relate d tre n ds were n ote d.  T here was n o cli nicall y si g nifica nt effect o n platelet 
a g gre gati o n ( perf or me d wit h 1 0 µ M a de n osi ne 5’ di p h os p hate a n d 0. 5 m M arac hi d o nic 
aci d) at a n y d ose le vel.  I n Part 1, a n i ncrease i n blee di n g ti me of 4 0 % t o 6 6 % was 
o bser ve d o n Da y  1 at t he e n d of i nf usi o n c o m pare d wit h Da y -1 f oll o wi n g D S - 1 0 4 0 b 
d oses of 3 m g, 6 m g, a n d 1 2 m g.  All blee di n g ti me val ues i n Part 1 re mai ne d wit hi n t he 
n or mal ra n ge (less t ha n 1 0 mi n utes), a n d t hese c ha n ges i n blee di n g ti me were n ot 
c o nsi dere d si g nifica nt.  T he blee di n g ti me i n Part 2 a n d Part 3 di d n ot s h o w a n y  D S-
1 0 4 0 b d ose relate d tre n d.  T here were n o cli nicall y  si g nifica nt c ha n ges o n a n y ot her 
safety la b orat or y  para meters.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 7
Plas ma e x p os ure of D S -1 0 4 0a, a free f or m of D S -1 0 4 0 b, i ncrease d pr o p orti o nall y wit h 
i ncreases i n d ose. Hi g her e x p os ure le vels were o bser ve d i n el derl y s u bjects c o m pare d 
wit h y o u n g s u bjects, w hic h is d ue t o pr ol o n ge d s yste mic eli mi nati o n.  T he mea n half -life 
( T1/ 2) i n el derl y s u bjects was l o n ger t ha n t hat i n y o u n g s u bjects at c orres p o n di n g d oses.  
Wit h 2 4 - ho ur c o nti n u o us i nf usi o n, b y 1 2 h o urs after t he e n d of i nf usi o n, plas ma dr u g 
c o nce ntrati o ns decrease d t o < 1 0 % of t he e n d -of- i nf usi o n c o nce ntrati o n. 
D S -1 0 4 0 b a d mi nistrati o n res ulte d i n a d ose -de pe n de nt decrease i n T A FIa acti vit y  a n d 
5 0 % cl ot l y sis ti me.  A dr u g -relate d i ncrease of D-di mer was als o o bser ve d wit h o ut clear 
d ose de pe n de nc y  i n healt h y s u bjects.  T here were n o c ha n ges i n t he le vel of T A FI 
a nti ge n.
O verall, t he D S -1 0 4 0 b d oses were well t olerate d i n y o u n g a n d el derl y s u bjects.  T he m ost 
c o m m o n treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ) [e x perie nce d b y ≥ 2 s u bjects ] were 
c o ntact der matitis, d ys pe psia, ecc hy m osis, a n d pai n i n e xtre mit y . All T E A Es were mil d 
or m o derate i n se verit y.  N o ne of t he m o derate T E A Es were c o nsi dere d t o be dr u g 
relate d.  N o deat hs, dr u g-relate d seri o us a d verse e ve nts ( S A Es), or disc o nti n uati o ns were 
re p orte d d uri n g t he st u dy.
I n a P hase 1, o pe n-la bel, si n gle-d ose, dr u g -dr u g i nteracti o n st u d y  ( D S 1 0 4 0- E-1 0 2), t he 
safety a n d t olera bilit y of a si n gle, I V d ose of D S- 1 0 4 0 b was assesse d i n healt h y s u bjects 
after 5 da ys of as piri n treat me nt.  A t otal of 1 8 s u bjects were e nr olle d i n t his st u d y.  Eac h 
s u bject recei ve d a l oa di n g d ose of 3 0 0 m g as piri n o n t he m or ni n g of Da y 1 f oll o we d b y a 
dail y  d ose of 7 5 m g as piri n o n Da ys 2, 3, 4, a n d 5.  O n t he m or ni n g of Da y  5, t he dail y 
d ose of as piri n was f oll o we d i m me diatel y b y a 6 -m g I V i nf usi o n of D S -1 0 4 0 b o ver 0. 5 
h o urs.
A si n gle -I V d ose of D S-1 0 4 0 b f oll o wi n g 5 da y s of as piri n treat me nt was safe a n d well 
t olerate d, wit h n o ne w or u ne x pecte d safety c o ncer ns n ote d .  T he mea n blee di n g ti me 
i ncrease d f oll o wi n g as piri n d osi n g fr o m pre d ose baseli ne t o Da y 4.  T here was n o 
a d diti o nal i ncrease i n mea n blee di n g ti me f oll o wi n g c o -a d mi nistrati o n of D S - 1 0 4 0 b o n 
Da y  5.
St u d y  D S 1 0 4 0- A- U 1 0 4 was a P hase 1 st u dy t o e val uate t he safet y a n d t olera bilit y of D S -
1 0 4 0 b 2 0 m g I V i nf usi o n c oa d mi nistere d wit h e n o xa pari n 1 m g/ k g s u bc uta ne o us i n 
healt h y  s u bjects.  Preli mi nar y  res ults i n dicate t hat c oa d mi nistrati o n of a si n gle d ose of 
e n o xa pari n 1 m g/ k g S C i njecti o n wit h a si n gle d ose of D S- 1 0 4 0 b 2 0 m g i nf use d o ver 1 2 
h i n healt h y  s u bjects was safe a n d well t olerate d. D S - 1 0 4 0a plas ma c o nce ntrati o ns a n d 
P K para meters were c o m para ble w he n D S -1 0 4 0 b was a d mi nistere d al o ne or i n 
c o m bi nati o n wit h e n o xa pari n. Si milarl y , plas ma e n o xa pari n (a nti- F Xa) le vels a n d P K 
para meters re mai ne d c o m para ble w he n e n o xa pari n was a d mi nistere d al o ne or wit h D S -
1 0 4 0 b. D S -1 0 4 0 b a d mi nistrati o n le d t o a mar ke d decrease i n T A FIa acti vit y  w hic h 
ret ur ne d t o baseli ne val ues wit hi n 3 6 h o urs after t he e n d of t he i nf usi o n. N o f urt her 
i m pact o n T A FIa acti vit y c o ul d be o bser ve d f oll o wi n g c oa di mi nstrati o n of D S- 1 0 4 0 b 
wit h e n o xa pari n. A d mi nistrati o n of e n o xa pari n al o ne di d n ot affect T A FIa acti vit y . T he 
m ost c o m m o n T E A Es (e x perie nce d b y ≥ 2 s u bjects) were at t he i nj ecti o n site of 
e n o xa pari n a n d D S -1 0 4 0 b I V i nf usi o n site, w hic h was re p orte d f oll o wi n g a d mi nistrati o n 
of e n o xa pari n or e n o xa pari n wit h D S- 1 0 4 0 b, a n d hea dac he, w hic h was re p orte d after 
a d mi nistrati o n of e n o xa pari n wit h D S- 1 0 4 0 b.  N o s p o nta ne o us blee di n g or b r uisi n g 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 8
occ urre d. All T E A Es re p orte d d uri n g t he st u d y  were mil d. N o a p pare nt effect of D S -
1 0 4 0 b or e n o xa pari n or t heir c o m bi nati o n o n a P T T c o ul d be o bser ve d.
1. 2. 
St u d y R ati o n ale
D S - 1 0 4 0 b is a n i n hi bit or of T A FIa i nte n de d f or use i n t he treat me nt of t hr o m b otic 
diseases i ncl u di n g V T E a n d ac ute isc he mic str o ke ( AI S).
Ve n o us t hr o m b oe m b olis m , w hic h e nc o m passes 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), is ass ociate d wit h a hi g h m or bi dit y a n d if left u ntreate d, ma y 
pr o gress t o a fatal o utc o me.  Ve n o us t hr o m b oe m b olis m is a c o m m o n dis or der wit h 
esti mate d a n n ual i nci de nce of a p pr o xi matel y  2 t o 3 per 1 0 0 0 i n di vi d uals.  Of t he 2 
c o m p o ne nts P E has m ore se vere c o nse q ue nces as it is ass ociate d wit h i ncrease d m ortal it y 
rates f or u p t o 3 m o nt hs after t he i n de x P E e ve nt.  T here are m ore t ha n 1 0 0 0 0 0 cases 
a n n uall y i n t he U S of P E wit h as ma n y as 2 5 % of patie nts e x perie nci n g s u d de n deat h3, 4.  
A ntic oa g ula nt t hera p y is t he mai nsta y  of t hera py f or s u bjects wit h ac ute V T E, wit h t he 
mai n o bjecti ve t o pre ve nt t hr o m b us e xte nsi o n a n d f urt her e m b olizati o n, ( b ot h earl y a n d 
late rec urre nces).  T he classical ma na ge me nt of s u bjects wit h V T E i n t he U S c o nsists of 
a n i nitial treat me nt wit h b o d y wei g ht-a dj uste d s u bc uta ne o us ( S C) l o w m olec ular wei g ht 
he pari n, a dj uste d -d ose I V o r fi xe d-d ose S C u nfracti o nate d he pari n ( U F H), or b o d y  
wei g ht -a dj uste d S C f o n da pari n u x, f oll o we d b y  l o n g-ter m treat me nt wit h a n oral vita mi n 
K a nta g o nist ( V K A) or a n o vel oral a ntic oa g ula nt ( N O A C) 5.  S yste mic or cat heter-
directe d fi bri n ol yt ic t hera p y is use d f or treat me nt of massi ve P E a n d f or ma na ge me nt of 
selecte d patie nts wit h s u b massi ve P E, w hereas cat heter-directe d fi bri n ol yt ic t hera py is 
use d i n s o me patie nts wit h e xte nsi ve ili ofe m oral D V T. Cli nical trial data i n patie nts wit h 
P E s h o we d t hat t hr o m b ol y sis was ass ociate d wit h l o wer ris k of rec urre nce of P E. I n 
patie nts wit h i nter me diate -ris k P E, t he be nefit of re d uce d m ortality ass ociate d wit h 
t hro m b ol y sis is offset b y i ncrease d ris k of maj or blee di n g e ve nts4.  Li mitati o ns of 
e xisti n g a ntit hr o m b otic dr u gs ha ve pr o m pte d a searc h f or n o vel a ge nts 6.  D S-1 0 4 0 b, a 
t os ylate salt of D S-1 0 4 0a, is a l o w m olec ular wei g ht c o m p o u n d t hat is u n der 
de vel o p me nt b y Daiic hi Sa n k y o I nc. as a n i njecta ble f or m ulati o n.  D S -1 0 4 0 b i n hi bits 
e nz ymatic acti vit y  of T A FIa a n d e n ha nces t hr o m b ol ytic acti vit y tri g gere d b y en d o ge n o us 
or e x o ge n o usl y a d mi nistere d t -P A.  T heref ore, D S -1 0 4 0 b is e x pecte d t o e n ha nce t he 
effect of t - P A a n d t o pr o vi de a n o vel a ntit hr o m b otic t hera p y i n V T E a n d AI S wit h o ut 
i ncreasi n g blee di n g ris k.   
1. 3. 
Ris k s a n d Be nefits f or St u d y S u bjects
N o cli nical s t u dies ha ve bee n c o n d ucte d i n h u ma n s u bjects t o e val uate t he efficac y of 
D S - 1 0 4 0 b.  H o we ver, t he res ults fr o m n o ncli nical st u dies s u g gest treat me nt wit h D S-
1 0 4 0 b ma y  e n ha nce fi bri n ol ysis i n t hr o m b oe m b olic disease.
N o a ntici pate d ris ks of D S -1 0 4 0 b ha ve bee n esta blis he d.  O verall, I V i nf usi o n of 
D S -1 0 4 0 b was safe a n d well t olerate d i n healt h y  yo u n g a n d el derl y s u bjects.  All T E A Es 
i n t he 3 c o m plete d P hase 1 cli nical st u dies were mil d or m o derate i n se verit y.  N o ne of 
t he m o derate T E A Es were c o nsi dere d t o be dr u g relate d.  N o deat hs, dr u g-relate d S A Es, 
or disc o nti n uati o ns were re p orte d i n t he c o m plete d cli nical st u dies.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 9
2. 
S T U D Y O B J E C TI V E S A N D H Y P O T H E SI S
2. 1. 
St u d y O bjecti ves
T he pri mar y  o bjecti ve of t his st u d y is t o e val uate t he safety a n d t olera bilit y usi n g 
blee di n g as t he pri mar y  e n d p oi nt. Sec o n daril y , t his st u d y will ser ve as a pr o of- of-
c o nce pt b y e val uati n g t he effect t hat D S -1 0 4 0 b a d mi nistrati o n has o n t otal t hr o m b us 
v ol u me re d ucti o n fr o m baseli ne t o t he e n d of i nf usi o n, assesse d b y  c o ntrast e n ha nce d 
c o m p ute d t o m o gra p h y sca n ( C T an gi o gra p h y or C T A). T his st u d y  will als o e val uate t he 
p har mac o ki netic/ p har mac o d y na mic ( P K/ P D ) a n d bi o mar ker acti vit y of D S-1 0 4 0 b i n 
s u bjects wit h ac ute P E a n d t he c orrelati o n wit h i ma gi n g.
2. 1. 1. 
Pri m ar y O bjecti ves
T he pri mar y  o bjecti ve of t he st u d y is t o assess t he safety a n d t olera bilit y of asce n di n g 
d oses of D S -1 0 4 0 b gi ve n as a si n gle I V i nf usi o n o ver 1 2, 2 4, 4 8 a n d 7 2 h o urs, 
res pecti vely, w he n a d de d t o sta n dar d of care (S O C ) a ntic oa g ulati o n t hera p y, c o mpare d t o 
p lace b o b y  e val uati n g t he rate of cli nically rele va nt blee di n g ( I nter nati o nal S ociet y of 
T hr o m b osis a n d Hae m ostasis (I ST H ) maj or or cli nicall y rele va nt no n- maj or blee di n g
[ C R N M]).
2. 1. 2. 
Sec o n d ar y O bjecti ves
T he sec o n dar y  objecti ves i ncl u de t he f oll o wi n g:
1.
R elati ve re d ucti o n (% re d ucti o n) i n t otal t hr o m b us v ol u me fr o m baseli ne t o ≤ 1 2 h 
fr o m e n d of D S-1 0 4 0 b i nf usi o n, assesse d b y  C T A i n se g me ntal or lar ger 
p ul m o nar y  arteries;
2.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % greater relati ve red ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S - 1 0 4 0 b i nf usi o n a n d c o m pare d t o place b o;
3.
Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % greater relati ve red ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y  C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S - 1 0 4 0 b i nf usi o n a n d c o m pare d t o place b o;
4.
Rec urre nce of V T E ( C o m p osite of rec urre nt P E, ne w or rec urre nt D V T, V T E -
relate d deat h; as well as t he i n di vi d ual c o m p o ne nts) u p t o h os pital d isc har ge a n d 
u p t o Da y  3 0 Visit after d osi n g;
5.
Deat h, maj or car di o vasc ular e ve nts ( [M A C E ]: defi ne d as a c o m p osite of 
car di o vasc ular deat h, n o n -fatal my ocar dial i nfarcti o n, str o ke, or s yste mic e m b olic 
e ve nts [ S E E]), he m o d yna mic dec o m pe nsati o n, treat me nt escalati o n ( defi ne d as 
catec h ola mi ne i nf usi o n, sec o n dar y t hr o m b ol ysis, e n d otrac heal i nt u bati o n, 
car di o p ul m o nar y res uscitati o n, or e mer ge nc y s ur gical e m b olect o my or t hr o m b us 
fra g me ntati o n by cat heter) u p t o h os pital d isc har ge a n d u p t o Da y  3 0 Visit after 
d osi n g ;
6.
O verall safet y e val uati o n ( S A Es, T E A Es, cli nical la b orat or y para meters) ;
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 0
7.
P har mac o ki netics of D S -1 0 4 0 b i n s u bjects wit h P E ;
8.
Assess t he P D effect of D S - 1 0 4 0 b o n T A FIa acti vit y , T A FI a nti ge n a n d D-di mer 
fi bri n ol ysis bi o mar kers, i n s u bjects wit h P E .
2. 1. 3. 
E x pl or at or y O bjecti ves
Assess t he effect of D S - 1 0 4 0 b o n cl ot l ysis as a bi o mar ker f or T A FIa acti vit y i n s u bjects 
wit h P E .
2. 2. 
St u d y H y p ot hesis
Res ults fr o m n o ncli nical st u dies s u g gest treat me nt wit h D S -1 0 4 0 b ma y  e n ha nce 
fi bri n ol ysis i n t hr o m b oe m b olic disease .  I n healt h y s u bjects I V a d mi nistrati o n of D S -
1 0 4 0 b i n d oses u p t o 4 0 m g o ver 2 4 h o urs was well t olerate d a n d res ulte d i n d ose -
de pe n de nt decrease s i n T A FIa acti vit y a n d 5 0 % cl ot l ysis ti me as well as dr u g-relate d 
i ncreases i n D-di mer, b ut wit h n o c lear d ose de pe n de nc y.
T his st u d y  will test t he h yp ot hesis t hat i n s u bjects wit h ac ute P E c haracterize d as l o w -
ris k, i nter me diate-ris k, or s u bmassi ve, treate d wit h S O C a ntic oa g ulati o n t hera p y, a d di n g
D S - 1 0 4 0 b, gi ve n at a d ose t hat pr o vi des c o m plete i n hi biti o n of T A FIa acti vit y, will res ult 
i n a greater re d ucti o n i n t otal t hr o m b us v ol u me fr o m baseli ne t o t he e n d of t he st u d y dr u g 
i nf usi o n, wit h n o i ncrease i n cli nicall y rele va nt blee di n g, w he n c o m pare d t o place b o.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 2
S u bjects m ust be h os pitalize d f or ac ute P E cate g orize d as l o w ris k, or i nter me diate -ris k, 
or s u b massi ve P E, ha ve C T A c o nfir mati o n of P E lesi o ns i n a se g me ntal or lar ger 
p ul m o nar y  arter y, a n d n ot ha ve s yste mic t hr o m b ol ytic or cat heter-base d t hera p y  pla n ne d 
i n or der t o be c o nsi dere d f or i ncl usi o n.  S u bjects s h o ul d be i n ot her wise satisfact or y
healt h i n t he o pi ni o n of t he I n vesti gat or a n d ma y  be alrea d y o n L M W ( He pari n) at 
ra n d o mizati o n, pr o vi de d t hat it was starte d wit hi n 3 6 h o urs of ra n d o mizati o n.
At t he ti me of ra n d o mizati o n, eli gi ble s u bjects m ust i nitiate or be tra nsiti o ne d t o t he 
st u d y-s pecifie d e n o xa pari n re gi me n.  After ra n d o mizati o n, t he s u bjects will recei ve a n I V 
i nf usi o n wit h bli n de d st u d y dr u g (eit her D S-1 0 4 0 b or place b o) o ver a peri o d of ti me 
ra n gi n g fr o m 1 2 h t o 7 2 h de pe n di n g o n t he c o h ort.  T he i nf usi o n d urati o n will be t he sa me 
f or all s u bjects e nr olle d wit hi n eac h c o h ort (Ta ble 3. 1 ). T he assi g n me nt t o eit her acti ve 
dr u g or place b o will be bli n de d t o t he s u bjects a n d st u d y  site staff w h o ma y c o me i n 
direct c o ntact wit h t he s u bjects as well as t o t he S p o ns or a n d Me d pace st u d y  tea m.    
F oll o wi n g t he e n d of st u d y  dr u g i nf usi o n t he a d mi nistrati o n of e n o xa pari n will c o nti n ue 
f or a n a d diti o nal 7 2 h t o c o nti n ue t o pr o vi de a u nif or m t hera pe utic bac k gr o u n d w hile 
P K/ P D sa m ple c ollecti o n is c o m plete d a n d a n a de q uate was h o ut peri o d bef ore s u bjects 
are s witc he d t o t he oral a ntic oa g ula nt, w hic h i n t his st u d y  will be e d o xa ba n. E n o xa pari n 
a d mi nistrati o n a n d P K/ P D sa m ple c ollecti o n after t he e n d of st u d y dr u g i nf usi o n ma y be 
d o ne i n a n a m b ula t or y setti n g if s u bjects are disc har ge d h o me.
Efficac y  will be e val uate d b y meas uri n g re d ucti o n i n t otal t hr o m b us v ol u me fr o m 
baseli ne t o ≤ 1 2 h p ost e n d of bli n de d st u d y  dr u g i nf usi o n usi n g i ma gi n g data, t heref ore 
c o nfir mati o n of meas ura ble P E lesi o n(s) b y C T A sca n i n a se g me ntal or lar ger p ul m o nar y 
arter y is ma n dat or y pri or t o ra n d o mizati o n.  In or der t o be i ncl u de d i n t he efficac y  
e val uati o n, s u bjects will ha ve t o s uccessf ull y  c o m plete t he I V i nf usi o n wit h bli n de d st u d y 
dr u g a n d ha ve vali d , i nter preta ble C T A sca ns, at b ot h baseli ne a n d at t he e n d of t he I V 
i nf usi o n. A sec o n d p ost -baseli ne C T A sca n is pla n ne d at Da y  3 0. All C T A sca ns will be 
rea d ce ntrally b y t he C ore I ma gi n g La b orat or y , w hic h will i de ntif y t he n u m ber a n d size 
of i n di vi d ual p ul m o nar y  lesi o ns at se g me ntal a n d hi g her p ul m o nar y arter y le vel a n d 
calc ulate t otal t hr o m b us v ol u me .  T he i ma gi n g met h o d will be vali date d usi n g t he data 
ge nerate d fr o m t he first 1 0 s u bjects i n C o h ort 1 acc or di n g t o t he vali dati o n pla n t o be 
de vel o pe d b y t he C ore Ima g i n g L a borat or y .  S h o ul d t he first vali dati o n fail, data fr o m t he 
ne xt 1 0 s u bjects e nr olle d i n eit her C o h orts 1 or 2 will be use d t o vali date t he met h o d.
A n i n de pe n de nt, u n bli n de d, Data M o nit ori n g C o m mittee ( D M C) will re vie w ke y  safety 
para meters f or eac h c o h ort a n d pr o vi de its e n d orse me nt f or t he c o nti n uati o n of t he st u d y  
a n d t he d ose escalati o n decisi o ns. T his st u d y  ma y be ter mi nate d at a n y ti me f or safety 
reas o ns u p o n a d vice of t he D M C. A n i n de pe n de nt, bli n de d Cli nical E ve nts C o m mittee 
( C E C) will be esta blis he d t o classif y blee di n g e ve nts, w hic h are t he pri mar y e n d p oi nt i n 
t his st u d y.  T he details o n t he r oles a n d res p o nsi bilities of b ot h D M C a n d C E C will be 
pr o vi de d i n t heir res pecti ve c harters.
I n C o h orts 1 a n d 2 eli gi ble s u bjects will be ra n d o mize d i n a 2: 1 rati o t o eit her D S -1 0 4 0 b 
or p lace b o. Be gi n ni n g wit h C o h ort 3 t he ra n d o mizati o n rati o will c ha n ge t o 3: 1.
St u d y  e nr oll me nt will be d o ne i n pairs of c o h orts, be gi n ni n g wit h C o h orts 1 a n d 2, 
f oll o we d b y C o h orts 3 a n d 4, t he n 5 a n d 6.
Wit hi n each pair of c o h orts, s u bject 
e nr oll me nt will be sta g gere d f or safet y , ie, enr oll me nt i n C o h orts 2, 4, a n d 6 will be gi n 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 4
a d mi nistrati o n f or C o h orts 3- 6 are s h o w n as ra n ges si nce t he y  will be c h ose n base d o n 
t he res ults of t he t w o pla n ne d d ose o pti mizati o n e val uati o ns.
T a ble 3 .1 : 
D osi n g R a n ges a n d I nf usi o n Dur ati o n b y C o h ort
C o h ort
T ot al D ose 1
( mg)
T ot al 
D ur ati o n of 
Bli n de d 
St u d y Dr u g 
I nf usi o n
L o a di n g I nf usi o n o ver 0. 5 h 
M ai nte n a nce I nf usi o n
D ose ( m g) 
D ur ati o n 
D ose ( m g) 
D ur ati o n
1
2 0
1 2 h
3
0. 5 h
1 7. 0 
1 1. 5 h
2
4 0
2 4 h
3
0. 5 h
3 7. 0 
2 3. 5 h
D O S E O P TI MI Z A TI O N E V A L U A TI O N B A S E D O N I M A GI N G A N D BI O M A R K E R D A T A
3
> 4 0 -≤8 0 1
2 4 h
3- 6
0. 5 h
3 7 - 7 4. 0 
2 3. 5 h
4
> 4 0 -≤1 2 0 1
4 8 h
3- 6
0. 5 h
3 7 -1 1 4 . 0 
4 7. 5 h
D O S E O P TI MI Z A TI O N E V A L U A TI O N B A S E D O N I M A GI N G A N D BI O M A R K E R D A T A
5
> 4 0 -≤1 6 0 1
4 8 h 2
3- 6
0. 5 h
3 7 -1 5 4 
4 7. 5 h
6
> 4 0 - ≤1 8 01
7 2 h 2
3- 6
0. 5 h
3 7 -1 5 4 
7 1. 5 h
1T otal d oses f or c o h orts 3, 4, 5 a n d 6 w ill be m ulti ples of t he o pti mal d ose calc ulate d base d o n t he res ults 
of t he i nteri m d ose o pti mizati o n e val uati o n pla n ne d after C o h orts 2 a n d 4, res pecti vel y.
2T he fi nal d urati o n f or C o h ort s 5 a n d 6 will be c h ose n bas e d o n t he res ults of  t he d ose o pti mizati o n 
e val uati o ns pla n ne d after C o h orts 2 a n d 4, res pecti vel y.
Si m ulate d P K pr ofiles f or t he first t w o c o h orts are s h o w n i n Ta ble 3. 2.  T he si m ulati o ns 
were c o n d ucte d usi n g a p o p ulati o n P K m o del esta blis he d fr o m t he earlier si n gle-
asce n di n g d ose st u d y i n healt h y y o u n g a n d el derl y s u bjects ( St u d y D S 1 0 4 0 -A- U 1 0 1), 
ass u mi n g a li near P K f or D S- 1 0 4 0 b o ver t he d oses t o be assesse d. Si m ulate d P K val ues 
s h o w n i n Ta ble 3. 2 refer t o t h ose i n t ypical s u bjects wit h b o d y  wei g ht of 7 5 kg a n d 
creati ni ne cleara nce ( Cr C L) of 6 0 a n d 9 0 m L / mi n, res pecti vely.
T a ble 3. 2:  
Si m ul ate d P K Pr ofiles f or C o h orts 1 a n d 2
C o h ort 
D osi n g Re gi me n
Cr C L 
( m L/ mi n)
Si m ul ate d Pl as m a P K P ar a meters
T ot al 
D ose
L o a di n g 
D ose
M ai nte n a nce 
D ose
C 0 5 
n g/ m L
C m a x
( n g/ m L)
T m a x
( hr)
A U C 
(n g * hr/
m L)
1
2 0 
m g
3 m g/ 0. 5 
h
1 7 m g/ 1 1. 5 h
6 0  
2 4 3  
3 0 1  
1 2  
4 7 9 7
9 0  
2 3 8  
2 5 5  
1 2  
3 9 3 5
2
4 0 
m g
3 m g/ 0. 5 
h
3 7 m g/ 2 3. 5 h
6 0  
2 4 3  
3 3 8  
2 4  
9 5 9 4
9 0  
2 3 8  
2 8 4  
2 4  
7 8 6 9
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 5
3. 3. 
St o p pi n g R ules
St o p pi n g r ules a n d or criteria t o st o p or m o dif y  d ose escalati o n d uri n g t he st u d y will be 
s pecifie d i n t he D M C c harter.  
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 6
4. 
S T U D Y P O P U L A TI O N
T his st u d y  will e nr oll s u bjects h os pitalize d f or ac ute P E c haracterize d as l o w-ris k, 
i nter me diate-ris k, or s u b massi ve f or w h o m t he pla n is t o be treate d wit h S O C 
a ntic oa g ulati o n t hera p y al o ne.
4. 1. 
I ncl usi o n Criteri a
S u bjects m ust satisf y  all of t he f oll o wi n g 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, a ge 1 8 t o 7 5 years a n d b o d y wei g ht bet wee n 5 0 a n d 
1 2 0 k g, i ncl usi ve;
2.
S u bjects a d mitte d t o h os pital wit h a cli nical dia g n osis of ac ute P E cate g ori ze d as 
l o w ris k or i nter me diate-ris k or s u b massi ve P E a n d f or w h o m cat heter-base d 
t hera py is n ot pla n ne d ;
a.
S u bjects m ust ha ve a C T A sca n c o nfir mi n g t he P E dia g n osis a n d wit h at 
least o ne meas ura ble i n de x lesi o n i n a se g me ntal or lar ger p ul m o nar y 
arter y pri or t o ra n d o mizati o n;
b.
S u bjects s h o ul d be i n ot her wise satisfact or y healt h i n t he o pi ni o n of t he 
I n vesti gat or;
c.
S u bjects ma y  ha ve c onc urre nt D V T a n d ha ve a n i nferi or ve na ca va (I V C)
filter place d pri or t o ra n d o mizati o n;   
d.
S u bjects ma y  alrea dy be o n S O C l o w m olec ular wei g ht [ L M W] ( He pari n) 
at t he ti me of ra n d o mizati o n b ut f or n o l o n ger t ha n 3 6 h o urs.
3.
A ble t o pr o vi de writte n i nf or me d c o nse nt.
4. 2. 
E xcl usi o n Criteri a
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be dis q ualifie d fr o m e nteri n g t he 
st u d y:
1.
S u bjects wit h ac ute P E cate g orize d as hi g h- ris k or massi ve, or w h o are 
he m o d y na micall y u nsta ble, e vi de nce d b y a heart rate > 1 2 0 / mi n a n d a s ys t olic 
bl o o d press ure ( S B P) of < 9 0 m m H g f or m ore t ha n 1 5 c o nsec uti ve mi n utes or a 
dr o p i n S B P of > 4 0 m m H g si nce prese ntati o n ;
2.
S u bjects f or w h o m use of a t hr o m b ol y tic, eit her syste mic or via cat heter, is 
pla n ne d ;
3.
S u bjects wit h P E lesi o ns o nl y  i n the s u b -se g me ntal or s maller arteries, w hic h d ue 
t o li mitati o ns of t he i ma gi n g met h o d ma y n ot be c o nsiste ntl y i de ntifie d a n d 
meas ure d ;
4.
S u bjects u na ble or u n willi n g t o ta ke t he st u d y-s o urce d S O C a ntic oa g ulati o n 
t hera py;
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 7
5.
S u bjects recei vi n g a n y V K As pri or t o ra n d o mizati o n or recei vi n g m ore t ha n 3 6 
h o urs treat me nt wit h L M W( He pari n) i n t hera pe utic d oses pri or t o ra n d o mizati o n ;
6.
S u bjects w h o ha d pri or i ntracra nial he m orr ha ge, k n o w n arteri o ve n o us 
malf or mati o n or a ne ur y s m, or e vi de nce of acti ve blee di n g;
7.
S u bjects wit h a p latelet c o u nt 1 0 0, 0 0 0, I N R 1. 7, or a n ele vate d partial 
t hr o m b o plasti n ti me;
8.
S u bjects w h o wit hi n 4 8 h o urs of ra n d o mizati o n ha ve use d a n a nti - Fact or IIa a ge nt 
s uc h as da bi gatra n or a n a nti- F Xa a ge nt s uc h as ri var o xa ba n, a pi xa ba n, or 
e d o xa b a n;
9.
S u bjects wit h hist or y  of e n d ocar ditis;
1 0. S u bjects wit h < 6 m o nt h hist or y  of ac ute c or o nar y s yn dr o me ( A C S) w het her or 
n ot t he y  ha ve u n der g o ne perc uta ne o us c or o nar y i nter ve nti o n ( P CI);
1 1. S u bjects w h o re q uire o n g oi n g d ual a nti platelet t hera p y or t reat me nt wit h as piri n
al o ne i n a d osa ge of m ore t ha n 1 0 0 m g/ per da y;
1 2. 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 3. S u bjects wit h u nc o ntr olle d h y perte nsi o n at ra n d o mizati o n, e vi de nce d by s ys t olic 
bl o o d press ure 1 8 0 m m H g or diast olic bl o o d press ure > 1 2 0 m m H g, or w h o 
re q uire pare nteral me dicati o n t o mai ntai n bl o o d press ure bel o w t hese li mits;
1 4. S u bjects w h o wit hi n 3 m o nt hs pri or t o ra n d o mizati o n ha ve ha d i ntracra nial 
s ur ger y, cli nically si g nifica nt hea d tra u ma (i n t he o pi ni o n of t he Pri nci pal 
I n vesti gat or), a str o ke, or ha ve recei ve d t hr o m b ol ytic treat me nt;
1 5. S u bjects wit h E C G e vi de nce of 2 n d de gre e or hi g her atri o ve ntric ular ( A V ) bl oc k 
or wit h Q Tc B or Q Tc F > 4 5 0 ms;
1 6. S u bjects w h o wit hi n 2 1 da y s pri or t o ra n d o mizati o n ha ve ha d gastr oi ntesti nal or 
ge nit o uri nar y  blee di n g;
1 7. S u bjects w h o wit hi n 1 4 da y s pri or t o ra n d o mizati o n ha ve ha d maj or s ur ger y or a 
l u mbar p u nct ure ( or e pi d ural ster oi d i njecti o n);
1 8. S u bjects wit h he m o gl o bi n < 1 0 g/ d L;
1 9. S u bjects wit h a n esti mate d gl o mer ular filtrati o n rate ( usi n g M o dificati o n of Diet 
i n Re nal Disease e q uati o n) 6 0 m L / mi n/ 1. 7 3 m2;
2 0. S u bjects wit h dia g n ose d acti ve li ver disease or wit h ele vati o n of li ver 
e nz ymes/ bilir u bi n: 
a.
Ala ni ne tra nsa mi nase ( A L T) or as partate tra nsa mi nase ( A S T) ≥ 2 ti mes 
u p per li mit of n or mal ( U L N)
b.
T otal bilir u bi n ( T B L) ≥1. 5 ti mes U L N (e xce pt d ue t o c o nfir me d Gil bert’s 
s yn dr o me)
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 8
2 1. S u bjects wit h k n o w n hist or y  of testi n g p ositi ve f or He patitis B a nti ge n or 
He patitis C a nti b o d y  bef ore ra n d o mizati o n;
2 2. S u bjects wit h k n o w n hist or y  of testi n g p ositi ve f or t he h u ma n i m m u n o deficie nc y 
vir us ( HI V) ;
2 3. S u bjects wit h acti ve mali g na nc y  ( dia g n ose d wit hi n 5 years) e xce pt f or a de q uatel y  
treate d n o n- mela n o ma s ki n ca ncer or ot her n o n-i n vasi ve or i n-sit u ne o plas m (e g, 
cer vical ca ncer i n sit u);
2 4. S u bjects u n der g oi n g c he m ot hera p y or ra diati o n t hera p y i n t he 3 0 da ys pri or t o 
ra n d o mizati o n or e x pecte d t o i nitiate s uc h t hera py d uri n g st u d y p artici pati o n ;
2 5. S u bjects wit h c o n gesti ve heart fail ure;
2 6. S u bjects wit h c hr o nic o bstr ucti ve p ul m o nar y  disease;
2 7. Fe male s u bjects of c hil d beari n g p ote ntial wit h a p ositi ve pre g na nc y  test or w h o 
are lactati n g, or u n willi n g t o use relia ble mea ns of c o ntrace pti o n ( p hys ical barrier,
patie nt or part ner) i n c o nj u ncti o n wit h a s per mici dal pr o d uct, c o ntra ce pti ve ( pill, 
patc h, i njecta ble) , or i ntra uteri ne de vices (I U Ds) f oll o wi n g treat me nt peri o d a n d 
t hr o u g h t he Da y 3 0 fi nal f oll o w-u p visit ;
2 8. S u bjects c urre ntl y partici pat i n g i n a n ot her i n vesti gati o nal st u d y or w h o ha ve 
partici pate d i n a n i n vesti gati o nal dr u g st u d y  wit hi n 3 0 da ys or pri or t o 
ra n d o mizati o n;
2 9. S u bjects u nli kel y  t o c o m pl y wit h t he pr ot oc ol (e g, u nc o o perati ve attit u de, 
i na bilit y t o ret ur n f or s u bse q ue nt visits, an d/ or ot her wise c o nsi dere d b y t he 
i n vesti gat or t o be u nli kel y t o c o m plete t he st u d y);
3 0. S u bjects wit h a n y  c o n diti o n (i ncl u di n g la b orat or y a b n or malities) t hat, i n t he 
o pi ni o n of t he I n vesti gat or, w o ul d p ote ntiall y  place t he s u bject at i ncrease d ris k of 
har m t hr o u g h partici pati o n i n t his st u d y .
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 9
5. 
S T U D Y T R E A T M E N T( S)
5. 1. 
Assi g ni n g S u bjects t o Tre at me nts a n d Bli n di n g
5. 1. 1. 
Tre at me nt Gr o u p (s)
O pe n -l a bel, b ac k gr o u n d S O C a ntic o a g ul ati o n re gi me n :
All s u bjects i ncl u de d i n t his st u d y  re gar dless of t he c o h ort or t he treat me nt ar m t o w hic h 
t he y are ra n d o mize d will recei ve S O C a ntic oa g ulati o n per t he c urre nt g ui deli nes f or 
treat me nt of patie nts wit h ac ute P E, t o e ns ure a n effecti ve t hera pe utic bac k gr o u nd. D ue 
t o t he early sta ge of de vel o p me nt a n d i n or der t o mi ni mize varia bilit y t he a ntic oa g ulati o n 
re gi me n f or t his st u d y was sta n dar dize d f or all s u bjects t o e n o xa pari n 1 m g/ k g,
s u bc uta ne o us q 1 2 h f or 5 da y s ( 6 da ys f or C o h ort 6) f oll o we d by e d o xa ba n 6 0 m g ( 3 0 m g 
f or s u bjects re q uiri n g d ose a dj ust me nt), per oral o nce dail y f or t he re mai n der of t he st u d y, 
t hr o u g h Da y 3 0.  B ot h e n o xa pari n a n d e d o xa ba n will be pr o vi de d b y  t he S p ons or as o pe n 
la bel a n d will be use d acc or di n g t o t heir a p pr o ve d l ocal la bel f or t his i n dicati o n. S u bjects 
m ust be o n t he sta n dar dize d, st u d y -s o urce d e n o xa pari n at t he ti me of ra n d o mizati o n, 
bef ore t he bli n de d st u d y  dr u g a d mi nistrati o n ma y be gi n. T he d urati o n of t he e n o xa pari n 
a d mi nistrati o n of 5 da ys f or C o h orts 1-5 a n d 6 da y s f or C o h ort 6 is dictate d b y t he nee d 
t o pr o vi de a u nif or m a ntic oa g ulati o n bac k gr o u n d d uri n g t he i nf usi o n wit h bli n de d st u d y 
dr u g (ra n gi n g fr o m 1 2 t o 7 2 h) a n d f or a n a d diti o nal 7 2 h o urs f oll o wi n g t he e n d of t he 
st u d y dr u g i nf usi o n t o all o w t he P K/ P D sa m ple c ollectio n t o c o m plete a n d t o pr o vi de a n 
a de q uate was h o ut peri o d bef ore t he s witc h t o t he oral a ntic oa g ula nt.     
F oll o wi n g t he e n d of t he st u d y , Sa va y sa ® / Li xia na® (e d o xa ba n, per oral, o nce daily) will 
be ma de a vaila ble at n o c ost t o t he patie nts f or at least 9 0 da y s, at t he i n vesti gat or’s 
discreti o n per t he c urre nt treat me nt g ui deli nes 1.
D o u b le- bli n d tre at me nt gr o u ps:
Wit hi n eac h c o h ort s u bjects alrea d y recei vi n g t he st u d y-s o urce d S O C e n o xa pari n will be 
ra n d o mize d t o o ne of t he f oll o wi n g t w o treat me nt gr o u ps:
1.
D S - 1 0 4 0 b, or
2.
D S -1 0 4 0 b p lace b o
5. 1. 2. 
Met h o d of Tre at me nt All oc ati o n
S u bjects will be ra n d o mi ze d t o t he st u d y b y re gisteri n g t he s u bject i n t he I nteracti ve 
V oice/ We b Res p o nse S yste m ( I xR S ).  At ra n d o mizati o n, t he a p pr o priate site pers o n nel
will c o ntact t he I xR S t o ra n d o mize s u bject t o t he a p pr o priate treat me nt c o h ort.  Ix R S will 
pr o vi de a u ni q ue s u bject i de ntificati o n n u m ber, all ocate t he treat me nt gr o u p assi g n me nt 
wit hi n t he c o h ort f or t he s u bject a n d pr o vi de t he a p pr o priate dr u g s u p pl y n u m ber( s). A 
fa x or e-mail will be se nt b y  t he Ix R S t o pr o vi de t he a p pr o priate c o h ort assi g n me nt a n d
dr u g s u p pl y.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 0
5. 1. 3. 
Bli n di n g
T he ra n d o mizati o n sc he d ule will be pr o d uce d b y a statisticia n fr o m t he Bi ostatistics 
C R O, acc or di n g t o t he s pecificati o ns pr o vi de d b y t he S p o ns or statisticia n.  A d u m m y  
sc he d ule will be pr o d uce d bef ore t he st u d y start a n d will be c hec ke d b y t he S p o ns or 
statisticia n.  After a p pr o val of t he d u m m y sc he d ule, t he Bi ostatistics C R O will m o dif y 
t he ra n d o m ge nerat or a n d iss ue t he fi nal ra n d o mizati o n t o a S p o ns or statisticia n n ot 
i n v ol ve d i n t his st u d y, w h o will a p pr o ve t he fi nal ra n d o mizati o n.  
Ra n d o mizati o n will be bli n de d t o t he s u bjects, I n vesti gat ors, S p o ns or ( Daiic hi Sa n k y o) 
st u d y tea m, a n d C R O ( Me d pace) a n d A R O (I T R E A S) staff.
T he d ose o pti mizati o n e val uati o n(s) will be carrie d o ut i n a n u n bli n de d fas hi o n b y  a 
se parate, desi g nate d tea m wit h t he a p pr o priate fire walls i n place t o pre ve nt acci de ntal 
u n bli n di n g of t he st u d y tea m.
5. 1. 4. 
E mer ge nc y U n b li n di n g Pr oce d ure
I n t he case of a n e mer ge nc y w here, i n t he o pi ni o n of t he I n vesti gat or, disc o nti n uati o n of 
st u d y dr u g i nf usi o n is n ot s ufficie nt a n d t he st u dy t reat me nt m ust be u n bli n de d i n or der t o 
e val uate f urt her a c o urse of me dical treat me nt , t he In vesti gat or ca n perf or m t he 
u n bli n di n g b y  directly accessi n g t he I xR S .
I n t he e ve nt of a n e mer ge nc y u n bli n di n g, t he s u bject will be i nf or me d a b o ut t heir 
treat me nt assi g ne d.  I nf or mati o n a b o ut t he treat me nt assi g n me nt m ust be restricte d t o 
desi g nate d st u d y  ce nter staff/ pers o n nel w h o are pr o vi di n g i m me diate care t o t he s u bject.  
A n y  d oc u me ntati o n of t he treat me nt assi g n me nt m ust be mai ntai ne d se paratel y (ie, i n a 
sec ure d file).  T he i nf or mati o n m ust n ot be i ncl u de d i n t he s u bject’s s o urce files t o 
e ns ure t he treat me nt assi g n me nt will re mai n bli n de d t o all ot her parties at t he site a n d 
fr o m t he C R O n ot i n v ol ve d wit h t he s u bject’s i m me dia te care.  
W he n a n e mer ge nc y  u n bli n di n g has occ urre d, a n a ut o matic n otificati o n ( via e-mail) will 
be se nt t o t he i n vesti gat or a n d selecte d Daiic hi Sa n k y o I nc. st u d y pers o n nel fr o m t he 
I xR S ve n d or.  T he n otificati o n will n ot c o ntai n a n y  u n bli n di n g i nf or matio n.  T his will 
tri g ger t he f oll o w-u p pr ocess t o d oc u me nt t he u n bli n di n g b y  c o m pleti n g t he E mer ge nc y 
U n bli n di n g b y I n vesti gat or F or m (t o be pr o vi de d b y st u d y pers o n nel u p o n recei pt of 
I xR S n otificati o n) a n d s u b missi o n t o Daiic hi Sa n k y o I nc. Cli nical Safet y a n d 
P har mac o vi gila nce ( C S P V); please refer t o t he f or m f or c o m pleti o n i nstr ucti o ns.
5. 2. 
St u d y Dr u g (s)
5. 2. 1. 
Descri pti o n
T he I n vesti gati o nal Pr o d ucts (I P) f or t his st u d y are:

D S -1 0 4 0 b ( 1 0 m g/ 1 0 m L )

D S - 1 0 4 0 b place b o ( 0. 9 % s o di u m c hl ori de i njecti o n)
All s u bjects will recei ve bac k gr o u n d S O C a ntic oa g ulati o n t hera p y per t he c urre nt 
sta n dar d of care f or patie nts wit h ac ute P E, w hic h f or t his st u d y  will i ncl u de e n o xa pari n 
f or 5 d a y s ( 6 d a y s f or C o h ort 6) f oll o we d b y  e d o xa ba n t hr o u g h t he e n d of st u d y visit at 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 1
Da y  3 0.
Bot h will be pr o vi de d as o pe n la bel a n d use d i n acc or da nce t o t heir a p pr o ve d 
la bel. T he a d mi nistrati o n of t he I P will ta ke place w hile s u bjects are recei vi n g 
e n o xa pari n, w hic h will c o nti n ue f or a n a d diti o nal 7 2 h after t he e n d of t he I V i nf usi on 
wit h bli n de d st u d y  dr u g. F oll o wi n g t he e n d of t he st u d y , Sa va y sa ® / Li xia na® (e d o xa ba n, 
per oral, o nce dail y) will be ma de a vaila ble at n o c ost t o t he patie nts f or at least 9 0 da y s, 
at t he i n vesti gat or’s discreti o n per t he c urre nt treat me nt g ui deli nes 1.
5. 2. 2. 
L a beli n g a n d P ac k a gi n g
D S -1 0 4 0 b I njecti o n 1 0 m g/ 1 0 m L will be pr o vi de d i n a clear glass vial. Details of t he 
pac k a gi n g a n d la beli n g of D S -1 0 4 0 b I njecti o n 1 0 m g/ 1 0 m L  will be pr o vi de d i n t he 
p har mac y  ma n ual.
E n o xa pari n will be s u p plie d i n pre-fille d s yri n ges.
Sa va y s a® / Li xia na® (e d o xa ba n) 6 0 m g a n d 3 0 m g ta blets will be pr o vi de d i n 3 0 c o u nt 
b ottles.
Pac ka gi n g a n d la beli n g will be perf or me d i n acc or da nce wit h G o o d Ma n ufact uri n g 
Practice.
5. 2. 3. 
Pre p ar ati o n
D S - 1 0 4 0 b Injecti o n 1 0 m g/ 1 0 m L a n d place b o will be pre pare d acc or di n g t o t he detaile d
pr oce d ures f or dr u g pre parati o n t hat are pr o vi de d i n t he p har mac y  ma n ual b y  a n 
u n bli n de d me m ber of t he site staff.
5. 2. 4. 
A d mi nistr ati o n
D S -1 0 4 0 b I njecti o n 1 0 m g/ 1 0 m L vial will be tra nsferre d i nt o I V i nf usi o n s ol uti o n ( 0. 9 % 
S o di u m C hl ori de I njecti o n, U S P).  T he p lace b o f or D S-1 0 4 0 b will be 0. 9 % S o di u m 
C hl ori de I njecti o n, U S P w hic h will be s o urce d at t he site .  
T he bli n de d s ol uti o n c o ntai ni n g eit her D S -1 0 4 0 b or p lace b o will be a d mi nistere d as a 
si n gle, c o nti n u o us I V i nf usi o n. T he I V i nf usi o n will c o nsist of a n i nitial l oa di n g d ose of 
3- 6 m g ( de pe n di n g o n t he c o h ort) a d mi nistere d as a 0. 5 h o ur i nf usi o n f oll o we d b y a 
mai nte na n ce d ose wit h t he bala nce of t he t otal d ose a d mi nistere d o ver t he re mai ni n g ti me 
f or t he res pecti ve c o h ort ( 1 1. 5 h f or C o h ort 1, 2 3. 5 h f or C o h orts 2 a n d 3, u p t o 4 7. 5 h f or 
C o h orts 4 a n d 5, a n d u p t o 7 2 h f or C o h ort 6). 
T he D S -1 0 4 0 b t otal d oses f or C o h orts 1 a n d 2 are 2 0 m g o ver 1 2 h a n d 4 0 m g o ver 2 4 h, 
res pecti vely. T hese d oses ha ve bee n s h o w n i n healt h y  v ol u nteers t o be safe a n d well 
t olerate d a n d t o pr o vi de a n al m ost c o m plete i n hi biti o n of T A FI acti vit y. U p t o t w o d ose 
o pti mizati o n e val uati o ns are pla n ne d usi n g i ma gi n g, P K/ P D, a n d bi o mar ker data fr o m 
C o h orts 1- 2 a n d 1 -4, res pecti vel y, t o o pti mize t he t otal d ose of D S -1 0 4 0 b a n d i nf usi o n 
d urati o n f or t he re mai ni n g c o h orts. 
Bac k gr o u n d a ntic oa g ulati o n t hera p y  per t he c urre nt S O C will be sta n dar dize d acr oss all
st u d y sites a n d s u bjects t o e n o xa pari n 1 m g/ k g s u bc uta ne o us, e ver y 1 2 h o urs f or 5 da ys 
( 6 da ys f or C o h ort 6) f oll o we d b y e d o xa ba n 6 0 m g ( 3 0 m g f or s u bjects re q uiri n g d ose 
a dj ust me nt), per oral, o nce dail y, t hr o u g h t he e n d of st u d y visit, at Da y 3 0 . B ot h 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 2
e n o xa pari n a n d e d o xa ba n will be pr o vi de d as o pe n la bel a n d use d i n acc or da nce t o t heir 
a p pr o ve d la bels.   F oll o wi n g t he e n d of t he st u d y , Sa va y sa ® / Li xia na® (e d o xa ba n, per oral, 
o nce dail y) will be ma de a vaila ble at n o c ost t o t he patie nts f or at least 9 0 da ys , at t he 
In vesti gat or’s discreti o n per t he c urre nt treat me nt g ui deli nes 1.
5. 2. 5. 
St or a ge
Dr u g s u p plies m ust be st ore d i n a sec ure, li mite d access st ora ge area u n der t he la bele d 
st ora ge c o n diti o ns:

D S -1 0 4 0 b I njecti o n 1 0 m g/ 1 0 m L s h o ul d be st ore d u p t o 2 5° C (e xc ursi o ns 
per mitte d u p t o 3 0° C);

D S -1 0 4 0 b I V s ol uti o n i n -use sta bilit y  will be pr o vi de d i n t he p har mac y 
ma n ual.
I n t he e ve nt of a n e xc ursi o n fr o m st ora ge re q uire me nts, t he site will q uara nti ne t he 
I n vesti gati o nal Pr o d uct a n d t he S p o ns or will deter mi ne w het her t he I n vesti gati o nal 
Pr o d uct ca n be use d.
L o ve n o x (e n o xa pari n) a n d Sa va y s a ® / Li xia na® (e d o xa ba n) s h o ul d be st ore d i n acc or da nce 
t o t heir la bel i nstr ucti o ns.
5. 2. 6.   
Dr u g Acc o u nt a bilit y
W he n a dr u g s hi p me nt is recei ve d, t he I n vesti gat or or desi g nee will c hec k t he a m o u nt 
a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal la n g ua ge i n t he la bel, dr u g 
e x pirati o n date, a n d si g n t he Recei pt of S hi p me nt F or m pr o vi de d.  Recei pt of s hi p me nt 
s ho ul d be ma de b y c o ntacti n g t he I x R S.  T he ori gi nal Recei pt of S hi p me nt F or m will be 
si g ne d a n d retai ne d at t he site.
I n a d diti o n, t he I n vesti gat or or desi g nee s hall c o ntact Me d pace pers o n nel as s o o 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 st u d y dr u g.  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 st u d y dr u g recei ve d, s u bject’s 
i de ntificati o n n u m ber f or w h o m t he st u d y dr u g was dis pe nse d , t he date a n d q ua ntit y of 
st u d y dr u g dis pe nse d a n d re mai ni n g, as well as t he i nitials of t he dis pe nser.
At t he e n d of t he st u d y, or as directe d, all D S -1 0 4 0 b, i ncl u di n g u n use d, partiall y  use d, or 
e m pt y c o ntai ners, will be destr o ye d at t he site.  I n t he e ve nt a site ca n n ot de str o y t he 
D S - 1 0 4 0 b, it will be ret ur ne d t o a desi g nee as i nstr ucte d by S p o ns or.  I n vesti gati o nal 
Pr o d uct 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 fi nal 
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 ret ur n of I n vesti gati o nal 
Pr o d uct m ust be d oc u me nte d a n d t he d oc u me ntati o n i ncl u de d i n t he s hi p me nt.  At t he 
e n d of t he st u d y, a fi nal I n vesti gati o nal Pr o d uct rec o nciliati o n state me nt m ust be 
c o m plete d b y t he I n vesti gat or or desi g nee a n d pr o vi de d t o t he S p o ns or.  U n use d dr u g 
s u p plies ma y be destr o ye d b y t he I n vesti gat or w he n a p pr o ve d i n writi n g b y S p o ns or a n d 
S p o ns or has recei ve d c o pies of t he site’s dr u g ha n dli n g a n d dis p ositi o n Sta n dar d 
O perati n g Pr oce d ures ( S O Ps).
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 3
All I nvesti gati o nal P r o d uct i n ve nt or y f or ms m ust be ma de a vaila ble f or i ns pecti o n b y  a 
S p o ns or a ut h orize d re prese ntati ve or desi g nee a n d re g ulat or y  a ge nc y i ns pect ors.  T he 
I n vesti gat or is res p o nsi ble f or t he acc o u nta bilit y of all use d a n d u n use d st u d y s u p plies at 
t he site.
5. 3. 
C o ntr ol Tre at me nt
T he c o ntr ol i n t his st u d y will be place b o beca use f or patie nts wit h ac ute P E c haracterize d 
as l o w ris k, i nter me diate-ris k, or s u b massi ve, w hic h is t he p o p ulati o n tar gete d f or 
i ncl usi o n i n t his st u d y, t he c urre nt S O C d oes n ot pr o vi de a n y ot her treat me nt o pti o ns 
be si des a ntic oa g ulati o n.
All s u bjects partici pati n g i n t his st u d y will recei ve S O C a ntic oa g ulati o n t hera p y  as per 
t he c urre nt treat me nt g ui deli nes f or patie nts wit h ac ute P E, t o e ns ure a n effecti ve 
t hera pe utic bac k gr o u n d.  D ue t o t he earl y sta ge of de vel o p ment a n d i n or der t o li mit 
varia bilit y , t he bac k gr o u n d a ntic oa g ulati o n re gi me n use d i n t his st u d y will be 
sta n dar dize d f or all s u bjects t o e n o xa pari n, 1 m g/ k g, s u bc uta ne o us, e ver y 1 2 h o urs f or u p 
t o 6 da ys f oll o we d b y Sa va ys a ® / Li xia na® (e d o xa ba n) 6 0 m g ( 3 0 m g f or s u bjects re q uiri n g 
d ose a dj ust me nt) ( per oral o nce daily) t hr o u g h t he e n d of st u d y visit, at Da y 3 0. After 
disc o nti n uati o n of t he e n o xa pari n, t he first d ose of Sa va y sa ® / Li xia na® s h o ul d be ta ke n at 
t he ne xt sc he d ule d a d mi nistrati o n of e n o xa parin 7, 8.  T he a d mi nistrati o n of D S - 1 0 4 0 b or
p lace b o via I V i nf usi o n will ta ke place w hile st u d y s u bjects are bei n g treate d wit h 
e n o xa pari n.  B ot h e n o xa pari n a n d e d o xa ba n will be pr o vi de d as o pe n la bel a n d use d i n 
acc or da nce t o t heir a p pr o ve d la bels. F oll o wi n g t he e n d of t he st u d y , Sa va ysa ® / Li xia na®
(e d o xa ba n, per oral, o nce dail y) will be ma de a vaila ble at n o c ost t o t he patie nts f or at 
least 9 0 da ys, at i n vesti gat or’s discreti o n per t he c urre nt treat me nt g ui deli nes 1.
5. 4. 
D ose I nterr u pti o ns a n d Re d ucti o ns
S u bjects ma y  i nterr u pt t he I V i nf usi o n wit h bli n de d st u d y dr u g at a n y ti me d ue t o safety 
reas o ns a n d i n t hese cases st u d y dr u g a d mi nistrati o n s h o ul d be per ma ne ntl y disc o nti n ue d.  
Please refer t o Secti o n 5. 7. 1 f or a d diti o nal i nf or mati o n.  S h ort i nterr u pti o ns t o a d dress I V 
li ne bl oc ka ge are per mitte d.
D os e re d ucti o ns are n ot per mitte d f or st u dy dr u g i n t his st u d y.
5. 5. 
Met h o d of Assessi n g Tre at me nt C o m pli a nce
All s u bjects i n t his st u d y  will recei ve t he I V i nf usi o n wit h D S-1 0 4 0 b or p lace b o as 
h os pital i n patie nts a n d u n der n ursi n g s u per visi o n.
Si nce D S - 1 0 4 0 b a n d place b o I V i nf usi o ns will be a d mi nistere d at t he site, treat me nt 
c o m plia nce will n ot be m o nit ore d i n t his st u d y. H o we ver, t he ti me of a d mi nistrati o n a n d 
d ose a m o u nt will be ca pt ure d f or eac h s u bject. A d mi nistrati o n of st u d y  dr u g will be 
rec or de d i n t he e C R F.
E n o xa pari n a n d e d o xa ba n will be use d i n acc or da nce wit h t heir res pecti ve la bels a n d per 
t he S O C t o pr o vi de a u nif or m a n d effecti ve a ntic oa g ulati o n re gi me n f or all s u bjects i n 
t his st u d y. Si nce e n o xa pari n will be a d mi nistere d at t he site or by a visiti n g n urse at t he 
s u bject’s h o me, treat me nt c o m plia nce will n ot be meas ure d. H o we ver, t he date a n d ti me 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 4
of a d mi nistrati o n a n d d ose a m o u nt will be ca pt ure d f or eac h s u bject i n t he electr o nic case 
re p ort f or m (e C R F). Si milarl y  t he date a nd ti me w he n t he e d o xa ba n t hera p y  is i nitiate d 
will be rec or de d i n t he e C R F.
5. 6. 
Pri or a n d C o nc o mit a nt Me dic ati o ns
D uri n g st u d y dr u g a d mi nistrati o n a n d f or t he s pecifie d n u m ber of da y s f oll o wi n g t he 
c o m pleti o n of st u d y dr u g i nf usi o n or u p o n earl y wit h dra wal, t h e f oll o wi n g me dicati o ns 
are n ot all o we d:

A nti platelet a ge nts (as piri n, cl o pi d o grel) :
After 2 4 h o urs p ost-st u d y dr u g 
a d mi nistrati o n , use of a nti platelet a ge nt will be at t he discreti o n of t he 
Pri nci pal I n vesti gat or.

A n y  t hr o m b olyt ic a ge nt, use d eit her sys te micall y or cat heter -directe d f or at 
least 7 2 h o urs after t he e n d of st u d y dr u g i nf usi o n.
D uri n g t he st u d y , c o nc o mita nt me dicati o ns re q uire d t o treat T E A Es will be per mitte d. 
Ot her c o nc o mita nt me dicati o ns f or pre -e xisti n g c o n diti o ns (ie, h yperte nsi o n, dia b etes, 
etc.) are per mitte d, u nless ot her wise s pecifie d a b o ve. C o nc o mita nt me dicati o n usa ge will 
be at t he discreti o n of t he Pri nci pal I n vesti gat or.
A n y  me dicati o n ( ot her t ha n st u d y dr u g) ta ke n by s u bjects d uri n g t he c o urse of t he st u d y  
will be rec or de d a n d c o de d usi n g t he W orl d Healt h Or ga nizati o n ( W H O) dr u g dicti o nar y .
5. 7. 
S u bject Wit h dr a w al/ Disc o nti n u ati o n
5. 7. 1. 
Re as o ns f or Wit h dr a w al
Te m p orar y  i nterr u pti o ns i n t he a d mi nistrati o n of st u d y dr u g i nf usi o ns, ot her t ha n brief 
o nes t o a d dress a bl oc ke d I V li ne, are n ot all o we d i n t his st u d y . If a s u bjects nee ds t o 
i nterr u pt a d mi nistrati o n of t he st u d y dr u g i nf usi o n, t he n st u d y dr u g a d mi nistrati o n m ust 
be per ma ne ntl y disc o nti n ue d. T he reas o n f or t he st u d y  dr u g disc o nti n uati o ns will be 
rec or de d i n the e C R F. A s u bject ma y  disc o nti n ue st u d y dr u g f or a n u m ber of reas o ns 
i ncl u di n g t h ose liste d bel o w.

Reas o ns Relate d t o a d verse e ve nts ( A E s):

I nitiati n g or 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 A E or ot her safet y c o ncer n t hat is relate d t o st u d y dr u g treat me nt;

Maj or life -t hreate ni n g blee di n g ( per I S T H defi niti o n);

Wit h dra wal b y  S u bject

P h y sicia n Decisi o n

Deat h

Pr ot oc ol De viati o n

St u d y  Ter mi nate d b y S p o ns or
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 5

Ot her
5. 7. 2.   
Wit h dr a w al Pr oce d ures
If a s u bject is wit h dra w n fr o m t he st u d y, t he I n vesti gat or will c o m plete a n d re p ort t he 
o bser vati o ns as t h or o u g hl y  as p ossi ble u p t o t he date of wit h dra wal i ncl u di n g t he date of 
last treat me nt a n d t he reas o n f or wit h dra wal.
If t he s u bject is wit h dra w n d ue t o a n a 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.
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d d uri n g wit h dra wal:

O btai n s u pi ne vital si g n assess me nts;

Perf or m a 1 2 -lea d E C G i n tri plicate;

O btai n bl o o d sa m ples f or safet y la b orat or y  assess me nts (ser u m c he mistr y a n d 
he mat ol o g y );

C ollect uri ne sa m ple f or uri nal y sis;

Uri ne pre g na nc y  test;

Assess s u bject f or A E s;

Rec or d c o nc o mita nt me dicati o ns.
5. 7. 3. 
S u bjects L ost t o F oll o w -u p
If a s u bject bec o mes l ost t o f oll o w -u p, t he sites will be gi ve n i nstr ucti o ns o n acti o ns t o 
ta ke t o tr y t o l ocate t he s u bject.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 6
6. 
S T U D Y P R O C E D U R E S
A sc he matic st u d y visit sc he d ule is pr o vi de d i n A p pe n di x 1 7. 1 .
6. 1. 
S t u d y Q u alific ati o n/ Pre- Ra n d o miz ati o n
T he s u bject will be h os pitalize d d uri n g t his peri o d.  
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 nf or me d c o nse nt f or m (I CF) .  T he s u bject 
d oes n ot nee d t o re peat rece ntl y 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 pre -
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 o n.  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 hat t he 
s u bject is eli gi ble f or t he st u d y:

Si g n I C F;

Assess i ncl usi o n/e xcl usi o n criteria (see Secti o n 4. 1 a n d Secti o n 4. 2 );

R e vie w me dical hist or y ;

R e vie w a n y pri or a n d c o nc o mita nt me dicati o ns;

E ns ure t hat t he s u bject has a dia g n osis of P E i n a se g me ntal or lar ger arter y
c o nfir me d b y a p pr o priate i ma gi n g met h o ds;

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 (see Secti o n 4. 2 ):
Sa m ples ta ke n as part of r o uti ne care o utsi de st u d y a us pices ma y  be a nalyz e 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 4 8 h o urs of ra n d o mizati o n.  Alter nati vel y , t he ce ntral la b orat or y ma y be utilize d 
f or t he a b o ve st u d y q ualificati o n la b orat or y tests.

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 ur es 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.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 7
6. 2. 
D a y 0 : B aseli ne Visit
T he s u bject c o nti n ues t o be h os pitalize d d uri n g t his peri o d.

Re gister t he s u bject i n t he I nteracti ve V oice/ We b Res p o nse S y ste m (Ix R S )

Rec or d a n y pri or a n d c o nc o mita nt me dicati o ns (c o nfir m t hat s u bject di d n ot 
be gi n treat me nt wit h L M W
he pari n earlier t ha n 3 6 h o urs pri or t o d osi n g) ;

Assess s u bjects f or A Es;

Perf or m p h ys ical e xa mi nati o n, i ncl u di n g wei g ht;

O btai n s u pi ne vital si g n assess me nts;

Perf or m a 1 2- lea d E C G i n tri plicate;

O btai n bl o o d sa m ples f or ce ntral la b orat or y safety assess me nts (ser u m 
c he mistr y a n d he mat ol o g y, see Secti o n 9. 8 a n d A p pe n di x 1 7. 2 )

O btai n bl o o d sa m ple f or C oa g ulati o n Pa nel (see Secti o n 9. 8 a n d
A p pe n di x 1 7. 2 ) ;

O btai n a uri ne sa m ple f or ce ntral la b orat or y uri nal y sis (see Secti o n 9. 8 a n d 
A p p e n di x 1 7. 2 );

O btai n a ser u m or uri ne sa m ple f or pre g na nc y testi n g i n w o me n of 
c hil d beari n g p ote ntial.  T he pre g na nc y  test will be perf or me d wit h eit her 
ser u m or uri ne sa m ples f oll o wi ng sta n dar d practice at t he site ;

O btai n P K bl o o d sa m ple s (see Secti o n Secti o n 8. 1 a n d A p pe n di x 1 7. 2 );

O btai n P D bl o o d sa m ple ( see Secti o n Secti o n 8. 2 a n d A p pe n di x 1 7. 2 );

Rec or d C T sca n f or t hr o m b us meas ure me nt;

I nitiate or tra nsiti o n s u bject t o t he st u d y-s pecifie d e n o xa pari n re gi me n;

Start t he st u d y dr u g i nf usi o n .
A n o pti o nal P G x sa m ple ca n be o btai ne d at a n y ti me after d osi n g.
6. 3. 
D a y 1 -3: D o u ble -Bli n d Tre at me nt Peri o d
T he s u bject c o nti n ues t o be h os pitalize d d uri n g t his peri o d.  T he f oll o wi n g pr oce d ures are 
t o be perf or me d at t he e n d of t he bli n de d st u d y  dr u g i nf usi o n:

Rec or d a n y pri or a n d c o nc o mita nt me dicati o ns;

Assess s u bjects f or A Es;

O btai n s u pi ne vital si g n assess me nts;

Perf or m a 1 2 -lea d E C G i n tri plicate;

O btai n C oa g ulati o n Pa nel bl o o d sa m ple s;

O btai n P K bl o o d sa m ple s;
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 8

O btai n P D bl o o d sa m ple s;

Rec or d C T sca n f or t hr o m b us meas ure me nt ( n o m ore t ha n 1 2 h o urs after t he 
e n d of i nf usi o n).
6. 4. 
D a y 4 -6: 7 2 h o ur After E n d of I nf usi o n F oll o w- u p

Rec or d a n y pri or a n d c o nc o mita nt me dicati o ns;

Assess s u bjects f or A Es;

O btai n s u pi ne vital si g n assess me nts;

Perf or m a 1 2-lea d E C G i n tri plicate ( o pti o nal);

O btai n bl o o d sa m ples f or safet y la b orat or y  assess me nts (ser u m c he mistr y a n d 
he mat ol o g y ) wit hi n 1 2 h o urs after t he e n d of i nf usi o n or at t he ti me of 
disc har ge ;

O btai n a uri ne sa m ple f or uri nal y sis wit hi n 1 2 h o urs after t he e n d of i nf usi o n
or at t he ti me of disc har ge ;

O btai n C oa g ulati o n Pa nel bl o o d sa m ple s;

O btai n P K bl o o d sa m ple s;

O btai n P D bl o o d sa m ple s.
S u bjects m ust re mai n h os pitalize d d uri n g st u d y  dr u g i nf usi o n ( D S-1 0 4 0 or place b o) a n d 
ma y  be disc har ge d a n y ti me after t he e n d of st u dy dr u g i nf usi o n C T sca n is o btai ne d, at 
t he In vesti gat or’s discreti o n.  H o we ver, it will be necessar y f or s u bjects t o c o nti n ue 
a ntic oa g ulati o n treat me nt wit h e n o xa pari n, u ntil s witc hi n g t o e d o xa ba n, as well as t o 
o btai n P K/ P D sa m ples fr o m s u bjects f or a n a d diti o nal 7 2 h o urs p ost- st u d y dr u g i nf usi o n.  
T his ma y  be acc o m plis he d b y kee pi n g t he s u bject h os pitalize d f or t he a d diti o nal ti me 
nee de d, or usi n g h o me n ursi n g ser vices if t he s u bject is disc har ge d bef ore c o m pleti n g 
t hese st u d y pr oce d ures.  
6. 5. 
D a y 3 0 ± 3 d a ys : L o n g ter m F oll o w -u p Peri o d
T his visit will be perf or me d i n a n o ut patie nt setti n g.

Rec or d a n y pri or a n d c o nc o mita nt me dicati o ns;

Assess s u bjects f or A Es;

O btai n s u pi ne vital si g n assess me nts;

Perf or m p h ys ical e xa mi nati o n;

Rec or d C T sca n f or t hr o m b us meas ure me nt.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 9
7. 
E F FI C A C Y A S S E S S M E N T S
7. 1. 
Pri m ar y Effic ac y E n d p oi nt (s)

R elati ve re d ucti o n ( %re d ucti o n) i n t otal t hr o m b us v ol u me fr o m baseli ne t o ≤ 
1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n assesse d b y  C T A) i n se g me ntal or lar ger 
p ul m o nar y  arteries;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % greater relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % great er relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n.
7. 2. 
Sec o n d ar y Effic ac y E n d p oi nt (s)

Rec urre nce of V T E ( C o m p osite of rec urre nt P E, ne w or rec urre nt D V T, V T E -
relate d deat h; as well as t he i n di vi d ual c o m p o ne nts) u p t o h os pital disc har ge 
a n d u p t o Da y  3 0 Visit;

Deat h, he m o d y na mic dec o m pe nsati o n, or treat me nt escalati o n ( defi ne d as 
catec h ola m i ne i nf usi o n, sec o n dar y t hr o m b ol ysis, e n d otrac heal i nt u bati o n, 
car di o p ul m o nar y res uscitati o n, or e mer ge nc y s ur gical e m b olect o my or 
t hr o m b us fra g me ntati o n b y cat heter) u p t o h os pital disc har ge a n d u p t o Da y  
3 0 p ost ra n d o mizati o n;

M A C E
(defi ne d as a c o m p osit e of car di o vasc ular deat h, or n o n-fatal 
m y ocar dial i nfarcti o n, str o ke, or S E E ) u p t o h os pital disc har ge a n d u p t o Da y  
3 0 Visit .
7. 3. 
E x pl or at or y Effic ac y E n d p oi nt(s)
E val uati o n of T A FIa acti vit y  usi n g cl ot l ysis as a bi o mar ker.
7. 4. 
A p pr o pri ate ness of Selecte d Effic ac y E n d p oi nt (s)
I n or der t o assess t he o bjecti ve of a ntic oa g ula nt t hera p y t o pre ve nt t hr o m b us e xte nsi o n 
a n d f urt her e m b olizati o n, t he relati ve re d ucti o n i n t otal t hr o m b us v ol u me , defi ne d as 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S - 1 0 4 0 b i nf usi o n, was selecte d as ke y efficac y 
e n d p oi nt.  Si nce t here is n o e vi de nce of D S -1 0 4 0 b effects o n re d ucti o n i n t otal t hr o m b us 
v ol u me f or s u bjects wit h ac ute P E c haracterize d as l o w-ris k or i nter me diate-ris k or 
s u b massi ve P E, b ot h c o nti n u o us a n d dic h ot o m o us e val uati o ns will be c o n d ucte d.
F urt her m ore, t o detect a n y  si g nals f or efficac y o n cli nical e n d p oi nts, rec urre nce of V T E, 
deat h, he m o d y na mic dec o m pe nsati o n, or treat me nt escalati o n, a n d M A C E u p t o h os pital 
disc har ge a n d u p t o Da y  3 0 Visit will be assesse d.
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8. 
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C 
A S S E S S M E N T S
Bl o o d sa m ples f or P K/ P D a nal ys es will be o btai ne d at t he ti me p oi nts s pecifie d i n t he 
Sc he d ule of E ve nts ( A p pe n di x 1 7. 1 ).  I nstr ucti o ns f or t he ha n dli n g of bl o o d sa m ples a n d 
s hi p pi n g of plas ma sa m ples f or P K/ P D a nalys es are i ncl u de d i n t he se parate la b orat or y  
ma n ual.  T he act ual ti me of st u d y  dr u g a d mi nistrati o n a n d t he e xact ti me of bl o o d 
sa m pli n g f or P K a nalys is m ust be rec or de d o n t he e C R F.
Plas ma c o nce ntrati o ns of D S -1 0 4 0a will be deter mi ne d b y  a vali date d li q ui d 
c hr o mat o gra p h y – ta n de m mass s pectr o metr y met h o d.  Details a b o ut t he assa y met h o d 
a n d vali dati o n res ults are i ncl u de d i n a se parate d oc u me nt pre pare d b y t he bi oa na l ytical 
la b orat or y.
8. 1. 
P h ar m ac o k i netic ( P K) E n d p oi nt (s)
Bl o o d sa m ples f or P K assess me nt will be c ollecte d i n eac h c o h ort at t he f oll o wi n g ti me 
p oi nts :

C o h ort 1 : 0, 0. 5 (i m me diatel y pri or t o e n d of l oa di n g i nf usi o n), 3, 6, 1 2 
(i m me diatel y pri or t o e n d of mai nte na nce i nf usi o n), 1 8, 2 4, 4 8 , a n d 7 2 h o urs

C o h orts 2 a n d 3 : 0, 0. 5 (i m me diatel y pri or t o e n d of l oa di n g i nf usi o n), 6, 1 2, 
2 4 (i m me diatel y  pri or t o e n d of mai nte na nce i nf usi o n), 3 6, 4 8, 7 2 , a n d 9 6 
h o urs

C o h orts 4 a n d 5 : 0, 0. 5 (i m me diatel y pri or t o e n d of l oa di n g i nf usi o n), 1 2, 
2 4, 4 8 (i m me diatel y  pri or t o e n d of mai nte na nce i nf usi o n), 6 0, 7 2, 9 6 , a n d 1 2 0 
h o urs

C o h ort 6 : 0, 0. 5 (i m me diatel y pri or t o e n d of l oa di n g i nf usi o n), 1 2, 2 4, 4 8, 7 2 
(i m me diatel y pri or t o e n d of mai nte na nce i nf usi o n), 8 4, 9 6, 1 2 0, a n d 1 4 4 
h o urs
P K sa m pli n g sc he me f or C o h orts 3- 6 is pr o visi o nal, w hic h ma y  be m o difie d de pe n di n g 
o n t he o pti mal d ose/re gi me n t o be c h ose n.   
T he f oll o wi n g P K para meters will be calc ulate d fr o m t he plas ma c o nce ntrati o ns of 
D S -1 0 4 0a usi n g n o nc o m part me ntal a nal ys is:

area u n der c o nce ntrati o n- vers us -ti me c ur ve, fr o m ti me 0 t o t he last 
q ua ntifia ble c o nce ntrati o n sa m pli n g p oi nt ( A U C last);

ma xi m u m ( pea k) o bser ve d plas ma c o nce ntrati o n ( C
ma x );

ti me of ma xi m u m o bser ve d c o nce ntrati o n  ( Tma x );

plas ma c o nce ntrati o n i m me diatel y pri or t o t he e n d of c o nti n u o us i nf usi o n
If data per mit, t he f oll o wi n g para meters will be esti mate d: 
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
t he area u n der t he c o nce ntrati o n-vers us -ti me c ur ve, fr o m ti me 0 e xtra p olate d 
t o i nfi nit y ( A U C0- i nf);

eli mi nati o n half-life (T 1/ 2);

cleara nce ( C L).
8. 2. 
P h ar m ac o d y n a mic ( P D) E n d p oi nt (s)
Bl o o d sa m ples f or P D assess me nt of t otal T A FIa acti vit y , T A FI a nti ge n, D -di mer , a n d 
cl ot l ysis will be c ollecte d i n eac h c o h ort at t he f oll o wi n g ti me p oi nts:

C o h ort 1 : Baseli ne ( pre d ose) , 0. 5 (e n d of l oa di n g i nf usi o n), 6, 1 2 (e n d of 
mai nte na nce i nf usi o n), 2 4 a n d 4 8 h o urs

C o h orts 2 a n d 3 : Baseli ne ( pre d ose) , 0. 5 (e n d of l oa di n g i nf usi o n), 2 4 (e n d of 
mai nte na nce i nf usi o n), 3 6, 4 8 , a n d 7 2 h o urs

C o h orts 4 a n d 5 : Baseli ne ( pre d ose) , 0. 5 (e n d of l oa di n g i nf usi o n), 4 8 ( e n d of 
mai nte na nce i nf us i o n), 6 0, 7 2, a n d 9 6 h o urs

C o h ort 6 : Baseli ne ( pre d ose) , 0. 5 (e n d of l oa di n g i nf usi o n), 7 2 (e n d of 
mai nte na nce i nf usi o n), 8 4, 9 6, a n d 1 2 0 h o urs
P har mac o d y na mic a nal ysis f or t otal T A FIa acti vit y, D -di mer, T A F I a nti ge n a n d cl ot l ysis 
(a n e x pl orat or y bi o mar ker) will be perf or me d.  Re mai ni n g bl o o d sa m ples will be use d f or 
p ost -h oc a nal ys es f or bi o mar kers t hat are i n v ol ve d i n T A FI pat h wa y s or disease-relate d 
pat h wa y s t o better u n dersta n d t he acti o n of T A FIa i n hi biti o n, t hera pe utic res p o nse or 
disease pr o gressi o n.  I nstr ucti o ns f or t he a nal ys es will be c o vere d i n a se parate d oc u me nt 
pre pare d b y t he res pecti ve a nalyt ical la b orat ories.
8. 3. 
Bi o m ar k er E n d p oi nt (s)
See Secti o n 8. 2 a b o ve.
8. 4. 
I m m u n o ge nicit y
N ot a p plica ble .
8. 5. 
P h ar m ac o ge n o mic A n al ysis
As part of t his st u d y , a si n gle 4 m L bl o o d sa m ple will als o be c ollecte d f or 
p har mac o ge n o mic ( P G x ) a nalys is.  De o x yri b o n ucleic aci d ( D N A) bi o mar kers will be 
e xa mi ne d t o e val uate t he relati o ns hi p bet wee n T A FI -relate d a n d/ or disease-relate d ge nes 
a n d res p o nse t o t he st u d y dr u g, a n d/ or t he t hera pe utic res p o nse t o t he disease c o n diti o n 
(e g, V T E).  I n a d diti o n, t he relati o ns hi p bet wee n T A FI-relate d a n d/ or disease-relate d 
ge nes a n d disease c o n diti o n (e g, V T E) will be e x pl ore d.  All partici pa nts s h o ul d be 
prese nte d wit h t he P G x I C F at ra n d o mizati o n.  Partici pati o n i n t his p orti o n of t he st u d y is 
o pti o nal f or all s u bjects.  T h us, t h ose w h o c h o ose n ot t o pr o vi de a sa m ple f or P G x 
a nal ys is ma y still partici pate i n t he mai n p orti o n of t he st u d y.
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T he bl o o d P G x sa m ple s h o ul d be c ollecte d f or s u bjects w h o si g n t he P G x I C F after 
d osi n g.
As e mer gi n g i nf or mati o n re gar di n g t he safety a n d efficac y of D S-1 0 4 0 b ma y  bec o me 
a vaila ble i n t he f ut ure, sa m ples will be retai ne d f or p ossi ble f ut ure researc h.  T he sa m ple 
will be retai ne d u ntil t he D N A has bee n e x ha uste d or u ntil t he S p o ns or i nstr ucts t he 
ge n ot y pi n g c o ntract or t o destr o y t he sa m ple i n acc or da nce wit h la b orat or y pr oce d ures.  
D uri n g t his ti me, t he D N A sa m ple will n ot be i m m ortalize d or s ol d t o a n y o ne.  S u bjects 
will ha ve t he ri g ht t o wit h dra w c o nse nt a n d ha ve t heir sa m ple destr o ye d at a n y  ti me as 
l o n g as t here is D N A re mai ni n g.
T o e ns ure s u bject c o nfi de ntialit y , sa m ple t u bes will be i de ntifie d o nl y b y a barc o de la bel.  
T his barc o de will be li n ke d t o t he s u bject’s i de ntificati o n n u m ber.
I nstr ucti o ns f or sa m ple c ollecti o n, pre parati o n, ha n dli n g, st ora ge, a n d s hi p me nt will be 
pr o vi de d i n a se parate ma n ual.
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9. 
S A F E T Y E V A L U A TI O N A N D R E P O R TI N G
9. 1. 
A d verse E ve nt C ollecti o n a n d Re p orti n g
All cli nical A Es (see Secti o n 9. 4. 1 f or defi niti o ns) occ urri n g after t he s u bject si g ns t he 
I CF a n d u p t o t he Da y 3 0 f oll o w-u p visit , w het her o bser ve d by t he i n vesti gat or or 
re p orte d by t he s u bject, will be rec or de d o n t he A d verse E ve nt C R F pa ge.  Me dical 
c o n diti o ns (i ncl u di n g la b orat or y  values/ vital si g ns t hat are o ut of ra n ge) t hat were 
dia g n o se d or k n o w n t o e xist pri or t o i nf or me d co nse nt will be rec or de d as part of me dical 
hist or y .  
All A E s a n d S A Es are t o be re p orte d acc or di n g t o t he pr oce d ures i n Secti o n 9. 5 .  
All la b orat or y  res ults, vital si g ns, a n d E C G res ults or fi n di n gs s h o ul d be a p praise d b y t he 
I n vesti gat or t o deter mi ne t heir cli nical si g nifica nce. Is olate d a b n or mal la b orat or y res ults, 
vital si g n fi n di n gs, or E C G fi n di n gs (ie, n ot part of a re p orte d dia g n osis) s h o ul d be 
re p orte d as A Es if t he y are sy m pt o matic, lea d t o st u d y  dr u g disc o nti n uati o n, re q uire 
c orrecti ve treat me nt, or c o nstit ute a n A E i n t he i n vesti gat or ’s cli nical j u d g me nt.
At eac h visit, t he i n vesti gat or will deter mi 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 ny s pecific 
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 nte d i n t he site’s s o urce d oc u me ntati o n wit h t he 
I n vesti gat or’s si g nat ure.  
Al wa y s re p ort t he dia g n osis as t he A E or S A E ter m.  W he n a dia g n osis is u na vaila ble, 
re p ort t he pri mar y si g n or s 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 ym 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 s y 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.  
Pre - 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 oce d ures or treat me nt s
re q uiri n g h os pitalizati o n f or pre-e xisti n g c o n diti o ns t hat d o n ot w orse n i n se verit y s h o ul d 
n ot be 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 w a ys be re p orte d as a n 
S A E.  
A n y  seri o us, u nt o war d e ve nt t hat ma y occ ur s u 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.
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T he I n vesti gat or s h o ul d f oll o w s u bjects wit h a d verse e ve nts u ntil t he e ve nt has res ol ve d 
o r t he c o n diti o n has sta bilize d.  I n case of u nres ol ve d a d verse e ve nts, i ncl u di n g 
si g nifica nt a b n or mal la b orat or y val ues at t he e n d of st u d y assess me nt, t hese e ve nts will 
be f oll o we d u ntil res ol uti o n or u ntil t he y bec o me cli nicall y  n ot rele va nt.
As Daiic hi Sa n k y o I nc. is t he Mar ket A ut h orizati o n H ol der f or e d o xa ba n, S A Es re p orte d 
d uri n g t he 3 0- d a y  foll o w -u p peri o d s h o ul d i n dicate i n t he e ve nt narrati ve w het her t he 
e ve nts are attri b ute d t o e d o xa ba n t hera py, w hic h is pr o vi de d as t he N O A C per S O C; 
t hese e ve nts are s u bject t o re g ulat or y re p orti n g re q uire me nts f or a mar kete d pr o d uct.  
After st u d y co m pleti o n, all e ve nts o bser ve d wit h e d o xa ba n t hera py s h o ul d be re p orte d as 
s p o nta ne o us cases t o Daiic hi Sa n k yo I nc. per c o ntact i nf or mati o n o n t he pr o d uct la bel.
9. 2. 
S afet y E n d p oi nt E v e nt(s)
9. 2. 1. 
Blee di n g
T he pri mar y  safety e n d p oi nt i n t his st u d y  is:

Cli nicall y  rele va nt blee di n g (defi ne d as maj or or C R N M blee di n g) .
Blee di n g defi niti o ns ( per I S T H 9) are pr o vi de d bel o w:  
Maj or blee di n g is defi ne d as cli nicall y o vert blee di n g wit h o ne or m ore of t he f oll o wi n g:

ass ociate d wit h a fall i n he m o gl o bi n of 2 g/ d L or m ore, 

lea di n g t o a tra nsf usi o n of 2 or m ore u nits of pac ke d re d bl o o d cells or w h ole 
bl o o d,

occ urri n g i n a critical site: i ntracra nial, i ntras pi nal, i ntra oc ular, pericar dial, 
i ntra- artic ular, i ntra m usc ular wit h c o m part me nt s y n dr o me, retr o perit o neal, 

c o ntri b uti n g t o deat h.
Cli nical l y rele va nt n o n- maj or ( C R N M) blee di n g is defi ne d as o vert blee di n g n ot meeti n g 
t he criteria f or maj or blee di n g b ut eg, re q uires me dical atte nti o n or is ass ociate d wit h 
disc o mf ort f or t he s u bject s uc h as pai n, or i m pair me nt of acti vities of dail y life.  
All ot her o vert blee di n g e pis o des n ot meeti n g t he criteria f or maj or or C R N M blee di n g 
will be classifie d as n uisa nce blee di n g .
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 vesti 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.  
9. 3. 
E ve nts of S peci al I nterest
N o e ve nts of s pecial i nterest ha ve bee n defi ne d f or t his st u d y .
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9. 4. 
A d verse E ve nt
9. 4. 1. 
Defi niti o n of A d verse E ve nt
A n a d verse e ve nt is an y  u nt o war d me dical occ urre nce i n a s u bject a d mi nistere d a 
p har mace utical pr o d uct a n d t hat d oes n ot necessaril y  ha ve t o ha ve a ca usal relati o ns hi p 
wit h t his treat me nt.  A n A E ca n t heref ore be a n y u nfa v 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), sy 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 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).
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 nsi dere d a d verse e ve nts.
9. 4. 2. 
Seri o us A d verse E ve nt
A seri o us a d verse e ve nt is a n y  u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h,

Is life-t hreate ni n g,

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 
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 velo p me nt of dr u g de pe n de nc y  or dr u g a b use.
N ote:

P r oce d ures are n ot A E s or S A E s, b ut t he reas o n f or t he pr oce d ure ma y be a n 
A E or S A E.   

Pre - pla n ne d ( pri or t o si g ni n g t he I nf or me d C o nse nt F or m) pr oce d ures or 
treat me nts re q uiri n g h os pitalizati o ns f or pre-e xisti n g c o n diti o ns t hat d o n ot 
w orse n i n se verit y  are n ot S A Es.
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9. 4. 3. 
Se verit y Assess me nt
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 d verse e ve nts:

Mil d: A ware ness of si g n or s y m pt o m, b ut easil y t olerate d, ie, d oes n ot 
i nterfere wit h s u bject’s us ual f u ncti o n.

M o derate: Disc o mf ort e n o u g h t o ca use i nterfere nce wit h us ual acti vit y .

Se vere: I nca pacitati n g wit h i na bilit y  t o w or k or d o us ual acti vit y, ie, i nterferes 
si g nifica ntly wit h s u bject’s us ual f u ncti o n.
Se verit y  vers us Seri o us ness: Se verit y  is use d t o descri be t he i nte nsity of a s pecific e ve nt 
w hile t he e ve nt itself, h o we ver, ma y  be of relati vel y mi n or me dical si g nifica nce (s uc h as 
se vere hea dac he).  T his is n ot t he sa me as "seri o us ness," w hic h is base d o n patie nt/e ve nt 
o utc o me at t he ti me of t he e ve nt.
9. 4. 4. 
C a us alit y Assess me nt
T he I n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n a d verse e ve nt a n d t he st u d y  
dr u g o n t he basis of 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 m ust be ma de base d o n t he a va ila 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.

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, dise ase 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).
or

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 reacti 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 gy.

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  dr u g 
a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s cli nical 
state or ot her fact ors (e g, disease u n der st u dy, 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 St u d y Dr u g (s)
N o d ose m o dificati o ns (i ncreases or re d ucti o ns) are per mitte d i n t his st u d y a n d neit her 
are i nterr u pti o ns i n t he a d mi nistrati o n of t he I V i nf usi o n wit h bli n de d st u d y dr u g l o n ger 
t ha n t o a d dress a bl oc ke d I V li ne ( Secti o n 5. 7. 1 ) T heref ore t he c h oices f or acti o n ta ke n 
wit h t he st u d y dr u g i n t his st u d y are li mite d t o t he f oll o wi n g:

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.

Dr u g Wit h dra w n: T he st u d y  dr u g was per ma ne ntl y  st o p pe d.
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
D ose I ncrease d: T he d osa ge of st u d y dr u g was i ncrease d.

N ot A p plica ble: S u bject die d , st u d y treat me nt ha d bee n c o m plete d pri or t o 
reacti o n/e ve nt, or reacti o n/e ve nt occ urre d pri or t o start of treat me nt
9. 4. 6. 
Ot her Acti o n T a ke n f or E v e nt

N o ne.

N o treat me nt was re q uire d.

Me dicati o n re q uire d.

Prescri pti o n a n d/ or o ver -t he-c o u nter (O T C ) me dicati o n was re q uire d t o 
treat t he a d verse e ve nt.

H os pitalizati o n or pr ol o n gati o n of h os pitalizati o n re q uire d.

H os pitalizati o n was re q uire d or pr ol o n ge d d ue t o t he A E , w het her or n ot 
me dicati o n was re q uire d.

Ot her.
9. 4. 7. 
A d verse E ve nt O utc o me

Rec o vere d/ Res ol ve d

T he s u bject f ull y rec o vere d fr o m t he a d verse e ve nt wit h n o resi d ual effect 
o bser ve d.

Rec o veri n g/ Res ol vi n g

T he a d verse e ve nt i m pr o ve d b ut has n ot f ull y res ol ve d.

N ot Rec o vere d/ N ot Res ol ve d

T he a d verse e ve nt itself is still prese nt a n d o bser va ble.

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.

Fatal

Fatal s h o ul d be use d w he n d eat h is a direct o utc o me of t he a d verse e ve nt.

U n k n o w n
9. 5. 
Seri o us A d verse E ve nts Re p orti n g – Pr oce d ure for I n vesti g at ors
All A Es a n d S A Es will be re p orte d i n t he C R F /e C R F.  All S A Es m ust be re p orte d o n a 
Daiic hi Sa n k y o I nc. Seri o us A d verse E ve nt Re p ort ( S A V E R) f or m wit hi n 2 4 h o urs of 
a ware ness, a n d usi n g t he desi g nate d fa x tra ns mittal f or m.
All e ve nts (seri o us a n d n o n -seri o us) m ust be re p orte d wit h i n vesti gat or’s assess me nt of 
t he e ve nt’s seri o us ness, se verity, a n d ca usalit y t o t he b li n de d st u d y dr u g.  A detaile d 
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narrati ve s u m marizi n g t he c o urse of t he e ve nt, i ncl u di n g its e val uati o n, treat me nt, a n d 
o utc o me s h o ul d be pr o vi de d.  S pecific or esti mate d dates of e ve nt o nset, treat me nt, a n d 
res ol uti o n s h o ul d be i ncl u de d w he n a vaila ble.  Medical hist or y , c o nc o mita nt me dicati o ns, 
a n d la b orat or y data t hat are rele va nt t o t he e ve nt s h o ul d als o be s u m marize d i n t he 
narrati ve.  F or fatal e ve nts, t he narrati ve s h o ul d state w het her a n a ut o ps y was or will be 
perf or me d, a n d i ncl u de t he res ults if a va ila ble.  All S A Es re p orte d d uri n g t he 3 0 -da y  
f oll o w- u p peri o d s h o ul d i n dicate i n t he e ve nt narrati ve w het her t he e ve nts are relate d t o 
e d o xa ba n t hera p y.  S o urce d oc u me nts (i ncl u di n g me dical re p orts ) will be retai ne d at t he
st u d y ce nter a n d s h o ul d n ot be s ub mitte d t o t he S p o ns or f or S A E re p orti n g p ur p oses.
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 o n 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. 
Please call t he l ocal S A E H otli ne (see St u d y  Ma n ual) or y o ur st u d y m o nit or f or a ny 
q uesti o ns o n S A E re p orti n g.  
9. 6. 
N otif yi n g Re g ul at or y A ut h orities, I n vesti g at ors, a n d 
Instit uti o n al R e vie w B o ar d / Et hics Co m mittee
Daiic hi Sa n k y o I nc. a n d/ or Me d pace will i nf or m I n vesti gat ors, Instit uti o nal R e vie w 
B oar ds / Et hics C o m mittees ( I R Bs/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 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 y o I nc. st u dies of t he i n vesti gati o nal dr u g , 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 
st u d y dr u g, u nless dele gate d t o t he S p o ns or, it is t he I n 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 o pea 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. 7. 
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 I nc. 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 st u d y me dicati o n or u p t o t he last safet y f oll o w -u p visit ( 3 0 ± 3 da y s after t he 
last a d mi nistrati o n of st u d y me dicati o n or wit h dra wal fr o m t he st u d y, w hic he ver occ urs 
later).
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 or t o recei ve t he EI U Re p orti n g F or 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  a n d c o m plete t he EI U Re p orti n g F or m wit h c o m plete 
pre g na nc y  o utc o me i nf or mati o n, i ncl u di n g n or mal deli ver y a n d i n d uce d a b orti o n.  T he 
a d verse pre g na nc y o utc o me, eit her seri o us or n o n-seri o us, s h o ul d be re p orte d i n 
acc or da nce wit h st u d y pr oce d ures.  If t he o utc o me of t he pre g na nc y meets t he criteria f or 
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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 or 
i n d uce d 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. 8. 
Cli nic al L a b or at or y E v al u ati o ns
T he f oll o wi n g cli nical la b orat or y  tests will be perf or me d:
Alt h o u g h it is per missi ble t o use l ocal la b res ults t o q ualif y  s u bjects f or ra n d o mizati o n t o 
t he st u d y if 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 , la b sa m ples 
will be c ollecte d at baseli ne a n d s u bse q ue nt t o ra n d o mizati o n f or testi n g b y a ce ntral 
la b orat or y.

Ser u m c he mistr y , he mat ol o g y a n d uri nal ysis sa m ples will be c ollecte d at 
baseli ne a n d wit hi n 1 2 h o urs after c o m pleti n g st u d y  dr u g i nf usi o n or at t he 
ti me of disc har ge (see A p pe n dices Secti o n 1 7. 1 a n d Secti o n 1 7. 2 ). 

C oa g ulati o n Para meters : P T, a P T T, I N R a n d fi bri n o ge n will be assesse d at 
baseli ne ( pre d ose), e n d of l oa di n g i nf usi o n, e n d of mai nte na nce i nf usi o n a n d 
2 4 h o urs after t he e n d of i nf usi o n (see A p pe n di x 1 7. 2 ), as f oll o ws:

C o h ort 1 : pre d ose , 0. 5 (e n d of l oa di n g i nf usi o n), 1 2 (e n d of mai nte na nce 
i nf usi o n), a n d 4 8 h o urs

C o h orts 2 a n d 3 : pre d ose , 0. 5 (e n d of l oa di n g i nf usi o n), 2 4 (e n d of 
mai nte na nce i nf usi o n), a n d 4 8 h o urs

C o h orts 4 a n d 5 : pre d ose , 0. 5 (e n d of l oa di n g i nf usi o n), 4 8 (e n d of 
mai nte na nce i nf us i o n), a n d 7 2 h o urs

C o h ort 6 : pre d ose , 0. 5 (e n d of l oa di n g i nf usi o n), 7 2 (e n d of mai nte na nce 
i nf usi o n), a n d 9 6 h o urs

Ser u m or uri ne pre g na nc y test (f or w o me n of c hil d beari n g p ote ntial).  T he 
pre g na nc y  test will be perf or me d wit h eit her ser u m or uri ne sa m ples f oll o wi n g 
sta n dar d practice at t he site;
T he pr oce d ures f or sa m ple c ollecti o n f or a nalys is b y t he ce ntral la b orat or y will be 
defi ne d i n a st u d y la b orat or y m a n ual. T he res ults will be re vie we d a n d c o m pare d wit h t he 
ce ntral la b orat or y’s n or mal ra n ges.
All la b orat or y  val ues m ust be a p praise d by t he I nvesti gat or as t o cli nical si g nifica nce. 
All a b n or mal la b orat or y  val ues c o nsi dere d cli nicall y si g nifi ca nt by t he I n vesti gat or m ust 
be rec or de d i n t he a d verse e ve nt pa ge of t he e C R F. A b n or mal la b orat or y  val ues 
occ urri n g d uri n g t he cli nical st u d y  will be f oll o we d u ntil re peat test res ults ret ur n t o 
n or mal ( or baseli ne), sta bilize, or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt .
9. 9. 
Vit al Si g ns
Vital si g n meas ure me nts will i ncl u de s y st olic bl o o d press ure, diast olic bl o o d press ure,
a n d heart rate. 
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9. 1 0. 
Electr oc ar di o gr a ms
Sta n dar d s u pi ne 1 2 -lea d E C Gs will be perf or me d b y q ualifie d tec h nicia ns i n tri plicate o n 
t he E C G mac hi ne de dicate d t o t his st u d y . Electr ocar di o gra ms will be re vie we d at t he site 
f or treat me nt of a ny ur ge nt iss ues. T he cli nical si g nifica nce of a n y E C G c ha n ge m ust be 
assesse d b y t he I n vesti gat or i n t he c o nte xt of t he s u bject’s me dical hist or y , p hys ical 
e xa mi nati o n, a n d c o nc o mita nt me dicati o ns. T he I n vesti gat or or dele gate d p h y sicia n will 
re vie w, si g n, a n d date all E C Gs.
9. 1 1. 
P h ysic al E x a mi n ati o ns
A c o m plete p h ys ical e xa mi nati o n, wit h t he e xce pti o n of t he ge nit o uri nar y s yste m a n d 
pr ostate, will be perf or me d o n eac h s u bject at baseli ne a n d at t he f oll o w u p visit o n Da y  
3 0. B o d y wei g ht will be meas ure d ( or best esti mate d if n ot feasi ble t o meas ure) f or all 
s u bjects at st u d y q ualificati o n/ pre-ra n d o mizati o n.
9. 1 2. 
Ot her E x a mi n ati o ns
See Secti o n 1 0 .
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1 0. 
O T H E R A S S E S S M E N T S
I m a gi n g Ev al u ati o ns :
T hree c o ntrast -e n ha nce d C T sca ns are pla n ne d i n t his st u d y, at baseli ne, wit hi n 1 2 h o urs 
after t he e n d of st u d y dr u g i nf usi o n a n d at Da y 3 0 ± 3 , t o e val uate t he effect of st u d y dr u g 
a d mi nistrati o n o n t he t hr o m b us size/ v ol u me.  I n or der t o be ra n d o mize d i n t his st u d y  
s u bjects m ust ha ve a baseli ne C T sca n c o nfir mi n g t he P E dia g n osis a n d wit h at least o ne 
meas ura ble i n de x lesi o n i n a se g me ntal or lar ger p ul m o nar y  arter y.  Details re gar di n g t he 
i ma gi n g e val uati o ns i ncl u di n g t he vali dati o n of t he met h o d ma y be f o u n d i n t he I ma gi n g 
Ac q uisiti o n Ma n ual f or site de vel o pe d a n d pr o vi de d b y  t he C ore Ima gi n g L a borat or y .
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1 1. 
S T A TI S TI C A L M E T H O D S 
Detaile d statistical met h o d s will be descri be d i n t he Statistical A nal ysis Pla n ( S A P).  T he 
S A P will be fi nalize d pri or t o data base l oc k.
1 1. 1. 
A n al ysis Sets
Safet y  A nalys is Set:  Safet y  a nalys is set will i ncl u de all s u bjects w h o recei ve d at least 1 
d ose of t he In vesti gati o nal P r o d uct.
Ef ficac y A nalys is Set:  Efficac y  anal ys is set will i ncl u de all s u bjects i n t he safety a nal ysis 
set w h o ha ve vali d C T i ma gi n g e val uati o ns at b ot h t he baseli ne a n d at t he 1 2 h p ost -e n d of 
i nf usi o n ti me p oi nts a n d has s uccessf ull y c o m plete d a d mi nistrati o n of t he st u d y dr u g 
i nf usi o n.
P K A nal y sis Set:  P K a nal y sis set will i ncl u de all s u bjects i n t he safety a nal y sis set w h o 
ha ve at least 1 P K sa m ple wit h meas ura ble c o nce ntrati o n of D S - 1 0 4 0a.
P D A nal y sis Set:  P D a nal y sis set will i ncl u de all s u bjects i n t he safety a nal y sis set w h o 
ha ve at least 1 p ost d ose P D assess me nt.
1 1. 2. 
Ge ner al St atistic al C o nsi der ati o ns
All q ua ntitati ve efficac y, P K, P D, a n d safet y data will be ta b ulate d wit h descri pti ve 
s u m mar y statistics: arit h metic mea n; sta n dar d de viati o n ( S D); me dia n, mi ni m u m a n d 
ma xi m u m val ues; n u m ber of o bser vati o ns.  I n a d diti o n, ge o metric mea n a n d ge o metric 
c oefficie nt of variati o n ( C V) % will be pr o vi de d f or A U C 0- i nf, A U Clast, a n d Cma x val ues.  
Fre q ue nc y  c o u nts a n d perce nta ges will be pr o vi de d f or cate g orical data.  S u m maries will 
be pr o vi de d f or eac h d ose ar m a n d o n t he p o ole d place b o ar m.  W he n data are a vaila ble 
f or b ot h pre-d ose a n d p ost d ose assess me nts, s u m maries will be pr o vi de d o n pre -d ose 
assess me nts, p ost d ose assess me nts, a n d c ha n ge fr o m pre- d ose t o p ost d ose assess me nts, 
res pecti vely.
1 1. 3. 
St u d y P o p ul ati o n D at a
S u bject dis p ositi o n will be s u m marize d f or eac h treat me nt gr o u p a n d i n t otal f or t he 
safety a nal ysis set.  T he n u m ber of s u bjects f or eac h defi ne d a nal ys is set b y treat me nt 
gr o u p as well as i n t ota l p o p ulati o n will als o be ta b ulate d.
T he de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d descri pti vel y  f or t he 
safety a nal ysis set.  C o nti n u o us de m o gra p hic varia bles (a ge [calc ulate d fr o m date of birt h 
t o t he date of d ose], wei g ht, hei g ht, a n d b o d y  mass i n de x [B MI ]) f or all s u bjects will be 
s u m marize d wit h descri pti ve statistics.  Cate g orical de m o gra p hic varia bles (se x, race, a n d 
et h nicit y) will be s u m marize d wit h fre q ue nc y c o u nts a n d c orres p o n di n g perce nta ges.
St u d y  dr u g e x p os ure a n d st u d y d urati o n will be s u m marize d usi n g descri pti ve statistics 
b y  treat me nt gr o u p f or t he safety a nal ys is set.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 3
1 1. 4. 
St atistic al A n al ysis
1 1. 4. 1. 
Effic ac y A n al yses
Efficac y  para meters will i ncl u de t otal t hr o m b us v ol u me , rec urre nce of V T E, deat h, 
M A C E, he m o d y na mic dec o m pe nsati o n, a n d treat me nt escalati o n.
Efficac y  a nalys es i n ge neral will be descri pti ve a n d will be prese nte d i n ta b ular f or mat 
wit h t he a p pr o priate s u m mar y  statistics.
Val ues f or efficac y  assess me nts will be s u m marize d b y treat me nt gr o u p.  All place b o-
treate d s u bjects will be p o ole d acr oss c o h orts as o ne gr o u p i n t he s u m mar y of efficac y  
res ults.
1 1. 4. 1. 1. 
Pri m ar y Effic ac y A n al yses
T he f oll o wi n g pri mar y efficac y e n d p oi nts will be s u m marize d a n d c o m pare d b et wee n
D S -1 0 4 0 b ar ms a n d p o ole d place b o ar m:

R elati ve red ucti o n ( % re d ucti o n) i n t otal t hr o m b us v ol u me fr o m baseli ne t o ≤ 
1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n assesse d b y  C T A i n se g me ntal or lar ger 
p ul m o nar y  arteries;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % greater relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o ≤ 1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % greater relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseline t o ≤ 1 2 h fr o m e n d of D S -1 0 4 0 b i nf usi o n.
T he relati ve re d ucti o n i n t otal t hr o m b us v ol u me of eac h D S - 1 0 4 0b d ose will be c o m pare d 
wit h p o ole d place b o ar m usi n g t w o sa m ple t -test statistics a n d p-val ue wit h n o m ulti ple 
c o m paris o ns a dj ust me nt . 
T he pr o p orti o ns of s u bjects w h o ac hie ve 2 0 % a n d 5 0 % relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me of eac h D S - 1 0 4 0b d ose will be c o m pare d wit h p o ole d place b o ar m
usi n g c hi -s q uare statistics a n d p-val ue wit h n o m ulti ple c o m paris o ns a dj ust me nt .
1 1. 4. 1. 2. 
Sec o n d ar y Effic a c y A n al yses
T he f oll o wi n g sec o n dar y efficac y e n d p oi nts will be s u m marize d a n d c o m pare d bet wee n
D S -1 0 4 0 b ar ms a n d p o ole d place b o ar m:

Rec urre nce of V T E ( C o m p osite of rec urre nt P E, ne w or rec urre nt D V T, V T E -
relate d deat h; as well as t he i n di vi d ual c o m p o ne nts) u p t o h os pital disc har ge 
a n d u p t o Da y  3 0 Visit after d osi n g;

Deat h, he m o d y na mic dec o m pe nsati o n, or treat me nt escalati o n u p t o h os pital 
disc har ge a n d u p t o Da y  3 0 Visit after d osi n g;

Rec urre nce of P E u p t o h os pital disc har ge a n d u p t o Da y  3 0 after d osi n g;

M A C E u p t o h os pital disc har ge a n d u p t o Da y  3 0 Visit after d osi n g.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 4
Ti me t o e ve nt data fr o m ra n d o mizati o n will be s u m mariz e d b y Ka pla n -Meier
met h o ds.
1 1. 4. 1. 3. 
E x pl or at or y Effic ac y A n al yses
T he f oll o wi n g e n d p oi nts will be s u m marize d a n d c o m pare d b y bet wee n D S - 1 0 4 0 b ar ms 
a n d p o ole d place b o ar m:

Relati ve re d ucti o n ( % re d ucti o n) i n t otal t hr o m b us v ol u me fr o m baseli ne t o 
Da y  3 0 Visit fr o m e n d of D S-1 0 4 0 b i nf usi o n assesse d b y  C T A i n se g me ntal 
or lar ger p ul m o nar y  arteries;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 2 0 % greater relati ve re d ucti o n i n t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o Da y 3 0 Visit;

Pr o p orti o n of s u bjects w h o ac hie ve a ≥ 5 0 % greater relati ve re d ucti o n in t otal 
t hr o m b us v ol u me assesse d b y C T A i n se g me ntal or lar ger p ul m o nar y arteries, 
fr o m baseli ne t o Da y 3 0.
T he relati ve re d ucti o n i n t otal t hr o m b us v ol u me of eac h D S -1 0 4 0 b d ose will be c o m pare d 
wit h p o ole d place b o ar m usi n g t w o sa m ple t -test statistics a nd p- val ue wit h n o m ulti ple 
c o m paris o ns a dj ust me nt .
1 1. 4. 2. 
P h ar m ac o ki netic/ P h ar m ac o d y n a mic A n al yses
1 1. 4. 2. 1. 
P h ar m ac o ki netic A n al yses
Descri pti ve statistics (sa m ple size [ N], n u m ber missi n g [ N missi n g], arit h metic mea n, 
sta n dar d de viati o n, c oefficie nt of variati o n [ % C V], mi ni m u m, ma xi m u m, a n d me dia n) of 
D S -1 0 4 0a plas ma c o nce ntrati o ns at eac h sa m pli n g ti me p oi nt a n d all P K para meters will 
be prese nte d b y treat me nt.  I n a d diti o n, t he ge o metric mea n a n d % C V f or ge o metric 
mea n will als o be calc ulate d f or t he P K para meters A U C
0- i nf, A U Clast, Cma x a n d plas ma 
c o nce ntrati o n pri or t o e n d of c o nti n u o us i nf usi o n. 
Mea n a n d me dia n plas ma c o nce ntrati o n vers us ti me data will be prese nte d gra p hicall y f or 
all treat me nts usi n g ori gi nal a n d se mi -l o g scales.
Act ual sa m pli n g ti mes t hat differ f r o m t he sc he d ule d sa m pli n g ti mes by m ore t ha n 5 
mi n utes wit hi n t he first h o ur, or b y  m ore t ha n 3 0 mi n utes wit hi n t he first 1 2 h o urs, or b y 
m ore t ha n 1 h o ur t hereafter, will be liste d b ut e xcl u de d fr o m s u m mar y  statistics a n d mea n 
a n d me dia n gra p hs.
T he rela ti o ns hi p bet wee n d ose a n d e x p os ure para meters ( A U Clast a n d A U C 0- i nf) will be 
e xa mi ne d gra p hicall y.
1 1. 4. 2. 2. 
P h ar m ac o d y n a mic A n al yses
Ra w val ues f or t otal T A FIa acti vity, T A FI a nti ge n, cl ot l ysis ti me, a n d D- di mer will be 
prese nte d gra p hicall y b y s u bject, a n d will als o be s u m marize d b y ti me p oi nt a n d 
treat me nt.  C ha n ge fr o m baseli ne val ues (a bs ol ute val ue a n d perce nta ge) will als o be 
s u m marize d.  P o ole d place b o data of all c o h orts will be s u m marize d.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 5
1 1. 4. 2. 3. 
Bi o m ar ker A n al yses
N ot a p plica ble .
1 1. 4. 2. 4. 
P h ar m ac o ge n o mic A n al yses
E x pl or at or y P G x a nal yses f or t he p otential pre dicti ve be nefits of D S -1 0 4 0 b ma y  be 
assesse d later i n a se parate re p ort .
1 1. 4. 3. 
S afet y A n al yses
Safet y  para meters will i ncl u de S A Es, T E A Es, p h ysical e xa mi nati o n fi n di n gs, vital si g ns 
meas ure me nts, sta n dar d cli nical la b orat or y  para meters, blee di n g e ve nts, a n d E C G 
para meters.
Safet y  a nalys es i n ge neral will be descri pti ve a n d will be prese nte d i n ta b ul ar f or mat wit h 
t he a p pr o priate s u m mar y statistics.
Val ues f or safet y assess me nts will be s u m marize d b y treat me nt gr o u p.  All place b o -
treate d s u bjects will be p o ole d acr oss c o h orts as o ne gr o u p i n t he s u m mar y of safety
res ults.
1 1. 4. 3. 1. 
A d verse E ve nt A n al yses
All A E s will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
c o di n g dicti o nar y (latest versi o n).  All A Es, i ncl u di n g S A Es, will be ma p pe d t o s yste m 
or ga n class a n d preferre d ter m a n d will be liste d i n t he data listi n g.  A T E A E is defi ne d as 
a n A E t hat e mer ges d uri n g treat me nt, ha vi n g bee n a bse nt pretreat me nt, or w orse ni n g 
relati ve t o t he pre-treat me nt state.  T he n u m ber a n d perce nta ge of s u bjects re p orti n g 
T E A Es will be calc ulate d o verall, b y s ys te m or ga n class, b y preferre d ter m, a n d b y 
treat me nt.  T he T E A Es will be f urt her s u m marize d b y  se verity a n d relati o ns hi p t o st u d y  
dr u g.  Si milarl y, t he n u m ber a n d perce nta ge of s u bjects re p orti n g treat me nt -e mer ge nt 
S A Es will be ta b ulate d, as well as T E A Es lea di n g t o disc o nti n uati o n of st u d y treat me nts.
A b y -s u bject A E (i ncl u di n g treat me nt-e mer ge nt) data listi n g i ncl u di n g b ut n ot li mite d t o 
ver bati m ter m, preferre d ter m, s y ste m or ga n class, se verity, a n d relati o ns hi p t o st u d y 
treat me nt will be pr o vi de d.  Deat hs, ot her S A Es, a n d ot her si g nifica nt A Es, i ncl u di n g 
t h ose lea di n g t o disc o nti n uati o n of st u d y treat me nts, will be liste d.
1 1. 4. 3. 2. 
Cli nic al L a b or at or y E v al u ati o n A n al yses
He mat ol o g y , ser u m c he mistr y, uri nalys is, a n d c oa g ulati o n at eac h pla n ne d assess me nt 
a n d c ha n ge fr o m baseli ne at eac h pla n ne d p ost -basel i ne assess me nt will be s u m marize d 
f or t he safety a nal ys is set b y treat me nt.  S hift ta bles (i n cate g ories of l o w, n or mal, a n d 
hi g h, w he n a p pr o priate) will be pr o vi de d f or eac h treat me nt, as well.  S u bjects wit h 
a b n or mal val ues will be n ote d i n t he data list i n gs.
1 1. 4. 3. 3. 
Vit al Si g n A n al yses
Vital si g n e val uati o ns at eac h pla n ne d assess me nt a n d c ha n ge i n vital si g n val ues fr o m 
baseli ne at eac h pla n ne d p ost -baseli ne assess me nt will be s u m marize d f or t he safet y 
a nal ys is set b y treat me nt.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 6
1 1. 4. 3. 4. 
Electr oc ar di o gr a m A n al yses
T he E C G para meters ( P R, R R, Q R S, Q T, Q T i nter val c orrecte d ( Q Tc) usi n g Bazett’s 
f or m ula [ Q Tc B], a n d Fri dericia’s f or m ula [ Q Tc F ]) a n d heart rate at eac h pla n ne d 
assess me nt will be s u m marize d b y  treat me nt.  T he Q T i nter vals will be c orrecte d f or 
heart rate b y t he Bazett’s a n d Fri dericia’s f or m ula ( Q Tc B = Q T/[ R R] 1/ 2 a n d Q Tc F = 
Q T/[ R R] 1/ 3 res pecti vel y).  T he i nci de nce of o utliers i n a bs ol ute Q T, Q Tc F a n d Q Tc B 
i nter vals ( > 4 5 0 ms, > 4 8 0 ms, a n d > 5 0 0 ms), a n d t he c ha n ge fr o m pre d ose baseli ne i n 
Q T, Q Tc F a n d Q Tc B i nte r vals ( > 3 0 ms a n d > 6 0 ms) f or tri plicate E C Gs will be 
s u m marize d b y treat me nt.
1 1. 4. 3. 5. 
P h ysic al E x a mi n ati o n A n al yses
P h y sical e xa mi nati o n data at eac h e val uati o n will be liste d.  S u bjects wit h cli nicall y 
si g nifica nt a b n or mal fi n di n gs will be n ote d i n t he data listi n gs.
1 1. 4. 3. 6. 
Blee di n g E ve nts A n al yses
Blee di n g e ve nts will be s u m marize d as I S T H maj or or C R N M blee di n g b y  treat me nt.  
Res ults fr o m place b o -treate d s u bjects will be p o ole d acr oss c o h orts w he n c o m pari n g wit h 
D S -1 0 4 0 b treate d s u bjects.
Ti me t o e ve nt data f or t he blee di n g e ve nts fr o m ra n d o mizati o n will be a nal yze d b y 
Ka pla n -Meier met h o ds.
1 1. 4. 4. 
Ot her A n al ysis
U p t o t w o d ose o pti mizati o n e val uati o ns are pla n ne d i n t his st u d y , w hic h will i ncl u de 
safety, i ma gi n g ( t otal t hr o m b us v ol u me re d ucti o n fr o m baseli ne t o 1 2 h o urs p ost e n d of 
i nf usi o n), p har mac o ki netic a n d select bi o mar ker data fr o m s u bjects w h o reac h 7 2 h p ost 
e n d of bli n de d st u d y dr u g i nf usi o n. T he first o ne will i ncl u de s u bjects fr o m C o h orts 1 - 2 
a n d t he sec o n d fr o m C o h orts 1 - 4. T hese d ose o pti mizati o n e val uati o ns w ill deter mi ne t he 
t otal d oses a n d t he d urati o n of a d mi nistrati o n t o be use d i n C o h orts 3 - 4 a n d C o h orts 5- 6, 
res pecti vely. T he d ose o pti mizati o n e val uati o n will be carrie d o ut i n a n u n bli n de d 
fas hi o n b y a desi g nate d tea m. S u bject e nr oll me nt will be te m p or aril y s us pe n de d w hile 
t hese e val uati o ns are o n g oi n g.  Details f or t hese a nal y ses will be pr o vi ded i n a se parate, 
de dicate d statistical a nal ysis pla n.
1 1. 5. 
I nteri m A n al yses
N o i nteri m a nal ys is has bee n pla n ne d.
1 1. 6. 
S a m ple Size Deter mi n ati o n
A p pr o xi matel y 2 2 s u bjects will be e nr olle d per c o h ort, t o y iel d at least 1 8 e val ua ble 
s u bjects f or C o h ort 1- 2 a n d at least 2 0 f or C o h ort 3- 6 wit h a t otal of 11 8 e val ua ble 
s u bjects.  T he ra n d o mizati o n rati os of D S - 1 0 4 0 b t o place b o are 2: 1 f or C o h orts 1 - 2 a n d 
of 3: 1 f or C o h orts 3- 6. A s u bject will be dee me d e val ua ble if he/s he has vali d C T 
i ma gi n g e val uati o ns at b ot h baseli ne a n d at t he ≤1 2 h p ost -e n d of i nf usi o n a n d has 
s uccessf ully c o m plete d a d mi nistrati o n of t he bli n de d st u d y dr u g i nf usi o n. Ra n d o mize d 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 7
s u bjects w h o d o n ot c o mplete t he bli n de d st u d y  dr u g a d mi nistrati o n (ie, s u bjects w h o 
st o p t he IV i nf usi o n earl y d ue t o A Es) will still be f oll o we d f or safet y t hr o u g h Da y  3 0.
T he pla n n e d sa m ple size is base d o n t he t w o sa m ple t -test wit h a n al p ha le vel of 0. 1 0 
( o ne-si de d), p o wer of o ver 0. 8 5, 3 0 % t o 5 0 % hi g her re d ucti o n of D S - 1 0 4 0 c o m pare d t o 
place b o i n t otal t hr o m b us v ol u me , a n d sta n dar d de viati o n of 4 0 %, i n or der t o detect at 
least 5 0 % hi g her re d ucti o n at C o h ort 1, 4 0 % at C o h ort 2, 3 5 % at C o h ort 3 t o 5, a n d 3 0 % 
at C o h ort 6.
1 1. 7. 
St atistic al A n al ysis Pr ocess
T he S A P will pr o vi de t he statistical met h o ds a n d defi niti o ns f or t he a nal ys is of t he 
efficac y a n d safety data, as well as descri be t he a p pr oac hes t o be ta ke n f or s u m marizi n g 
ot her cli nical st u d y i nf or mati o n s uc h as s u bject dis p os iti o n, de m o gra p hic a n d baseli ne 
c haracteristics, st u d y dr u g e x p os ure, a n d pri or a n d c o nc o mita nt me dicati o ns.  T he S A P 
will als o i ncl u de a descri pti o n of h o w missi n g, u n use d, a n d s p uri o us data will be 
a d dresse d.
T he S A P will be fi nalize d pri or t o u n bli n di n g t o preser ve t he i nte grity of t he statistical 
a nal ys is a n d cli nical st u d y c o ncl usi o ns.  
T he statistical s oft ware S A S Versi o n 9. 3 or hi g her will be use d t o a nal yz e t he data.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 8
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
1 2. 1. 
M o nit ori n g a n d I ns pecti o ns
T he Daiic hi Sa n k y o I nc. m o nit or / desi g nee a n d re g ulat or y a ut h orit y i ns pect ors are 
res p o nsi ble f or c o ntacti n g a n d visiti n g t he I n vesti gat or f or t 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, C R Fs, s o u rce 
data, a n d ot her perti ne nt d oc u me nts).
T he verificati o n of 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 IC 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 will be acc o m plis he d t hr o u g h a c o m bi nati o n of o nsite visits b y t he m o nit or a n d 
re vie w of st u dy data re m otel y.   T he fre q ue nc y  of t he m o nit ori n g visit will var y base d o n 
t he acti vit y at eac h st u d y site.  T he m o nit or is res p o nsi ble f or i ns pecti n g t he C R Fs a n d 
e ns uri n g c o m plete ness of t he s t u d y esse ntial d oc u me nts.  T he m o nit or s h o ul d ha ve access 
t o s u bject me dical rec or ds a n d ot her st u dy- relate d rec or ds nee de d t o verif y t he e ntries o n 
t he C R Fs.  Detaile d i nf or mati o n is pr o vi de d i n t he m o nit ori n g pla n.
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 (s) 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 o r t o e ns ure t hat a ny 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 t o t he satisfacti o n of t he 
S p o ns or a n d d oc u me nte d.
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 v es fr o m t he S p o ns or.  A u dit of st u d y ce nter facilities (e g, 
p har mac y , dr u g st ora ge areas, la b orat ories) 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 plica ble re g ulat or y re q uire me nts.  The I n vesti gat or s h o ul d res p o n d t o a u dit fi n di n gs .  
I n t he e ve nt t hat a re g ulat or y a ut h orit y i nf or ms t he i n vesti gat or t hat it i nte n ds t o c o n d uct 
a n i ns pecti o n, t he S p o ns or s hall be n otifie d i m me diatel y .
1 2. 2. 
D at a C ollecti o n
All rele va nt o bser vati o ns a n d data relate d t o t he st u d y , as per t he st u d y pr ot oc ol, will be 
rec or de d o n e C R F pa ges.  A re prese ntati ve of Daiic hi Sa n k yo I nc. or t heir desi g nee will 
pr o vi de i nstr ucti o n f or c o m pleti n g t he e C R F.  A de q uate a n d acc urate case rec or ds s h o ul d 
be mai ntai ne d, i ncl u di n g t he e val uati o n of i ncl us i o n a n d e xcl usi o n criteria, me dical 
hist or y , p h ysical e xa mi nati o ns, cli nical assess me nts, a rec or d of cli nical safety la b orat or y 
sa m ple c ollecti o n, dr u g a d mi nistrati o n, A Es, a n d fi nal e val uati o n.  
T he e C R F data e ntr y  s hall be c o m plete d wit hi n 7 2 h o urs of t he visit.  T he i n vesti gat or 
m ust electr o nicall y si g n a n d date t he e C R F.  T he si g nat ure s hall i n dicate t hat t he 
i n vesti gat or has re vie we d t he data a n d data q ueries rec or de d o n e C R Fs a n d t he site 
n otificati o ns, a n d a grees wit h t he c o nte nt.  After t he c o m ple ti o n of t he st u d y, e C R Fs 
i ncl u di n g a u dit trail will be ret ur ne d t o Daiic hi Sa n k yo I nc. a n d st ore d i n t he arc hi ves.  
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 9
T he I n vesti gat or will recei ve a c o p y of t heir site’s e C R Fs i ncl u di n g a u dit trail o n 
electr o nic me dia.
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 by 
t he Sp 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 st u d y ce nters, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecificati o n s gi ve n 
t o S p o ns or or desi g nee .  Data will be vette d b ot h electr o nicall y  a n d ma n uall y f or C R Fs 
a n d t he 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 
a p plicati o n.  Q ueries ge nerate d b y r ules a n d raise d b y re vie wers will be ge nerate d wit hi n 
t he electr o nic data ca pt ure ( E D C ) a p plicati o n.  D uri n g t his re vie w, s u bject data will be 
c hec ke d f or c o nsiste nc y, c o m plete ness 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 f or pa per C R Fs ,
data q ueries , a n d/ or st u d y ce nter n otificati o ns will be se nt t o t he st u d y ce nter f or 
c o m pleti o n a n d ret ur n t o t he S p o ns or/ Me d pace ; w hereas, C R Fs q ueries will be raise d a n d 
res ol ve d wit hi n t he E DC a p plicati o n.  I n a d diti o n, t he data will be re vi e we d f or a d here nce 
t o t he pr ot oc ol a n d G C P.  F or e C R Fs, t he data will be electr o nically vette d b y 
pr o gra m me d data r ules wit hi n t he a p plicati o n.  Q ueries ge nerate d b y r ules a n d raise d by 
re vie wers will be ge nerate d wit hi n t he electr o nic data ca pt ure ( E D C) ap plicati o n a n d als o 
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 bs will be rec o ncile d t o t he cli nical 
data base.
Seri o us A d verse E ve nts i n t he cli nical data base will be rec o ncile d wit h t he safet y 
data base.
All A Es (e xce pt ter ms pre-s pecifie d o n t he e C R F) will be c o de d usi n g Me d D R A. All 
pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g W H O Dr u g Dicti o nar y .
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 will mai ntai n a Si g nat ure List of a p pr o priatel y q ualifie d pers o ns t o 
w h o m he/s he has dele gate d st u d y  d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or 
c orrecti o ns o n C R Fs will be i ncl u de d o n t he Si g nat ure L ist.
I n vesti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects, date a n d o utc o me of scree ni n g pr ocess.
I n vesti gat ors will be e x pecte d t o mai ntai n a n E nr oll me nt Lo g of all s u bjects e nr olle d i n 
t he st u d y i n dicati n g t heir assi g ne d st ud y  n u m ber.
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his 
c o nfi de ntial list of na mes of all s u bjects all ocate d t o st u d y  n u m bers o n e nr olli n g i n t he 
st u d y all o ws t he I n vesti gat or t o re veal t he i de ntit y of a ny s u bject w he n necessar y .
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 0
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds fr o m w hic h t he s u bject’s 
C R F data are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o h os pital rec or ds, cli nical a n d 
office c harts, la b orat or y  a n d p har mac y rec or ds, i ma gi n g rec or ds, a n d c orres p o n de nce.
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, data c orrecti o n f or ms, 
C R Fs, i n ve nt or y  of st u d y dr u g, 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 n t 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 n d ret ur n rec or ds), a n d 
ot her S p o ns or c orres p o n de nce pertai ni n g t o t he st u d y  m ust be ke pt i n a p pr o priate st u d y 
files at t he st u d y ce nter ( Trial Master File).  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 necessar y  f or 
t he e val uati o n a n d rec o nstr ucti o n of t he cli nical st u d y.  T hese rec or ds will be retai ne d i n a 
sec ure file f or t he perio d re q uire d b y t he i nstit uti o n or st u d y ce nter 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.
1 2. 5. 
Rec or d Kee pi n g
T he I n vesti gat or a n d st u d y staff a re 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 C R Fs, i nf or me d c o nse nt f or ms, 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 rele va nt esse ntial d oc u me nts re q uire d pri or t o 
c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d fr o m t he E C/I R B 
a n d t he S p o ns or.

Rec or ds relate d t o t he st u d y dr u g(s) i ncl u di n g ac k n o wle d g me nt of recei pt at 
st u d y ce nter, acc o u nta bilit y rec or ds a n d fi nal reco 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 C R Fs m ust be 
mai ntai ne d a n d be rea dil y  a vaila ble.
All esse ntial d oc u me ntati o n will be retai ne d b y t he I n vesti gat or u ntil at least 2 y ears after 
t he last a p pr o val of a mar keti n g a p plicati o n i n a n I nter nati o nal C o nfere nce o n 
Har m o nisati o n re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I nter nati o nal C o nfere nce o n Har m o nisati o n re gi o n or at least 2 y ears 
ha ve la pse d si nce t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he 
I n vesti gati o nal Pr o d uct.  T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, 
h o we ver, if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h 
t he S p o ns or.  It is t he res p o nsi bilit y of t he S p o ns or t o i nf or m t he I n vesti gat or/i nstit uti o n 
as t o w he n t hese d oc u me nts n o l o n ger nee d t o be retai ne d.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 1
S u bject's me dical files s h o ul d be retai ne d i n acc or da nce wit h a p plica ble le gislati o n a n d i n 
acc or da nce wit h t he ma xi m u m peri o d of ti me per mitte d b y  t he h os pital, i nstit uti o n or 
pri vate practice. 
N o st u d y  d oc u me nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt bet wee n 
S p o ns or a n d t he I n vesti gat or.  S h o ul d t he I n vesti gat or wis h t o assi g n t he st u d y  rec or ds t o 
a n ot her part y or mo ve t he m t o a n ot her l ocati o n, he/s he m ust n otif y  S p o ns or i n writi n g of 
t he ne w res p o nsi ble pers o n a n d/ or t he ne w l ocati o n.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 2
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 dy a gree me nt wit h t he S p o ns or. T his a gree me nt will i ncl u de t he fi na ncial i nf or mati o n 
a gree d u p o n b y t he parties.
1 3. 2. 
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce
T he S p o ns or pr o vi des i ns ura nce f or st u d y s u bjects t o ma ke a vaila ble c o m pe nsati o n i n 
case of st u d y- relate d i nj ur y.
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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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 4
1 5. 
E T HI C S A N D S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N
1 5. 1. 
C o m pli a nce St ate me nt, Et hics a n d Re g ul at or y C o m pli a nce
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter nati o nal C o nfere nce o n 
Har m o nisati 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) i ncl u di n g t he f oll o wi n g:

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 missi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) a n d/ or;

U S 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, parts 1 1, 5 0, 5 4, 5 6 a n d 3 1 2 as a p pr o priate 
a n d/ or;

Ja pa nese Mi nistr y of Healt h, La b or a n d Welfare Or di na nce N o. 2 8 of 2 7 
Marc h, 1 9 9 7 a n d/ or;

T he  Act o n Sec uri n g Q ualit y , Efficac y a n d Safet y of P har mace uticals, 
M e dical De vices, Re ge nerati ve a n d Cell ular T hera p y Pr o d ucts, Ge ne T hera p y 
Pr o d ucts, a n d C os metics N o. 1 of 2 5 N o ve m ber, 2 0 1 4 ;

Ot her a p plica ble l ocal re g ulati o ns.
1 5. 2. 
S u bject C o nfi de nti alit y
T he I n vesti gat ors a n d t he S p o ns or will preser ve t he c o nfi de ntialit y of all s u bjects ta ki n g 
part i n t he st u d y , i n acc or da nce wit h G C P a n d l ocal re g ulati o ns.
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 C R Fs or 
ot her d oc u me nts s u b mitte d t o t he S p o ns or or t he C R O, 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 b y 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 t he S p o ns or or t he C R O (e g, si g ne d I C F) 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 I C H G C P G ui deli nes, it is re q uire d that 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 ny, of t he re g ulat or y a ge nc y(s), 
a n d t he I R B/ E C 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 I nvesti gat or is o bli gate d t o i nf or m 
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. 3. 
I nf or me d C o nse nt 
Bef ore a s u bject’s partici pati o n i n t he st u d y , it is t he I n vesti gat or’s res p o nsi bilit y t o 
o btai n freel y gi ve n c o nse nt, i n writi n g, fr o m t he s u bject 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 n y 
pr ot oc ol -s pecific pr oce d ures or a ny st u d y  dr u gs are a d mi nistere d.  S u bjects s h o ul d be 
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 5
gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d recei ve satisfact or y  a ns wers t o t heir i n q uiries, 
a n d s h o ul d ha ve a de q uate ti me t o deci de w het her or n ot t o partici pate i n t he st u d y .  T he 
writte n I C F s h o ul d be pre pa re 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 h eir 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 E C or I R B 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 d oc u me nte d i n t he s u bject’s me dical 
rec or ds.  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 a n d b y t he 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).  T he 
ori gi nal si g ne d I C F 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.  T he date a n d ti me (if 
a p plica ble) 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.
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 K, 
etc) are pr o vi de d i n t he S p o ns or’s IC F 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 st u d y ce nter.  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 S p o ns or .
F or st u dies i n t he U S, a n 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).  Als o, a se parate s pecial c o nse nt will be 
re q uire d f or phar mac o ge n o mic testi n g f or t his pr ot oc ol.
1 5. 4. 
Re g ul at or y C o m pli a nce
T he st u d y  pr ot oc ol, s u bject i nf 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 ny 
s u bject 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 nta ti o n e vi de nci n g t he In vesti gat or’s 
q ualificati o ns s h o ul d be s u b mitte d t o t he 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 b y na me a n d versi on.
C ha n ges i n t he c o n d uct of t he st u d y  or pla n ne d a nal ysis will be d oc u me nte d i n a pr ot oc ol 
a me n d me nt a n d/ or t he S A P.
T he I n vesti gat or a n d/ or S p o ns or/ Me d pace
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 E C or I R B f or all s u bse 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 CF.  T he I n vesti gat or s h o ul d n otif y  t he E C or I R B of de viati o ns fr o m t he pr ot oc ol or 
S A Es occ urri n g at t he st u d y ce nter a n d ot her A E re p orts recei ve d fr o m t he 
S p o ns or/ Me d pace , i n acc or da nce wit h l ocal pr oce d ures.
As re q uire d b y l ocal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y  Affairs gr o u p or 
re prese ntati ve t o w h o m t his res p o nsi bilit y has bee n dele gate d will e ns ure all le gal as pects 
are c o vere d, a n d a p pr o val fr o m 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 
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Pa ge 7 6
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 a p pr o val b y t he rele va nt re g ulat or y b o dies.
I n t he e ve nt of a ny pr o hi b iti o n or restricti o n i m p ose d (e g, cli nical h ol d) b y a n a p plica ble
Re g ulat or y A ut h orit ies i n a n y area of t he worl d, or if t he i n vesti gat or is a ware of a n y ne w
i nf or mati o n w hic h mi g ht i nfl ue nce t he e val uati o n of t he be nefits a nd ris ks of t he
i n vesti gati o nal dr u g , t he S p o ns or s h o ul d be i nf or me d i m me diatel y.  
I n a d diti o n, t he i n vesti gat or will i nf or m t he S p o ns or i m me diatel y of a n y ur ge nt safety 
meas ures ta ke n b y t he i n vesti gat or t o pr otect t he st u d y s u bjects a gai nst a n y i m me diate
hazar d, a n d of a n y s us pecte d/act ual seri o us G C P n o n- c o m plia nce t hat t he i n vesti gat or 
bec o mes a ware of.
1 5. 5. 
Pr ot oc ol De vi ati o ns
T he i n 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 RBs/ E Cs.
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y state d criteria will n ot be all o we d 
i n t his st u d y e xce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  
S p o ns or m ust be n otifie d of all i nte n de d or u ni nte n de d de viati o ns t o t he pr ot oc ol (e g, 
i ncl usi o n/e xcl usi o n criteria, d osi n g, misse d st u d y visits) o n a n e x pe dite d basis.
T he i n vesti gat or, or pers o n desi g nate d b y t he i n vesti gat or, s h o ul d d oc u me nt a n d e x pla i 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 or st u d y treat me nt, a n d ha d at 
least 1 a d mi nistrati o n of st u d y dr u g, data s h o ul d be c ollecte d f or safety p ur p oses.
If a p plica ble, the I n vesti gat or s h o uld n otif y t he E C or I R B 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.
1 5. 6. 
S u p pl y of Ne w I nf or m ati o n Affecti n g t he C o n d uct of t he St u d y
W he n ne w i nf or mati o n bec o mes a vaila ble t hat ma y  a d versely affect t he safet y of s u bjects 
or t he c o n d uct of t he st u d y , t he S p o ns or will i nf or m all In vesti gat ors i n v ol ve d i n t he 
cli nical st u d y, E Cs/I R Bs, a n d re g ulat or y a ut h orities of s uc h i nf or mati o n, a n d w he n 
nee de d, will a me n d t he pr ot oc ol a n d/ or s u bject i nf or mati o n.
T he I n vesti gat or s h o ul d i m me diatel y  i nf orm t he s u bject w he ne ver ne w i nf or mati o n 
bec o mes a vaila ble t hat ma y  be rele va nt t o t he s u bject’s c o nse nt or ma y i nfl ue nce t he 
s u bject’s willi n g ness t o c o nti n ue partici pati o n i n t he st u d y.  T he c o m m u nicati o n s h o ul d 
be d oc u me nte d o n me dical rec or ds, f or e xa m pl e, a n d it s h o ul d be c o nfir me d w het her t he 
s u bject is willi n g t o re mai n i n t he st u d y. 
If t he s u bject i nf or mati o n is re vise d, it m ust be re-a p pr o ve d b y t he I E C/IR B.  T he 
I n vesti gat or s h o ul d o btai n writte n i nf or me d c o nse nt t o c o nti n ue partici pati o n wit h t he 
re vise d writte n i nf or mati o n e ve n if s u bjects were alrea dy i nf or me d of t he rele va nt 
i nf or mati o n.  T he I n vesti gat or or ot her res p o nsi ble pers o n nel w h o pr o vi de d e x pla nati o ns 
a n d t he s u bject s h o ul d si g n a n d date t he re vise d I C F.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 7
1 5. 7. 
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 I n vesti gat or b y  Daiic hi Sa n k yo I nc. or Me d pace .  
Als o, t he S p 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.
A gl o bal pr ot oc ol a me n d me nt will affect st u d y c o n d uct at all st u d y ce nters i n all re gi o ns 
of t he w orl d.  S uc h a me n d me nts will be i nc or p orate d i nt o a re vise d pr ot oc ol d oc u me nt.  
C ha n ges ma de b y s uc h a me n d me nts will be d oc u me nte d i n a S u m mar y of C ha n ges 
d oc u m e nt.  T hese 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 l ocal pr ot oc ol a me n d me nt will affect st u d y  c o n d uct at a partic ular st u d y ce nter(s) 
a n d/ or i n a partic ular re gi o n/c o u ntr y.  S p o ns or a p pr o val of l ocal a me n d me nts will be 
clearl y d oc u me nte d.
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 
a n d b y re g ulat or y a ut h orities w here a p pr o priate, 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.
1 5. 8. 
St u d y Ter mi n ati o n
T his st u d y  ma y be ter mi nate d at a n y ti me f or safet y reas o ns u p o n a d vice of t he D M C.
I n a d diti o n, ke y safety para meters, i ncl u di n g t he pri mar y  e n d p oi nt (a dj u dicate d cli nicall y 
rele va nt blee di n g, defi ne d as I ST H maj or or cli nicall y rele va nt n o n-maj or blee di n g ) as 
well as ot her rele va nt safet y  i nf or mati o n, s uc h as S A Es a n d pa nic la b orat or y val ues will 
be m o nit ore d i n real ti me, i n a bli n de d fas hi o n, b y t he st u d y tea m as per t he st u d y-
s pecific me dical m o nit ori n g pla n a n d t he D M C will recei ve re p orts fr o m t his tea m .
S u bject e nr oll me nt is pla n ne d i n t hree pairs of c o h orts wit h t w o i nteri m e val uati o ns t o 
o pti mize t he d oses usi n g safet y, efficac y , a n d p har mac o ki netic/ bi o mar ker data. As a n 
a d de d meas ure of safet y s u bject e nr oll me nt wit hi n eac h pair of c o h orts will be sta g gere d 
E nr oll me nt i n t he sec o n d c o h ort of t he pair will be gi n o nl y after D M C has re vie we d t he 
data of t he first 1 0 s u bjects fr o m t he first c o h ort of t he pair ha ve cleare d t he 7 2 h p ost e n d 
of i nf usi o n ti me p oi nt, a n d t here was n o i ncrease i n cli nicall y rele va nt blee di n g n or ot her 
maj or safet y c o ncer ns.
1 5. 9. 
D at a a n d S afet y M o nit ori n g B o ar d
T he pri mar y  r ole f or t he D M C will be t o e xa mi ne t he u n bli n de d safety a n d efficac y data 
( blee di n g e ve nts, S A Es, V T E , a n d M A C E) i n a n o n g oi n g ma n ner a n d alert t he of t he 
st u d y lea ders hi p tea m i n case of a n y cli nically c o ncer ni n g safet y iss ues .
I n a d diti o n t he y will re vie w :
a.
ke y  safety para meters (e g, cli nicall y rele va nt blee di n g, S A Es a n d pa nic 
la b orat or y val ues) of t he first 1 0 s u bjects fr o m t he first c o h ort of eac h pair 
after t he s u bjects cleare d t he 7 2 h p ost e n d of i nf usi o n ti me p oi nt), a n d
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 2
1 6. 
R E F E R E N C E S
1.
S K o nsta nti ni des et al. 2 0 1 4 E S C g ui deli nes o n t he dia g n osis a n d ma na ge me nt of 
ac ute p ul m o nar y  e m b olis m. E ur Heart J 2 0 1 4 ; 3 5: 3 0 3 3- 8 0.
2.
D S - 1 0 4 0 b Gl o bal I n vesti gat or ’s Br oc h ure Versi o n 4. 0 , 0 5 Ja n 2 0 1 6.
3.
Bec k ma n M G, H o o per W C, Critc hle y  S E, Ortel T L. Ve n o us t hr o m b oe m b olis m:a 
p u blic healt h c o ncer n. A m J Pre v Me d. 2 0 1 0; 3 8 ( 4)(s u p pl): S 4 9 5 -S 5 0 1
4.
C hatterjee S, C ha kra b ort y A,  Wei n ber g I, et al. T hr o m b ol y sis f or P ul m o nar y 
E m b olis m a n d Ris k of All -Ca use M ortalit y , Maj or Blee di n g, a n d I ntracra nial 
He m orr ha ge, A Meta- a nal ysis. J A M A. 2 0 1 4; 3 1 1( 2 3): 2 4 1 4-2 4 2 1
5.
G or d o n H. G u yatt; Elie A. A kl; Mar k Cr o wt her; Da vi d D. G utter ma n, F C C P; 
H ol ger J. Sc h u ü ne ma n n; f or t he A mer ica n C olle ge of C hest P h ysicia ns 
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 Pa nel. E xec uti ve 
S u m mar y : 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, 9t h e d: 
A merica n C olle ge of C hest P h y sicia 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 7 S-e 4 7 S.
6.
Jeffre y I. Weitz; J o h n W. Ei kel b o o m; Me yer Mic hel Sa ma ma. Ne w 
A ntit hr o m b otic Dr u gs: 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, 
9t h e d: A merica n C olle ge of C hest P h y sicia ns E vi de nce- Base d Cli nical Practice 
G ui del i nes; C hest. 2 0 1 2; 1 4 1( 2 _s u p pl):e 1 2 0 S-e 1 5 1 S. 
7.
E d o xa ba n - U S prescri bi n g i nf or mati o n: htt p:// w w w.sa va y sa.c o m/
8.
E d o xa ba n -S u m mar y  of Pr o d uct C haracteristics : 
htt ps:// w w w. me dici nes. or g. u k/e mc/ me dici ne/ 3 0 5 0 6
9.
Sc h ul ma n S, Kear o n C, S u bc o m mittee o n C o ntr ol of A ntic oa g ulati o n of t he 
Scie ntific a n d Sta n dar dizati o n C o m mittee of t he I nter nati o nal S ociet y o n 
T hr o m b osis a n d Hae m ostasis. Defi niti o n of maj or blee di n g i n cli nical 
i n vesti gati o ns of a nti he m ostatic me dici nal pr o d ucts i n n o n-s ur gical patie nts. 
J T hr o m b Hae m ost. 2 0 0 5; 3: 6 9 2 - 4.
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 3
1 7. 
A P P E N DI C E S
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 6
1 7. 2. 
Listi n g of L a b or at or y Ass a ys
T he t otal bl o o d v ol u me t hat will be dra w n fr o m eac h s u bject ra n ges bet wee n 1 2 0- 1 4 1 m L .  
T he variati o ns are d ue t o differe nces i n t he t otal n u m ber of P K a n d P D sa m ples t o be 
c ollecte d d uri n g st u d y dr u g treat me nt a n d after st u d y  dr u g a d mi nistrati o n is st o p pe d 
base d o n d osi n g c o h ort .
Test
V ol u me 
per test 
( m L)
N u m ber of 
Ti me p oi nts per 
S u bject
T ot al V ol u me ( m L)
B aseli ne / Pre d ose
Ser u m c he mistr y, ser u m pre g na nc y 
( All C o h orts)
7
1
7
He mat ol o g y ( All C o h orts)
3
1
3
C oa g ulati o n Pa nel ( All C o h orts)
6
1
6
P K Pa nel ( All c o h orts)
3
1
3
P D Pa nel ( All c o h orts)
4. 5 x 2
1
9
Ge n ot y pi n g ( o pti o nal)
4
1
4
Tre at me nt Peri o d
C oa g ulati o n Pa nel ( All C o h orts)
6
2
1 2
P K Pa nel ( C o h orts 1 - 5)
3
4
1 2
P K Pa nel ( C o h ort 6)
3
5
1 5
P D Pa nel ( C o h ort 1)
4. 5 x 2
3
2 7
P D Pa nel ( C o h orts 2 - 6)
4. 5 x 2
2
1 8
P ost d ose
Ser u m c he mistr y ( All C o h orts)
7
1
7
He mat ol o g y ( All C o h orts)
3
1
3
C oa g ulati o n Pa nel ( All C o h orts)
6
1
6
P K Pa nel ( All C o h orts)
3
4
1 2
P D Pa nel ( C o h ort 1)
4. 5 x 2
2
1 8
P D Pa nel ( C o h orts 2 - 6)
4. 5 x 2
3
2 7
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Pr ot oc ol D S 1 0 4 0 - B-U 1 0 7
Versi o n 1. 0, 2 1 Ja n 2 0 1 6
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 7
Ser u m C he mistr y P a nel 

S o di u m, P otassi u m, C hl ori de, Bicar b o nate, T otal Pr otei n, Al b u mi n, Calci u m, 
Ma g nesi u m, P h os p h or o us, Ser u m Gl uc ose, B U N, Uric Aci d, C K, A L T, A S T, 
A L P, Creati ni ne, Cr Cl, T otal Bilir u bi n ( Direct & I n direct)
He m at ol o g y P a nel

R B C a n d W B C c o u nt, M C H, M C H C, M C V, H g b, Hct, Differe ntial ( % a n d/ or 
A bs ol ute Val ues f or Ne utr o p hils, L y m p h oc y tes, M o n oc ytes, E osi n o p hils a n d 
Bas o p hils), Platelet c o u nt
C o a g ul ati o n P a nel

I N R, P T, a P T T, a n d fi bri n o ge n
Uri n al ysis P a nel

C ol or, Clarit y , p H, Pr otei n, Bl o o d, Ket o nes, Ur o bili n o ge n, Gl uc ose, 
Le u k oc y te Esterase, Nitrite, S pecific Gra vit y, Bilir u bi n, wit h micr osc o pic 
a nal ys is i n t he e ve nt t here is a b n or mal Bl o o d, Nitrite, Le u k oc yte Esterase, or 
Pr otei n
P D P a nel

T A F Ia acti vity, cl ot l ysis, T A FI a nti ge n, D -di mer
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