Conditions: Atrial Fibrillation
Keywords: anticoagulants DU-176b edoxaban factor Xa oral prevention atrial fibrillation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 984
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of edoxaban in patients with non-valvular NVAF aged 80 years or older who are ineligible for available oral anticoagulation therapy.

Detailed description:

Arms:
arm 1: DU-176b orally administered at a dose of 15 mg once daily. arm 2: Placebo orally administered once daily.

Interventions: intervention 1: Du-176b intervention 2: placebo
Intervention descriptions: intervention 1: DU-176b orally administered at a dose of 15 mg once daily. intervention 2: Placebo orally administered once daily.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
C o nfi de ntial  
1  
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A P H A S E 3, 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, P A R A L L E L -G R O U P, 
M U L TI C E N T E R S T U D Y O F  D U -1 7 6 B I N P A TI E N T S  
WI T H N O N V A L V U L A R A T R I A L FI B RI L L A TI O N A G ED 
8 0 Y E A R S O R O L D E R W H O A R E I N E LI GI B L E F O R  
A V AI L A B L E O R A L A N TI C O A G U L A TI O N T H E R A P Y  
 
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
 
T his d oc u me nt is pr o prietar y i nf or mati o n f or pr o visi o n t o c o or di nati n g i n vesti gat ors, t he 
i n vesti gat or, s u bi n vesti gat ors, st u d y staff, st u d y dr u g ma na gers, st u d y sites, a n d 
i nstit uti o nal re vie w b oar ds partici pati n g i n this st u d y. D o n ot re veal t his d oc u me nt t o a n y 
t hir d part y or use it f or a n y p ur p ose ot her t ha n t his st u d y wit h o ut t he writte n c o nse nt of 
Daiic hi Sa n k y o, e xce pt f or e x plai ni n g t he details of t his st u d y t o s u bjects or le gall y 
acce pta ble re prese ntati ves.  
 
S p o ns or: Daiic hi Sa n k y o  
 
Versi o n 0 1. 0 8 . 0 0 0/ Date of pre parati o n: 1 7 Ma y  2 0 1 9  
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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P R O T O C O L S Y N O P SI S  
Pr ot oc ol N u m ber:  
D U 1 7 6 b -C -J 3 1 6 
I n vesti gati o nal 
Pr o d uct:  
D U -1 7 6 b  
Ge neric Na me:    
e d o xa ba n t os ylate h y drate  
St u d y Title:    
A p hase 3, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, 
parallel -gr o u p, m ultice nter st u d y of D U -1 7 6 b i n patie nts wit h 
n o n val v ular atrial fi brillati o n a ge d 8 0 years or ol der w h o are 
i neli gi ble f or a vaila ble oral a ntic oa g ulati o n t hera p y 
P hase of 
De vel o p me nt:  
P hase 3  
Pla n ne d 
I n dicati o n: 
To re d uce t he ris k of str o ke a n d s yste mic e m b olis m i n patie nts wit h 
n o n val v ular atrial fi brillati o n ( N V A F)  
St u d y O bjecti ve:    
To e val uate  t he efficac y a n d safet y of 1 5 m g of D U-1 7 6 b i n patie nts 
wit h N V A F a ge d 8 0 years or ol der w h o are i neli gi ble f or a vaila ble 
oral a nt ic oa g ula nts ( warfari n, da bi gatra n, ri var o xa ba n, a pi xa ba n, or 
e d o xa ba n) at t he a p pr o ve d d osa ge. * To e val uate t he s u peri orit y of 
1 5 m g of D U -1 7 6 b c o m pare d t o place b o i n a c o m p osite e n d p oi nt of 
str o ke a n d s yste mic e m b olis m as t he pri mar y efficac y e n d p oi nt.  
S t u d y Desi g n:   
A ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d, parallel -gr o u p, 
m ultice nter,  e ve nt -dri ve n st u d y  
Pla n ne d St u d y 
D urati o n:  
2 4 Ma y 2 0 1 6 t o 3 0  Se p 2 0 2 0  
St u d y Sites:    
See Attac h me nt 1  
Pla n ne d Sa m ple 
Size:  
A t otal of 8 0 0 s u bjects ( 4 0 0 i n t he D U -1 7 6 b gr o u p a n d 4 0 0 i n t he 
place b o gr o u p)  
S u bject Eli gi bilit y 
Criteria : 
I ncl usi o n Criteria 
• 
Hist or y of atrial fi brillati o n ( A F ) d oc u me nte d b y a n y electrical 
traci n g wit hi n t he 1 year pri or t o t he da y of i nf or me d c o nse nt 
• 
C H A D S 2 i n de x sc ore ≥ 2  
• 
Patie nts  wit h a ge  ≥ 8 0 years o n t he da y of i nf or me d c o nse nt  
• 
Patie nts  w h o are i neli gi ble f or a vaila ble oral a ntic oa g ula nts 
( warfari n, da bi gatra n, ri var o xa ba n, a pi xa ba n, or e d o xa ba n) at 
 
*: F or warfari n, i nter nati o nal n or malize d rati o (I N R) c o ntr olle d at bet wee n 1. 6 a n d 2. 6  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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t he a p pr o ve d d osa ge, a n d wit h at least 1 of t he f oll o wi n g 
blee di n g ris ks:  
i)  
Se vere re nal i m pair me nt ( creati ni ne cleara nce [ C Lcr ] 
calc ulate d b y t he C oc kcr oft -Ga ult f or m ula ≥ 1 5 m L/ mi n 
a n d < 3 0 m L/ mi n)  
ii) 
Hist or y of blee di n g fr o m critical area or or ga n (s uc h as 
i ntracra nial, i ntra oc ular, or gastr oi ntesti nal blee di n g) 
iii) L o w b o d y wei g ht ( ≤ 4 5 k g)  
i v) C o nti n u o us use of aci dic n o n -ster oi dal 
a nti -i nfla m mat or y dr u gs (N S AI Ds ) 
v)  
Patie nts  usi n g 1 a nti platelet dr u g (f or a p ur p ose ot her 
t ha n pr o p h yla xis of car di oe m b olic str o ke) 
 
Maj or E xcl usi o n Criteria  
• 
Tra nsie nt A F sec o n dar y t o ot her re versi ble dis or ders  
• 
Patie nts  w h o r ecei ve d  da bi gatra n, ri var o xa ba n, a pi xa ba n, or 
e d o xa ba n wit hi n t he 8 wee ks pri or t o t he da y of ra n d o mizati o n  
• 
Patie nts  recei vi n g warfari n wit h I N R c o ntr olle d at ≥ 1. 6 i n 2 of 
t he 3 m ost rece nt e xa mi nati o ns, i ncl u di n g t he eli gi bilit y 
assess me nt e xa mi nati o n, meas ure d at least 4 wee ks a part 
(s u bjects wit h I N R ≥ 1. 6 at t he eli gi bilit y assess me nt 
e xa mi nati o n are e xcl u de d)  
• 
Patie nts  wit h partic ularl y hi g h blee di n g ris k meeti n g a n y of t he 
f oll o wi n g criteria: 
i)  
Acti ve blee di n g o n t he da y of i nf or me d c o nse nt  
ii) 
U nres ol ve d pe ptic  ulcer o n t he da y of i nf or me d c o nse nt  
iii) He m o gl o bi n < 9 g/ d L, or platelet c o u nt < 1 0 ×  1 0 4/μ L at 
t he eli gi bilit y assess me nt e xa mi nati o n  
i v) Here ditar y  he m orr ha gic disease  
• 
Cere bral i nfarcti o n or tra nsie nt isc he mic attac k wit hi n t he 3 0 
da ys pri or t o t he da y of ra n d o mizati o n  
• 
U nc o ntr olle d h y perte nsi o n (s yst olic bl o o d press ure persiste ntl y 
> 1 6 0 m m H g or diast olic bl o o d press ure persiste ntl y >  1 0 0 
m m H g)  
• 
C Lcr calc ulate d b y t he C oc kcr oft -Ga ult f or m ula < 1 5 m L/ mi n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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• 
Patie nts  w h o ha ve starte d he m o dial ysis or w h o ma y start 
he m o dial ysis b y t he ti me of t he e xa mi nati o n at c o m pleti o n of 
st u d y treat me nt 
• 
Patie nts  recei vi n g d ual a nti platelet t hera p y at t he ti me of 
i nf or me d c o nse nt, or t h ose e x pecte d t o recei ve d ual a nti platelet 
t hera p y after t he ti me of i nf or me d c o nse nt, w h o ca n n ot safel y 
disc o nti n ue use of eit her of t he a nti platelet dr u gs  
• 
Patie nts  wit h he patic f u ncti o n dis or der acc o m pa nie d b y 
c oa g ulati o n dis or der  
• 
Hist or y of ac ute m y ocar dial i nfarcti o n wit hi n t he 3 0 da ys pri or 
t o t he da y of ra n d o mizati o n 
• 
Seri o us heart disease s uc h as car diac  fail ure wit h Ne w Yor k 
Heart Ass ociati o n ( N Y H A) classificati o n ≥ 3 or u nsta ble 
a n gi na pect oris  
D ose a n d R o ute of 
A d mi nistrati o n:  
D U -1 7 6 b 1 5 m g or place b o will be a d mi nistere d orall y o nce dail y. 
A d mi nistrati o n of t he st u d y dr u g will be c o nti n ue d u ntil t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt perf or me d wit hi n 6 0 
da ys after t he declarati o n of c o m pleti o n of t he st u d y. C o m pleti o n of 
t he st u d y will be declare d w he n t he pla n ne d n u m ber of s u bjects wit h 
pri mar y efficac y e n d p oi nt e ve nts has bee n c ollecte d. T he pla n ne d 
mea n d urati o n of st u d y treat me nt is 2 t o 2. 5 years.  
W he n t he i n vesti gat or or s u bi n vesti gat or re q uires t o k n o w t he st u d y 
treat me nt assi g n me nt f or eac h s u bject t o deter mi ne t he s u bse q ue nt 
treat me nt after t he fi nal a d mi nistrati o n of t he st u d y dr u g, t he st u d y 
treat me nt ca n  be c o nti n ue d u ntil t he fi nal f oll o w -u p e xa mi nati o n 
after o btai ni n g  c o nse nt fr o m t he s u bject . T he pla n ne d d urati o n of 
t he a d diti o nal st u d y treat me nt fr o m t he e xa mi nati o n at c o m pleti o n 
of st u d y treat me nt t o t he fi nal f oll o w -u p e xa mi n ati o n is 3  t o 4  
m o nt hs.  
Pr o hi bite d 
C o nc o mita nt 
Me dicati o n:  
• 
A ntic oa g ula nts  
• 
T hr o m b ol ytic  dr u gs  
• 
A nti platelet dr u gs (i ncl u di n g o ver -t he-c o u nter dr u gs c o ntai ni n g 
as piri n) a d mi nistere d t o re d uce t he ris k of car di oe m b olic str o ke 
base d o n A F, d ual a nti platelet t h era p y  
St u d y Pr oce d ures:  
See t he st u d y pr oce d ure a n d s peci me n c ollecti o n sc he d ule ( pa ge 5)  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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E n d p oi nts:    
Pri mar y E n d p oi nts  
Efficac y: C o m p osite of str o ke a n d S E E  
Safet y: M aj or blee di n g  
Sec o n dar y E n d p oi nts  
Efficac y:  
• 
C o m p osite of str o ke, S E E, a n d deat h d ue t o C V  
• 
Maj or a d verse car di o vasc ular e ve nts ( M A C E ) † 
• 
S tr o ke, s yste mic e m b olis m, a n d all-ca use m ortalit y  
• 
S tr o ke, s yste mic e m b olis m, maj or blee di n g, a n d all-ca use 
m ortalit y  
• 
A ll-ca use m ortalit y  
Safet y:  
• 
M aj or blee di n g a n d cli nicall y rele va nt n o n -maj or blee di n g  
• 
C li nicall y rele va nt n o n -maj or blee di n g  
• 
M i n or blee di n g 
• 
A ll blee di n g e ve nts 
Pri mar y Statistical 
A nal ysis : 
F or t he c o m p osite e n d p oi nt of str o ke a n d s yste mic e m b olis m 
o bser ve d fr o m ra n d o mizati o n u p t o t he e xa mi nati o n  at c o m pleti o n 
of st u d y treat me nt , t he ti me t o o nset of t he i nitial e ve nt, t he 
treat me nt gr o u p will be c o m pare d base d o n a C o x pr o p orti o nal 
hazar d m o del wit h t he C H A D S 2 sc ore (≤ 2 or ≥ 3) as c o variate. 
(si g nifica nce le vel: 5 %, 2-si de d) 
 
†: N o n-fatal m y ocar dial i nfarcti o n, n o n-fatal str o ke, n o n-fatal s yste mic e m b olis m, or 
deat hs d ue t o car di o v asc ular disease or blee di n g  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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ti me of Visit 3. 
e: St u d y treat me nt will be starte d o n t h e sa me date t h at n otificati o n of st u d y dr u g i d e ntifiers  is gi ve n. 
St u d y treat me nt will be c o nti n ue d u ntil t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt, w hi c h 
will be perf or me d wit hi n t he 6 0 da ys after t he d eclarati o n of c o m pl eti o n of t h e st u d y t hat is ma de 
w he n t h e pla n ne d n u m ber of s u bjects wit h pri mar y e fficac y e n d p oi nt e ve nts (str o ke a n d s yste mic 
e m b olis m) has  bee n c ollecte d.  
f: T he st u d y dr u g will be a d mi nistere d o nl y t o s u bj ects w h o pr o vi de d c o nse nt f or t he a d diti o n al st u d y 
treat me nt d uri n g t h e peri o d fr o m t he e x a mi nati o n at c o m pleti o n of st u d y treat me nt t o t he fi n al 
f oll o w-u p e xa mi nati o n . 
g:  T hese will be meas ure d at t h e ce ntral la b orat or y.  
h : Will be p erf or me d o n ce e ver y 8 wee ks ( Wee k 4 t o Wee k 4 8: Visit 3, Visit 5, Visit 7, Visit 9, Visit 
1 1, Visit 1 3/ Wee k 4 8 o n war d: Visit 1 4, Visit 1 5, Visit 1 6...).  
i: Will be c alc ulate d wit h t he C oc kcr oft -Ga ult f or m ul a. 
j: Will be p erf or me d o n ce e ver y 1 2 wee ks ( Visit 4, Visit 7, Visit 1 0, Visit 1 3).  
k : Will be p erf or me d o n ce e ver y 2 4 wee ks ( Visit 1 6, Visit 1 9, Visit 2 2...).  
l: If t his is perf or me d wit hi n 4 wee ks before t he d a y of i nf or me d c o nse nt as part of a p h ysical 
e xa mi n ati o n, t h e res ults ma y be use d f or t h e eli gi bilit y assess me nt e xa mi nati o n, wit h t h e c o nse nt 
of t he s u bj ect.  
m : D uri n g t h e peri o d fr o m t h e e xa mi n ati o n at c o m pleti o n of st u d y treat me nt t o t h e fi n al f oll o w-u p 
e xa mi n ati o n , o nl y seri o us a d verse e ve nts will be  m o nit ore d . 
n:  C hec ks o n w het her seri o us a d verse e ve nts ha ve occ urre d, w het her efficac y e ve nts h a ve occ urre d, 
w het her blee di n g e ve nts ha ve occ urre d, w het her t he f oll o wi n g dr u gs ha ve bee n use d: 
a ntic oa g ul a nts, t hr o m b ol ytics, a nti pl atelet dr u gs, i ntra ve n o us a ntiarr h yt h mics, a n d aci di c N S AI Ds, 
bl o o d press ure/ p ulse rate (if t he s u bject has ma de a visit), a n d la b orat or y tests deter mi ne d t o be 
a p pr o priate b y t he i n vesti gat or or s u bi n vesti gat or ( if t he s u bject has ma de a visit . If warfari n is 
bei n g use d, meas ure me nt of P T -I N R is ma n dat or y) will b e c o n d ucte d e ver y 8 wee ks. 
o : Will be p erf or me d o n Visit 3.  
p : Will be p erf or me d o nl y at st u d y sites w here it is p ossi ble.  
q : Will be p erf or me d fr o m Visit 2 o n war ds . 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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T A B L E O F C O N T E N T S  
P R O T O C O L S Y N O P SI S  ................................................................................................. 2  
LI S T O F I N -T E X T T A B L E S  ......................................................................................... 1 0  
LI S T O F I N-T E X T FI G U R E S  ...................................................................................... 1 0  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  ................................. 11  
1.  I N T R O D U C TI O N .................................................................................................... 1 3  
2.  S T U D Y O B J E C TI V E S  ............................................................................................ 1 6  
3.  S T U D Y D E SI G N  ...................................................................................................... 1 7  
4.  S T U D Y P O P U L A TI O N  ........................................................................................... 2 0  
4. 1  Selecti o n of S u bjects  ................................................................................................ 2 0  
4. 2  I n di vi d ual S u bject I nterr u pti o n or Disc o nti n uati o n of St u d y Dr u g, I n di vi d ual S u bject 
Disc o nti n uati o n of St u d y Partici pati o n, a n d Ter mi nati o n of t he E ntire St u d y  ......... 2 5  
5.  M E T H O D O L O G Y  ................................................................................................... 2 8  
5. 1  St u d y Dr u g  ............................................................................................................... 2 8  
5. 2  St u d y Treat me nt s A d mi nistere d ............................................................................... 2 9  
5. 3  Pr o hi bite d C o nc o mita nt Me dicati o ns a n d Pr o hi bite d Tests  ...................................... 3 2  
6.  S T U D Y P R O C E D U R E S  .......................................................................................... 3 3  
6. 1  St u d y Pr oce d ure a n d S peci me n C ollecti o n Sc he d ule  ............................................... 3 3  
6. 2  Baseli ne S u bject C haracteristics ............................................................................... 3 5  
6. 3  St u d y Dr u g C o m plia nce  ........................................................................................... 3 6  
6. 4  C o nc o mita nt Me dicati o ns (I ncl u di n g O ver -t he-c o u nter Dr u gs)  ............................... 3 6  
6. 5  Hea d I ma gi n g  ........................................................................................................... 3 7  
6. 6  T wel ve -lea d Electr ocar di o gra m ................................................................................ 3 7  
6. 7  Vital Si g ns  ................................................................................................................ 3 7  
6. 8  La b orat or y Tests  ....................................................................................................... 3 8  
6. 9  Creati ni ne Cleara nce  ................................................................................................ 3 9  
6. 1 0  S ur ger y  ..................................................................................................................... 4 0  
6. 1 1  H os pitalizati o n  ......................................................................................................... 4 0  
6. 1 2  Plas ma Dr u g C o nce ntrati o n, P har mac o ki netic I n dicat ors, a n d Bi o mar kers  ............. 4 1  
6. 1 3  A d verse E ve nts  ......................................................................................................... 4 3  
6. 1 4  Efficac y E ve nts  ......................................................................................................... 4 3  
6. 1 5  Blee di n g E ve nts  ........................................................................................................ 4 4  
6. 1 6  L o n g -ter m St ora ge of Cli nical S peci me ns f or Ge n o mic a n d Ge netic A nal ysis  ........ 4 5  
7.  E F FI C A C Y E N D P OI N T S  ....................................................................................... 4 6  
7. 1  Pri mar y E n d p oi nt  ..................................................................................................... 4 6  
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7. 2  Sec o n dar y E n d p oi nts  ................................................................................................ 4 7  
7. 3  Ot her E n d p oi nts  ........................................................................................................ 4 7  
8.  P H A R M A C O KI N E TI C E N D P OI N T S  ................................................................... 4 7  
9.  S A F E T Y E N D P OI N T S  ............................................................................................ 4 7  
9. 1  Blee di n g E ve nts  ........................................................................................................ 4 8  
9. 2  Defi niti o n of A d verse E ve nts  ................................................................................... 4 9  
9. 3  Defi niti o n of Seri o us A d verse E ve nts  ...................................................................... 5 0  
9. 4  A d verse E ve nt I nf or mati o n t o Be Re p orte d  ............................................................. 5 0  
9. 5  Defi niti o n of A d verse Dr u g Reacti o ns  ..................................................................... 5 2  
9. 6  Acti o n W he n a n A d verse E ve nt Occ urs  ................................................................... 5 2  
1 0.  O T H E R E N D P OI N T S  ............................................................................................. 5 2  
1 0. 1  P har mac o d y na mics ( P har mac o d y na mic I n dicat ors a n d Bi o mar kers)  ...................... 5 2  
11.  S T A TI S TI C A L A N A L Y S E S  .................................................................................... 5 2  
1 1. 1  O bjecti ve of A nal ysis  ............................................................................................... 5 2  
1 1. 2  A nal ysis Sets  ............................................................................................................ 5 3  
1 1. 3  Ha n dli n g of Data  ...................................................................................................... 5 4  
1 1. 4  Sta tistical A nal ysis Ite ms a n d A nal ysis Met h o ds ..................................................... 5 5  
1 1. 5  C ha n ges t o t he A nal ysis Pla n  ................................................................................... 5 9  
1 1. 6  Pla n ne d Sa m ple Size  ................................................................................................ 5 9  
1 2.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  ....................................... 6 0  
1 3.  FI N A N CI N G F O R P A R TI CI P A TI O N, C O M P E N S A TI O N F O R 
S T U D Y -R E L A T E D I N J U RI E S, A N D I N S U R A N C E  ............................................ 6 0  
1 3. 1  Fi na nci n g f or Partici pati o n  ....................................................................................... 6 0  
1 3. 2  C o m pe nsati o n f or St u d y -relate d I nj uries .................................................................. 6 0  
1 3. 3  I ns ura nce .................................................................................................................. 6 1  
1 4.  P U B LI C A TI O N P O LI C Y  ........................................................................................ 6 1  
1 5.  S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N  .................................................... 6 2  
1 5. 1  Et hics  ........................................................................................................................ 6 2  
1 5. 2  S u bject C o nfi de ntialit y  ............................................................................................. 6 2  
1 5. 3  I nf or me d C o nse nt ..................................................................................................... 6 3  
1 5. 4  I nf or me d C o nse nt f or P har mac o ge n o mics a n d Bi o mar ker Researc h ....................... 6 5  
1 5. 5  Pr o visi o n of Ne w I nf or mati o n Affecti n g t he C o n d uct of t he St u d y  ......................... 6 6  
1 5. 6  Pla n ne d St u d y D urati o n  ............................................................................................ 6 6  
1 5. 7  Pr ot oc ol A m e n d me nt  ................................................................................................ 6 6  
1 5. 8  Ter mi nati o n or I nterr u pti o n of t he St u d y  .................................................................. 6 7  
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1 5. 9  Pr oce d ures f or Pre pari n g t he Case Re p ort F or m a n d Re mar ks  ................................ 6 8  
1 5. 1 0  St ora ge of S o urce D oc u me nts a n d Ot her Rec or ds  ................................................ 6 9  
1 5. 1 1  Direct Access t o S o urce D oc u me nts  ..................................................................... 7 1  
1 5. 1 2  Or ga nizati o n  ......................................................................................................... 7 1  
1 5. 1 3  E mer ge nc y C o ntact I nf or mati o n  ........................................................................... 7 8  
1 6.  R E F E R E N C E S  ......................................................................................................... 7 9  
A T T A C H M E N T  ............................................................................................................. 8 2  
A P P E N DI C E S  ................................................................................................................ 8 3  
 
LI S T O F I N -T E X T T A B L E S  
Ta ble of St u d y Pr oce d ure a n d S peci me n C ollecti o n Sc he d ule  ........................................... 6  
Ta ble 6 -1  St u d y Pr oce d ure a n d S peci me n C ollecti o n Sc he d ule  .................................... 3 4  
Ta ble 6 -2  Ti mes of Bl o o d Sa m pli n g f or Meas uri n g Plas ma Dr u g C o nce ntrati o n  ......... 4 1  
Ta ble 9 -1  I nf or mati o n t o Be Re p orte d W he n a n A d verse E ve nt Occ urs  ....................... 5 1  
Ta ble 1 5. 9 -1  T he E D C S yste m  ...................................................................................... 6 8  
 
LI S T O F I N -T E X T FI G U R E S  
Fi g ure 3 -1  St u d y Desi g n  ............................................................................................... 1 8  
Fi g ure 4. 1 -1  E nr oll me nt Pr oce d ure f or S u bjects  ........................................................... 2 3  
 
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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
List of A b bre vi ati o ns  
A b bre viati o n  
Defi niti o n  
A F  
atrial fi brill ati o n 
A L P  
al kali ne p h os p hatase  
A L T  
L -ala ni n e ami n otra nsferase  
a P T T  
acti v ate d p artial t hr o m b o plasti n ti me  
A S T  
L -as partate ami n otra nsferase  
B MI  
b o d y m ass in d e x  
B N P  
brai n natri ureti c pe pti de  
B U N  
b l o o d u rea n itr o ge n 
C K  
creati n e ki nase  
C Lcr  
creati ni ne cleara nce 
C T  
c o m p ut e d t o m o gra p h y  
C V  
car di o v asc ular  
D V T  
dee p vei n t hr o m b osis  
E C G  
electr ocar di o gra m  
E D C  
electr o nic data ca pt ure  
F 1 + 2  
pr ot hr o m bi n fra g me nt 1 + 2  
G C P  
g o o d cli ni cal p ractice 
G G T  
ga m ma g l uta m yl tra nsferase  
I C H 
Inter nati o n al C o u n cil f or  H ar m o nisati o n of T ec h ni cal R e q uire me nts 
f or P har mace uticals f or H u ma n U se 
I N R 
i nter nati o nal n or malize d rati o 
I R B 
i nstit uti o n al re vie w b oar d 
I R T 
interacti v e res p o nse tec h n ol o g y  
I T T 
I nte nt-t o-treat 
IW R S  
interacti v e w e b res p o nse syste m  
L C -M S/ M S  
li q ui d c hr o mat o gra p h y ta n de m mass s pectr o metr y 
L D H  
lactic aci d ( lactate) d e h y dr o g e nase  
M A C E  
maj or a d verse car di o vasc ular e ve nt  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti v ities 
MI  
m y ocar di al i nfarcti o n  
mI T T  
M o difie d i nt e nt -t o-treat 
M RI  
ma g netic res o n a nce i ma gi n g  
N S AI Ds  
n o n -ster oi dal a nti-i nfla m mat or y dr u gs 
N V A F  
n o n -val v ular atrial fi brill ati o n  
N Y H A  
Ne w Yor k Heart Ass ociati o n  
P D  
p har mac o d y na mics  
P -g p  
P -gl yc o pr otei n  
P G x  
p har mac o ge n o mics  
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P K  
p har mac o ki n etics  
P P S  
per pr ot oc ol set  
P T  
pr ot hr o m bi n ti me  
P T E  
p ul m o nar y t hr o m b oe m b olis m  
P T -I N R 
pr ot hr o m bi n ti me e x presse d as i nt er nati o nal n or malize d rati o  
S E E  
s yste mic e m b olic e ve nt 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
TI A  
tra nsie nt isc he mic att ac k 
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 oli c e ve nt  
Xa  
acti v ate d c oa g ulati o n fact or X  
 
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1.  
I N T R O D U C TI O N 
Atrial fi brillati o n ( A F) is a c o m m o n t y pe of arr h yt h mia i n t he el derl y, a n d is a n 
i n de pe n de nt ris k fact or f or str o ke.1) ,2)  Si nce a gi n g is als o a n i n de pe n de nt ris k fact or f or 
str o ke, a n d si nce i n ge neral ma n y el derl y pe o ple als o ha ve c o nc urre nt ris k fact ors s uc h as 
h y perte nsi o n or c o n gesti ve  car diac fail ure, el derl y patie nts wit h A F are a p o p ulati o n at 
hi g h ris k fr o m str o ke .3) ,4)  It is k n o w n t hat t he pre vale nce of A F i ncreases wit h a ge,5) a n d 
gi ve n t hat t he Ja pa nese p o p ulati o n is set t o a ge f urt her i n t he f ut ure, t here is c o nsi dere d t o 
be a n i ncreasi n g tre n d i n t he n u m ber of el derl y patie nts wit h A F at hi g h ris k fr o m str o ke.  
Ma n y str o kes t hat occ ur i n patie nts wit h A F are car di oe m b olic str o kes, a n d as t he y are 
ofte n se vere, t he y are a fact or t hat i ncreases t he b ur de n of n ursi n g care d ue t o se q uelae 
a n d l o n g -ter m e xte nsi o n of h os pitalizati o n peri o ds.  F or t hese reas o ns, a n d als o t o 
pre ve nt patie nts fr o m bec o mi n g be dri d de n, t he pre ve nti o n of str o ke i n el derl y patie nts 
wit h A F is hi g hl y cli nicall y si g nifica nt.  
N ot o nl y i n Ja pa n b ut als o gl o ball y, oral a ntic oa g ula nt t hera p y is rec o m me n de d as t he 
sta n dar d of care  f or t he pre ve nti o n of str o ke i n patie nts wit h A F .6) ,7)  Assess me nt of 
w het her oral a ntic oa g ula nt t hera p y is i n dicate d f or a patie nt is ma de base d o n w het her 
ris k fact ors f or str o ke are prese nt.  If t he C H A D S 2 i n de x sc ore, a n assess me nt i n dicat or 
f or t he ris k of str o ke i n patie nts wit h A F, is use d, oral a ntic oa g ula nt t hera p y is 
rec o m me n de d or s uita ble f or c o nsi derati o n i n patie nts a ge d 7 5 years or ol der e ve n if t he y 
d o n ot ha ve a n y ot her ris k fact ors . 6)  As state d a b o ve, el derl y patie nts wit h A F are a 
p o p ulati o n wit h a partic ularl y hi g h ris k of str o ke, f or w hic h oral a ntic oa g ula nt t hera p y t o 
pre ve nt str o ke is rec o m me n de d.  H o we ver, i n cli nical practice, oral a ntic oa g ula n t 
t hera p y is ofte n n ot a g gressi vel y a d mi nistere d t o el derl y patie nts wit h A F.  Acc or di n g t o 
ta b ulate d data as of J u n 2 0 1 2 i n T he F us hi mi A F Re gistr y,8) a s ur ve y ce nteri n g o n 
F us hi mi -k u i n K y ot o Cit y w h ose o bject i ves i ncl u de s ur ve yi n g t he baseli ne fact ors of 
patie nts wit h A F, s ur ve yi n g t he state of t heir treat me nt, a n d f oll o wi n g u p o n t heir 
pr o g n oses, oral a ntic oa g ula nt t hera p y was n ot a d mi nistere d t o at 5 0 % or m ore of patie nts 
wit h A F i n t heir 8 0s a n d 7 0 % or m ore  of patie nts wit h A F i n t heir 9 0s.  I n a d diti o n, 
al m ost all patie nts i n t heir 8 0s or ol der ha ve a C H A D S 2 i n de x sc ore of at least 2.  T h us, 
t he s ur ve y s h o ws t hat t here are ma n y patie nts n ot recei vi n g oral a ntic oa g ula nt t hera p y 
des pite ha vi n g a hi g h ris k of str o ke.  I n ta b ulate d data as of J ul 2 0 1 4 i n T he F us hi mi A F 
Re gistr y ,9) oral a ntic oa g ula nt t hera p y was n ot a d mi nistere d t o 5 8. 7 % of patie nts wit h A F 
a ge d 8 5 years or ol der.  Si milar sit uati o ns ha ve als o bee n re p orte d o verseas .1 0) ,1 1) ,1 2)  
O ne maj or reas o n t hat oral a ntic oa g ula nt t hera p y is n ot a g gressi vel y a d mi nistere d is t hat 
t here is a hi g h ris k of blee di n g i n el derl y patie nts wit h A F.  A gi n g itself is a blee di n g 
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ris k f or oral a ntic oa g ula nt t hera p y , a n d i n rece nt years, cli nical st u dies of 
n o n -vita mi n -K -a nta g o nist oral a ntic oa g ula nt s c o n d ucte d i n patie nts wit h A F ha ve als o 
s h o w n t hat t he s u b gr o u p of el derl y patie nts te n ds t o ha ve a hi g her i nci de nce of blee di n g 
e ve nts .1 3) ,1 4) ,1 5) ,1 6) ,1 7)   A m o n g el derl y patie nts wit h A F, t here are patie nts wit h f urt her 
blee di n g ris ks, s uc h as a me dical hist or y of blee di n g, a falli n g ris k, re nal i m pair me nt, a n d 
c o nc o mita nt a nti pla telet me dicati o n, a n d it is t h o u g ht t hat a d mi nistrati o n of oral 
a ntic oa g ula nt t hera p y is u ns uita ble f or t hese patie nts.  T h us, des pite t he hi g h ris k of 
str o ke i n el derl y patie nts wit h A F, t here are c urre ntl y m ore t ha n a fe w cases w here t he 
sta n dar d t hera p y, oral a ntic oa g ula nt t hera p y, is n ot a d mi nistere d beca use of c o ncer ns 
a b o ut blee di n g, a n d s o it is c o nsi dere d  t hat a n oral a ntic oa g ula nt t hera p y  wit h a re d uce d 
blee di n g ris k is necessar y i n cli nical practice.  
D U -1 7 6 b ( g e neric na me: e d o xa ba n t osilate h y drate) is a n oral a ntic oa g ula nt t hat 
s pecificall y a n d re versi bl y i n hi bits acti vate d plas ma cl otti n g  fact or X, a n d is use d i n 
cli nical practice as Li xia na ®  Ta blets 1 5  m g, 3 0  m g, a n d 6 0  m g w it h t he i n dicati o n t o 
re d uce t he ris k of str o ke a n d s yste mic e m b olic e vents ( S E Es) i n patie nts wit h n o n val v ular 
atrial fi brillati o n ( N V A F).  I n a p hase 3 gl o bal st u d y (E N G A G E A F -TI MI 4 8) i n patie nts 
wit h N V A F, e d o xa ba n 6 0  m g  ( or 3 0 m g i n s u bjects wit h fact ors re q uiri n g d osa ge 
a dj ust me nt ‡) a d mi nistere d orall y o nce dail y was f o un d t o be n o n -i nferi or t o warfari n f or 
c o m p osite of str o ke a n d  S E E, a n d t h us t he a p pr o ve d d osa ge i n patie nts wit h N V A F is 
3 0  m g  or 6 0  m g  orall y o nce dail y.  I n t he E N G A G E A F -TI MI 4 8 st u d y, t he efficac y a n d 
safet y of e d o xa ba n a d mi nistere d orall y at 3 0  m g  ( or 1 5  m g i n s u bjects wit h fact ors 
re q uiri n g d osa ge a dj ust me nt) o nce dail y (e d o xa ba n 3 0 -m g  gr o u p) were e val uate d.  T he 
e d o xa ba n 3 0 -m g  gr o u p was als o f o u n d t o be n o n -i nferi or t o warfari n f or c o m p osite of 
str o ke a n d  S E E, b ut w he n a nal ysis was restricte d t o o ral a d mi nistrati o n of 1 5  m g o nce 
dail y i n t he s u bjects wit h fact ors re q uiri n g d osa ge a dj ust me nt, t he a n n ual i nci de nce of 
c o m p osite of str o ke a n d  S E E was hi g her t ha n i n t he warfari n gr o u p, partic ularl y i n t he 
Ja pa nese p o p ulati o n ( 2. 7 9 %/ year vs. 1. 2 0 %/ year, C o x  pr o p orti o nal hazar ds m o del P  = 
0. 1 1 4 1).  T h us, t he E N G A G E A F -TI MI 4 8 st u d y c o m pari n g e d o xa ba n wit h warfari n, 
w here t he i nter nati o nal n or malize d rati o (I N R) was strictl y c o ntr olle d, di d n ot clearl y 
s h o w t he efficac y of e d o xa ba n 1 5 m g  a d mi nistere d orall y o n ce dail y, a n d at prese nt, 
1 5  m g o nce dail y is n ot rec o m me n de d as a d osa ge in a d mi nistrati o n t o patie nts wit h 
N V A F.  
 
‡ Fact ors re q uiri n g d osa ge a dj ust me nt were a n y of t he f oll o wi n g: b o d y wei g ht ≤ 6 0  k g, 
creati ni ne cleara nce ( C Lcr) ≤ 5 0  m L/ mi n, or c o nc o mita nt a d mi nistrati o n of vera pa mil  or 
q ui ni di ne  
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H o we ver, t he a n n ual i nci de nce of c o m p osite of str o ke a n d S E E i n t he p o p ulati o n 
a d mi nistere d e d o xa ba n at 1 5  m g o nce dail y d ue t o d os a ge  a dj ust me nt at t he ti me of 
ra n d o m assi g n me nt in t he e d o xa ba n 3 0 -m g gr o u p of t he E N G A G E A F -TI MI 4 8 st u d y 
was 2. 3 6 %/ year f or t he o verall p o p ulati o n a n d 2. 7 9 %/ year f or t he Ja pa nese p o p ulati o n 
( 2. 2 1 %/ year a n d 1. 2 0 %/ year res pecti vel y, i n t he warfari n gr o u p).  I n meta-a nal ysis 
usi n g data fr o m ra n d o mize d cli nical st u dies of vita mi n K a nta g o nists ( V K As) c o n d ucte d 
i n patie nts wit h A F i n t he past, it was re p orte d t hat t he a n n ual i nci de nce of n o n-fatal 
str o ke i n t he c o ntr ol gr o u p ( u ntreate d) was 7. 6 %/ year ( 2. 5 %/ year i n t he V K A gr o u p) .1 8)  
H o we ver, at prese nt, d ue t o c ha n ges i n t he me dical e n vir o n me nt, t he i nci de nce of t he 
e ve nts str o ke or S E E ma y ha ve decrease d, b ut it is still c o nsi dere d  t o be a hi g h i nci de nce.  
Gi ve n t hese res ult s, it is e x pecte d  t hat e ve n if e d o xa ba n is a d mi nistere d at 1 5 m g  o nce 
dail y, it will be effecti ve at re d uci n g t he ris k of str o ke t o a certai n e xte nt, base d o n its 
a ntic oa g ula nt effect.  T he a n n ual i nci de nce of c o m p osite of str o ke a n d  S E E d uri n g 
a d mi nistrat i o n of e d o xa ba n at 1 5 m g o nce dail y i n s u bjects age d 8 0 years or ol der i n t he 
E N G A G E A F -TI MI 4 8 st u d y was 2. 3 3 %/ year f or t he o verall st u d y p o p ulati o n, w hic h is 
si milar t o t he res ult ( 2. 3 6 %/ year) f or all s u bjects a d mi nistere d 1 5  m g o nce dail y 
re gar dless of a ge.  In a d diti o n, i n t he A V E R R O E S st u d y 1 6) e val uati n g  t he efficac y of 
a pi xa ba n i n patie nts wit h A F a n d V K A is n ot  i n dicate d, t he a n n ual i nci de nce of 
c o m p osite of str o ke a n d  S E E i n t he as piri n gr o u p, w hic h was t he c o ntr ol gr o u p, was 
3. 7 %/ year, a n d t h us t he a n n ual i nci de nce d uri n g a d mi nistrati o n of e d o xa ba n at 1 5  m g 
o nce dail y i n t he E N G A G E A F -TI MI 4 8  st u d y was l o wer t ha n t his.  As piri n is n ot 
p ositi o ne d as a sta n dar d of care  f or re d uci n g t he ris k of str o ke i n patie nts wit h A F, a n d is 
n ot rec o m me n de d as a ntit hr o m b otic t hera p y i n patie nts wit h A F,6) b ut it is e x pecte d  t hat 
a d mi nistrati o n of e d o xa ba n at 1 5  m g  o nce dail y will s h o w a greater re d ucti o n of t he ris k 
of str o ke t ha n as piri n.  
Fr o m t he safet y sta n d p oi nt, n o he m orr ha gic str o ke was f o u n d d uri n g a d mi nistrati o n of 
e d o xa ba n at 1 5  m g o nce d ail y i n t he E N G A G E A F -TI MI 4 8 st u d y, a n d t he a n n ual 
i nci de nce of i ntracra nial he m orr ha ge was 0. 1 4 %/ year, l o wer t ha n t he i nci de nce i n t he 
warfari n gr o u p of 1. 2 6 %/ year, a n d als o l o wer t ha n t he i nci de nce of 0. 5 7 %/ year i n 
s u bjects a d mi nistere d e d o xa ba n at 3 0 m g o nce dail y d ue t o d os a ge  a dj ust me nt.  T he 
a n n ual i nci de nce of maj or blee di n g was 1. 5 0 % /year wit h a d mi nistrati o n of e d o xa ba n at 
1 5  m g  o nce dail y, w hic h was l o wer t ha n t he i nci de nces of 4. 8 5 %/ year i n t he warfari n 
gr o u p a n d 3. 0 5 %/ year wit h a d mi nistrati o n of d os a ge -a dj uste d e d o xa ba n at 3 0  m g  o nce 
dail y.  I n a d diti o n, e ve n if a nal ysis is restricte d t o s u bjects a ge d 8 0 years or ol der i n t he 
E N G A G E A F -TI MI 4 8 st u d y, t he a n n ual i nci de nce of maj or blee di n g was 1 . 9 9 %/ year 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
1 6  
wit h a d mi nistrati o n of e d o xa ba n 1 5  m g  o nce dail y, 6. 7 7 %/ year i n t he warfari n gr o u p, a n d 
4. 2 8 %/ year wit h a d mi nistrati o n of d os a ge -a dj uste d e d o xa ba n at 3 0  m g  o nce dail y, 
s h o wi n g that e ve n i n el derl y patie nts wit h A F, t he blee di n g ris k fr o m a d mi nistrati o n of 
e d o xa ba n at 1 5  m g  o nce dail y is l o wer t ha n t hat of warfari n or of e d o xa ba n at t he 
a p pr o ve d d osa ge.  
T h us, a d mi nistrati o n of e d o xa ba n at 1 5  m g  o nce dail y is ass ociate d wit h a l o we r blee di n g 
ris k t ha n t he a vaila ble oral a ntic oa g ula nt warfari n or a d mi nistrati o n of e d o xa ba n at 3 0  m g  
or 6 0  m g  o nce dail y, a n d fr o m t he efficac y sta n d p oi nt, it is c o nsi dere d t o be effecti ve at 
re d uci n g t he ris k of str o ke t o a certai n e xte nt.  T heref ore, it is c o nsi dere d t hat 1 5 m g  of 
e d o xa ba n o nce dail y ca n be a d mi nistere d t o el derl y patie nts wit h A F w h o ha ve n ot 
recei ve d a g gressi ve a ntic oa g ula nt t hera p y d ue t o c o ncer ns a b o ut blee di n g.  
Acc or di n gl y, we pla n ne d a ra n d o mize d, d o u ble -bli n d , place b o -c o ntr olle d  st u d y t o 
e val uate t he efficac y a n d safet y of a d mi nistrati o n of e d o xa ba n at 1 5  m g o nce dail y i n 
el derl y patie nts wit h N V A F w h o are i neli gi ble  f or the sta n dar d of care , oral 
a ntic oa g ula nts, at t he a p pr o ve d d osa ge § d ue t o c o ncer ns a b o ut blee di n g.  A c o m p osite 
of str o ke a n d  S E E  was s electe d  f or pri mar y efficac y e n d p oi nt, t o e val uate t he s u peri orit y 
of a d mi nistrati o n of e d o xa ba n at 1 5  m g  o nce dail y i n re d uci n g t he ris k of str o ke a n d  S E E 
c o m pare d t o t he place b o gr o u p.  
Maj or blee di n g was selecte d f or t he pri mar y safet y 
e n d p oi nt, a n d c o m pare d wit h t he place b o gr o u p, a n d cli nical acce pta bilit y was als o 
assesse d wit h refere nce t o t he i nci de nce of maj or blee di n g wit h a vaila ble oral 
a ntic oa g ula nt t hera pies.  If t his st u d y fi n ds t hat a d mi nistrati o n of e d o xa ba n at 1 5  m g  
o nce dail y is effecti ve, a n d t hat its safet y is cli nicall y acce pta ble, it is e x pecte d t o pr o vi de 
a ne w o pti o n f or str o ke pre ve nti o n i n el derl y patie nts wit h N V A F w h o ha ve n ot recei ve d 
a g gressi ve treat me nt wit h sta n dar d of care . 
 
2.  
S T U D Y O B J E C TI V E S  
To e val uate  t he efficac y a n d safet y of 1 5 m g  of D U -1 7 6 b i n patie nts wit h N V A F  a ge d 8 0 
years or ol der w h o are i neli gi ble f or a vaila ble oral a ntic oa g ula nts ( warfari n, da bi gatra n, 
ri var o xa ba n, a pi xa ba n, or e d o xa ba n) at t he a p pr o ve d d osa ge. * *  To e val uate t he  
s u peri orit y of 1 5  m g  of D U -1 7 6 b c o m pare d t o place b o i n a c o m p osite e n d p oi nt of str o ke 
a n d S E E as t he pri mar y efficac y e n d p oi nt.  
 
 
§: I N R c o ntr olle d at bet wee n 1. 6 a n d 2. 6 wit h warfari n  
* *: F or warfari n, I N R c o ntr olle d at bet wee n 1. 6 a n d 2. 6  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
1 7  
3.  
S T U D Y D E SI G N  
T he efficac y a n d safet y of 1 5  m g of D U -1 7 6 b  o nce dail y  will be e val uate d i n a 
ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d, pa rallel-gr o u p, m ultice nter, e ve nt -dri ve n 
st u d y i n patie nts wit h N V A F a ge d 8 0 years or ol der w h o are i neli gi ble f or a vaila ble oral 
a ntic oa g ula nts ( warfari n, da bi gatra n, ri var o xa ba n, a pi xa ba n, or e d o xa ba n) at t he 
a p pr o ve d d osa ge. * *   
T he w or kfl o w fr o m i nf or me d c o nse nt t o t he fi nal f oll o w -u p e xa mi nati o n is s h o w n i n 
Fi g ure 3 -1 . 
T he i n vesti gat or or s u bi n vesti gat or will o btai n c o nse nt fr o m p ote ntial s u bjects f or t his 
st u d y a n d t he n e nter t heir s u bject i nf or mati o n i nt o i nte racti ve res p o nse tec h n ol o g y (I R T).  
Wit hi n 3 0 da ys after i nf or me d c o nse nt, a n eli gi bilit y assess me nt e xa mi nati o n will be 
perf or me d t o deter mi ne  w het her or n ot  t he s u bjects meet all i ncl usi o n criteria a n d 
e xcl usi o n criteria, a n d t he eli gi bilit y assess me nt r es ults f or t he s u bjects will be e ntere d 
i nt o I R T.  S u bject e nr olle d i n I R T will be assi g ne d ra n d o ml y t o t he D U-1 7 6 b gr o u p or 
place b o gr o u p i n a 1: 1 rati o.  
After ra n d o mizati o n, st u d y treat me nt  will be starte d o n t he sa me date t hat n otificati o n of 
st u d y dr u g i de ntifiers is gi ve n.  C o m pleti o n of t he st u d y will be declare d w he n t he 
pla n ne d n u m ber of s u bjects wit h pri mar y efficac y e n d p oi nt e ve nts (str o ke a n d S E E)  has 
bee n c ollecte d .  A d mi nistrati o n of t he st u d y dr u g will be c o nti n ue d u ntil t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt perf or me d wit hi n 6 0 da ys after t he 
declarati o n of c o m pleti o n of t he st u d y .  W he n t he i n vesti gat or or s u bi n vesti gat or 
re q uires t o k n o w t he st u d y treat me nt assi g n me nt f or eac h s u bject t o deter mi ne t he 
s u bse q ue nt treat me nt after t he fi nal a d mi nistrati o n of t he st u d y dr u g, t he st u d y treat me nt 
ca n be c o nti n ue d u ntil t he fi nal f oll o w -u p e xa mi nati o n after o btai ni n g  c o nse nt fr o m t he 
s u bject.  T he fi nal f oll o w -u p e xa mi nati o n  will be perf or me d  i n t he s u bjects, i n pri nci ple, 
wit hi n a m o nt h a fter n otif yi n g t heir st u d y treat me nt assi g n me nts. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
1 8  
Fi g ure 3 -1   St u d y Desi g n  
 
a: S u bjects w h o pr o vi d e d c o nse nt will c o nti n ue t o recei v e t he st u d y treat me nt. T he pla n ne d d urati o n 
of  t he a d diti o n al st u d y treat me nt is 3  t o 4  m o nt hs.  
b:  C o m pleti o n of t he st u d y will be  declare d w he n t h e pla n ne d n u m ber of s u bjects wit h pri mar y 
efficac y e n d p oi nt  e ve nts has bee n c ollecte d . 
c: F or s u bjects w h o d o n ot c o nti n ue t he st u d y treat me nt, t he fi n al f oll o w -u p e xa mi nati o n will be 
perf or me d wit hi n 3 0  t o 3 7 da ys after t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt.  
F or s u bjects w h o c o nti n ue t he st u d y treat me nt , t he fi nal f oll o w-u p e xa mi nati o n  will be perf or me d , 
i n pri n ci ple, wit hi n a m o nt h after n otif yin g t h eir st u d y treat me nt assi g n me nts. 
 
< Rati o nale >  
T he o bjecti ve of a d mi nisteri n g oral a ntic oa g ula nt t hera p y t o patie nts wit h N V A F is t o 
re d uce t he ris k of t hr o m b oe m b olis ms s uc h as str o ke or S E E, a n d cli nical st u dies of 
a ntic oa g ula nt t hera p y i n patie nts wi t h N V A F ge nerall y use t he occ urre nce of str o ke a n d 
S E E as efficac y e n d p oi nts.  To assess t he i nci de nce of cli nical e ve nts s uc h as t hese, it is 
necessar y t o c ollect a certai n n u m ber of s u bjects wit h efficac y e ve nts, a n d t heref ore t his 
st u d y will be c o n d ucted as a n e ve nt -dri ve n st u d y.  As t here is n o s pecificati o n a b o ut t he 
peri o d f or w hi c h it is necessar y t o re d uce t he ris k of t hr o m b oe m b olis m i n patie nts wit h 
N V A F, t he d urati o n of st u d y treat me nt f or eac h s u bject will n ot be s pecifie d, a n d i nstea d 
t he st u d y treat me nt will be c o nti n ue d u ntil t he visit directl y after c o m pleti o n of t he st u d y 
is declare d, w he n t he re q uire d n u m ber of efficac y e ve nts ha ve bee n c ollecte d. 
T he st u d y s u bjects are patie nts wit h N V A F wit h a hi g h ris k of str o ke b ut w h o ha ve n ot 
recei ve d oral a ntic oa g ula nts ( n o n -V K A oral a ntic oa g ula nts or warfari n) d ue t o c o ncer ns 
a b o ut blee di n g, or w h o are recei vi n g warfari n at a n a ntic oa g ula nt stre n gt h n ot 
Eli gi bilit y assess me nt p eri o d, 
u p t o 3 0  d a y s 
Mea n d urati o n  of st u d y treat m e nt,  
 2  t o 2 .5  y ears  
Wit hi n t h e 6 0  d a ys after 
d eclarati o n of c o m pleti o n 
of t h e st u d y  
A d diti o n al  
st u d y treat m e nt a 
I nf or me d c o ns e nt 
I R T e ntr y (e ntr y of s u bj ect 
i nf or mati o n) 
Eli gi bilit y assess me nt/ eli gi bilit y 
ass ess me nt e x a mi n ati o n  
I R T e ntr y (e ntr y of eli gi bilit y 
ass ess me nt res ult) 
Ra n d o mi zati o n  
D U -1 7 6 b gr o u p  
1 5  m g of D U -1 7 6 b a d mi nist ere d orall y 
o n ce d ail y  
Pl ace b o gr o u p  
Pl ace b o a d mi nist ere d orall y o nce d ail y  
* Decl arati o n of c o m pl eti o n 
of t h e st u d y b 
E x a mi n ati o n at c o m pl eti o n  of 
st u d y treat me nt 
Fi n al f oll o w -u p e x a mi nati o n c 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
1 9  
rec o m me n de d i n t he g ui deli nes.† †  F or t his reas o n, it is n ot p ossi ble t o use warfari n or 
n o n -V K A or a l a ntic oa g ula nts at t he a p pr o ve d d osa ge ‡ ‡ as a c o ntr ol.  A nti platelet dr u gs 
are als o u ns uita ble as t he c o ntr ol i n t his st u d y, si nce t he y are n ot t he sta n dar d of care  f or 
re d uci n g t he ris k of str o ke i n patie nts wit h A F, a n d a nti platelet t hera p y i n patie nts w it h 
A F is n ot rec o m me n de d.  T h us, as it is n ot feasi ble t o select a s pecific me dicati o n as a 
c o ntr ol dr u g, we ha ve deci de d t o use a place b o as a c o ntr ol t o e val uate t he efficac y a n d 
safet y of a d mi nistrati o n of 1 5 m g of D U -1 7 6 b o nce dail y.  To mi ni mize s u bj ect 
selecti o n bias, we ha ve deci de d t o c o n d uct ra n d o mizati o n after t he eli gi bilit y of s u bjects 
has bee n deter mi ne d , a n d t o mi ni mize treat me nt bias a n d assess me nt bias, we ha ve 
selecte d d o u ble-bli n di n g as t he bli n di n g le vel.  T he cli nical e ve nts selecte d as  efficac y 
a n d safet y e n d p oi nts will be assesse d u n der bli n de d c o n diti o ns b y e ve nt assess me nt 
c o m mittees i n de pe n de nt of t he i n vesti gat ors a n d S p o ns or.  
 
† †: I N R c o ntr olle d at bel o w 1. 6 
‡ ‡: F or warfari n, I N R c o ntr olle d at bet wee n 1. 6 a n d 2. 6  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 0  
4.  
S T U D Y P O P U L A TI O N  
4. 1  
Selecti o n of S u bjects  
S u bjects w h o meet all of t he f oll o wi n g i ncl usi o n criteria a n d e xcl u si o n criteria, a n d 
pr o vi de writte n c o nse nt of t heir o w n free will, will be selecte d.  I n t he case of patie nts 
wit h c o nc urre nt de me ntia w h o are u na ble t o pr o vi de writte n c o nse nt i n pers o n, writte n 
a p pr o ve d c o nse nt fr o m a le gall y acce pta ble re prese ntati ve wi ll be ma n dat or y (see “1 5. 3  
I nf or me d C o nse nt”). 
 
4. 1. 1  
I ncl usi o n Criteri a 
1)  Patie nts wit h N V A F wit h hist or y of A F d oc u me nte d b y a n y electrical traci n g wit hi n 
t he 1 year pri or t o the da y of i nf or me d c o nse nt  
2)  Patie nts  wit h at least 2 of t he f oll o wi n g t hr o m b oe m b olis m ris k fact ors ( C H A D S
2 
i n de x sc ore ≥ 2)  
i)  
C o n gesti ve heart fail ure  
ii) 
H y perte nsi o n  
iii) A ge ≥ 7 5 years  
i v) Di a betes mellit us  
v)  
Hist or y of tra nsie nt isc he mic attac k ( TI A) or cere bral i nfarct i o n (e xcl u di n g 
occ urre nces wit hi n t he 3 0 da ys pri or t o  t he da y of ra n d o mizati o n) 
3)  Patie nts wit h a ge d  ≥ 8 0 years o n t he da y of i nf or me d c o nse nt  
4)  Patie nts  w h o are i neli gi ble § § f or a vaila ble oral a ntic oa g ula nts ( warfari n, da bi gatra n, 
ri var o xa ba n, a pi xa ba n, or e do xa ba n) at t he a p pr o ve d d osa ge, * * * a n d wit h at least 1 of 
t he f oll o wi n g blee di n g ris ks: 
i)  
Se vere re nal i m pair me nt ( creati ni ne cleara nce [ C Lcr ] calc ulate d b y t he 
C oc kcr oft -Ga ult f or m ula ≥ 1 5 m L/ mi n a n d < 3 0 m L/ mi n)  
ii) 
Hist or y of blee di n g fr o m critical area or or ga n (s uc h as i ntracra nial, 
i ntra oc ular, or gastr oi ntesti nal blee di n g) 
iii) L o w b o d y wei g ht ( ≤ 4 5 k g)  
i v) C o nti n u o us use of aci dic n o n -ster oi dal a nti-i nfla m mat or y dr u gs (N S AI Ds ) 
v)  
Patie nts  usi n g 1  a nti platelet dr u g  (f or a p ur p ose ot her t ha n pr o p h yla xis of 
 
§ § S u bjects s uc h as t h ose n ot eli gi ble f or c o nti n ue d a d mi nistrati o n at t he a p pr o ve d d osa ge 
f or t he dr u g d ue t o c o ncer ns a b o ut blee di n g ris k, or t h ose w h o ha ve n ot bee n 
a d mi nistere d a vaila ble oral a ntic oa g ula nts at t he a p pr o ve d d osa ge b ut are e x pecte d t o 
ha ve a hi g h blee di n g ris k fr o m a vaila ble oral a ntic oa g ula nts at t he a p pr o ve d d osa ge . 
* * *: F or warfari n, I N R c o ntr olle d at bet wee n 1. 6 a n d 2. 6  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 1  
car di oe m b olic str o ke) 
 
< Rati o nale >  
T he st u d y s u bjects are el derl y patie nts wit h N V A F a ge d  ≥ 8 0 years w h o are i neli gi ble f or 
oral a ntic oa g ula nts ( warfari n, da bi gatra n, ri var o xa ba n, a pi xa ba n, or e d o xa ba n) at t he 
a p pr o ve d d osa ge. * * *  T he st u d y will e nr oll  t he patie nts wit h N V A F dia g n ose d  b y t heir 
p h ysicia n t o be i neli gi ble t o recei ve treat me nt wit h a vaila ble oral a ntic oa g ula nts at t he 
a p pr o ve d d osa ge after c o nsi derati o n of t he blee di n g ris k fr o m a d mi nistrati o n of warfari n, 
a n d a ls o c o nsi derati o n of blee di n g ris k i n acc or da nce wit h t he preca uti o nar y te xt i n t he 
War ni n gs secti o n of t he pac ka ge i nserts f or n o n -V K A oral a ntic oa g ula nts stati n g “w he n 
usi n g t his dr u g, a caref ul c o nsi derati o n  s h o ul d be gi ve n t o w het her a d mi nistrati o n of t his 
dr u g is a p pr o priate, ta ki n g blee di n g ris k i nt o c o nsi derati o n. ” 
1)  To e ns ure t hat t he patie nt is a n A F patie nt.  
2)  A C H A D S 2 i n de x sc ore ≥ 2, at w hic h le vel all a vaila ble oral a ntic oa g ula nts are 
rec o m me n de d i n t he G ui deli nes f or P har mac ot hera p y of Atrial Fi br illati o n, 6) was 
selecte d. 
3)  Patie nts wit h a ge d  ≥ 8 0 years 8) were selecte d, si nce patie nts of t his a ge acc o u nt f or at 
least half of t he patie nts wit h N V A F f or w h o m a ntic oa g ula nt t hera p y is 
rec o m me n de d b ut w h o d o n ot recei ve a ntic oa g ula nts des pite bei n g at partic ularl y 
hi g h ris k fr o m str o ke.  
4)  Re nal i m pair me nt, l o w b o d y wei g ht, a n d c o nc o mita nt a d mi nistrati o n of a nti platelet 
dr u gs are c o nsi dere d t o be fact ors relate d t o t he occ urre nce of maj or blee di n g d uri n g 
a ntic oa g ula nt t hera p y. 6)  Blee di n g s uc h as i ntracra nial, i ntra oc ular, i ntrat hecal, 
retr o perit o neal, or i ntraartic ular blee di n g, or a hist or y of blee di n g fr o m critical areas 
o r or ga ns s uc h as gastr oi ntesti nal tract blee di n g 1 9) ,2 0) ,2 1)  or c o nc o mita nt 
a d mi nistrati o n of aci dic N S AI Ds 2 2) are c o nsi dere d t o be fact ors f or blee di n g ris k.  
 
4. 1. 2  
E xcl usi o n Criteri a  
1)  Tra nsie nt A F sec o n dar y t o ot her re versi ble dis or ders (e. g. t h yr ot o xic osis, car diac or 
t h oracic s ur ger y, p ne u m o nia, se vere a ne mia) 
2)  Patie nts  w h o recei ve d wa rfari n, da bi gatra n, ri var o xa ba n, a pi xa ba n, or e d o xa ba n 
wit hi n t he 8 wee ks pri or t o t he da y of ra n d o mizati o n  
3)  Patie nts  recei vi n g warfari n wit h I N R c o ntr olle d at ≥ 1. 6 i n 2 of t he 3 m ost rece nt 
e xa mi nati o ns, i ncl u di n g t he eli gi bilit y assess me nt e xa mi nati o n, m eas ure d at least 4 
wee ks a part ( patie nts  wit h I N R ≥ 1. 6 at t he eli gi bilit y assess me nt e xa mi nati o n are 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 2  
e xcl u de d)  
4)  Patie nts  wit h partic ularl y hi g h blee di n g ris k meeti n g a n y of t he f oll o wi n g criteria:  
i)  
Acti ve blee di n g o n t he da y of i nf or me d c o nse nt
* 
*: S u b c ut a n e o us blee di n g will b e i n cl u de d if t here is at least 1 he mat o ma wit h a 
ma xi mal dia meter of at least 5  c m, a n d uri n ar y fi n di n gs will be i ncl u de d if fra n k 
he mat uria is o bser ve d.  
ii) 
U nres ol ve d pe ptic ulcer o n t he da y of i nf or me d c o nse nt  
iii) He m o gl o bi n < 9 g/ d L, or pl atelet c o u nt < 1 0 ×  1 0 4/μ L at t he eli gi bilit y 
assess me nt e xa mi nati o n  
i v) Here ditar y  he m orr ha gic disease  
5)  Cere bral i nfarcti o n or TI A  wit hi n t he 3 0 da ys pri or t o t he da y of ra n d o mizati o n  
6)  Patie nts  wit h r he u matic val ve disease  
7)  Hist or y of pr ost hetic  val ve re place me nt ( mec ha nical or  bi ol o gi cal val ve s) * 
*: Hist or y of mitral val ve re pair is all o we d i n t he st u d y.  
8)  Patie nts  wit h i nfecti ve e n d ocar ditis  
9)  Patie nts  wit h atrial m y x o ma  
1 0)  O bser ve d prese nce of left ve ntric ular or atrial t hr o m b us  
1 1)  O bser ve d here ditar y t hr o m b o p hilia  
1 2)  Patie nts  wit h sc he d ule d elec trical or p har mac ol o gic defi brillati o n bet wee n t he da y of 
i nf or me d c o nse nt a n d t he ti me of t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt  
1 3)  U nc o ntr olle d h y perte nsi o n (s yst olic bl o o d press ure persiste ntl y  > 1 6 0  m m H g or 
diast olic bl o o d press ure persiste ntl y  >  1 0 0  m m H g)  
1 4)  C Lcr calc ulate d b y t he C oc kcr oft -Ga ult f or m ula < 1 5  m L/ mi n  
1 5)  Patie nts  w h o ha ve starte d he m o dial ysis or w h o ma y start he m o dial ysis b y t he ti me of 
t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt  
1 6)  Patie nts  recei vi n g d ual a nti platelet t hera p y (e. g. , as piri n pl us a t hie n o p yri di ne) at t he 
ti me of i nf or me d c o nse nt, or t h ose e x pecte d t o recei ve d ual a nti platelet t hera p y after 
t he ti me of i nf or me d c o nse nt, w h o ca n n ot safel y disc o nti n ue use of eit her of t he 
a nti platelet dr u gs  
1 7)  Patie nts  wit h he patic f u ncti o n dis or der acc o m pa nie d b y c oa g ulati o n dis or der  
1 8)  Hist or y of ac ute m y ocar dial i nfarcti o n ( MI) wit hi n t he 3 0 da ys pri or t o t he da y of 
ra n d o mizati o n 
1 9)  Seri o us heart disease s uc h as car diac fail ure wit h Ne w Yor k Heart Ass ociati o n 
( N Y H A) classificati o n ≥ 3 or u nsta ble a n gi na pect oris  
2 0)  Patie nts  w h o c urre ntl y ha ve  mali g na nc y.  Patie nts  dia g n ose d wit h mali g na n c y 
wit hi n t he 2  years pri or t o t he da y of i nf or me d c o nse nt, or w h o ha ve recei ve d 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 3  
treat me nt wit h ca ncer t hera p y ( dr u gs, ra diati o n, a n d/ or s ur ger y) wit hi n t he 2  years 
pri or t o t he da y of i nf or me d c o nse nt , e xce pt f or  patie nts  wit h a de q uatel y treate d  
basal cell carci n o ma of t he s ki n, resecte d s q ua m o us cell carci n o ma of t he s ki n, a n d 
cer vi x carci n o ma i n sit u.  
2 1)  Hist or y of recei vi n g a n y ot her st u d y dr u gs wit hi n t he 6 0 da ys pr i or t o t he da y of 
i nf or me d c o nse nt 
2 2)  Patie nts  t he i n vesti gat or or s u bi n vesti gat or c o nsi ders i neli gi ble 
 
< Rati o nale >  
1 t o 3)    
To select eli gi ble  s u bjects f or t his st u d y. 
4)    
D ue t o t he p ossi bilit y of a n i ncrease d ris k of maj or blee di n g fr o m t he st u d y 
treat me nt. 
5 t o 1 1)   
D ue t o t he mar ke dl y hi g h ris k of t hr o m b oe m b olis m.  
1 2 t o 2 2)  To e ns ure t he safet y of s u bjects a n d t o c o n d uct t his st u d y a p pr o priatel y.  
 
4. 1. 3  
S u bject E nr oll me nt  
4. 1. 3. 1   
Wor kfl o w of S u bject E nr oll me nt  
S u bjects will be e nr olle d i n t he st u d y usi n g I R T, i ncl u di n g I W R S, usi n g t he I nter net.  
T he e nr oll me nt pr oce d ure f or s u bjects is s h o w n i n  Fi g ure 4. 1 -1 . 
 
Fi g ure 4. 1 -1   E nr oll me nt Pr oce d ure f or S u bjects  
 
 
 
   
 
 
 
 
 
 
 
 
After o btai ni n g writte n i nf or me d c o nse nt fr o m t he s u bjects ( or le gall y acce pta ble 
re prese ntati ves), t he i n vesti gat or or s u bi n vesti gat or will assi g n s u bject i de ntificati o n 
c o des a n d pre pare a s u bject scree ni n g list, a n d assess t he eli gi bilit y of s u bjects, wit hi n 
S u bject i nf or mati o n e ntere d i nt o I R T  
St u d y site  
I R T 
S u bject i de ntificati o n c o de assi g ne d  
Scree ni n g list pre pare d  
I ncl usi o n crit eria a n d e xcl usi o n criteria c hec ke d 
N otificati o n of st u d y dr u g i de ntifier  
Ra n d o mizati o n of s u bjects  
S u bject e nr oll me nt det ails e ntere d i nt o I R T  
St u d y dr u g i de ntifiers c hec ke d  
St u d y dr u gs wit h t he s pecifie d st u d y dr u g 
i de ntifiers a d mi nistere d 
If det er mi ne d  eli gi ble:  
S u bject n u m ber assi g ne d  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 4  
3 0  da ys.  
T he i n vesti gat or or s u bi n vesti gat or will e nter t he re q uire d ite ms f or all s u bjects fr o m 
w h o m c o nse nt has bee n o btai ne d  (i ncl u di n g c o nse nt fr o m le gall y acce pta ble 
re prese ntati ves) i nt o I R T.  T he I R T will assi g n st u d y-s pecific s u bject n u m bers. 
Ne xt, t he i n vesti gat or or s u bi n vesti gat or will e nter t he eli gi bilit y assess me nt res ults f or 
t he s u bjects i nt o I R T.  T he da y of e nr oll me nt is defi ne d as t he date e ntere d i nt o I R T as 
t he date w he n eli gi bilit y was deter mi ne d.  T he da y of wit h dra wal is define d as t he date 
e ntere d i nt o I R T as t he date w he n i neli gi bilit y was deter mi ne d.  I R T will perf or m 
ra n d o mizati o n o n t he e nr olle d s u bjects a n d assi g n t he m st u d y dr u g i de ntifiers.  
T he i n vesti gat or or s u bi n vesti gat or will c o nfir m t he st u d y dr u g i de ntifiers dis pla ye d i n 
I R T a n d t he n a d mi nister t he st u d y dr u gs mar ke d wit h t h ose st u d y dr u g i de ntifiers, o n t he 
sa me date n otificati o n of st u d y dr u g i de ntifiers is gi ve n.  
If t he i n vesti gat or or s u bi n vesti gat or deter mi ne d  t hat a s u bject is i neli gi ble, t he 
i n vesti gat or o r s u bi n vesti gat or will e x plai n t he reas o n f or t his t o t he s u bject ( or le gall y 
acce pta ble re prese ntati ve) a n d a d mi nister re g ular treat me nt.  If t here are a n y s u bjects 
fr o m w h o m c o nse nt was o btai ne d  b ut w h o were deter mi ne d  i neli gi ble, t he i n vesti gat or or 
s u bi n vesti gat or will e nter t he fact t hat t hese s u bjects are i neli gi ble i n t he s u bject 
scree ni n g list.  If t he i n vesti gat or or s u bi n vesti gat or later deter mi nes  t hat a s u bject is 
eli gi ble  f or t his st u d y, t he i n vesti gat or or s u bi n vesti gat or will o btai n writte n c o nse nt fr o m 
t he s u bject ( or le gall y acce pta ble re prese ntati ve) a gai n, a n d e nr oll t he s u bject acc or di n g 
t o t he pr oce d ure s pecifie d i n t his secti o n. 
 
4. 1. 3. 2   
If N otific ati o n Is Recei ve d T h at t he S u bject Is Recei vi n g Tre at me nt fr o m 
A n ot her P h ysici a n  
T he i n vesti gat or or s u bi n vesti gat or  will fi n d o ut w het her or n ot s u bjects fr o m w h o m 
c o nse nt was recei ve d are recei vi n g treat me nt fr o m a n ot her p h ysicia n (a n ot her de part me nt 
at t he st u d y site or a n ot her me dical i nstit uti o n) .  If a s u bject is recei vi n g treat me nt fr o m 
a n ot her p h ysicia n , t he i n vesti gat or or s u bi n vesti gat or will n otif y t he ot her p h ysicia n t hat 
t he s u bject is partici pati n g i n t he cli nical st u d y, wit h t he c o nse nt of t he s u bject ( or le gall y 
acce pta ble re prese ntati ve).  T he fact t hat t his n otificati o n has bee n gi ve n will be 
rec or de d, f or e xa m ple i n me dical rec or ds. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 5  
4. 2  
I n di vi d u al S u bject I nterr u pti o n or Disc o nti n u ati o n of St u d y Dr u g, I n di vi d u al 
S u bject Disc o nti n u ati o n of St u d y P artici p ati o n, a n d Ter mi n ati o n of t he E ntire 
St u d y  
4. 2. 1  
St u d y Dr u g I nterr u pti o n  
4. 2. 1. 1   
I nterr u pti o n a n d Resu m pti o n of St u d y Dr u g  
If s yst olic bl o o d press ure persiste ntl y  e xcee ds 1 6 0  m m H g or diast olic bl o o d press ure 
persiste ntl y  e xcee ds 1 0 0  m m H g o n t he sa me da y, st u d y treat me nt f or t he rele va nt s u bject 
will be pr o m ptl y i nterr u pte d.  After treat me nt is te m p oraril y i nterr u pte d, re peat 
meas ure me nts will be ma de at least o ne wee k a part, a n d if it is f o u n d t hat t he a b o ve 
c o n diti o ns are n ot met, t he st u d y treat me nt will be res u me d.  
T he st u d y treat me nt ma y be te m p oraril y i nterr u pte d at t he discreti o n of t he i n vesti gat or 
or s u bi n vesti gat or, f or e xa m ple d ue t o t he occ urre nce of a n a d verse e ve nt or i n vasi ve 
treat me nt or tests bei n g perf or me d.  E xce pt i n e mer ge ncies, s ur ger y or i n vasi ve 
treat me nt or tests will be perf or me d w he n at least 2 4 h o urs ha ve passe d si nce st u d y 
treat me nt.  To deter mi ne  w het her or n ot st u d y treat me nt ca n be res u me d bef ore t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt, t he i n vesti gat or or s u bi n vesti gat or will 
assess t he s u bject ’s cli nical state wit hi n t he 7 da ys after t he st u d y dr u g i nterr u pti o n, a n d 
at least e ver y 8 wee ks t hereafter.  If t he i n vesti gat or or s u bi n vesti gat or deter mi nes  t hat 
t he st u d y treat me nt ca n be res u me d, a n d t he s u bject ( or le gall y acce pta ble re prese ntati ve) 
c o nse nts t o t his, t he st u d y treat me nt will be res u me d, a n d t he st u d y pr oce d ures at t he 
s pecifie d visit directl y after res u m pti o n will als o be res u me d.  If t he st u d y treat me nt has 
n ot bee n res u me d at t he ti me of t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt, it will 
be c o nsi dere d  t hat st u d y treat me nt has bee n disc o nti n ue d  at t his p oi nt.  
If t he st u d y treat me nt is i nterr u pte d, t he i n vesti gat or or s u bi n vesti gat or will e nter t he 
d urati o n of st u d y dr u g i nterr u pti o n, t he reas o n f or i nterr u pti o n, a n d w het her or n ot t he 
st u d y treat me nt ca n be res u me d o n t he case re p ort f or m.  If t he st u d y treat me nt is 
i nterr u pte d d ue t o a n a d verse e ve nt, t he i n vesti gat or or s u bi n vesti gat or will e nter 
i nf or mati o n o n t he case re p ort f or m i n acc or da nce wit h “9. 4  A d verse E ve nt I nf or mati o n 
t o Be Re p orte d” a n d “9. 6  Acti o n W he n a n A d verse E ve nt Occ urs .” 
 
4. 2. 1. 2   
F oll o w -u p S ur ve y D uri n g St u d y Dr u g I nterr u pti o n  
T he i n vesti gat or or s u bi n vesti gat or wil l s ur ve y t he f oll o wi n g ite ms u ntil t he e xa mi nati o n 
at c o m pleti o n of st u d y treat me nt or u ntil t he res u m pti o n of treat me nt at t he visit s pecifie d 
i n “6 . S T U D Y P R O C E D U R E S ” at least e ver y 8 wee ks at a visit or b y tele p h o ne, a n d will 
e nter t he i nf or mati o n o n t he case re p ort f or m.  If t he s u bject ca n n ot be c o ntacte d b y 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
2 6  
tele p h o ne, s ur ve ys will be perf or me d b y letter. 
1)  W het her a n y seri o us a d verse e ve nts ha ve occ urre d  
2)  W het her a n y efficac y e ve nts ha ve occ urre d 
3)  W het her a n y blee di n g e ve nts ha ve occ urre d  
4)  W het her a n y of t he f oll o wi n g dr u gs (i ncl u di n g o ver -t he-c o u nter dr u gs) ha ve bee n 
use d: a ntic oa g ula nts, t hr o m b ol ytic dr u gs, a nti platelet dr u gs, i ntra ve n o us 
a ntiarr h yt h mic dr u gs, or aci dic  N S AI Ds  
5)  Bl o o d press ure a n d p ulse rate ( o nl y if t he s u bject ma kes a visit)  
6)  La b orat or y tests deter mi ne d t o be a p pr o priate b y t he i n vesti gat or or s u bi n vesti gat or 
( o nl y if t he s u bject ma kes a visit).  H o we ver, if warfari n is bei n g a d mi nistere d, 
meas ure me nt of P T -I N R is ma n dat or y. 
 
4. 2. 2  
St u d y Dr u g Disc o nti n u ati o n  
4. 2. 2. 1   
St u d y Dr u g Disc o nti n u ati o n Criteri a  
If a s u bject meets a n y of t he f oll o wi n g criteria, t he i n vesti gat or or s u bi n vesti gat or will 
pr o m ptl y disc o nti n ue t he st u d y treat me nt  of  t he rele va nt s u bject, a n d ta ke s uitable acti o n 
i n res p o nse.  As far as p ossi ble, t he i n vesti gat or or s u bi n vesti gat or will perf or m t he 
e xa mi nati o n at disc o nti n uati o n a n d ma ke e ver y atte m pt t o e ns ure t he safet y of t he s u bject, 
a n d will e nter t he reas o n f or disc o nti n uati o n o n t he case re p ort f o r m. 
1)  If he m o dial ysis is starte d 
2)  If t he s u bject ref uses t o recei ve t he st u d y dr u g, or t he le gall y acce pta ble 
re prese ntati ve ref uses t o all o w t he s u bject t o recei ve t he st u d y dr u g, base d o n a 
re q uest ma de of his/ her o w n free will (if c o nse nt is gi ve n f or t he f oll o w-u p s ur ve y 
s pecifie d i n “4. 2. 2. 2  F oll o w -u p S ur ve y After St u d y Dr u g Disc o nti n uati o n ” after 
st u d y dr u g disc o nti n uati o n, t he f oll o w-u p s ur ve y will be perf or me d)  
3)  If t he st u d y treat me nt is i nterr u pte d a n d is n ot res u me d b y t he ti me of t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt  
4)  If t he i n vesti gat or or s u bi n vesti gat or deter mi nes  t hat t he st u d y treat me nt s h o ul d be 
disc o nti n ue d  f or a n y ot her reas o n 
 
I n t he case of s u bjects w h o meet criteri o n 2) a b o ve ( wit h dra wal of c o nse nt f or t he st u d y 
treat me nt), if c o nse nt t o res u me t he st u d y treat me nt at t he free will of t he s u bject ( or 
le gall y acce pta ble re prese ntati ve) is o btai ne d bef ore t he e xa mi nati o n at c o m pleti o n of 
st u d y treatme nt, a n d t he i n vesti gat or or s u bi n vesti gat or c o nsi ders  t hat t here are n o 
pr o ble ms wit h t he s u bject ’s cli nical state, t he st u d y treat me nt ma y be res u me d.  If t he 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
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st u d y treat me nt is res u me d, t he st u d y pr oce d ures at t he s pecifie d visit directl y after 
res u m pti o n will be perf or me d. 
 
4. 2. 2. 2   
F oll o w -u p S ur ve y After St u d y Dr u g Disc o nti n u ati o n  
T he i n vesti gat or or s u bi n vesti gat or will s ur ve y t he f oll o wi n g ite ms u ntil t he e xa mi nati o n 
at c o m pleti o n of st u d y treat me nt  at least e ver y 8 wee ks at a visit or b y tele p h o ne, a n d will  
e nter t he i nf or mati o n o n t he case re p ort f or m.  If t he s u bject ca n n ot be c o ntacte d b y 
tele p h o ne, s ur ve ys will be perf or me d b y letter.  I n t he case of s u bject meeti n g 
“4. 2. 2. 1 -2)  St u d y Dr u g Disc o nti n uati o n Criteria ” ( wit h dra wal of c o nse nt f or t he st u d y 
treat me nt), t he i n vesti gat or or s u bi n vesti gat or will als o fi n d o ut w het her t he s u bject ( or 
le gall y acce pta ble re prese ntati ve) is willi n g t o res u me t he st u d y treat me nt, a n d will e nter 
t he res ults o n t he case re p ort f or m. 
1)  W het her a n y seri o us a d verse e ve nts ha ve occ urre d  
2)  W het her a n y efficac y e ve nts ha ve occ urre d  
3)  W het her a n y blee di n g e ve nts ha ve occ urre d  
4)  W het her a n y of t he f oll o wi n g dr u gs (i ncl u di n g o ver -t he-c o u nter dr u gs) ha ve bee n 
use d: a ntic oa g ula nts, t hr o m b ol ytic dr u gs, a nti platelet dr u gs, i ntra ve n o us 
a ntiarr h yt h mic dr u gs, or aci dic N S AI Ds  
5)  Bl o o d press ure a n d p ulse rate ( o nl y if t he s u bject ma kes a visit)  
6)  La b orat or y tests deter mi ne d t o be a p pr o priate b y  t he i n vesti gat or or s u bi n vesti gat or 
( o nl y if t he s u bject ma kes a visit).  H o we ver, if warfari n is bei n g a d mi nistere d, 
meas ure me nt of P T -I N R is ma n dat or y. 
 
4. 2. 3  
Disc o nti n u ati o n of St u d y P artici p ati o n a n d Ter mi n ati o n of t he E ntire St u d y  
4. 2. 3. 1   
Disc o nti n u ati o n of St u d y P artici p ati o n D ue t o Wit h dr a w al b y S u bj ect  
If a s u bject ( or le gall y acce pta ble re prese ntati ve) ma kes a re q uest t o wit h dra w n ot o nl y 
fr o m recei vi n g t he st u d y dr u g b ut als o fr o m partici pati o n i n t he st u d y, i ncl u di n g all st u d y 
pr oce d ures or f oll o w -u p  s ur ve y relate d t o t he st u d y, t he i n vesti gat or or s u bi n vesti gat or 
will pr o m ptl y wit h dra w t he rele va nt s u bject fr o m t he st u d y a n d ta ke t he s uita ble acti o n 
f or t he s u bject i n res p o nse.  The i n vesti gat or or s u bi n vesti gat or will als o perf or m t he 
e xa mi nati o n at disc o nti n uati o n a n d ma ke e ver y a tte m pt t o e ns ure t he safet y of t he s u bject 
as far as t he s u bject ( or le gall y acce pta ble re prese ntati ve) is willi n g t o c o o perate, a n d will 
e nter t he date of disc o nti n uati o n  a n d t he reas o n f or disc o nti n uati o n  o n t he case re p ort 
f or m. 
 
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
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4. 2. 3. 2   
Disc o nti n u ati o n of St u d y P artici p ati o n i n t he E ve nt of a M aj or Pr ot oc ol 
De vi ati o n  
I n t he e ve nt of a maj or de viati o n (a sit uati o n w here it is n ot feasi ble t o c o nti n ue t he st u d y 
safel y) relati n g t o a s u bject, t he i n vesti gat or or s u bi n vesti gat or will pr o m ptl y wit h dra w 
t he rele va nt s u bject fr o m t he st u d y a n d ta ke t he s uita ble acti o n f or t he s u bject i n res p o nse .  
T he i n vesti gat or or s u bi n vesti gat or will perf or m f oll o w -u p s ur ve y  of a b n or mal fi n di n gs 
at t he ti me of disc o nti n uati o n, a n d as far as t he s u bject ( or le gall y acce pta ble 
re prese ntati ve) is willi n g t o c o o perate, will perf or m t he e xa mi nati o n at disc o nti n uati o n  
a n d ma ke e ver y atte m pt t o e ns ure t he safet y of t he s u bject, a n d will e nter t he date of 
disc o nti n uati o n a n d t he reas o n f or disc o nti n uati o n o n t he case re p ort f or m.  
 
4. 2. 3. 3   
Disc o nti n u ati o n of St u d y P artici p ati o n D ue t o t he De at h of a S u bject  
If a s u bject dies, t he s u bject will be dee me d t o ha ve bee n wit h dra w n fr o m st u d y 
partici pati o n at t he ti me of deat h.  T he i n vesti gat or or s u bi n vesti gat or will s ur ve y 
i nf or mati o n s uc h as t he date a nd ti me of deat h a n d t he reas o n f or t he deat h acc or di n g t o 
“6. 1 4  Efficac y E ve nts ” a n d e nter t he i nf or mati o n o n t he case re p ort f or m.  
 
4. 2. 3. 4   
Ter mi n ati o n of t he E ntire St u d y b y S p o ns or  
If t he S p o ns or deci des t o ter mi nate t he e ntire st u d y acc or di n g t o t he re g ulati o ns s pecifie d 
i n “1 5. 8. 1  Ter mi nati o n or I nterr u pti o n of t he St u d y ,” t he i n vesti gat or or s u bi n vesti gat or 
will pr o m ptl y wit h dra w s u bjects fr o m t he st u d y a n d ta ke t he s uita ble acti o n f or s u bjects 
i n res p o nse.  T he i n vesti gat or or s u bi n vesti gat or will perf or m f oll o w-u p s ur ve y  of 
a b n or mal fi n di n gs at t he ti me of disc o nti n uati o n , a n d as far as t he s u bjects ( or le gall y 
acce pta ble re prese ntati ve s) are willi n g t o c o o perate, will perf or m t he e xa mi nati o n at 
disc o nti n uati o n  a n d ma ke e ver y atte m pt t o e ns ure t he safet y of s u bject s, a n d will e nter 
t he date of disc o nti n uati o n a n d t he reas o n f or disc o nti n u ati o n o n case re p ort f or m s. 
 
5.  
M E T H O D O L O G Y  
5. 1  
St u d y Dr u g  
Details of t he st u d y dr u g a n d h o w t o ha n dle it are a vaila ble i n t he I n vesti gat or’s Br oc h ure 
a n d St u d y Dr u g Ma na ge me nt Pr oce d ures.  
 
5. 1. 1  
I n vesti g ati o n al Pr o d uct 
1)  C o de  na me : D U-1 7 6 b  
2)  Ge neric na me: e d o xa ba n t os ilate h y drate  
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
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3)  C o nte nt a n d d osa ge f or m: Yell o w fil m -c oate d ta blet s c o ntai ni n g 1 5  m g of e d o xa ba n 
per ta blet  
4)  L ot n u m ber: Please refer t o t he St u d y Dr u g Ma na ge me nt Pr oce d ure s 
 
5. 1. 2  
Pl ace b o  
1)  C o nte nt a n d d osa ge f or m: Yell o w fil m -c oate d ta blet s n ot c o ntai ni n g a n y acti ve 
i ngre die nt, wit h a n a p peara nce (s ha pe, c ol or, a n d o d or) i n disti n g uis ha ble fr o m t hat of 
t he I n vesti gati o nal Pr o d uct  
2)  L ot n u m ber: Please refer t o t he St u d y Dr u g Ma na ge me nt Pr oce d ure s 
3)  Pr o vi der : Daiic hi Sa n k y o C o., Lt d. 
 
5. 1. 3  
L a beli n g a n d P ac k a gi n g  
T he pac ka gi n g of t h e st u d y dr u g a n d t he c o nte nts of la bels are s h o w n i n t he St u d y Dr u g 
Ma na ge me nt Pr oce d ures . 
 
5. 1. 4  
St u d y Dr u g Acc o u nt a bilit y  
After c o ncl u di n g a st u d y c o ntract, t he S p o ns or will dis pe nse  t he st u d y dr u g t o t he st u d y 
site.  T he st u d y dr u g ma na gers  will st ore t he dr ug at r o o m te m perat ure a n d ma na ge it.  
Ma na ge me nt a n d c ollecti o n of t he st u d y dr u g will be perf or me d acc or di n g t o t he St u d y 
Dr u g Ma na ge me nt Pr oce d ures . 
 
5. 2  
St u d y Tre at me nts A d mi nistere d  
5. 2. 1  
D ose a n d R o ute of A d mi nistr ati o n  
After ra n d o mizati o n, st u d y treat me nt will  be starte d o n t he sa me date t hat n otificati o n of 
st u d y dr u g i de ntifiers is gi ve n.  O ne ta blet of D U -1 7 6 b 1 5  m g or place b o will be 
a d mi nistere d orall y o nce dail y.  A d mi nistrati o n of t he st u d y dr u g will be c o nti n ue d u ntil 
t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt perf or me d wit hi n 6 0 da ys after t he 
declarati o n of c o m pleti o n of t he st u d y .  C o m pleti o n of t he st u d y will be declare d w he n 
t he pla n ne d n u m ber of s u bjects wit h pri mar y efficac y e n d p oi nt e ve nts (str o ke a n d S E E) 
has bee n c ollecte d.  T he pla n ne d m ea n d urati o n of st u d y treat me nt is 2  t o 2. 5 years. 
W he n t he i n vesti gat or or s u bi n vesti gat or re q uires t o k n o w t he st u d y treat me nt assi g n me nt 
f or eac h s u bject t o deter mi ne t he s u bse q ue nt treat me nt after t he fi nal a d mi nistrati o n of 
t he st u d y dr u g, t he st u d y treat me nt ca n be c o nti n ue d u ntil t he fi nal f oll o w -u p e xa mi nati o n 
(i n pri nci ple, wit hi n a m o nt h after n otif yi n g t heir st u d y treat me nt assi g n me nts) after 
o btai ni n g  c o nse nt fr o m t he s u bject .  T he pla n ne d d urati o n of t he a d diti o nal st u d y 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
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treat me nt fr o m t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt t o t he fi nal f oll o w-u p 
e xa mi nati o n is 3  t o 4  m o nt hs.  
 
< Rati o nale >  
F or t he D U -1 7 6 b gr o u p, a d osa ge of 1 5  m g  o nce dail y was selecte d, s o t hat it is e x pecte d  
t o be effecti ve at re d uci n g t he ris k of str o ke, a n d s o t hat t he blee di n g ris k is l o wer t ha n 
t hat f or t he a p pr o ve d e d o xa ba n d os a ge. 
I n a p hase 3 gl o bal st u d y of D U-1 7 6 b i n patie nts wit h N V A F ( E N G A G E A F -TI MI 4 8), 
t he a n n ual i nci de nce of c o m p osite of str o ke a n d S E E wit h a d mi nistrati o n of e d o xa ba n at 
1 5  m g o nce dail y w as 2. 3 6 %/ year f or t he o verall p o p ulati o n a n d 2. 7 9 % / year f or t he 
Ja pa nese p o p ulati o n ( 2. 2 1 %/ year a n d 1. 2 0 %/ year res pecti vel y, i n t he warfari n gr o u p).  
At prese nt, d ue t o c ha n ges i n t he me dical e n vir o n me nt, t he i nci de nce of e ve nts s uc h as 
t hese ma y ha ve decrease d, b ut i n meta -a nal ysis usi n g data fr o m ra n d o mize d cli nical 
st u dies of V K As c o n d ucte d i n patie nts wit h A F i n t he past, it was re p orte d t hat t he a n n ual 
i nci de nce of n o n-fatal str o ke i n t he c o ntr ol gr o u p ( u ntreate d) was 7. 6 %/ year ( 2. 5 %/ year 
i n t he V K A gro u p) .  Gi ve n t his, fr o m t he res ults of t he E N G A G E A F -TI MI 4 8  st u d y, it 
is e x pecte d  t hat e ve n if e d o xa ba n is a d mi nistere d at 1 5 m g  o nce dail y, it will be effecti ve 
at re d uci n g t he ris k of str o ke t o a certai n e xte nt, base d o n its a ntic oa g ula nt effect.  T he 
an n ual i nci de nce of c o m p osite of str o ke a n d  S E E d uri n g a d mi nistrati o n of e d o xa ba n at 
1 5  m g o nce dail y i n s u bjects age d 8 0 years or ol der i n t he E N G A G E A F -TI MI 4 8 st u d y 
was 2. 3 3 %/ year f or t he o verall st u d y p o p ulati o n, w hic h is si milar t o t he res ult 
( 2. 3 6 %/ year) f or all s u bjects a d mi nistere d 1 5  m g o nce dail y re gar dless of a ge.  In 
a d diti o n, i n t he A V E R R O E S st u d y 1 6) e val uati n g  t he efficac y of api xa ba n  i n patie nts wit h 
A F a n d V K A is n ot i n dicate d , t he a n n ual i nci de nce of c o m p osite of str o ke a n d  S E E i n t he 
as piri n gr o u p, w hic h was t he c o ntr ol gr o u p, was 3. 7 %/ year, a n d t h us t he a n n ual i nci de nce 
d uri n g a d mi nistrati o n of e d o xa ba n at 1 5  m g o nce dail y i n t he E N G A G E A F -TI MI 4 8  
st u d y was l o wer t ha n t his.  As piri n is n ot p ositi o ne d as a sta n dar d of care  f or re d uci n g 
t he ris k of str o ke i n patie nts wit h A F, a n d is n ot rec o m me n de d as a ntit hr o m b otic t hera p y 
i n patie nts wit h A F6), b ut it is e x pecte d  t hat a d mi nistrati o n of e d o xa ba n at 1 5 m g  o nce 
dail y will s h o w a greater re d ucti o n of t he ris k of str o ke t ha n as piri n. 
Fr o m t he safet y sta n d p oi nt, n o he m orr ha gic str o ke was f o u n d d uri n g a d mi nistrati o n of 
e d o xa ba n at 1 5  m g o nce dail y i n t he E N G A G E A F -TI MI 4 8 st u d y, a n d t he a n n ual 
i nci de nce of i ntracra n ial he m orr ha ge was 0. 1 4 %/ year, l o wer t ha n t he i nci de nce i n t he 
warfari n gr o u p of 1. 2 6 %/ year, a n d als o l o wer t ha n t he i nci de nce of 0. 5 7 %/ year i n 
s u bjects a d mi nistere d e d o xa ba n at 3 0 m g o nce dail y d ue t o d osa ge a dj ust me nt.  T he 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
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a n n ual i nci de nce of maj or  blee di n g was 1. 5 0 %/ year wit h a d mi nistrati o n of e d o xa ba n at 
1 5  m g o nce dail y, w hic h was l o wer t ha n t he i nci de nces of 4. 8 5 %/ year i n t he warfari n 
gr o u p a n d 3. 0 5 %/ year wit h a d mi nistrati o n of d osa ge -a dj uste d e d o xa ba n at 3 0 m g o nce 
dail y.  I n a d diti o n, e ve n if a nal ysis is restricte d t o s u bjects a ge d 8 0 years or ol der i n t he 
E N G A G E A F -TI MI 4 8 st u d y, t he a n n ual i nci de nce of maj or blee di n g was 1. 9 9 %/ year 
wit h a d mi nistrati o n of e d o xa ba n 1 5 m g o nce dail y, 6. 7 7 %/ year i n t he warfari n gr o u p, a n d 
4. 2 8 %/ year wit h a d mi nist rati o n of d osa ge-a dj uste d e d o xa ba n at 3 0 m g o nce dail y, 
s h o wi n g t hat e ve n i n el derl y patie nts wit h A F, t he blee di n g ris k fr o m a d mi nistrati o n of 
e d o xa ba n at 1 5 m g o nce dail y is l o wer t ha n t hat of warfari n or of e d o xa ba n at t he 
a p pr o ve d d osa ge.  
T h us, a d mi nis trati o n of e d o xa ba n at 1 5 m g o nce dail y is ass ociate d wit h a l o wer blee di n g 
ris k t ha n t he a vaila ble  oral a ntic oa g ula nt warfari n or a d mi nistrati o n of e d o xa ba n at 3 0  m g 
or 6 0  m g o nce dail y, a n d fr o m t he efficac y sta n d p oi nt, it is c o nsi dere d t o be effecti ve a t 
re d uci n g t he ris k of str o ke t o a certai n e xte nt.  T heref ore,  a d mi nistrati o n at 1 5  m g o nce 
dail y was selecte d as t he d osa ge i n t he D U -1 7 6 b gr o u p of t his st u d y.  
 
5. 2. 2  
R a n d o miz ati o n a n d Bli n di n g  
5. 2. 2. 1   
Met h o d of Assi g ni n g S u bjects t o Tre at me nts  
A n i n de pe n de nt b i ostatisticia n will pre pare a ra n d o mizati o n sc he d ule i n acc or da nce wit h 
t he S p o ns or’s directi o ns.  Base d o n t he i nf or mati o n e ntere d i nt o I R T, s u bjects will be 
assi g ne d t o t he D U -1 7 6 b gr o u p or  place b o gr o u p i n a 1: 1 rati o usi n g a stratifie d 
ra n d o mizati o n met h o d with t he C H A D S 2 i n de x sc ore (≤ 2 p oi nts, ≥ 3 p oi nts) as a fact or.  
 
5. 2. 2. 2   
Bli n di n g  
T his st u d y will be a d o u ble -bli n d st u d y, a n d bli n di n g will be perf or me d f or all relate d 
parties (s u bjects, i n vesti gat or s, a n d t he S p o ns or) ot her t ha n t he i n de pe n de nt 
b i ostatisticia n, t h ose i n v ol ve d i n assi g n ment a n d pac ka gi n g of t he st u d y dr u g a n d q ualit y 
ass ura nce, a n d t h ose relati n g t o t he dr u g c o nce ntrati o n meas ure me nt la b orat or y.  
 
5. 2. 2. 3   
U n bli n di n g Pr oce d ure f or E mer ge ncies  
5. 2. 2. 3. 1    
If t he I n vesti g at or or S u bi n vesti g at or C o nsi ders T h at U n bli n di n g Is 
A bs ol utel y Necess ar y  
If t he i n vesti gat or or s u bi n vesti gat or c o nsi ders  t hat i nf or mati o n o n w hic h treat me nt gr o u p 
a s u bject bel o n gs t o is a bs ol utel y necessar y t o treat a n a d verse e ve nt, t he i n vesti gat or  or 
s u bi n vesti gat or will u n bli n d usi n g I R T.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 2  
 
5. 2. 2. 3. 2    
If a Seri o us A d verse E ve nt Occ urrin g i n T his St u d y Is Re p orte d t o t he 
Re g ul at or y A ut h orit y  
T he assi g ne d pers o n f or li mite d u n bli n di n g of safet y i nf or mati o n will u n bli n d usi n g I R T.  
 
5. 2. 2. 4   
U n bli n di n g Pr oce d ure  
W he n ite ms 1), 2), a n d 3) bel o w ha ve bee n c hec ke d a n d it has bee n c o nsi dere d  t hat t here 
are n o pr o ble ms, t he S p o ns or will u n bli n d.  
1)  T he data base has bee n l oc ke d.  
2)  T he a nal ysis pla n has bee n fi nalize d.  
3)  T he decisi o ns o n w het her or n ot t o i ncl u de s u bjects i n a nal ysis sets a n d o n t he 
ha n dli n g of data ha ve bee n fi nalize d.  
 
5. 3  
Pr o hi bite d C o nc o mit a nt Me d ic ati o ns a n d Pr o hi bite d Tests 
5. 3. 1  
Pr o hi bite d C o nc o mit a nt Me dic ati o ns  
Bet wee n t he ti me of i nf or me d c o nse nt a n d t he fi nal d ose of st u d y dr u g (e xcl u di n g t he 
f oll o w-u p s ur ve y peri o ds d uri n g st u d y dr u g i nterr u pti o n  a n d after st u d y dr u g 
disc o nti n uati o n ), c o nc o mita nt a d mi nistrati o n of a ntic oa g ula nts or t hr o m b ol ytic dr u gs will 
be pr o hi bite d.  M o n o a nti platelet t hera p y (i ncl u di n g o ver -t he-c o u nter dr u g c o ntai ni n g 
as piri n) will be per mitte d  o nl y w he n a d mi nistere d  t o treat c o nc urre nt  diseases , b ut 
c o nc o mita nt a d mi nistrati o n of a nti platelet t hera p y t o re d uce t he ris k of car di oe m b olic 
str o ke base d o n A F will be pr o hi bite d. 
If it bec o mes necessar y t o a d mi nister pr o hi bite d c o nc o mita nt me dicati o ns after t he 
i nitiati o n of st u d y treat me nt, t he treat me nt will be i nterr u pte d (see “4. 2. 1  St u d y Dr u g 
I nterr u pti o n”).  
 
< Rati o nale >  
C o nc o mita nt a d mi nistrati o n of a ntic oa g ula nts, a nti platelet dr u gs t o re d uce t he ris k of 
car di oe m b olic str o ke base d o n A F, a n d  t hr o m b ol ytic dr u gs has bee n pr o hi bite d i n t his 
st u d y beca use t hese dr u gs will affect t he efficac y assess me nt of t he st u d y dr u g.  As 
c o nc o mita nt a d mi nistrati o n of d ual or m ulti dr u g a nti platelet t hera p y ca uses a partic ularl y 
lar ge i ncrease i n blee di n g ris k, it has als o bee n pr o hi bite d, t o e ns ure t he safet y of 
s u bjects. 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 3  
5. 3. 2  
Pr o hi bite d Tests  
To e ns ure bli n di n g, tests affecti n g bli n di n g will be pr o hi bite d at t he st u d y site fr o m t he 
i nitiati o n of st u d y treat me nt u ntil 2 da ys after t he da y of t he e xa mi nati o n at c o m p leti o n of 
st u d y treat me nt (e xcl u di n g t he d urati o n of f oll o w-u p  at least 3 da ys after t he date of st u d y 
dr u g disc o nti n uati o n  or t he date of st u d y dr u g i nterr u pti o n) or t he fi nal f oll o w -u p 
e xa mi nati o n ( w he n t he st u d y treat me nt is c o nti n ue d after t he e xa mi nat i o n at c o m pleti o n 
of st u d y treat me nt) , s uc h as t he f oll o wi n g: p har mac o d y na mic ( P D) i n dicat or tests 
( pr ot hr o m bi n ti me [ P T], acti vate d partial t hr o m b o plasti n ti me [aP T T]), a n d bi o mar ker 
tests ( D-di mer, p r ot hr o m bi n fra g me nt 1 + 2 [F 1 + 2 ], acti vate d c oa g ulati o n f act or X  [ Xa]).  
H o we ver, cases w here testi n g is u na v oi da ble, f or e xa m ple t o treat a n a d verse e ve nt or i n 
a n e mer ge nc y, will be per mitte d.  
W het her P D a n d bi o mar ker tests were perf or me d 
d uri n g t he peri o d  fr o m t he i nitiati o n of st u d y treat me nt t o t he da y of t he e xa mi nati o n at 
c o m pleti o n of st u d y treat me nt , t he date of c o n d ucti o n of t hese tests, a n d t he c o ncer ne d 
test ite ms will be rec or de d o n case re p ort f or ms.  
 
6.  
S T U D Y P R O C E D U R E S  
6. 1  
St u d y Pr oc e d ure a n d S peci me n C ollecti o n Sc he d ule  
T he ti mi n g of st u d y pr oce d ures a n d s peci me n c ollecti o n i n t his st u d y is s h o w n i n  Ta ble  
6 -1 .  T he i n vesti gat or or s u bi n vesti gat or will rec or d i nf or mati o n s uc h as t he res ults of 
st u d y pr oce d ures, t he dates a n d ti mes of s peci me n c ollecti o n, t he stat e of s peci me ns at 
t he ti me of sa m pli n g, a n d c o m me nts a b o ut t hese. 
T he e xa mi nati o n at c o m pleti o n of st u d y treat me nt  will be perf or me d wit hi n 6 0 da ys after 
t he declarati o n of c o m pleti o n of t he st u d y, i ncl u di n g s u bjects f or w h o m st u d y treat me nt 
has bee n i nter r u pte d or disc o nti n ue d .  C o m pleti o n of t he st u d y will be declare d w he n 
t he pla n ne d n u m ber of s u bjects wit h pri mar y efficac y e n d p oi nt e ve nts (str o ke a n d S E E) 
has bee n c ollecte d.  
T he fi nal f oll o w -u p e xa mi nati o n will be perf or me d wit hi n t he 3 0 t o 3 7 da ys afte r t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt.  F or s u bjects w h o c o nti n ue t he st u d y 
treat me nt after t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt, t he fi nal f oll o w-u p 
e xa mi nati o n  will be perf or me d , i n pri nci ple, wit hi n a m o nt h after n otif yi n g t heir st u d y 
treat me nt assi g n me nts. 
F oll o w -u p s ur ve y of s u bjects f or w h o m st u d y treat me nt has bee n i nterr u pte d or 
disc o nti n ue d  will be perf or me d acc or di n g t o “4. 2. 1. 2  F oll o w -u p S ur ve y D uri n g St u d y  
Dr u g I nterr u pti o n ” a n d “4. 2. 2. 2  F oll o w -u p S ur ve y After St u d y Dr u g Disc o nti n uati o n ” 
res pecti vel y. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 5  
a: Will n ot be perf or me d o n s u bjects wit h dra w n fr o m t he st u d y.  
b:  Will be p erf or me d  i n s u bjects w h o c o nti n u e t h e st u d y treat me nt, i n pri nci ple, wit hi n a m o nt h after 
n otif yi n g t h eir st u d y treat me nt assi g n me nts. 
c: Will be c alc ulate d b y ta ki n g t he date of t he sc he d ul e d visit t o be Da y 0.  
d : F alli n g sc ore, frailt y assess me nt, a n d o n e -le g sta n di n g test wit h e yes o pe n will be  s ur ve ye d b y t he 
ti me of Visit 3. 
e: St u d y treat me nt will be starte d o n t h e sa me date t h at n otificati o n of st u d y dr u g i d e ntifiers is gi ve n.  
St u d y treat me nt will be c o nti n ue d u ntil t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt , w hi c h 
will be perf or me d wit hi n  t he 6 0 da ys after t he d eclarati o n of c o m pl eti o n of t h e st u d y t hat is ma de 
w he n t h e pla n ne d n u m ber of s u bjects wit h pri mar y efficac y e n d p oi nt e ve nts (str o ke a n d S E E) has 
bee n c ollecte d.  
f: T he st u d y dr u g will be a d mi nistere d o nl y t o s u bj ects w h o pr o vi de d c o nse nt f or t he a d diti o n al st u d y 
treat me nt d uri n g t h e peri o d fr o m t he e x a mi nati o n at c o m pleti o n of st u d y treat me nt t o t he fi n al 
f oll o w-u p e xa mi nati o n . 
g:  T hese will be meas ure d at t h e ce ntral la b orat or y.  
h : Will be p erf or me d o n ce e ver y 8 wee ks ( Wee k 4 t o We e k 4 8: Visit 3, Visit 5, Visit 7, Visit 9, Visit 
1 1, Visit 1 3/ Wee k 4 8 o n war d: Visit 1 4, Visit 1 5, Visit 1 6...).  
i: Will be c alc ulate d wit h t he C oc kcr oft -Ga ult f or m ul a.  
j: Will be p erf or me d o n ce e ver y 1 2 wee ks ( Visit 4, Visit 7, Visit 1 0, Visit 1 3).  
k : Will  be p erf or me d o n ce e ver y 2 4 wee ks ( Visit 1 6, Visit 1 9, Visit 2 2...).  
l: If t his is perf or me d wit hi n 4 wee ks bef ore t he d a y of i nf or me d c o nse nt as part of a p h ysical 
e xa mi n ati o n , t h e res ults ma y be use d f or t h e eli gi bilit y assess me nt e xa mi nati o n, wit h t h e co nse nt 
of t he s u bj ect.  
m : D uri n g t h e peri o d fr o m t h e e xa mi n ati o n at c o m pleti o n of st u d y treat me nt t o t h e fi n al f oll o w -u p 
e xa mi n ati o n , o nl y seri o us a d verse e ve nts will be  m o nit ore d . 
n:  C hec ks o n w het her seri o us a d verse e ve nts ha ve occ urre d, w het her efficac y  e ve nts h a ve occ urre d, 
w het her blee di n g e ve nts ha ve occ urre d, w het her t he f oll o wi n g dr u gs ha ve bee n use d: 
a ntic oa g ul a nts, t hr o m b ol ytics, a nti pl atelet dr u gs, i ntra ve n o us a ntiarr h yt h mic s, a n d aci di c N S AI Ds, 
bl o o d press ure/ p ulse rate (if t he s u bject has ma de a visit), a n d la b orat or y tests deter mi ne d t o be 
a p pr o priate b y t he i n vesti gat or or s u bi n vesti gat or ( if t he s u bj ect has ma de a visit.  If warfari n is 
bei n g use d, meas ure me nt of P T -I N R is ma n dat or y) will b e c o n d ucte d e ver y 8 wee ks. 
o : Will be p erf or me d o n Vi sit 3. 
p : Will be p erf or me d o nl y at st u d y sites w here it is p ossi ble.  
q : Will be p erf or me d fr o m Visit 2 o n war ds.  
 
6. 2  
B aseli ne S u bject C h ar acteristics  
Bet wee n t he da y of i nf or me d c o nse nt ( Visit 0) a n d ra n d o mizati o n, t he f oll o wi n g baseli ne 
s u bject c haracteristics will be s ur ve ye d a n d e ntere d o n case re p ort f or ms.  
1)  Date of i nf or me d c o nse nt, date of e nr oll me nt, s u bject n u m ber, a n d st u d y dr u g 
i de ntifier 
2)  De m o gra p hic  
Date of birt h, a ge (at c o nse nt), se x, a n d alc o h ol use  
3)  Varia bles relati n g t o disease a n d pr o g n osis  
Ty pe  of A F , ris k fact ors f or t hr o m b oe m b olis m ( C H A D S2 i n de x sc ore a n d 
C H A 2D S 2-V A Sc i n de x sc ore 6)) ( w het her prese nt or n ot a n d details), H A S-B L E D 
sc ore 6) ( w het her prese nt or n ot a n d details), me dical hist or y ( w het her prese nt or n ot 
a n d details), i n patie nt/ o ut patie nt stat us, hist or y of a d mi nistrati o n of oral 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 6  
a ntic oa g ula nts ( w het her prese nt or n ot a n d details), blee di n g ris k ( w het her prese nt or 
n ot a n d details), P T-I N R,* w het h er certifie d as re q uiri n g n ursi n g care a n d gra de of 
care re q uire d, falli n g ris k ( w het her prese nt or n ot a n d details), t he f oll o wi n g ite ms 
will be s ur ve ye d b y Visit 3 (see A p pe n di x): falli n g sc ore ,2 3) frailt y assess me nt ,2 4) ,2 5) 
o ne -le g sta n di n g test wit h e yes o pe n 2 6) 
* : If t he s u bject was recei vi n g warfari n bef ore i nf or me d c o nse nt was recei v e d  
 
6. 3  
St u d y Dr u g C o m pli a nce  
Fr o m t he i nitial d ose of st u d y dr u g date (t he sa me date as t he date of n otificati o n of t he 
st u d y dr u g i de ntifier) t o t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt or t he 
e xa mi nati o n at disc o nti n uati o n, † † † me dical i nter vie ws will be perf or me d a n d st u d y dr u g 
c o m plia nce ( n u m ber of ta blets a d mi nistere d) will be deter mi ne d  fr o m t he re mai ni n g dr u g 
c ollecte d fr o m s u bjects.  T he f oll o wi n g i nf or mati o n will be e ntere d o n case re p ort 
f or ms: w het her st u d y treat me nt was a d mi nistere d, t he date of t he start of treat me nt, t he 
date of c o m pleti o n of treat me nt, w het her st u d y dr u g i nterr u pti o n occ urre d, date of st u d y 
dr u g i nterr u pti o n , date of st u d y dr u g res u m pti o n , a n d t he reas o ns f or st u d y dr u g 
i nterr u pti o n. 
 
6. 4  
C o nc o mit a nt Me dic ati o ns (I ncl u di n g O ver -t he-c o u nter Dr u gs)  
T he f oll o wi n g i nf or mati o n a b o ut c o nc o mita nt me dicati o ns a n d dr u gs use d t o treat 
a d verse e ve nts fr o m t he ti me of i nf or me d c o nse nt ( Visit 0) t o t he e xa mi nati o n at 
c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uatio n † † †: w het her dr u gs 
were use d, dr u g na mes, d urati o n of treat me nt, a n d reas o n f or use.  If pr o hi bite d 
c o nc o mita nt me dicati o ns, i ntra ve n o us a ntiarr h yt h mic dr u gs, P -gl yc o pr otei n  ( P-g p) 
i n hi bit ors, or aci dic N S AI Ds were a d mi nistere d, t he d ose a n d r o ute will als o be e ntere d 
o n case re p ort f or ms i n a d diti o n t o t he a b o ve. 
I n t he d urati o n of f oll o w-u p  d uri n g st u d y dr u g i nterr u pti o n  a n d after st u d y dr u g 
disc o nti n uati o n , w het her t he f oll o wi n g dr u gs ha ve bee n use d will be s ur ve ye d at least 
e ver y 8 wee ks, a n d if t he y ha ve, t he sa me i nf or mati o n will be s ur ve ye d as i n t he case 
w here dr u gs s uc h as pr o hi bite d c o nc o mita nt me dicati o ns were use d, a n d e ntere d o n t he 
case re p ort f or m.  
• 
A ntic oa g ula nts,  t hr o m b ol ytic dr u gs, a nti platelet dr u gs, i ntra ve n o us a ntiarr h yt h mic  
dr u g s, aci dic N S AI Ds 
 
† † †: F or s u bjects wit h dra w n fr o m st u d y treat me nt a n d s u bjects wit h dra w n fr o m st u d y 
partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 7  
 
Testi n g dr u gs, fl ui d i nf usi o ns, fl ui d s u p ple me ntati o n, n utriti o nal f or m ulati o ns, 
disi nfecta nts, a n d a nest hetics, ot her t ha n t h ose use d f or treati n g a d verse e ve nts, will n ot 
be e ntere d o n case re p ort f or ms.  
 
6. 5  
He a d I m a gi n g  
I n t he eli gi bilit y assessme nt e xa mi nati o n, hea d i ma gi n g (c o m p ute d t o m o gra p h y [ C T] a n d 
ma g netic res o na nce i ma gi n g [ M RI]) will be perf or me d.  It will be c o nfir me d t hat t here 
are n o fi n di n gs of acti ve blee di n g, a n d t he i ma gi n g met h o d, date of i ma gi n g, a n d 
blee di n g fi n di n gs will be e n tere d o n case re p ort f or ms.  H o we ver, if i ma gi n g is 
perf or me d wit hi n t he 4 wee ks fr o m t he da y of i nf or me d c o nse nt as part of r o uti ne care, 
t he res ults of t his i ma gi n g ma y be use d t o q ualit y t he s u bject, wit h t he s u bject’s c o nse nt. 
 
6. 6  
T wel ve -le a d Electr oc ar dio gr a m  
T wel ve -lea d electr ocar di o gra p h y ( E C G) will be perf or me d at t he eli gi bilit y assess me nt 
e xa mi nati o n, d uri n g t he st u d y treat me nt peri o d ( o nce e ver y 1 2 wee ks fr o m Wee k 4 t o 
Wee k 4 8 [ Visit 4, Visit 7, Visit 1 0, a n d Visit 1 3], a n d o nce e ver y 2 4 wee ks fr o m Wee k 4 8 
o n war d [ Visit 1 6, Visit 1 9, Visit  2 2...]), at t he e xa mi nati o n at c o m pleti o n of st u d y 
treat me nt, a n d at t he fi nal f oll o w-u p e xa mi nati o n or t he e xa mi nati o n at disc o nti n uati o n ‡ ‡ ‡, 
a n d t he date of e xa mi nati o n, w het her A F was prese nt, a n d ot her fi n di n gs w ill be e ntere d 
o n case re p ort f or ms.  If a n y cli nicall y mea ni n gf ul c ha n ge c o m pare d wit h t he res ults of 
t he eli gi bilit y assess me nt e xa mi nati o n is o bser ve d in e xa mi nati o ns  after the i nitiati o n of 
st u d y treat me nt, t he i n vesti gat or or s u bi n vesti gat or will assess w het her t o ha n dle t his 
c ha n ge as a n a d verse e ve nt, a n d if it is c o nsi dere d  t o be a n a d verse e ve nt, it will be 
e ntere d i n t he a d verse e ve nt fiel d of t he case re p ort f or m.  
 
6. 7  
Vit al Si g ns  
6. 7. 1  
Hei g ht  
Hei g ht will be meas ure d at t he eli gi bilit y assess me nt e xa mi nati o n, a n d t he date of 
meas ure me nt a n d res ults will be e ntere d o n case re p ort f or ms.  B o d y mass i n de x ( B MI) 
will als o be calc ulate d usi n g t he b o d y wei g ht meas ure d at t he eli gi bilit y assess me nt 
e xa mi nati o n . 
 
 
‡ ‡ ‡: F or s u bjects wit h dra w n fr o m st u d y treat me nt a n d s u bjects wit h dra w n fr o m st u d y 
partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 8  
6. 7. 2  
B o d y Wei g ht  
B o d y wei g ht will be meas ure d at t he eli g i bilit y assess me nt e xa mi nati o n, all visits d uri n g 
t he st u d y treat me nt peri o d, t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt, a n d t he 
fi nal f oll o w-u p e xa mi nati o n or t he e xa mi nati o n at disc o nti n uati o n ‡ ‡ ‡, a n d t he date of 
meas ure me nt a n d res ults will be e n tere d o n case re p ort f or ms.  If a n y si g nifica nt c ha n ge 
c o m pare d wit h t he eli gi bilit y assess me nt e xa mi nati o n is o bser ve d i n e xa mi nati o ns after 
t he i nitiati o n of st u d y treat me nt, t he i n vesti gat or or s u bi n vesti gat or will assess w het her t o 
ha n dle t his c ha n ge a s a n a d verse e ve nt, a n d if it is c o nsi dere d t o be a n a d verse e ve nt, it 
will be e ntere d i n t he a d verse e ve nt fiel d of t he case re p ort f or m.  
 
6. 7. 3  
Bl o o d Press ure/ P ulse R ate  
S yst olic bl o o d press ure, diast olic bl o o d press ure, a n d p ulse rate will be meas ure d at t he 
eli gi bilit y assess me nt e xa mi nati o n, all visits d uri n g t he st u d y treat me nt peri o d, t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt, a n d t he fi nal f oll o w -u p e xa mi nati o n or t he 
e xa mi nati o n at disc o nti n uati o n ‡ ‡ ‡, a n d t he date of meas ure me nt a n d res ults will b e 
e ntere d o n case re p ort f or ms.  
If t he s u bject ma kes visits d uri n g st u d y dr u g i nterr u pti o n  or after st u d y dr u g 
disc o nti n uati o n , syst olic bl o o d press ure, diast olic bl o o d press ure, a n d p ulse rate will be 
meas ure d at least e ver y 8 wee ks, a n d t he dates of meas ure me nt s a n d res ults will be 
e ntere d o n t he case re p ort f or m.  
If a n y si g nifica nt c ha n ge c o m pare d wit h t he eli gi bilit y assess me nt e xa mi nati o n is 
o bser ve d i n tests after t he i nitiati o n of st u d y treat me nt, t he i n vesti gat or or s u bi n vesti gat or 
will assess w het h er t o ha n dle t his c ha n ge as a n a d verse e ve nt, a n d if it is c o nsi dere d t o be 
a n a d verse e ve nt, it will be e ntere d i n t he a d verse e ve nt fiel d of t he case re p ort f or m.  
D uri n g st u d y treat me nt, if s yst olic bl o o d press ure persiste ntl y e xcee ds 1 6 0  m m H g or 
diast ol ic bl o o d press ure persiste ntl y e xcee ds 1 0 0 m m H g o n t he sa me da y, st u d y treat me nt 
f or t he rele va nt s u bject will be pr o m ptl y i nterr u pte d.  After treat me nt is i nterr u pte d, 
re peat meas ure me nts will be ma de at least o ne wee k a part, t o c o nsi der w het her st u d y 
treat me nt ca n be res u me d (see “4. 2. 1. 1  I nterr u pti o n a n d Resu m pti o n of St u d y Dr u g ”). 
 
6. 8  
L a b or at or y Tests  
Bl o o d sa m ples a n d uri ne sa m ples f or la b orat or y tests will be c ollecte d  at t he eli gi bilit y 
assess me nt e xa mi nati o n, o nce e ver y 8 wee ks d uri n g t he st u d y treat me nt peri o d  (fr o m 
Wee k 4 t o Wee k 4 8, at Visit 3, Visit 5, Visit 7, Visit 9, Visit 1 1, a n d Visit 1 3/fr o m Wee k 
4 8 o n war d, at Visit 1 4, Visit 1 5, Visit 1 6...) , t he e xa mi nati on at c o m pleti o n of st u d y 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
3 9  
treat me nt, a n d t he fi nal f oll o w-u p e xa mi nati o n or t he e xa mi nati o n at disc o nti n uati o n. § § §  
All la b orat or y tests will be perf or me d as a batc h b y S R L, I nc.  
1)  He mat ol o g y  test 
Re d bl o o d cell c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell c o u nt, w hite bl o o d 
cell differe ntials ( ne utr o p hils, l y m p h oc ytes, m o n oc ytes, e osi n o p hils, a n d bas o p hils), 
platelet c o u nt, a n d P T-I N R* 
*: P T -I N R will be meas ure d if t he s u bj ect recei ve d warfari n wit hi n t he 8 wee ks pri or t o t he da y 
of i nf or me d c o nse nt, or if t he s u bject is recei vi n g warfari n d uri n g st u d y dr u g i nterr u pti o n or 
d uri n g t h e f oll o w -u p after st u d y dr u g disc o nti n uati o n.  
2)  Bl o o d c he mistr y test  
Total pr otei n, al b u mi n, t otal bilir u bi n, direct a n d i n direct bilir u bi n ,* * A S T, A L T, A L P, 
G G T, L D H, C K, B U N, creat i ni ne, uric aci d, Na, K, Cl, t otal c h olester ol, tri gl yceri de 
* *: Direct a n d i n direct assa ys will be perf or me d w he n t ot al bilir u bi n ≥ 2  m g/ d L  
3)  E n d ocri n ol o g y tests  
Tr o p o ni n I, h u ma n brai n natri uretic pe pti de  ( B N P) 
4)  Uri nal ysis  
Uri ne gl uc ose, uri ne pr otei n, uri ne bl o o d, uri nar y se di me nt (re d bl o o d cells)  
If t he s u bject ma kes visits d uri n g st u d y dr u g i nterr u pti o n  or after st u d y dr u g 
disc o nti n uati o n, meas ure me nt of la b orat or y test ite ms t he i n vesti gat or or s u bi n vesti gat or 
c o nsi ders  s uita ble (if warfari n is bei n g a d mi nistere d, P T-I N R is ma n dat or y) will be 
re q ueste d, a n d t he dates w he n s peci me ns were c ollecte d will be e ntere d o n case re p ort 
f or ms. 
If a n y a b n or mal la b orat or y data ( de viati o ns fr o m refere nce ra n ges) are o bser ve d, t he 
i n vesti gat or or s u bi n vesti gat or will assess w het her t o ha n dle t hese data as a n a d verse 
e ve nt, a n d if t he y are c o nsi dere d t o be a d verse e ve nt s, t he y will be e ntere d i n t he a d verse 
e ve nt fiel d of t he case re p ort f or m.  
 
6. 9  
Cre ati ni ne Cl e ar a nce  
C Lcr will be calc ulate d usi n g t he C oc kcr oft -Ga ult f or m ula at t he eli gi bilit y assess me nt 
e xa mi nati o n, o nce e ver y 8 wee ks d uri n g t he st u d y treat me nt peri o d  (fr o m Wee k 4 t o 
Wee k 4 8, at Visi t 3, Visit 5, Visit 7, Visit 9, Visit 1 1, a n d Visit 1 3/fr o m Wee k 4 8 o n war d, 
at Visit 1 4, Visit 1 5, Visit 1 6...) , t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt, a n d 
t he fi nal f oll o w-u p e xa mi nati o n or t he e xa mi nati o n at disc o nti n uati o n, * * * * a n d e ntere d o n  
case re p ort f or ms.  If a n y si g nifica nt c ha n ge c o m pare d wit h t he eli gi bilit y assess me nt 
 
§ § §: F or s u bjects wit h dra w n fr o m st u d y treat me nt a n d s u bjects wit h dra w n fr o m st u d y 
partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 0  
e xa mi nati o n is o bser ve d i n C Lcr after t he i nitiati o n of st u d y treat me nt, t he i n vesti gat or or 
s u bi n vesti gat or will assess w het her t o ha n dle t his c ha n ge as a n a d verse e ve nt, a n d if it is 
c o nsi dere d t o be a n a d verse e ve nt, it will be e ntere d i n t he a d verse e ve nt fiel d of t he case 
re p ort f or m. 
 
C oc kcr oft -Ga ult f or m ula  
Males : {( 1 4 0 − a ge ) × b o d y wei g ht ( k g )} ÷ { 7 2 × ser u m creati ni ne (m g/ d L )}    
Fe males : [ {( 1 4 0 − a ge ) × b o d y wei g ht ( k g )} ÷ { 7 2 × ser u m creati ni ne (m g/ d L )}] × 0. 8 5  
 
6. 1 0  S ur ger y  
If a s u bject recei ves s ur ger y bet wee n t he i nitiati o n of st u d y treat me nt a n d t he 
e xa mi nati o n  at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n ,* * * * 
t he i n vesti gat or or s u bi n vesti gat or will s ur ve y i nf or mati o n relati n g t o t he s ur ger y s uc h as 
t he date of s ur ger y, reas o n f or s ur ger y, a m o u nt of bl o o d l ost d uri n g s ur ger y, a n d w het her 
bl o o d tra nsf usi o n was perf or me d, a n d e nter t his o n t he case re p ort f or m.  If t he s ur ger y 
is d ue t o a n a d verse e ve nt, t he i n vesti gat or or s u bi n vesti gat or will perf or m a s ur ve y 
acc or di n g t o “9. 4  A d verse E ve nt I nf or mati o n t o Be Re p orte d ” a n d e nter i nf or mati o n 
a b o ut t he a d verse e ve nt i n t he a d verse e ve nt fiel d of t he case re p ort f or m.  
 
6. 1 1  H os pit aliz ati o n  
If a s u bject is h os pitalize d bet wee n t he i nitiati o n of st u d y treat me nt a n d t he e xa mi nati o n 
at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n ,* * * * t he 
i n vesti gat or or s u bi n vesti gat or will s ur ve y i nf or mati o n relati n g t o t he h os pitalizati o n  s uc h 
as t he date of h os pitalizati o n, t he reas o n f or h os pitalizati o n, a n d t he date of disc har ge, 
a n d e nter t his o n t he case re p ort f or m.  If t he h os pitalizati o n is d ue t o a n a d verse e ve nt, 
t he i n vesti gat or or s u bi n vesti gat or will perf or m a s ur ve y acc or di n g t o “9. 4  A d verse E ve nt 
I nf or mati o n t o Be Re p orte d” a n d e nter i nf or mati o n a b o ut t he a d verse e ve nt i n t he a d verse 
e ve nt fiel d of t he case re p ort f or m.  
 
 
* * * *: F or s u bjects wit h dra w n fr o m st u d y treat me nt a n d s u bjects wit h dra w n fr o m st u d y 
partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 1  
6. 1 2  Pl as m a Dr u g C o nce nt r ati o n, P h ar m ac o ki netic I n d ic at ors, a n d Bi o m ar kers 
6. 1 2. 1  Pl as m a Dr u g C o nce nt r ati o n  
6. 1 2. 1. 1  
Bl o o d S a m pli n g Ti mes a n d Me al Rec or ds f or Me as uri n g Pl as m a Dr u g 
C o nce ntr ati o n  
Bl o o d sa m pli n g f or meas ure me nt of plas ma dr u g c o nce ntrati o n will be perf or me d o n 
Wee k 8 ( Visit 3) of t he st u d y  treat me nt peri o d (see Ta ble 6 -2 ).  T he i n vesti gat or or 
s u bi n vesti gat or will i nstr uct t he s u bject t o ma ke a visit wit h o ut recei vi n g t he m or ni n g 
d ose of t he st u d y dr u g, will c ollect a bl o o d sa m ple at t he tr o u g h ti me pr o m ptl y after t h e 
s u bject ma kes a visit, a n d will rec or d t he date of bl o o d sa m pli n g a n d ti me of bl o o d 
sa m pli n g o n t he case re p ort f or m.  T he i n vesti gat or or s u bi n vesti gat or will als o e nter t he 
ti mes w he n t he st u d y dr u g was a d mi nistere d 2 da ys bef ore a n d 1 da y bef ore t he da y of 
bl o o d sa m pli n g, t he start ti mes of t he meals bef ore a n d after t he st u d y dr u g was 
a d mi nistere d  o n t he da y bef ore bl o o d sa m pli n g, a n d t he start ti mes of t he meals bef ore 
a n d after t he st u d y dr u g was a d mi nistere d o n t he da y of bl o o d sa m pli n g.  After t hi s, t he 
s u bject will recei ve t he st u d y dr u g at t he st u d y site, a n d a bl o o d sa m ple will be c ollecte d 
1 t o 3 h o urs after t he st u d y dr u g was a d mi nistere d, a n d t he ti me w he n t he st u d y dr u g was 
a d mi nistere d a n d t he ti me w he n t he bl o o d sa m ple was c ollecte d will b e e ntere d o n t he 
case re p ort f or m.  If p ossi ble, a bl o o d sa m ple will als o be c ollecte d bet wee n 4 a n d 8 
h o urs after t he st u d y dr u g was a d mi nistere d , a n d t he ti me w he n t he bl o o d sa m ple was 
c ollecte d will be e ntere d o n t he case re p ort f or m.  
 
Ta ble 6 -2   Ti mes of Bl o o d Sa m pli n g f or Meas uri n g Plas ma Dr u g C o nce ntrati o n  
Ti me of bl o o d sa m pli n g  
Re mar ks  
Tr o u g h  
M ust b e c oll ecte d  
Bet wee n 1 t o 3 h o urs after t he st u d y 
dr u g is a d mi nistere d  
M ust b e c oll ecte d  
Bet wee n 4 t o 8 h o urs after t he st u d y 
dr u g is a d mi nistere d  
Will be c ollecte d if p ossi ble  
 
6. 1 2. 1. 2  
Met h o d of Bl o o d S a m pli n g f or Me as uri n g Pl as m a Dr u g C o nce ntr ati o n, 
Pl as m a Is ol ati o n, a n d St or a ge  
A q ua ntit y of 5  m L of ve n o us bl o o d will be c ollecte d usi n g a 5  m L vac u u m bl o o d 
sa m plin g tu be c o ntai ni n g lit hi u m he pari n.  Directl y after sa m pli n g, t he bl o o d will be 
mi xe d b y i n versi o n a n d c o ole d.  T he s peci me n will be pr o m ptl y ce ntrif u ge d f or 
1 0  mi n utes at 1 5 0 0 ×  g .  T he plas ma will be i m me diatel y fracti o nate d i nt o a c o ntai ner 
f or s u b missio n, a n d st ore d at t he st u d y site at n o hi g her t ha n −2 0 ° C, pr otecte d fr o m li g ht 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 2  
u ntil it is c ollecte d b y S R L, I nc. (t he pr ocess fr o m sa m pli n g of i ntra ve n o us bl o o d t o 
st ora ge will be perf or me d wit hi n 1 h o ur).  S R L, I nc. will place t he set of s peci me ns 
st ore d acc or di n g t o t he S p o ns or ’s i nstr ucti o ns i n a c o ntai ner wit h dr y ice a n d se n d it t o 
t he dr u g c o nce ntrati o n meas ure me nt la b orat or y ( Q 2 S ol uti o ns).  
 
6. 1 2. 1. 3  
Me as ure me nt of Bl o o d Pl as m a C o nce ntr ati o n ( D U -1 7 6 b Gr o u p O nl y)  
T he dr u g c o nce ntrati o n meas ure me nt la b orat or y ( Q 2 S ol uti o ns) will meas ure t he plas ma 
D U -1 7 6 c o n ce ntrati o n pr o m ptl y after recei vi n g t he s peci me ns.  T he plas ma dr u g 
c o nce ntrati o n will be meas ure d b y li q ui d c hr o mat o gra p h y ta n de m mass s pectr o metr y 
( L C-M S/ M S).  
 
6. 1 2. 2  Me as ure me nt of P h ar m ac o d y n a mic I n dic at ors a n d Bi o m ar kers  
6. 1 2. 2. 1  
Ti mes of Bl o o d S a m pli n g f or Me as uri n g P h ar m ac o d y n a mic I n dic at ors  
At t he eli gi bilit y assess me nt e xa mi nati o n ( Visit 1) a n d Wee k 8 of t he st u d y treat me nt 
peri o d ( Visit 3), bl o o d sa m ples f or meas uri n g P D i n dicat ors ( P T a n d aP T T) will be 
c ollecte d, a n d t he date of sa m pli n g a n d t he ti me of sa m pli n g w ill be e ntere d o n t he case 
re p ort f or m.  T he ti mi n g of t he bl o o d sa m pli n g i n Wee k 8 of t he st u d y treat me nt peri o d 
( Visit 3) will be t he sa me as t he ti mi n g of t he bl o o d sa m pli n g f or meas uri n g plas ma dr u g 
c o nce ntrati o n (see “6. 1 2. 1. 1  Bl o o d Sa m pli n g Ti mes a n d Meal Rec or ds f or Meas uri n g  
Plas ma Dr u g C o nce ntrati o n ”). 
 
6. 1 2. 2. 2  
Ti mes of Bl o o d S a m pli n g f or Me as uri n g Bi o m ar kers  
A t t he eli gi bilit y assess me nt e xa mi nati o n ( Visit 1) a n d Wee k 8 of t he st u d y treat me nt 
peri o d ( Visit 3), bl o o d sa m ples f or meas uri n g bi o mar kers (D -di mer a n d F 1 + 2 ) will be 
c ollecte d, a n d t he date of sa m pli n g a n d t he ti me of sa m pli n g will be e ntere d o n t he case 
re p ort f or m.  T he ti mi n g of t he bl o o d sa m pli n g i n Wee k 8 of t he st u d y treat me nt peri o d 
( Visit 3) will be bef ore t he st u d y dr u g is ta ke n (t he tr o u g h ti me).  
 
6. 1 2. 2. 3  
Met h o d of Bl o o d S a m pli n g f or Me as uri n g P h ar m ac o d y n a mic i n dic at ors 
Bi o m ar kers, Pl as m a Is ol ati o n, a n d St or a ge  
A q ua ntit y of 4. 5  m L of ve n o us bl o o d will be c ollec te d usi n g a si n gle 4. 5 m L vac u u m 
bl o o d sa m pli n g tu be c o ntai ni n g citric aci d.  Pr o m ptl y after sa m pli n g, t he plas ma will be 
se parate d a n d fracti o nate d i nt o a c o ntai ner f or s u b missi o n, a n d st ore d fr oze n at t he st u d y 
site u ntil it is c ollecte d b y S R L, I nc.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 3  
6. 1 2. 2. 4  
Me as ure me nt of P h ar m ac o d y n a mic I n dic at ors a n d Bi o m ar kers  
Ce ntralize d meas ure me nt of P D i n dicat ors a n d bi o mar kers will be perf or me d at S R L, I nc.  
S R L, I nc. will meas ure P D i n dicat ors ( P T a n d aP T T) a n d bi o mar kers ( D-di mer a n d 
F 1 + 2) pr o m ptl y after recei vi n g s peci me ns .  T he res ults of meas ure me nt will n ot be 
discl ose d t o t he st u d y site or t he S p o ns or, e xce pt i n cases w here t his is u na v oi da ble, s uc h 
as w he n acti o n is ta ke n t o treat a d verse e ve nts or i n e mer ge ncies.  
 
6. 1 3  A d verse E v e nts  
If a n a d verse e ve nt occ urs bet ween  t he i nitiati o n of st u d y treat me nt a n d t he e xa mi nati o n 
at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n ,† † † † a s ur ve y will 
be perf or me d acc or di n g t o “ 9. 4  A d verse E ve nt I nf or mati o n t o Be Re p orte d ” a n d t he 
i nf or mati o n will be e ntere d o n t he case re p ort f or m. 
D uri n g st u d y dr u g i nterr u pti o n a n d after st u d y dr u g disc o nti n uati o n , a s ur ve y t o fi n d 
w het her a n y seri o us a d verse e ve nts ha ve occ urre d will be perf o r me d at least e ver y 
8  wee ks, a n d if t he y ha ve, a s ur ve y will be perf or me d acc or di n g t o “ 9. 4  A d verse E ve nt 
I nf or mati o n t o Be Re p orte d” a n d t he i nf or mati o n will be e ntere d  o n t he case re p ort f or m. 
Oc c urre nce of  a n y seri o us a d verse e ve nts will be m o nit ore d  u ntil t he fi nal f oll o w -u p 
e xa mi nati o n a n d will be re p orte d i n acc or da nce wit h t he Secti o n “9. 6. 2  Acti o n W he n a  
Seri o us A d verse E ve nt Occ urs .” 
 
6. 1 4  Effic ac y E ve nts  
If t he f oll o wi n g efficac y e ve nt s occ ur bet wee n ra n d o mizati o n a n d t he e xa mi nati o n at 
c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n, † † † † a s ur ve y will be 
perf or me d  acc or di n g t o “ 9. 4  A d verse E ve nt I nf or mati o n t o Be Re p orte d ” a n d a s ur ve y of 
i nf or mati o n s uc h as t he e ve nt classificati o n, details of t he e ve nt classificati o n, a n d, 
de pe n di n g o n t he sit uati o n i n w hic h t he e ve nt occ urre d, cere br o vasc ular e ve nts (i ncl u di n g 
i ntracra nial blee di n g), S E Es, car diac isc he mic e ve nts, a n d blee di n g e ve nts, will be 
perf or me d, a n d t he i nf or mati o n will be e ntere d o n t he case re p ort f or m.  C o pies of 
fi ndi n gs s uc h as hea d i ma gi n g sca ns a n d E C Gs t hat f or m t he e vi de nce f or t he dia g n osis 
of t he efficac y e ve nt will be s u b mitte d t o t he S p o ns or.  If t he efficac y e ve nt t hat 
occ urre d is a str o ke, it will be assesse d usi n g t he m o difie d Ra n ki n Scale  at 
(a p pr o xi matel y) 1  m o nt h f oll o wi n g str o ke o nset, a n d t he assess me nt will be e ntere d o n 
t he case re p ort f or m. 
• 
Str o ke  
 
† † † †: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 4  
• 
S E E  
• 
MI  
• 
TI A  
• 
H os pitalizati o n d ue t o car di o vasc ular disease ( C V) c o n diti o n (i ncl u di n g 
h os pitalizati o ns f or blee di n g)  
• 
All -ca use m ortalit y ( deat h d ue t o  C V a n d m ortalit y d ue t o all ot her ca uses)  
• 
Ve n o us t hr o m b oe m b olic e ve nt ( V T E) ( p ul m o nar y t hr o m b oe m b olis m [ P T E] a n d dee p 
vei n t hr o m b osis [ D V T])  
 
D uri n g st u d y dr u g i nterr u pti o n  a n d after st u d y dr u g disc o nti n uati o n, a s ur ve y of t he 
a b o ve will be perf or me d at least e ver y 8 wee ks, a n d t he i nf or mati o n will be e ntere d o n 
t he case re p ort f or m. 
If t he s u bject w h o de vel o pe d t he efficac y e ve nt is h os pitalize d at, or ma ki n g visits t o, 
a n ot her me dical i nstit uti o n, t he i n vesti gat or or s u bi n vesti gat or will c o ntact t he s u bject ’s 
p h ysicia n at t he me dical i nstit uti o n  w here t he s u bject is h os pitalize d or ma ki n g visits, a n d 
ma ke e ver y atte m pt t o o btai n detaile d i nf or mati o n, as far as p ossi ble.  
 
6. 1 5  Blee di n g E ve nts  
If a blee di n g e ve nt (see  9. 1  Blee di n g E ve nts ) occ ur s bet wee n t he i nitiati o n of st u d y 
treat me nt a n d t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at 
disc o nti n uati o n, ‡ ‡ ‡ ‡ a s ur ve y will be perf or me d acc or di n g t o “ 9. 4  A d verse E ve nt 
I nf or mati o n t o Be Re p orte d” a n d a s ur ve y of i nf or mati o n s uc h as t he e ve nt classificati o n, 
details of t he e ve nt classificati o n, a n d de pe n di n g o n t he sit uati o n i n w hic h  t he e ve nt 
occ urre d, la b orat or y tests, w het her bl o o d tra nsf usi o n was perf or me d, a n d t he a m o u nt of 
bl o o d tra nsf use d, will be perf or me d, a n d t he i nf or mati o n will be e ntere d o n t he case 
re p ort f or m.  I n res p o nse t o re q uests fr o m t he Cli nical Blee di n g E ve nt C om mittee or t he 
S p o ns or, t he i n vesti gat or or s u bi n vesti gat or will pr o vi de i nf or mati o n s uc h as i ma gi n g 
sca n res ults t hat f or m t he e vi de nce f or t he dia g n osis.  
D uri n g st u d y dr u g i nterr u pti o n  a n d after st u d y dr u g disc o nti n uati o n, a s ur ve y of t he 
a b o ve will be p erf or me d at least e ver y 8 wee ks, a n d t he i nf or mati o n will be e ntere d o n 
t he case re p ort f or m. 
If t he s u bject w h o de vel o pe d t he blee di n g e ve nt is h os pitalize d at, or ma ki n g visits t o, 
a n ot her me dical i nstit uti o n, t he i n vesti gat or or s u bi n vesti gat or will c o n tact t he s u bject’s 
p h ysicia n at t he me dical i nstit uti o n w here t he s u bject is h os pitalize d or ma ki n g visits, a n d 
 
‡ ‡ ‡ ‡ F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 5  
ma ke e ver y atte m pt t o o btai n detaile d i nf or mati o n, as far as p ossi ble.  
 
6. 1 6  L o n g -ter m St or a ge of Cli nic al S peci me ns f or Ge n o mic a n d Ge netic A n al ysis 
L o n g -ter m st ora ge ( ba n ki n g) of D N A s peci me ns e xtracte d fr o m t he s u bjects’ bl o o d b y 
t he f oll o wi n g pr oce d ure will be perf or me d, i n pre parati o n f or t he f ut ure case w here ne w 
ge n o mic or ge netic i nf or mati o n relati n g t o t he res p o nse t o D U -1 7 6 b ( p har mac o ki netic 
[ P K] or P D) is o btai ne d, or a seri o us a d verse dr u g reacti o n is o bser ve d i n a cli nical st u d y 
a n d ge n o mic a n d  ge netic a nal ysis is perf or me d t o disc o ver t he ca use.  A ne w researc h 
pla n will be s pecifie d w he n t he s pecific details of ge n o mic a n d ge netic a nal ysi s ha ve 
bee n fi nalize d.  
Details of t he ha n dli n g of s peci me ns are s h o w n se paratel y i n t he Pr oce d ure s f or t he 
Ha n dli n g a n d Tra ns p ortati o n of Ba n ki n g S peci me ns.  
 
6. 1 6. 1  Tar gete d S peci me ns  
At st u d y sites w here ba n ki n g is a p pr o ve d, a n e x pla nati o n of ba n ki n g will be gi v e n, a n d 
s peci me ns will be sa m ple d fr o m s u bjects w h o pr o vi de i nf or me d c o nse nt (i n -pers o n 
c o nse nt o nl y).  T he i n vesti gat or or s u bi n vesti gat or will e nter t he dates of i nf or me d 
c o nse nt o n t he case re p ort f or ms of s u bjects w h o pr o vi de i nf or me d c o nse nt f or ba n ki n g.  
T he i n vesti gat or or s u bi n vesti gat or will e nter a n y i nf or mati o n s uc h as me dical hist or y 
(f or e xa m ple, all o ge neic b o ne marr o w tra ns pla ntati o n) t hat ma y affect ge n o mic or 
ge netic i nf or mati o n o n t he case re p ort f or ms.  
 
6. 1 6. 2  S a m pli n g of B a n ki n g S peci me ns ( Bl o o d  S a m pli n g)  
At a n y visit d uri n g t he st u d y treat me nt peri o d fr o m Visit 2 o n war ds, 7  m L of ve n o us 
bl o o d will be sa m ple d fr o m a c uta ne o us vei n i n t he f orear m of eac h s u bject.  T he 
sa m ple d bl o o d will be st ore d fr oze n as w h ole bl o o d u ntil t he s peci me ns are c olle cte d (at 
a te m perat ure setti n g of −2 0 ° C or l o wer).  T he i n vesti gat or or s u bi n vesti gat or will e nter 
t he date of bl o o d sa m pli n g o n t he case re p ort f or m.  S o t hat t he s u bjects’ pers o nal 
i nf or mati o n is n ot lea ke d t o e xter nal parties, t he s peci me ns will be ma nage d b y la beli n g 
t he m wit h c o des t hat are u nrelate d t o t he s u bjects. 
 
6. 1 6. 3  D ur ati o n of St or a ge  
T he d urati o n of st ora ge of ba n ki n g s peci me ns will be a ma xi m u m of 2 0 years fr o m t he 
da y w he n n otificati o n of t his st u d y pr ot oc ol is s u b mitte d.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 6  
6. 1 6. 4  Discl os ure of t he Res ul ts of Ge n o mic a n d Ge netic A n al ysis Usi n g B a n ki n g 
S peci me ns  
At prese nt, t he ti me w he n p har mac o ge n o mics i n vesti gati o n usi n g ba n ki n g s peci me ns will 
be perf or me d, t he met h o d of ge n o mic a n d ge netic a nal ysis, a n d w het her or n ot t he 
discl os ure  will be re q uire d, h a ve n ot bee n deter mi ne d.  Acc or di n gl y, we d o n ot pla n t o 
discl ose t he res ults of ge n o mic a n d  ge netic a nal ysis t o parties s uc h as t he i n vesti gat or s or 
t o s u bjects. 
 
6. 1 6. 5  Dis p os al of B a n ki n g S peci me ns  
After t he e n d of t he d urati o n of st ora ge, or if t he s u bject wi t h dra ws c o nse nt d uri n g t he 
st ora ge peri o d, ba n ki n g s peci me ns will pr o m ptl y be dis p ose d of.  H o we ver, if ge netic 
a nal ysis has bee n perf or me d bef ore t he e n d of t he d urati o n of st ora ge or bef ore t he 
s u bject wit h dra ws c o nse nt, t he data relate d t o t hese will n o t be discar de d. 
 
7.  
E F FI C A C Y E N D P OI N T S  
T he f oll o wi n g efficac y e ve nts o bser ve d fr o m ra n d o mizati o n u p t o  t he e xa mi nati o n  at 
c o m pleti o n of st u d y treat me nt or t he e xa mi nati o n at disc o nti n uati o n § § § § will be assesse d.  
Efficac y e ve nts will be reassesse d b y a Cli nical Efficac y E ve nt C o m mittee i n de pe n de nt 
of t he assess me nt of t he i n vesti gat or or s u bi n vesti gat or, a n d t he assess me nt of t he 
Cli nical Efficac y E ve nt C o m mittee will be ta ke n as t he fi nal assess me nt.  
 
7. 1  
Pri m ar y E n d p oi nt  
F or t he c o m p osite e n d p oi nt of str o ke a n d S E E  o bser ve d fr o m ra n d o mizati o n u p t o  t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n ,§ § § § 
t he ti me t o o nset of t he i nitial e ve nt  will be assesse d.  
A str o ke is defi ne d as a n a br u pt o nset, o ver mi n utes t o h o urs, of f ocal ne ur ol o gical deficit 
s y m pt o ms t hat are ge nerall y i n t he distri b uti o n of a si n gle brai n arter y (i ncl u di n g t he 
reti nal arter y) a n d t hat is n ot d ue t o a n i de ntifia ble n o n-vasc ular ca use (i.e., brai n t u m or 
or tra u ma).  T he deficit s y m pt o ms m ust eit her last m or e t ha n 2 4 h o urs or res ult i n deat h 
wit hi n 2 4 h o urs of s y m pt o m o nset.  
A S E E is defi ne d as a n a br u pt e pis o de of arterial i ns ufficie nc y ass ociate d wit h cli nical or 
ra di ol o gic e vi de nce of arterial occl usi o n i n t he a bse nce of ot her li kel y mec ha nis ms (e. g., 
at he r oscler osis, i nstr u me ntati o n). 
Detaile d defi niti o ns of str o ke a n d S E E are s h o w n se paratel y i n t he Pr oce d ure s f or t he 
 
§ § § §: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 7  
Cli nical Efficac y E ve nt C o m mittee.  
 
< Rati o nale a n d S uita bilit y of E n d p oi nt >  
As t his is a cli nical st u d y t o c o nfir m t he effect of a ntic oa g ul a nts i n pre ve nti n g 
cere br oe m b olic str o ke i n patie nts wit h N V A F, we selecte d t he sta n dar d e n d p oi nt use d f or 
efficac y assess me nt.  
 
7. 2  
Sec o n d ar y E n d p oi nts  
F or t he f oll o wi n g e n d p oi nts, t he  ti me t o o nset of t he i nitial e ve nt o bser ve d fr o m 
ra n d o mizati o n u p t o t he exa mi nati o n  at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n 
at disc o nti n uati o n * * * * * will be assesse d.  Detaile d defi niti o ns of i n di vi d ual e ve nts are 
s h o w n se paratel y i n t he Pr oce d ures f or t he Cli nical Efficac y E ve nt C o m mittee  a n d t he 
Pr oce d ures f or t he Cli n ical Blee di n g E ve nt C o m mittee. 
1)  C o m p osite of str o ke, S E E, a n d deat h d ue t o C V  
2)  Maj or a d verse car di o vasc ular e ve nts ( M A C E): n o n -fatal MI , n o n-fatal str o ke, 
n o n -fatal S E E, or deat h s d ue t o C V or blee di n g  
3)  Str o ke, S E E, a n d all -ca use m ortalit y  
4)  Net cli nical be nefi t: str o ke, S E E, maj or blee di n g, a n d all-ca use m ortalit y  
5)  A ll-ca use m ortalit y  
 
7. 3  
Ot her E n d p oi nts  
T he f oll o wi n g e n d p oi nts will be use d.  
1)  H os pitalizati o n d ue t o C V c o n diti o n (i ncl u di n g h os pitalizati o ns f or blee di n g)  
2)  M o difie d Ra n ki n Scale (a p pr o xi matel y) 1 m o nt h after t he o nset of str o ke 
3)  S tr o ke, S E E, a n d TI A 
4)  N u m ber of occ urre nces of str o ke a n d S E E  
5)  V T E ( P T E a n d D V T)  
 
8.  
P H A R M A C O KI N E TI C E N D P OI N T S  
T he plas ma D U -1 7 6 c o n ce ntrati o n at Wee k 8 ( Visit 3) d uri n g t he st u d y treat me nt peri o d 
will be assesse d.  
 
9.  
S A F E T Y E N D P OI N T S  
T he  f oll o wi n g ite ms o bser ve d bet wee n t he i nitiati o n of st u d y treat me nt a n d t he 
 
* * * * *: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 8  
e xa mi nati o n at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n † † † † † 
will be assesse d.  
1)  Maj or blee di n g  
2)  Maj or blee di n g a n d  cli nicall y rele va nt n o n -maj or blee di n g  
3)  C li nicall y rele va nt n o n -maj or blee di n g  
4)  Mi n or blee di n g  
5)  All blee di n g e ve nts (c o m p osite of maj or blee di n g, cli nicall y rele va nt n o n -maj or 
blee di n g, a n d mi n or blee di n g)  
6)  A d verse e ve nts  
7)  A d verse dr u g reacti o ns  
 
9. 1  
Blee di n g E ve nts  
Blee di n g -relate d a d verse e ve nts o bser ve d b et wee n t he i nitiati o n of st u d y treat me nt a n d 
t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at 
disc o nti n uati o n † † † † †  will be assesse d  as blee di n g e ve nts.  Blee di n g e ve nts will be 
reassesse d b y a Cli nical Blee di n g E ve nt C o m mittee  i n de pe nde nt of t he assess me nt of t he 
i n vesti gat or or s u bi n vesti gat or, a n d t he assess me nt of t he Cli nical Blee di n g E ve nt 
C o m mittee will be ta ke n as t he fi nal assess me nt.  
Blee di n g e ve nts will be classifie d i nt o maj or blee di n g, cli nicall y rele va nt n o n -maj or 
blee di n g , a n d mi n or blee di n g acc or di n g t o t he f oll o wi n g defi niti o ns.  Detaile d 
defi niti o ns of blee di n g e ve nts are s h o w n se paratel y i n “Pr oce d ure s f or t he Cli nical 
Blee di n g E ve nt C o m mittee. ” 
 
9. 1. 1  
M aj or Blee di n g  
O vert blee di n g t hat meets at least 1 of t he f oll o wi n g crit eria will be ta ke n t o be maj or 
blee di n g.  
• 
Fatal blee di n g  
• 
Retr o perit o neal , i ntracra nial, i ntra oc ular, i ntrat hecal, i ntraartic ular, or periartic ular 
blee di n g, or s y m pt o matic i ntra m usc ular blee di n g acc o m pa nie d b y c o m part me nt 
s y n dr o me 
• 
Cli nicall y o vert blee di n g t hat decreases he m o gl o bi n b y at least 2. 0 g/ d L a n d 
re q uires bl o o d tra nsf usi o n * 
*:  Tra nsf usi o n of 1 u nit of re d cell c o n ce ntrates or w h ol e bl o o d (a b o ut 2 0 0  m L) will be 
c o n v erte d t o a decrease i n he m o gl o bi n of 1. 0  g/ d L.  F or blee di n g relate d t o a s ur gical 
 
† † † † †: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
4 9  
pr oce d ure, blee di n g i n e xcess of t he us ual q ua ntit y of blee di n g f or t he s ur ger y or pr oce d ure 
will be c o nsi dere d.  If t here are n o data f or he m o gl o bi n, t h e crit eri o n will b e blee di n g t h at 
decreases t he he mat o crit le vel b y at least 6. 0 % a n d re q uires bl o o d tra n sf usi o n. 
 
9. 1. 2  
Cli nic all y Rele v a nt N o n -m aj or Blee di n g  
Cli nicall y o vert blee di n g t hat re q uires treat me nt will be ta ke n t o be cli nicall y rele va nt 
n o n -maj or blee di n g.  F or e xa m ple, t his i ncl u des ( b ut is n ot li mite d t o) t he f oll o wi n g 
dia g n ostic tests a n d treat me nt.   T he defi niti o n of “ re q uiri n g treat me nt” d oes n ot i ncl u de 
o ut patie nt e xa mi nati o ns t hat d o n ot i n v ol ve t he f oll o wi n g me dical pr oce d ures ( dia g n ostic 
tests or treat me nt), or pr oce d ures si milar t o t hese.  Cli nicall y rele va nt n o n-maj or 
blee di n g m ust be vis uall y c o nfir me d b y tests or ra di ol o gical i ma gi n g.  
• 
H os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  
• 
La b orat or y tests  
• 
I ma gi n g tests 
• 
E n d osc o pic tests, C ol o n osc o p y tests, c yst osc o p y tests, br o nc h osc o p y  tests 
• 
Nasal ca vit y pac ki n g  
• 
Press ure he m ostasis  
• 
Ultr as o u n d -g ui de d c o m pressi o n f or a ne ur ys m  
• 
C oil e m b olizati o n  
• 
Car di oacti ve t hera p y  
• 
S ur ger y  
• 
I nterr u pti o n or disc o nti n uati o n  of t he st u d y dr u g at t he i nstr ucti o n of a p h ysicia n  
• 
C ha n ge i n c o nc o mita nt t hera p y at t he i nstr ucti o n of a p h ysicia n (s uc h as d ose 
re d ucti on or disc o nti n uati o n  of  as piri n)  
 
9. 1. 3  
Mi n or Blee di n g  
Ot her o vert blee di n g e ve nts t hat d o n ot meet t he criteria f or maj or blee di n g or cli nicall y 
rele va nt n o n-maj or blee di n g will be ta ke n t o be mi n or blee di n g  (f or e xa m ple, e pista xis 
t hat d oes n ot re q uire treat ment) . 
All e ve nts ot her t ha n t he a b o ve (s uc h as a decrease i n he m o gl o bi n wit h o ut o vert 
blee di n g) will all be classifie d as “n o blee di n g e ve nt. ” 
 
9. 2  
Defi niti o n of A d verse E ve nts  
A n a d verse e ve nt is a n y u nfa v ora ble or u ni nte n de d si g n (i ncl u di n g a b n or mal la b orat or y 
fi n di n gs or vital si g ns), s y m pt o m or disease b y t he e xa mi nati o n at c o m pleti o n  of st u d y 
treat me nt (t he fi nal f oll o w-u p e xa mi nati o n f or s u bjects w h o c o nti n ue t he st u d y treat me nt) 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 0  
or t he e xa mi nati o n at disc o nti n uati o n, ‡ ‡ ‡ ‡ ‡ a n d w hic h d oes n ot necessaril y ha ve t o ha ve a 
ca usal relati o ns hi p t o t his st u d y dr u g. 
S y m pt o ms or diseases occ urri n g bef ore t he st u d y treat me nt will be e ntere d o n case re p ort 
f or ms as c o nc urre nt c o n diti o ns, a n d will n ot be c o nsi dere d a d verse e ve nts.  H o we ver, if 
a c o nc urre nt c o n diti o n  bec o mes  a g gra vate d d uri n g t he st u d y treat me nt, it will be ha n dle d 
as a n a d verse e ve nt, a n d t he da y o n w hic h a g gra vati o n was f o u n d will be c o nsi dere d t o 
be t he o nset date of t he a d verse e ve nt.  
 
9. 3  
Defi niti o n of Seri o us A d verse E ve nts  
Seri o us a d verse e ve nts are a d vers e e ve nts t hat meet a n y of t he f oll o wi n g criteria.  
• 
Deat h  
• 
Is life-t hreate ni n g 
• 
Re q uir es 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  
• 
Disa bilit y  
• 
Ris k of disa bilit y  
• 
Seri o us e q ui vale nt t o t he a b o ve  
• 
Res ulti n g i n c o n ge nital disease or a n o m al y i n t he ne xt ge nerati o n 
 
9. 4  
A d verse E v e nt I nf or m ati o n t o Be Re p orte d  
If a n a d verse e ve nt occ urs d uri n g t he peri o d fr o m t he i nitiati o n of st u d y treat me nt t o t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt , t he ite ms s h o w n i n Ta ble 9 -1  will be 
s ur ve ye d a n d e ntere d o n d oc u me nts s uc h as t he case re p ort f or m.  W he n s y m pt o ms are 
s ur ve ye d b y me dical i nter vie w, t he q uesti o n “Ha ve y o u ha d a n y s y m pt o ms t hat c o ncer n 
y o u bet wee n y o ur last visit a n d t his visit? ” will be as ke d, t o elicit free res p o nses fr o m 
s u bjects.  
Me dical i nter vie ws or q uesti o n s heets a b o ut s pecific s y m pt o ms will n ot be 
use d t o c hec k f or a d verse e ve nts.  
 
 
‡ ‡ ‡ ‡ ‡: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 1  
Ta ble 9 -1   I nf or mati o n t o Be Re p orte d W he n a n A d verse E ve nt Occ urs 
Ite m of Inf or mati o n  
Details t o R e p ort  
Details of a d verse 
e ve nt  
A d verse e ve nt ter m a n d o nset date  
Acti o n ta ke n f or 
a d verse e ve nt  
Details of st u d y dr u g acti o n ta k e n a n d ot her acti o n ta ke n  
O utc o me  
O utc o me t y p e, da y of o utc o me assess me nt, a n d d ate of res ol uti o n  
   
O utc o me 
t y pe 
Rec o v ere d / 
res ol ve d 
T he a d verse e ve nt has bee n res ol ve d a n d t he s u bject h as 
rec o vere d t o t h e state b ef ore t he a d v erse e ve nt oc c urre d 
Rec o v eri n g/  
res ol vi n g 
T he a d verse e ve nt has bee n al m ost res ol ve d a n d t he 
s u bject h as nearl y  rec o vere d t o t he state bef ore t he 
a d verse e ve nt o cc urre d  
N ot rec o v ere d/  
n ot res ol ve d  
T he a d verse e ve nt has n ot be e n res ol ve d, a n d t he s u bj ect 
is i n a state si milar t o t hat w he n t h e a d verse e ve nt 
occ urre d ( u nc ha n g e d)  
Rec o v ere d/  
res ol ve d wit h 
se q uelae/resi d u al 
effect(s) prese nt  
T he a d verse e ve nt has bee n res ol ve d, b ut t h e s u bject h as 
se q uelae 
Fatal  
T his i n dicates t hat t h e i n vesti gat or s c o nsi d er t hat t he 
a d verse e ve nt is relate d t o t he deat h, or t h at a 
relati o ns hi p ca n n ot b e r ul e d o ut, a n d d oes n ot ap pl y i n 
cases w here t he de at h is d ue t o a ca use s uc h as 
a g gra v ati o n of t he disease  u n der st u d y  
U n k n o w n    
T here is n o i nf or mati o n a n d t he o ut c o me is u n k n o w n  
Se verit y  
Mil d  
D oes n ot i nterfere wit h s u bject ’s us ual f u n cti o n, a n d is 
easil y t olerate d  
M o derate    
E n o u g h t o ca use i nterfere nc e wit h us ual acti vit y  
Se vere    
E n o u g h t o ca use i n a bilit y t o d o us ual acti vit y  
Seri o us ness    
Seri o us/ n o nseri o us  
Ca usal relati o ns hi p   
Relati o ns hi p classificati o n  ( base d o n t he f oll o wi n g relati o ns hi p 
classificati o n ), reas o n f or ca us al relati o ns hi p assess me nt  
   
Relati o ns hi p 
classificati o n  
Relate d    
T he o nset of t h e a d verse e ve nt f oll o ws a reas o na ble 
te m p oral se q ue nce fr o m st u d y treat me nt, a n d ca n n ot be 
reas o na bl y c o nsi dere d  t o be d ue t o t he s u bject’s cli ni cal 
state or ot h er fact ors (e. g., disease u n der st u d y , 
c o nc urre nt disease s, a n d c o nc o mita nt me dicati o ns), a n d 
a relati o ns hi p wit h t h e st u d y dr u g ca n n ot be r ule d o ut  
T he o nset of t h e a d verse e ve nt f oll o w s a reas o na ble 
te m p oral se q ue nce fr o m st u d y treat me nt, a n d is a k n o w n 
reacti o n t o t he dr u g u n d er st u d y or its c he mical gr o u p, or  
ca n b e e x pl ai n e d b y k n o w n  p har mac ol o g y  
   
 
N ot relate d    
T he o nset of t h e a d verse e ve nt d oes n ot f oll o w a 
reas o na ble te m p oral se q ue nce fr o m st u d y treat me nt, or 
ca n b e reas o na bl y e x plai ne d b y t h e s u bject’s cli ni cal 
state or ot h er fact ors (e. g., disease u n der st u d y, 
c o nc urre nt diseases, a n d c o nc o mita nt me dicati o ns), a n d 
a relati o ns hi p wit h t h e st u d y dr u g ca n be r ule d o ut  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 2  
 
9. 5  
Defi niti o n of A d verse Dr u g Re acti o ns  
A d verse e ve nts f or w hic h t he relati o ns hi p wit h t he st u d y dr u g is c o nsi dere d  t o be 
“relate d” will be treate d as a d verse dr u g reacti o ns.  
 
9. 6  
Acti o n W he n a n A d verse E ve nt Occ urs  
9. 6. 1  
Acti o n W he n a n A d verse E ve nt Occ urs  
If a n a d verse e ve nt occ urs, t he i n vesti gat or or s u bi n vesti gat or will ta ke s uita ble acti o n, 
a n d re p ort t o t he  S p o ns or if necessar y, a n d, as far as p ossi ble, o bser ve t he s u bject ’s 
c o urse (e ve n after t he e n d of t he s pecifie d o bser vati o n peri o d) u ntil t he a d verse e ve nt is 
res ol ved  t o t he state bef ore o nset or is res ol vi n g.  H o we ver, e ve n if t he a d verse e ve nt is 
n ot res ol ved  a n d is n ot res ol vi n g, o bser vati o n will be e n de d i n t he st u d y, after a n 
e x pla nati o n is pr o vi de d t o t he s u bject ( or le gall y acce pta ble re prese ntati ve) if it ca n be 
c o nsi dere d  t hat t he s u bject’s c o n diti o n is sta ble a n d t he s u bject’s safet y is e ns ure d 
( h o we ver, treat me nt f or t he rele va nt s y m pt o ms will c o nti n ue). 
 
9. 6. 2  
Acti o n W he n a Seri o us A d verse E ve nt Occ urs  
If a seri o us  a d verse e ve nt occ urs, t he i n vesti gat or or s u bi n vesti gat or will ta ke s uita ble 
acti o n, a n d will pr o m ptl y re p ort t he details of t he e ve nt t o t he S p o ns or b y tele p h o ne or 
fa x.  T he i n vesti gat or will pr o m ptl y re p ort t hese details i n writi n g t o t he S p o ns or a n d 
t he direct or of t he st u d y site.  T he writte n re p ort t o t he direct or of t he st u d y site will 
f oll o w t he pr oce d ure a n d f or mat f or t he st u d y site.  T his acti o n will be ta ke n u ntil t he 
fi nal f oll o w-u p e xa mi nati o n.  
 
1 0.  O T H E R E N D P OI N T S  
1 0. 1  P h ar m ac o d y n a mics ( P h ar m ac o d y n a mic I n dic at ors a n d Bi o m ar kers)  
At Wee k 8 of t he st u d y treat me nt peri o d ( Visit 3), P D i n dicat ors ( P T a n d aP T T) a n d 
bi o mar kers ( D -di mer a n d F 1 + 2) will be assesse d.  
 
1 1.  S T A TI S TI C A L A N A L Y S E S  
T his is a n o ver vie w of t he statistical a nal ysis.  A m ore detaile d descri pti o n of a nal ytical 
met h o ds will be s pecifie d i n t he Statistical A nal ysis Pla n.  
 
1 1. 1  O bjecti ve of A n al ysis  
To e val uate t he s u peri orit y of 1 5  m g of D U -1 7 6 b c o m pare d t o place b o, wit h re gar d t o t he 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 3  
c o m p osite pri mar y efficac y e n d p oi nt of str o ke a n d S E E.  
 
1 1. 2  A n al ysis Sets  
After case re p ort f or ms ha ve bee n l oc ke d, a n d bef ore u n bli n di n g, t he S p o ns or will deci de 
o n t he ha n dli n g eac h s u bject, after disc ussi o n wit h t he me dical e x perts if necessar y.  
After recei vi n g a d vice fr o m t he me dical e x perts, t he S p o ns or will deci de o n t he ha n dli n g 
of s u bjects n ot s pecifie d i n t he pr ot oc ol.  
T he maj or efficac y a nal ysis set will be t he i nte nt -t o-treat (I T T) set, b ut a nal ysis of t he 
m o difie d i nte nt -t o-treat ( mI T T) set a n d per pr ot oc ol set  ( P P S) will als o be c o n d ucte d as 
se nsiti vit y a nal ysis. 
 
1 1. 2. 1  Effic ac y A n al ysis Sets  
1 1. 2. 1. 1  
I nte nt-t o-tre at Set 
T his set will i ncl u de all ra n d o mize d s u bjects, w het her or n ot t he y recei ve a si n gle d ose of  
t he st u d y dr u g.  A nal yses will be base d o n t he ra n d o mize d  treat me nt e ve n if a s u bject 
i na d verte ntl y recei ves t he i nc orrect dr u g or d osa ge.  T he refere nce date f or 
c o nsi derati o n of e n d p oi nts is t he ra n d o mizati o n date  (t he ti mes t o o nset of e ve nts will be 
calc ulate d starti n g fr o m t he ra n d o mizati o n date). 
 
1 1. 2. 1. 2  
M o difie d I nte nt -t o-tre at Set 
T his set will i ncl u de all ra n d o mize d s u bjects  w h o recei ve at least o ne ta blet of t he st u d y 
dr u g.  A nal yses will be base d o n t he ra n d o mize d treat me nt e ve n if a s u bject 
i na d verte ntl y recei ves t he i nc orrect dr u g or d osa ge.  T he refere nce date f or 
c o nsi derati o n of e n d p oi nts is t he i nitial d ose of st u d y dr u g date (t he ti mes t o o nset of 
e ve nts will be calc ulate d starti n g fr o m t he i nitial d ose of st u d y dr u g date).  
 
1 1. 2. 1. 3  
Per Pr ot oc ol Set  
T his  set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least o ne ta blet of t he st u d y 
dr u g  a n d d o n ot ha ve a n y maj or pr ot oc ol vi olati o ns (as defi ne d pri or t o  u n bli n di n g of t he 
data base f or fi nal a nal yses ).  A nal yses will be base d o n t he ra n d o mize d treat ment e ve n 
if a s u bject i na d verte ntl y recei ves t he i nc orrect dr u g or d osa ge.  T he refere nce date f or 
c o nsi derati o n of e n d p oi nts is t he i nitial d ose of st u d y dr u g date  (t he ti mes t o o nset of 
e ve nts will be calc ulate d starti n g fr o m t he i nitial d ose of st u d y dr u g date).  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 4  
1 1. 2. 2  P h ar m ac o ki netic A n al ysis Set  
T he P K a nal ysis set will i ncl u de all ra n d o mize d s u bjects w h o meet t he f oll o wi n g criteria. 
1)  S u bjects i n t he D U -1 7 6 b gr o u p.  
2)  S u bjects wit h n o maj or pr ot oc ol vi olati o ns affecti n g P K.  
3)  S u bjects wit h at least o ne usa ble plas m a D U -1 7 6  c o nce ntrati o n meas ure me nt.  
4)  S u bjects wit h usa ble i nf or mati o n o n a d mi nistrati o n.  
 
1 1. 2. 3  P h ar m ac o d y n a mic A n al ysis Set  
T he P D ( P D  i n dicat or a n d bi o mar ker) a nal ysis set will i ncl u de all ra n d o mize d s u bjects 
w h o meet t he f oll o wi n g criteria.  
1)  S u bjects wit h n o ma j or pr ot oc ol vi olati o ns affecti n g P D . 
2)  S u bjects wit h at least o ne usa ble P D i n dicat or or bi o mar ker meas ure me nt.  
 
1 1. 2. 4  S afet y A n al ysis Set  
T his set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least o ne ta blet of  t he st u d y 
dr u g.  A nal yses will be base d o n t he ra n d o mize d treat me nt, u nless a s u bject 
i na d verte ntl y recei ves t he i nc orrect dr u g or d osa ge d uri n g t he e ntire st u d y, i n w hic h case, 
t he s u bject will be gr o u pe d acc or di n g t o t he treat me nt act uall y recei ve d.  T he refere nce 
date f or  c o nsi derati o n of e n d p oi nts is t he i nitial d ose of st u d y dr u g date  (t he ti mes t o 
o nset of e ve nts will be calc ulate d starti n g fr o m t he i nitial d ose of st u d y dr u g date).  
 
1 1. 3  H a n dli n g of D at a  
Bef ore u n bli n di n g, t he S p o ns or will deci de o n t he ha n dli n g of data after disc ussi o n wit h 
t he me dical e x perts, base d o n t he criteria f or t he ha n dli n g of data i n t his secti o n, a n d t he n 
l oc k t he data. 
 
1 1. 3. 1  H a n dli n g of Pr ot oc ol De vi ati o n D at a  
Bef ore t he data base is l oc ke d, t he S p o ns or will c o nfir m wit h t he e x pert a b o ut t he cases t o 
be a nal yze d a n d t he crit eria f or ha n di n g t he data f or a nal ysis, a n d will disc uss a n d deci de 
o n t he ha n dli n g of pr o ble ms n ot s pecifie d at t he pla n ni n g sta ge, a n d pre pare rec or ds of 
t hese decisi o ns. 
 
1 1. 3. 2  H a n dli n g of S ur ve y a n d Me as ure me nt Ti mes  
T he eli gi bilit y assess me nt peri o d will be  wit hi n t he 3 0 da ys after t he da y of i nf or me d 
c o nse nt, w hic h will be c o u nte d as Da y 0.  T he wi n d o w f or s ur ve ys a n d meas ure me nts 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 5  
f or eac h visit will be wit hi n 1 4 da ys bef ore or after t he s pecifie d date, w hic h will be 
c o nsi dere d Da y 0.  T h e wi n d o w f or t he e x a mi nati o n at c o m pleti o n of st u d y treat me nt 
will be 6 0 da ys after t he date of declarati o n of c o m pleti o n of t he st u d y, w hic h will be 
c o nsi dere d Da y 0.  T h e wi n d o w f or t he e xa mi nati o n at disc o nti n uati o n  will be 7 da ys 
after t he da y of disc o nti n uati o n , w hic h will be c o nsi dere d Da y 0.  T he wi n d o w f or t he 
fi nal f oll o w-u p will be 3 0 t o 3 7 da ys after t he da y of t he e xa mi nati o n at c o m pleti o n of 
st u d y treat me nt, w hic h will be c o nsi dere d Da y 0  ( F or s u bjects w h o c o nti n ue t he st u d y 
treat me nt after t he c o m pleti o n of st u dy treat me nt, i n pri nci ple, wit hi n a m o nt h fr o m t he 
da y of n otif yi n g t heir st u d y treat me nt assi g n me nts as Da y 0.) .  If m ulti ple meas ure me nts 
are ma de wit hi n t he wi n d o w, t he meas ure me nts ma de o n t he da y nearest t o t he s pecifie d 
da y of meas ure me nt will be sel ecte d.  If t here are meas ure me nts bef ore a n d after t he 
s pecifie d da y t hat are t he sa me n u m ber of da ys a wa y, t he latter meas ure me nts will be 
selecte d. 
Data t hat d o n ot meet t he ha n dli n g criteria will be e xcl u de d fr o m a nal ysis.  If t here are 
n o data t hat mee t t he ha n dli n g criteria, t he rele va nt data p oi nt will be ha n dle d as bei n g 
missi n g.  
 
1 1. 3. 3  H a n dli n g of Missi n g D at a  
N o m issi n g data will be i m p ute d wit h esti mate d or calc ulate d val ues.  
 
1 1. 4  St atistic al A n al ysis Ite ms a n d A n al ysis Met h o ds  
1 1. 4. 1  B aseli ne S u bject C h ar acterist ics 
Distri b uti o ns a n d s u m mar y statistics will be calc ulate d b y treat me nt gr o u p f or baseli ne 
s u bject c haracteristics ( de m o gra p hic a n d refere nce ra n ges).  
 
1 1. 4. 2  Effic ac y A n al ysis  
1 1. 4. 2. 1  
Pri m ar y E n d p oi nt  
1 1. 4. 2. 1. 1  
Pri m ar y A n al ysis  
F or t he c o m p osite e n d p oi nt of str o ke a n d S E E o bser v e d fr o m ra n d o mizati o n u p t o t he 
e xa mi nati o n  at c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n ,§ § § § § 
t he ti me t o o nset of t he i nitial e ve nt * will be c o m pare d.  T he treat me nt gr o u p will be 
c o m pare d base d o n a C o x pr o p orti o nal hazar d m o del wi t h t he C H A D S 2 sc ore ( ≤ 2 or ≥ 3) 
as c o variate  (si g nifica nce le vel 5 %, 2 -si de d, c o nfi de nce c oefficie nt f or esti mates: 9 5 %). 
If a n y fact ors affecti n g t he pri mar y e n d p oi nt are f o u n d i n a bli n de d re vie w bef ore data are 
 
§ § § § §: F or s u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 6  
l oc ke d, t hese fact ors will als o be c o nsi dere d as c o variates.  
 
*: T his will a p pl y t o all e ve nts w het h er or n ot t he s u bject recei ves t he st u d y dr u g.  T he ti me t o o nset 
of t he i nitial e ve nt is defi ne d as t h e ti me fr o m t he d a y of ra n d o mizati o n t o t h e i nitial e v e nt 
e x perie nce d b y a s u bject.  F or s u bje cts w h o d o n ot e x p erie nc e a n e v e nt d uri n g t he st u d y, t h e ti me 
t o o nset of t h e i nitial e ve nt will be ce ns ore d at t h e da y of t he e xa mi nati o n at c o m pleti o n of st u d y 
treat me nt, t he da y of t h e e xa mi nati o n at disc o nti n u ati o n (f or s u bjects wit h dra w n fr o m st u d y 
pa rtici pati o n) or deat h, w hic he ver c o mes first. 
 
1 1. 4. 2. 1. 2  
Sec o n d ar y A n al ysis  
T he c u m ulati ve i nci de nce of e ve nts will be esti mate d f or eac h treat me nt gr o u p usi n g t he 
Ka pla n -Meier met h o d.  Se nsiti vit y a nal ysis of t he e ve nts t hat occ ur d uri n g t he 
“o n -treat me nt” peri o d * *  i n t he mI T T a nal ysis set a n d P P S will be perf or me d. 
 
* *: “O n -treat me nt” peri o d is defi n e d as t h e st u d y treat me nt p eri o d a n d u p t o 3 da ys after t he last d ose 
(a p pr o xi matel y fi ve ti mes t he half-life [T 1/ 2] of D U-1 7 6 c orres p o n ds t o 3 d a ys).  If t he s u bj ect 
res u mes st u d y dr u g, t he s u bject is c o nsi dere d at ris k a gai n.  H o we ver, i n a n al ysis, a s u bject w h o 
has recei ve d t h e st u d y dr u g u p t o t h e e xa mi nati o n at c o m pleti o n of st u d y treat me nt will n ot b e 
c o nsi d ere d at ris k after t h e da y of t h e e x a mi nati o n at c o m pleti o n of st u d y treat me nt, a n d e v e nts 
t hat occ ur o n or after t h e da y of t h e e xa mi n ati o n at c o m pleti o n of st u d y treat me nt  will n ot b e 
i ncl u de d i n a nal ysis.  F or s u bjects w h o d o n ot e x perie nc e a n e ve nt w hile at ris k, t he ti me t o o nset 
of t he i nitial e ve nt will be  ce ns ore d at 3 da ys after t he fi nal d ose, t he d a y of t h e e x a mi nati o n at 
c o m pleti o n of st u d y treat me nt , t he e xa mi nati o n at disc o nti n uati o n (f or s u bjects wit h dra w n fr o m 
st u d y partici pati o n), t h e da y of t he s u bject’s last assess me nt, or deat h, w hic he ver c o mes  first. 
 
1 1. 4. 2. 2  
Sec o n d ar y E n d p oi nts  
T he f oll o wi n g sec o n dar y e n d p oi nts will be a nal yze d i n t he sa me wa y as pri mar y 
e n d p oi nts.  
1)  C o m p osite of str o ke, S E E, a n d deat h d ue t o C V  
2)  M A C E  
3)  Str o ke, S E E , a n d all -ca use m ortalit y  
4)  Net cli nical be nefit : str o ke, S E E, maj or blee di n g,  a n d all -ca use m ortalit y  
5)  All -ca use m ortalit y  
 
1 1. 4. 2. 3  
Ot her E n d p oi nts  
T he f oll o wi n g ot her e n d p oi nts will be descri pti vel y s u m marize d.  
1)  H os pitalizati o n d ue t o C V c o n diti o n (i ncl u di n g h os pitalizati o ns f or blee di n g)  
2)  M o difie d Ra n ki n Scale (a p pr o xi matel y) 1 m o nt h after t he o nset of str o ke 
3)  Str o ke, S E E, a n d TI A  
4)  N u m ber of occ urre nces of str o ke a n d S E E  
5)  V T E  (P T E  a n d D V T ) 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 7  
 
1 1. 4. 2. 4  
Ot her A n al ysis Met h o ds  
S u b gr o u p a nal ysis usi n g t he maj or baseli ne s u bject c haracteristics ( de m o gra p hic a n d 
refere nce ra n ges) will be c o n d ucte d f or t he pri mar y e n d p oi nt.  Details of s u b gr o u ps will 
be s pecifie d i n t he Statistical A nal ysis Pla n.  
 
1 1. 4. 3  P h ar m ac o ki netic A n al ysis  
S u m mar y statistics f or plas ma D U -1 7 6 c o nce ntrati o n will be calc ulate d at eac h bl o o d 
sa m pli n g p oi nt, a n d a pl ot of t he ti me c o urse will be pre pa re d. 
 
1 1. 4. 4  P h ar m ac o d y n a mic A n al ysis  
S u m mar y statistics f or P D i n dicat ors ( P T a n d aP T T) a n d bi o mar kers ( D -di mer a n d F 1 + 2) 
will be calc ulate d at eac h bl o o d sa m pli n g p oi nt, a n d t he c ha n ges bef ore a n d after 
a d mi nistrati o n (ti me c o urse) will be pl otte d.  
 
1 1. 4. 5  S afet y A n al ysis  
U nless ot her wise state d, t he safet y a nal ysis set will be use d f or safet y a nal ysis.  
T he 
a nal ysis peri o d will be fr o m t he i nitiati o n of st u d y treat me nt t o t he e xa mi nati o n at 
c o m pleti o n of st u d y treat me nt  or t he e xa mi nati o n at disc o nti n uati o n * * * * * * .  Seri o us 
a d verse e ve nts o bser ve d d uri n g t he peri o d fr o m t he e xa mi nati o n at c o m pleti o n of st u d y 
treat me nt t o t he fi nal f oll o w-u p e xa mi nati o n a n d data o btai ne d at t he fi nal f oll o w -u p 
e xa mi nati o n will be  ta b ulate d se paratel y, as necessar y.  A d verse e ve nts will be c o d e d 
usi n g t he I nter nati o nal C o u ncil f or  Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use (I C H) Me dical Dicti o nar y f or Re g ulat or y Acti vities  
( Me d D R A), a n d s yste m or ga n classes will be ta b ulate d usi n g Me d D R A S yste m Or ga n 
Classes, a n d a d verse e ve nt ter ms will be ta b ulate d usi n g Preferre d Ter ms.  
 
1 1. 4. 5. 1  
Blee di n g E ve nts  
Blee di n g e ve nts will be classifie d i nt o t he f oll o wi n g cate g ories a n d s u m marize d b y 
treat me nt gr o u p, a n d a nal yze d i n t he sa me wa y as t he pri mar y e n d p oi nt. 
1)  Maj or blee di n g  
2)  Maj or ble e di n g a n d  cli nicall y rele va nt n o n -maj or blee di n g  
3)  C li nicall y rele va nt n o n-maj or blee di n g  
4)  Mi n or blee di n g  
 
* * * * * *  S u bjects wit h dra w n fr o m st u d y partici pati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 8  
5)  All blee di n g e ve nts  
 
1 1. 4. 5. 2  
A d verse E v e nts  
I nci de nces of a d verse e ve nts will be calc ulate d b y treat me nt gr o u p.  Fre q ue ncies of 
a d verse e ve nts will als o be ta b ul ate d b y e ve nt a n d b y se verit y.  A d verse dr u g reacti o ns 
will be a nal yze d i n t he sa me wa y.  
I n ta b ulati o n b y S yste m Or ga n Class or Preferre d Ter m, if m ulti ple a d verse e ve nts wit h 
t he sa me S yste m Or ga n Class or Preferre d Ter m occ ur i n t he sa me s u bject, t hese will be 
c o u nte d as a si n gle e ve nt.  S yste m Or ga n Classes will be dis pla ye d i n t he i nter nati o nall y 
a gree d or der, a n d Preferre d Ter ms will be dis pla ye d i n c o de or der.  I n t his st u d y, a d verse 
e ve nts t hat occ ur after t he i nitiati o n of st u d y treat me nt (treat me nt e mer ge nt a d verse 
e ve nts [ T E A Es]) will be ta b ulate d.  
 
1 1. 4. 5. 3  
L a b or at or y D at a  
S u m mar y statistics f or he mat ol o g y a n d bl o o d c he mistr y tests will be calc ulate d b y ti me 
p oi nt a n d b y treat me nt gr o u p, a n d c ha n ges (ti me c o urses) bef ore a n d after a d mi nistrati o n 
will be pl otte d.  A s hift ta ble of assess me nt  o n n or mal a n d a b n or mal val ues will als o be 
pre pare d.  Fre q ue ncies of meas ure d i n dicat ors fr o m uri nal ysis (e xce pt f or uri nar y 
se di me nt) will als o be ta b ulate d b y ti me p oi nt a n d b y treat me nt gr o u p.  
 
1 1. 4. 5. 4  
Vit al Si g ns ( B o d y Wei g h t, Bl o o d Press ure, a n d P ulse R ate) 
S u m mar y statistics f or bl o o d press ure (s yst olic a n d diast olic), p ulse rate, a n d b o d y 
wei g ht will be calc ulate d b y ti me p oi nt a n d b y treat me nt gr o u p, a n d c ha n ges (ti me 
c o urses) bef ore a n d after a d mi nistrati o n of t he st u d y dr u g will be pl otte d.  
 
1 1. 4. 5. 5  
Electr oc ar di o gr a ms  
A fre q ue nc y ta ble b y ti me p oi nt a n d b y treat me nt gr o u p f or t he res ults of t he p h ysicia n’s 
assess me nt  of sta n dar d 1 2 -lea d E C Gs will be pre pare d. 
 
1 1. 4. 6  Bli n de d Re vie w  
Bef ore t he data base is l oc ke d, a bli n d e d re vie w will be c o n d ucte d.  Details of t he 
bli n d e d  re vie w are s pecifie d i n t he bli n de d re vie w pla n.  If it bec o mes necessar y t o 
ma ke a n y c ha n ges t o t he a nal ysis pla n i n t he bli n d e d re vie w, c ha n ges will be ma de 
acc or di n g t o t he pr oce d ure i n “1 1. 5  C ha n ges t o t he A nal ysis Pla n .” 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
5 9  
1 1. 5  C h a n ges t o t he A n al ysis Pl a n  
If a n y c ha n ges are t o be ma de t o t he met h o d f or ha n dli n g data, or a n y c ha n ges are t o be 
ma de t o t he a nal ysis pla n, f or e xa m ple i n or der t o perf or m c o n versi o n of varia bles, t he 
S p o ns or will first c o nsi der w het her t hese c ha n ges are a p pr o priate, a n d t he effect of t he 
c ha n ges o n t he assess me nt of t his st u d y, bef ore deci di n g w het her t he c ha n ges ca n be 
ma de.  T he S p o ns or will rec or d i nf or mat i o n i ncl u di n g t he c o nte nts of t he disc ussi o n, 
w het her c ha n ges were ma de, a n d t he reas o ns f or t his, i n writte n f or m, a n d will st ore t his 
i nf or mati o n.  If c ha n ges are ma de, t he details of t he c ha n ges a n d t he reas o ns f or t he m 
will be d oc u me nte d i n t he cli nica l st u d y re p ort.  C ha n ges t o t he pri mar y a nal ysis liste d 
i n t he pr ot oc ol will be ma de i n acc or da nce wit h “1 5. 7  Pr ot oc ol A me n d me nt .” 
 
1 1. 5. 1  S afet y D at a M o nit ori n g C o m mittee  
T he S p o ns or will esta blis h a n d r u n a safet y data m o nit ori n g c o m mittee as a t hir d part y 
i n de pe n de nt of t he S p o ns or, t he i n vesti gat or, a n d t he c o or di nati n g c o m mittee. 
T he safet y data m o nit ori n g c o m mittee will m o nit or safet y data as necessar y, a n d will 
c o nsi der m atters s uc h as w het her it is p ossi ble t o c o nti n ue t he st u d y a n d w het her it is 
necessar y t o c ha n ge t he pr ot oc ol, a n d will ma ke rec o m me n dati o ns t o t he S p o ns or.  
Details are s pecifie d i n t he Pr oce d ure f or t he Safet y Data M o nit ori n g C o m mittee.  
 
1 1. 6  Pl a n ne d S a m ple S ize 
F o ur h u n dre d s u bjects i n eac h gr o u p, f or a t otal of 8 0 0 s u bjects  
 
< Rati o nale >  
I n t his st u d y, 6 5 pri mar y e n d p oi nt e ve nts o bser ve d i n t he I T T a nal ysis set bet wee n 
ra n d o mizati o n a n d t he e xa mi nati o n  at c o m pleti o n of st u d y treat me nt  will be c ollecte d.  
U n der  t he c o n diti o ns t hat t he a n n ual i nci de nce i n t he place b o gr o u p is 5 %/ year, t he 
hazar d rati o of D U -1 7 6 b relati ve t o t he place b o gr o u p is 0. 5, t he si g nifica nce le vel is 5 %, 
2 -taile d, a n d t he p o wer is 8 0 %, t he n u m ber of e ve nts re q uire d t o e val uate t he s u peri orit y 
is 6 5.  Ass u mi n g t hat t he d urati o n of t he s u bject e nr oll me nt peri o d is 2 years a n d t he 
d urati o n of t he f oll o w -u p peri o d is 1. 5 years, it is esti mate d t hat a p pr o xi matel y 4 0 0 
s u bjects will be e nr olle d i n eac h gr o u p.  T h us, t he pla n ne d sa m ple size will b e a t otal of 
8 0 0 s u bjects.  T his st u d y is a n e ve nt -dri ve n st u d y, a n d t he t otal n u m ber of s u bjects ma y 
c ha n ge as necessar y de pe n di n g o n t he n u m ber of tar get e ve nts c ollecte d.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
6 0  
1 2.  Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T he S p o ns or will ass ure t hat t he c o n d uct of  t he st u d y a n d t he pre parati o n of data, rec or ds, 
a n d re p orts, are  i n c o m plia n ce wit h t he f oll o wi n g ite ms b y e m pl o yi n g q ualit y ass ura nce 
a n d q ualit y c o ntr ol s yste ms base d o n t he sta n dar d o perati n g pr oce d ures s pecifie d b y t he 
S p o ns or.  
1)  T he pr ot oc ol  
2)  T he sta n da r ds s pecifie d i n Article 1 4 Para gra p h 3 a n d Article 8 0-2 of t he Act  o n 
Sec uri n g Q ualit y, Efficac y a n d Safet y of P har mace uticals , Me 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 
(t he P har mace utical a n d Me dic al De vice  Act) . 
3)  T he G C P Mi nisterial Or di na nce  
 
To ass ure t he relia bilit y a n d acc urac y of all data relati n g t o t he st u d y, t he S p o ns or will 
c o n d uct q ualit y c o ntr ol o n t he ha n dli n g of data at eac h sta ge.  T he met h o ds f or q ualit y 
c o ntr ol will be pre pare d i n a d va nce i n acc or da nce wit h t he sta n dar d o perati n g pr oce d ure s 
s pecifie d b y t he S p o ns or, a n d rec or ds of c o n d ucti n g q ualit y c o ntr ol will be ke pt.  
T he S p o ns or ’s res p o nsi ble a u dit or will c o n d uct a G C P a u dit as part of q ualit y ass ura nce 
acti vities, t o assess w het h er t his st u d y is i n c o m plia n ce wit h G C P, t he pr ot oc ol, 
pr oce d ures, a n d t he li ke, i n de pe n de nt of a n d se parate fr o m us ual m o nit ori n g a n d st u d y 
q ualit y c o ntr ol w or k.  
 
1 3.  FI N A N CI N G F O R P A R TI CI P A TI O N, C O M P E N S A TI O N F O R 
S T U D Y -R E L A T E D I N J U RI E S, A N D I N S U R A N C E  
1 3. 1  Fi n a nci n g f or P artici p ati o n  
Pa y me nts s uc h as t h ose t o relie ve fi na ncial b ur de n will be ma de t o s u bjects acc or di n g t o 
t he r ules s pecifie d se paratel y b y t he st u d y site.  T his fi na nci n g will be f u n de d fr o m t he 
a m o u nts pai d b y t he S p o ns or t o t he st u d y site.  
 
1 3. 2  C o m pe ns at i o n f or St u d y-rel ate d I nj uries  
If t he s u bject de vel o ps a n y st u d y-relate d i nj uries, t he i n vesti gat or or s u bi n vesti gat or will 
pr o vi de treat me nt a n d ta ke ot her necessar y meas ures.  If t he s u bject ( or le gall y 
acce pta ble re prese ntati ve) re q uests a res p o nse t o s t u d y-relate d i nj uries, t he i n vesti gat or or 
s u bi n vesti gat or will pr o m ptl y c o ntact t he S p o ns or.  T he S p o ns or will s pecif y a 
pr oce d ure f or pr o vi di n g c o m pe nsati o n t o t he s u bject f or st u d y -relate d i nj uries, a n d ta ke 
meas ures s uc h as ta ki n g o ut i ns ura nce.  T he S p o ns or will bear t he pr o p orti o n of c osts 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
6 1  
re q uire d t o treat st u d y-relate d i nj uries t hat w o ul d be b or ne b y t he s u bject, e xcl u di n g t he 
a m o u nt pai d fr o m s o urces s uc h as healt h i ns ura nce.  If t he S p o ns or has res p o nsi bilit y 
f or c o m pe nsati o n f or se q uelae, disa bilities, or t he li ke, t he S p o ns or will pr o vi de 
c o m pe nsati o n c o m me ns urate wit h pa y me nts u n der t he A d verse Dr u g Reacti o n Relief 
S yste m .  H o we ver, c o m pe nsati o n will n ot necessar y be pr o vi de d i n t he case of t he 
f oll o wi n g i nj uries. 
1)  I nj uries pr o ve d t o ha ve a n o b vio us relati o ns hi p wit h a n ot her ca use  
2)  I nj uries f or w hic h t here is n o reas o na ble te m p oral relati o ns hi p bet wee n t he st u d y 
treat me nt a n d t he i nj ur y 
3)  I nj uries f or w hic h t here is o b vi o usl y a part y at fa ult, s uc h as r oa d traffic acci de nts  
4)  I nj uries d ue t o a lac k of t hera pe utic be nefit, d ue t o treat me nt bei n g i neffecti ve or d ue 
t o a d mi nistrati o n of place b o 
5)  I nj uries d ue t o t he s u bject or t he s u bject’s part ner bec o mi n g pre g na nt d uri n g t he 
st u d y peri o d 
6)  I nj uries d ue t o t he s u bject faili n g t o c o m pl y wit h t he pr ot oc ol wit h out a pr o per 
reas o n 
If t he st u d y-relate d i nj ur y is deter mi ne d t o be d ue t o t he deli berate fa ult or gr oss 
ne gli ge nce of t he st u d y site or t he s u bject, t he s u bject ma y n ot be eli gi ble f or 
c o m pe nsati o n, or t he a m o u nt of c o m pe nsati o n ma y be re d uce d.  
 
1 3. 3  I ns ur a nce 
T he S p o ns or will ta ke o ut t he i ns ura nce necessar y t o pr o vi de c o m pe nsati o n f or 
st u d y-relate d i nj uries.  T he st u d y site will ta ke o ut i ns ura nce a n d ta ke ot her necessar y 
meas ures i n rea di ness f or t he occ urre nce of me dical err ors.  
 
1 4.  P U B LI C A TI O N P O LI C Y  
 
 
  
 
  
 
 
 
 
 
  
 
 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
6 2  
 
1 5.  S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N  
1 5. 1  Et hics  
1 5. 1. 1  Et hic al C o n d uct of t he St u d y  
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 sta n dar ds s pecifie d i n t he 
P har mace utical a n d Me dical De vic e Act , Article 1 4, Para gra p h 3, a n d Article 8 0 -2 a n d 
Mi nistr y of Healt h a n d Welfare Or di na nce 2 8 date d  2 7 Mar 1 9 9 7, t he “Mi nisterial 
Or di na nce o n G o o d Cli nical Practice ( G C P) f or Dr u gs ” (t he G C P Or di na nce).  T he 
c o n d uct of t he st u d y will be i n c o m plia nce w it h 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, a n d t he h u ma n ri g hts, well-bei n g, a n d safet y of 
s u bjects will be pr otecte d  t o t he ma xi m u m e xte nt p ossi ble. 
I n a d diti o n t o t he a b o ve, ba n ki n g of cli nical s peci me ns f or ge n o mic a n d  ge netic a nal ysis 
a n d researc h usi n g t hese s peci me ns will be c o n d ucte d i n acc or da nce wit h t he “ Et hical 
G ui deli nes f or H u ma n Ge n o me/ Ge ne A nal ysis Researc h”
2 7) a n d “ Et hical G ui deli nes f or 
Me dical a n d Healt h Re searc h I n v ol vi n g H u ma n S u bjects” 2 8) ( o nl y at st u d y sites w here 
ge n o mic a n d ge netic a nal ysis or ba n ki n g is a p pr o ve d).  
 
1 5. 1. 2  I nstit uti o n al Re vie w B o ar d 
T his st u d y will be re vie we d a n d a p pr o ve d b y t he I nstit uti o nal Re vi e w B oar d (I R B) as 
s pecifie d i n t he G C P Or di na nce Article 2 7 bef ore bei n g c o n d ucte d.  D uri n g t he c o n d uct 
of t his st u d y, o nce per year, or m ore fre q ue ntl y if re q ueste d b y t he I R B, t he st u d y will be 
re vie we d t o deter mi ne w het her it ca n c o nti n ue.  I n a d diti o n, if i nf or mati o n t hat ma y 
affect t he safet y of s u bjects or t he c o n d uct of t he st u d y is o btai ne d, t he st u d y will be 
re vie we d t o deter mi ne w het her it ca n c o nti n ue. 
 
1 5. 2  S u bject C o nfi de nti alit y  
To pr otect t he c o nfi de ntialit y of i n di vi d ual s u bjects, d oc u me nts s u b mi tte d fr o m t he st u d y 
site t o a n e xter nal part y will use s u bject i de ntificati o n c o des t o i de ntif y s u bjects, a n d 
i de ntif yi n g i nf or mati o n a b o ut s u bjects s uc h as na mes or me dical rec or d n u m bers will n ot 
be use d.  Pers o ns w h o ma y lear n c o nfi de ntial i nf or mati o n a b o ut s u bjects ( or le gall y 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
6 3  
acce pta ble re prese ntati ves) i n t he c o urse of t heir w or k will mai ntai n t he c o nfi de ntialit y of 
t his i nf or mati o n. 
 
1 5. 3  I nf or me d C o nse nt 
Bef ore perf or mi n g t he e xa mi nati o ns s pecifie d i n t he pr ot oc ol f or t his st u d y, t he 
i n vesti gat or or s u bin vesti gat or will e x plai n t he f oll o wi n g i nf or mati o n t o t he s u bject (a n d 
als o t o t he le gall y acce pta ble re prese ntati ve, if t he le gall y acce pta ble re prese ntati ve will 
pr o vi de c o nse nt) i n a n easil y u n dersta n da ble wa y usi n g t he i nf or me d c o nse nt f or m, a n d 
o btai n  t he s u bject’s writte n i nf or me d c o nse nt t o partici pate i n t he st u d y, gi ve n of t he 
s u bject’s o w n free will.  
W he n o btai ni n g i nf or me d c o nse nt, t he i n vesti gat or or 
s u bi n vesti gat or will gi ve t he s u bject ( or le gall y acce pta ble re prese ntati ve) a m ple ti me t o 
deci de w het her or n ot t o partici pate i n t he st u d y, a n d will pr o vi de a n o p p ort u nit y t o as k 
q uesti o ns, a n d will pr o vi de t h or o u g h res p o nses t o t hese q uesti o ns.  As t he s u bjects of 
t his st u d y will be patie nts wit h N V A F a ged 8 0 years  or ol der , m ore t ha n a fe w of t he 
patie nts will ha ve de me ntia as a c o nc urre nt c o n diti o n, a n d t heref ore, if t he i n vesti gat or or 
s u bi n vesti gat or c o nsi ders  t hat it is n ot feasi ble t o o btai n writte n c o nse nt fr o m t he s u bject 
i n pers o n d ue t o deteri orati o n of c o g niti ve f u ncti o n, t he i n vesti gator  or s u bi n vesti gat or 
will als o e x plai n t he st u d y t o a le gall y acce pta ble re prese ntati ve a n d o btai n writte n 
c o nse nt, gi ve n of t he le gall y acce pta ble re prese ntati ve’s o w n free will.  A le gall y 
acce pta ble re prese ntati ve is a pers o n w h o is a ut h orize d t o pr o vide c o nse nt o n be half of a 
s u bject, a n d will be t he s u bject’s s p o use, g uar dia n, ot her care gi ver, or ot her si milar 
pers o n, w h o is li kel y t o act i n t he best i nterests of t he s u bject, gi ve n t he li vi n g 
circ u msta nces a n d e m oti o nal relati o ns hi p of t he t w o pe o ple.  
T he i n vesti gat or or s u bi n vesti gat or w h o pr o vi de d t he e x pla nati o n a n d t he s u bject ( or t he 
le gall y acce pta ble re prese ntati ve, if t he le gall y acce pta ble re prese ntati ve pr o vi ded  
c o nse nt ) will affi x  t heir na mes a n d seals t o, or si g n t he i nf or me d c o nse nt f or m, a n d eac h 
will als o e nter  t he date.  If a le gall y acce pta ble re prese ntati ve pr o vi de d c o nse nt, t he 
relati o ns hi p wit h t he s u bject will be state d o n t he c o nse nt f or m.  If a s u p ple me ntar y 
e x pla nati o n was pr o vi de d t o t he s u bject ( or le gall y acce pta ble re prese nta ti ve) b y st u d y 
staff desi g nate d  b y t he direct or of t he st u d y site, t he me m ber of t he st u d y staff will als o 
affi x his/ her na me a n d seals t o, or si g n t he c o nse nt f or m, a n d e nter t he date , i n a d diti o n t o 
t he i n vesti gat or or s u bi n vesti gat or.  A c o p y of t he c o nse nt f or m a n d writte n i nf or mati o n  
will be pr o vi de d  t o t he s u bject ( or le gall y acce pta ble re prese ntati ve), a n d t he ori gi nal 
c o nse nt f or m will be st ore d at t he st u d y site.  T he i n vesti gat or or s u bi n vesti gat or will 
rec or d t he fact t hat a c o p y of t he c o nse nt for m a n d writte n i nf or mati o n  ha ve  bee n 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
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pr o vi de d  t o t he s u bject ( or le gall y acce pta ble re prese ntati ve) o n a d oc u me nt (s uc h as t he 
ori gi nal c o nse nt f or m or me dical rec or ds).  
In a d diti o n, t he i n vesti gat or or s u bi n vesti gat or will o btai n  writte n v ol u ntar y c o nse n t, 
se paratel y fr o m i nf or me d c o nse nt at t he start of t his st u d y, fr o m t he s u bject ( or t he le gall y 
acce pta ble re prese ntati ve, if t he le gall y acce pta ble re prese ntati ve pr o vi de s c o nse nt ) w h o 
is f o u n d t o be necessar y t o c o nti n ue t he st u d y treat me nt u ntil t he final f oll o w -u p 
e xa mi nati o n at t he ti me of t he e xa mi nati o n at c o m pleti o n of st u d y treat me nt . 
 
[Ite ms t o be e x plai ne d t o t he s u bject ( or le gall y acce pta ble re prese ntati ve)] 
1)  T hat t he st u d y i n v ol ves researc h  
2)  T he o bjecti ve of t he st u d y  
3)  T he st u d y met h o d ol o g y (i nc l u di n g t he e x peri me ntal as pects of t he st u d y, t he 
i ncl usi o n criteria f or s u bjects, a n d, if ra n d o mizati o n will be perf or me d, t he 
pr o ba bilit y of bei n g assi g ne d t o eac h treat me nt) 
4)  T he pla n ne d d urati o n of s u bject’s partici pati o n i n t he st u d y  
5)  T he pla n ne d n u m ber  of s u bjects w h o will partici pate i n t he st u d y  
6)  T he e x pecte d be nefits t o t he s u bject ’s me ntal a n d p h ysical healt h fr o m t he st u d y dr u g 
( or t hat n o be nefits are e x pecte d, if t his is t he case) a n d t he e x pecte d disa d va nta ges 
t o t he s u bject 
7)  W het her t here are a n y  alt er nati ve  treat me nts, a n d t heir i m p orta nt p ote ntial be nefits 
a n d ris ks  
8)  T he c o m pe nsati o n a n d treat me nt a vaila ble t o t he s u bject i n t he e ve nt of  st u d y-relate d 
i nj uries 
9)  T hat t he s u bject ’s partici pati o n i n t he st u d y is v ol u ntar y, t hat t he s u bject or t he 
s u bject’s le gall y acce pta ble re prese ntati ve ma y  ref use t o partici pate i n t he st u d y or 
wit h dra w c o nse nt at a n y ti me, wit h o ut pe nalt y or l oss of be nefits t o w hic h t he s u bject 
is ot her wise e ntitle d 
1 0)  T hat t he s u bject or t he s u bject's le gall y acce pta ble re prese ntat i ve will be i nf or me d i n 
a ti mel y ma n ner if a n y i nf or mati o n bec o mes a vaila ble t hat ma y affect t he s u bject’s or 
le gall y acce pta ble re prese ntati ve’s willi n g ness t o c o nti n ue partici pati o n i n t he st u d y  
1 1)  T he circ u msta nces  or reas o ns u n der  w hic h t he s u bject ’s part ici pati o n i n t he st u d y 
ma y be ter mi nate d  
1 2)  T hat t he m o nit or, res p o nsi ble a u dit or, I R B, a n d re g ulat or y a ut h orit y will be gra nte d 
access t o ori gi nal me dical  rec or ds, wit h o ut vi olati n g t he c o nfi de ntialit y of t he s u bject, 
a n d t hat b y affi xi n g  t he na me s a n d seal s t o, or si g ni n g t he c o nse nt f or m, t he s u bject 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
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or t he s u bject’s le gall y acce pta ble re prese ntati ve is a ut h orizi n g s uc h access 
1 3)  T hat t he s u bject ’s c o nfi de ntialit y will be pr otecte d e ve n if t he res ults of t he st u d y are 
p u blis he d  
1 4)  T he  e x pe nses  t o t he s u bject, if a n y  
1 5)  T he  pa y me nts t o t he s u bject , if a n y 
1 6)  T he i n vesti gat or or s u bi n vesti gat or ’s na me, j o b title, a n d c o ntact i nf or mati o n 
1 7)  T he office at t he st u d y site t o ma ke e n q uiries t o or pers o n t o c o ntact  f or f urt her 
i nf or mati o n re gar di n g t he st u d y or t he ri g hts of s u bjects, a n d w h o m t o c o ntact i n t he 
e ve nt of st u d y-relate d i nj ur y 
1 8)  T he s u bject’s res p o nsi bilities  
1 9)  T he t y pe of I R Bs re vie wi n g w het her or n ot t he st u d y is acce pta ble, a n d t he ite ms 
re vie we d b y eac h I R B a n d ot her i nf or mati o n relati n g t o I R Bs i n v ol ve d i n t he st u d y  
 
1 5. 4  I nf or me d C o nse nt f or P h ar m ac o ge n o mics a n d Bi o m ar ker Rese arc h  
If l o n g-ter m st ora ge ( ba n ki n g) of s peci me ns f or ge n o mic a n d  ge netic a nal ysis wit h n o set 
ti mi n g is c o n d ucte d, t he i n vesti gat or or s u bi n vesti gat or will e x plai n t he f oll o wi n g 
i nf or mati o n t o t he s ubject i n a n easil y u n dersta n da ble wa y, a n d o btai n t he s u bject’s 
writte n i nf or me d c o nse nt, gi ve n of t he s u bject’s o w n free will , a n d se paratel y fr o m t he 
c o nse nt f or t he st u d y (c o nse nt o btai ne d fr o m a le gall y acce pta ble re prese ntati ve  is 
i n vali d).  T his c o nse nt will be o btai ne d bef ore s peci me ns are sa m ple d.  
1)  T he c haracteristics a n d nat ure of t he ge netic i nf or mati o n  
2)  T he o bjecti ve of t he researc h 
3)  T he researc h met h o d ol o g y  
4)  T he e x pecte d be nefits t o t he s u bject’s me ntal a n d p h ysical healt h  fr o m t he researc h, 
a n d t he  e x pecte d disa d va nta ges t o t he s u bject  
5)  T hat t he s u bject’s partici pati o n i n t he i n vesti gati o n of p har mac o ge n o mics is 
v ol u ntar y, t hat t he s u bject ma y ref use t o partici pate i n t he st u d y or wit h dra w c o nse nt 
at a n y ti me, wit h o ut pe nalt y, a n d t hat t he s u bject’ s partici pat i o n i n t he st u d y will n ot 
be affecte d if t he s u bject d oes n ot partici pate i n t his researc h  
6)  H o w s peci me ns a n d data will be ha n dle d if c o nse nt is wit h dra w n  
7)  T he met h o ds f or ha n dli n g s peci me ns, t he st ora ge peri o d of s peci me ns, a n d 
i nf or mati o n relati ng t o dis p osal of s peci me ns  
8)  C o m pe nsati o n a vaila ble t o t he s u bject 
9)  T he discl os ure a n d o w ners hi p of t he res ults of researc h  
1 0)  T he  e x pe nses  t o t he s u bject, if a n y 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
6 6  
1 1)  T hat s peci me ns will be pr o vi de d free of c har ge b y t he s u bject  
1 2)  T hat t he s u bject ’s c o nfi de ntialit y a nd ot her h u ma n ri g hts will be pr otecte d  
 
1 5. 5  Pr o visi o n 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  
If i nf or mati o n is o btai ne d t hat ma y affect t he s u bject’s ( or le gall y acce pta ble 
re prese ntati ve’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 h e i n vesti gat or or 
s u bi n vesti gat or will pr o m ptl y e x plai n t he rele va nt i nf or mati o n t o t he s u bject ( or le gall y 
acce pta ble re prese ntati ve) a n d c o nfir m t he s u bject’s ( or le gall y acce pta ble 
re prese ntati ve’s) willi n g ness t o c o nti n ue partici pati o n i n t he st u d y.  The i n vesti gat or or 
s u bi n vesti gat or will rec or d o n a d oc u me nt s uc h as me dical rec or ds t he date of 
e x pla nati o n, t he pers o n pr o vi di n g t he e x pla nati o n, t he c o nte nts of t he e x pla nati o n, t he 
willi n g ness of t he s u bject ( or le gall y acce pta ble re prese ntati ve), a n d t he date of 
c o nfir mati o n.  If necessar y, t he i n vesti gat or will als o pr o m ptl y a me n d t he i nf or me d 
c o nse nt f or m a n d s u b mit it t o t he S p o ns or a n d re p ort i t t o t he direct or of t he st u d y site 
a n d recei ve a p pr o val fr o m t he I R B.  If t here are a n y s u bjects alrea d y partici pati n g i n t he 
st u d y, t he i nf or me d c o nse nt of t he s u bjects ( or le gall y acce pta ble re prese ntati ves) will be 
o btai ne d a gai n i n t he sa me wa y as a b o ve usi n g t he a me n de d i nf or me d c o nse nt f or m, a n d 
t he s u bjects ( or le gall y acce pta ble re prese ntati ves) will be pr o vi de d  wit h c o pies of t he 
c o nse nt f or m  a n d writte n i nf or mati o n .  T he i n vesti gat or or s u bi n vesti gat or will rec or d 
t he fact t hat a c o p y of t he c o nse nt f or m  a n d writte n i nf or mati o n ha ve bee n pr o vi de d t o 
t he s u bject ( or le gall y acce pta ble re prese ntati ve) o n a d oc u me nt (s uc h as t he ori gi nal 
c o nse nt f or m or me dical rec or ds).  
 
1 5. 6  Pl a n ne d St u d y D ur ati o n  
2 4 Ma y  2 0 1 6 t o 3 0 Se p  2 0 2 0  
 
1 5. 7  Pr ot oc ol A m e n d me nt  
If t he pr ot oc ol is a me n de d after t he start of t he st u d y, t he S p o ns or will, if necessar y, 
disc uss wit h t he me dical e x perts w het her t he c ha n ges are a p pr o priate a n d t he i nfl ue nce 
o n t he assess me nt of t he st u d y, a n d will t he n ma ke a decisi o n a b o ut t he a me n d me nt.  
T he S p o ns or will ma ke a clear writte n rec or d of i nf or mati o n i ncl u di n g t he c o nte nts of t he 
disc ussi o n, w het her a n a me n d me nt was ma de, a n d t he reas o n f or t his, a n d will st ore t his 
rec or d. 
T he S p o ns or will pr o m ptl y i nf or m t he i n vesti gat or of t he details of t he pr ot oc ol 
a me n d me nt.  If t he versi o n n u m ber of t he pr ot oc ol is a me n de d, t he S p o ns or will a gai n 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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c o ncl u de a writ te n a gree me nt wit h t he i n vesti gat or a n d pr ocee d wit h t he pr ocess  
s pecifie d b y t he st u d y site. 
 
1 5. 8  Ter mi n ati o n or I nterr u pti o n of t he St u d y  
1 5. 8. 1  Ter mi n ati o n or I nterr u pti o n of t he St u d y  
If a n y of t he f oll o wi n g criteria are met, a n d t he S p o ns or deter mi nes  t hat it is n ot feasi ble 
t o c o nti n ue t he st u d y, t he S p o ns or will te m p oraril y disc o nti n ue t he w h ole or a part of t he 
st u d y.  After t his, t he S p o ns or will deci de w het her t o ter mi nate t he w h ole or a part of t he 
st u d y a n d ma ke a writte n rec or d of t his decisi o n.  
1)  If ne w safet y i nf or mati o n relati n g t o t he st u d y dr u g or i nf or mati o n a b o ut seri o us 
a d verse e ve nts is o btai ne d  
2)  If t here is a maj or breac h of G C P or a maj or de viati o n fr o m t he pr ot oc ol b y eit her t he 
S p o ns or, st u d y site, or i n vesti gat or  
3)  If a rec o m me n dati o n t o ter mi nate t he st u d y is recei ve d fr o m t he Safet y Data 
M o nit ori n g C o m mittee, f or e xa m ple d ue t o a maj or safet y pr o ble m ( detaile d 
sta n dar ds are s pecifie d i n t he Pr oce d ure f or t he Safet y Data M o nit ori n g C o m mittee)  
4)  If ot her ne w i nf or mati o n is o btai ne d d uri n g t he c o n d uct of t he st u d y  
 
If, i n disc ussi o n wit h parties s uc h as t he me dical e x perts, t he S p o ns or deci des t o 
ter mi nate a part or t he w h ole of t he st u d y, or deci des t o ter mi nate t he w h ole st u d y d ue t o 
t he rec o m me n dati o n of t he Safet y Data M o nit ori n g C o m mittee , t he S p ons or will 
pr o m ptl y pr o vi de writte n n otice of t his fact a n d t he reas o n f or it t o t he direct or of t he 
st u d y site.  The direct or of t he st u d y site will pr o m ptl y pr o vi de writte n n otice of t his fact 
a n d t he reas o n f or it  t o t he i n vesti gat or a n d t he I R B. 
Re gar dl ess of t he reas o n, if t he st u d y is ter mi nate d or te m p oraril y disc o nti n ue d, t he 
i n vesti gat or will pr o m ptl y n otif y s u bjects partici pati n g i n t he st u d y ( or le gall y acce pta ble 
re prese ntati ves) of t his fact, a n d will ta ke s uita ble meas ures a n d perf or m tests or t he li ke 
t o c o nfir m t he safet y of s u bjects. 
 
1 5. 8. 2  C o m pleti o n of t he St u d y  
Base d o n t he i nci de nce of e ve nts as t his st u d y pr o gresses, t he S p o ns or will disc uss wit h 
t he me dical e x perts a b o ut t he ti me t o perf or m t he e xa mi nati o n at c o m pleti o n of st u d y 
treat me nt f or t he s u bjects. 
W he n t he S p o ns or has deci de d o n t he ti me t o perf or m t he e xa mi nati o n at c o m pleti o n of 
st u d y treat me nt, t he S p o ns or will pr o vi de writte n n otice of t he fact a n d t he reas o n f or it t o 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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t he i n vesti gat or a n d t he direct or of t he st u d y site. 
T he i n ves ti gat or or s u bi n vesti gat or will pr o m ptl y n otif y s u bjects partici pati n g i n t he 
st u d y ( or le gall y acce pta ble re prese ntati ves) of t his fact, a n d will perf or m t he 
e xa mi nati o n at c o m pleti o n of st u d y treat me nt wit hi n 6 0 da ys.  
 
1 5. 9  Pr oce d ures f or Pre p ari n g t he C ase R e p ort F or m a n d Re m ar ks  
I n t his st u d y, t he f oll o wi n g will be pre pare d: case re p ort f or ms ( pre pare d b y t he 
i n vesti gat or), blee di n g e ve nt assess me nt f or ms ( pre pare d b y t he Cli nical Blee di n g E ve nt 
C o m mittee), efficac y e ve nt assess me nt f or ms ( pre pare d b y t he Cl i nical Efficac y E ve nt 
C o m mittee), la b orat or y meas ure me nt re p orts ( pre pare d b y t he ce ntral la b orat or y), dr u g 
c o nce ntrati o n meas ure me nt re p orts ( pre pare d b y t he ce ntral la b orat or y), P D i n dicat or 
meas ure me nt re p orts ( pre pare d b y t he ce ntral la b orat or y), a n d b i o mar ker meas ure me nt 
re p orts ( pre pare d b y t he ce ntral la b orat or y).  T he met h o d f or pre pari n g assess me nt 
f or ms a n d meas ure me nt re p orts will be s pecifie d else w here. 
 
1 5. 9. 1  St yle of t he C ase Re p ort F or m  
I n t his st u d y, case re p ort f or ms will be e ntere d electr o nically usi n g a n electr o nic data 
c ollecti o n s yste m f or pre pari n g case re p ort f or ms ( E D C s yste m,  Ta ble 1 5. 9 -1 ).  Case 
re p ort f or ms (i ncl u di n g a u dit traces) will be pre pare d f or eac h s u bject, a n d t he case re p ort 
f or ms si g ne d b y t he i n vesti gat or will be treate d as ori gi nals.  A vali date d E D C s yst e m 
will be use d.  
 
Ta ble 1 5. 9 -1   T he E D C S yste m  
Na me of E D C s yste m    
Me di d ata Ra ve
®  
C o m pa n y de vel o pi n g 
E D C s yste m  
Me di d ata S ol uti o ns , I nc. 
E ntr y met h o d    
We b -base d data e ntr y  
E ntr y ter mi nals    
Pers o nal c o m p uters at t h e me dical i nstit uti o n  
Pr o hi bite d O Ss    
N o ne  
Br o wser  
Me di d ata R A V E
®  s u p p orts br o wsers i n c o m plia n ce  wit h H T M L 5, a n d 
C S S 2.  Br o wsers m ust als o ha v e Ja v a Scri pt e na ble d.  
Rec o m me n de d scree n 
res ol uti o n 
1 0 2 4  ×  7 6 4 or hi g h er  
Rec o m me n de d 
c o n n ecti o n s pee d  
1 2 8 k b ps or hi g her  
Ot her  
A d o be Flas h Pla yer: v er. 1 0 or hi g h er  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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1 5. 9. 2  Pre p ari n g C ase Re p ort F or ms  
T he i n vesti gat or will recei ve trai ni n g i n di gital si g nat ures bef ore pre pari n g case re p ort  
f or ms, a n d t he rec or d of t his will be use d i n place of a list of si g nat ures a n d seal mar ks.  
1)  Case re p ort f or ms will be pre pare d f or all s u bjects fr o m w h o m c o nse nt has bee n 
recei ve d, i ncl u di n g cases w here c o nse nt was pr o vi de d b y a le gall y acce pta ble 
re presentati ve.  
2)  T he i n vesti gat or or s u bi n vesti gat or will pre pare case re p ort f or ms acc or di n g t o t he 
G ui de t o E nteri n g a n d E diti n g Case Re p ort F or ms pr o vi de d b y t he S p o ns or.  
3)  If t he st u d y staff assists i n t he pre parati o n of a case re p ort f or m, t he st u d y staff will 
f oll o w t he directi o ns of t he i n vesti gat or or s u bi n vesti gat or. 
4)  T he i n vesti gat or will s u b mit t he case re p ort f or ms t o t he S p o ns or a n d st ore c o pies of 
t he m. 
5)  If t here are a n y c o ntra dicti o ns bet wee n t he data e ntere d o n t he case re p ort f or ms a n d 
t he s o urce d oc u me nts, t he i n vesti gat or will se paratel y pre pare rec or ds e x plai ni n g t he 
reas o n f or t his a n d will s u b mit t he m t o t he S p o ns or, st ori n g a c o p y. 
 
1 5. 9. 3  Affi x ati o n of N a me a n d Se al or Si g n at ure t o C ase Re p ort F or ms  
T he i n vesti gat or will c o nfir m t he case re p ort f or ms pr e pare d at t he st u d y site a n d si g n 
t he m electr o nicall y. 
 
1 5. 9. 4  C h a n gi n g o r E diti n g t he C o nte nts E ntere d o n C ase Re p ort F or ms  
1)  T he i n vesti gat or, s u bi n vesti gat or, or st u d y staff will e dit case re p ort f or ms acc or di n g 
t o t he G ui de t o E nteri n g a n d E diti n g Case Re p ort F or ms pr o vi de d b y t he S p o ns or.  
2)  T he i n vesti gat or will ha ve res p o nsi bilit y f or t he c o nte nts e ntere d o n case re p ort 
f or ms, a n d will st ore c o pies of all rec or ds of t he m, i ncl u di n g c ha n ges a n d e dits.  
 
1 5. 1 0  St or a ge of S o urce D oc u me nts a n d Ot her Rec or ds  
1 5. 1 0. 1  Defi niti o n of S o urce D o c u me nts  
“S o urce d oc u me nts ” refers t o t he ori gi nal d oc u me nts or data a n d certifie d  c o pies  of t he m 
s pecifie d i n I C H-G C P 1. 5 2, a n d i ncl u des t he rec or ds (s o urce data) necessar y  f or t he 
rec o nstr ucti o n a n d e val uati o n  of t he c o urse of t he cli nical st u d y.  F or e xa m ple, h os pital 
rec or ds, cli nical  c harts, la b orat or y n otes, me m o ra n da, s u bject’s diaries or e val uati o n  
c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d data fr o m a ut o mate d i nstr u me nts, 
c o pies  or tra nscri pti o ns certifie d after  verificati o n as be i n g acc urate c o pies , micr ofic hes, 
p h ot o gra p hic ne gati ves, micr ofil ms or ma g netic me dia, X -ra y p h ot o gra p hs, s u bject files, 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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a n d rec or ds st ore d at p har macies, la b orat ories, a n d t he me dical tec h n ol o g y de part me nt 
i n v ol ve d i n t he cli nical st u d y. 
 
1 5. 1 0. 2  Rec or d Kee pi n g  
1 5. 1 0. 2. 1  I nstit uti o n al Re vie w B o ar d 
T he pers o n w h o esta blis he d t he I R B will st ore t he sta n dar d o perati n g pr oce d ure s, list of 
b oar d  me m bers, s u b mitte d d oc u me nts, mi n utes a n d s u m maries of meeti n gs, a n d rec or ds 
s uc h as letters u ntil t he later of t he date 1) or  2) bel o w.  If t he S p o ns or re q uires rec or ds 
t o be st ore d f or a l o n ger peri o d, t he pers o n w h o esta blis he d t he I R B will disc uss t he 
d urati o n of st ora ge a n d t he st ora ge met h o d wit h t he S p o ns or.  
1)  T he date of a p pr o val relati n g t o t his st u d y ( or, if de vel o p me nt is ter mi nate d , t he date 
3 years after t he da y w he n n otificati o n of ter mi nati o n of de vel o p me nt is recei ve d 
fr o m t he S p o ns or) 
2)  T he date 3 years after t he disc o nti n uati o n or c o m pleti o n of t he st u d y  
 
1 5. 1 0. 2. 2  St u d y Site  
T he direct or of t he st u d y site or t he pers o n res p o nsi ble f or re c or d  kee pi n g will st ore t he 
d oc u me nts or rec or ds relati n g t o t he cli nical st u d y t hat are t o be st ore d at t he st u d y site 
u ntil t he later of t he date 1) or 2) bel o w .  If t he S p o ns or re q uires rec or ds t o be st ore d f or 
a l o n ger peri o d, t he direct or of t he st u d y  site or t he pers o n res p o nsi ble f or rec or d  kee pi n g 
will disc uss t he d urati o n of st ora ge a n d t he st ora ge met h o d wit h t he S p o ns or.  W he n 
rec or ds are st ore d, a pers o n res p o nsi ble f or rec or d kee pi n g  will be desi g nate d f or eac h 
rec or d. 
T he direct or of t he st u d y  site or t he pers o n res p o nsi ble f or rec or d  kee pi n g  will ta ke 
meas ures t o e ns ure t hat t hese rec or ds are n ot l ost or discar de d d uri n g t he peri o d f or 
w hic h t he y are t o be st ore d, a n d s o t hat t he y ca n be prese nte d i n res p o nse t o re q uests.  
1)  T he da te of a p pr o val of t his I n vesti gati o nal Pr o d uct ( or, if de vel o p me nt is ter mi nate d, 
t he date 3 years after t he da y w he n n otificati o n of ter mi nati o n of de vel o p me nt is 
recei ve d fr o m t he S p o ns or) 
2)  T he da te 3 years after t he disc o nti n uati o n or  c o m pleti o n  of t he st u d y  
 
I n or der t o res p o n d t o t he wit h dra wal of c o nse nt f or l o n g-ter m st ora ge ( ba n ki n g) of 
s peci me ns f or ge n o mic a n d ge netic a nal ysis b y s u bjects after t he c o m pleti o n of t he st u d y, 
t he st u d y site will st ore t he s u bject scree ni n g list f or u p t o 2 0 years after t he c o m pleti on 
of t he st u d y.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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1 5. 1 0. 2. 3  S p o ns or  
T he S p o ns or will st ore  t he d oc u me nts or rec or ds relati n g t o t he cli nical st u d y t hat are t o 
be st ore d u ntil t he later of t he date 1) or 2) bel o w.  
1)  T he date 5 years after t he da y of a p pr o val relati n g t o t his st u d y ( or, if de vel o p me nt is 
ter mi nate d, t he date 3  years after t he da y w he n t he decisi o n t o ter mi nate de vel o p me nt 
is ma de ), or t he date of c o m pleti o n of ree xa mi nati o n, w hic he ver is later 
2)  T he date 3 years after t he disc o nti n uati o n  or c o m pleti o n of t he st u d y  
 
1 5. 1 1  Di rect Access t o S o urce  D oc u me nts  
W he n m o nit ori n g or a u diti n g is c o n d ucte d b y t he S p o ns or or re vie ws are c o n d ucte d b y 
t he re g ulat or y a ut h orit y or I R B, t he direct or of t he st u d y site a n d i n vesti gat or will pr o vi de 
direct access t o all rec or ds relati n g t o t he st u d y, i ncl u di n g s o urc e d oc u me nts.  T he 
S p o ns or will c o n d uct m o nit ori n g a n d a u diti n g, a n d directl y access rec or ds relati n g t o t he 
st u d y, i ncl u di n g s o urce d oc u me nts, at t he st u d y site, t o c o nfir m t hat t he st u d y is bei n g 
c o n d ucte d a p pr o priatel y a n d t hat t he relia bilit y of data is  t h or o u g hl y e ns ure d.  T he 
S p o ns or will h ol d pri or disc ussi o ns wit h t he i n vesti gat or a b o ut t he met h o d f or direct 
access t o s o urce d oc u me nts.  
 
1 5. 1 2  Or g a niz ati o n  
T he or ga nizati o n f or t his st u d y is as f oll o ws.  Eac h assi g ne d pers o n will w or k i n 
acc or da nce wit h t he Pr oce d ure f or Assi g n me nt of t he St u d y Or ga nizati o n at Daiic hi 
Sa n k y o C o ., Lt d. 
 
1 5. 1 2. 1  S p o ns or  
Daiic hi Sa n k y o C o., Lt d.  
3 -5 -1  Ni h o n bas hi -h o nc h o , C h u o-k u, To k y o 1 0 3 -8 4 2 6  
 
Vice p resi de nt of  clinical st u d y d e part me nt : 
 Vice Presi de nt, Cli nical De vel o p me nt 
De part me nt  
M o nit or (re prese ntati ve):  
 Cli nical St u d y Lea der, Cli nical 
De vel o p me nt De part me nt  
1 -2 -5 8 Hir o mac hi, S hi na ga wa -k u, To k y o 1 4 0 -8 7 1 0  
 
 
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Pers o n res p o nsi ble f or st u d y dr u g ma na ge me nt:  
Cli nical S u p pl y Ma na ge me nt De part me nt  
Pers o n res p o nsi ble f or P K a nal ysis:  
 Cli nical P har mac ol o g y De part me nt 
Pers o n res p o nsi ble f or c o nce ntrati o n meas ure me nts:  
 Bi o mar ker De part me nt 
S u b -F u ncti o nal Lea d of Data Ma na ge m e nt: 
 Bi ostatistics & Data Ma na ge me nt 
De part me nt  
S u b -F u ncti o nal Lea d of Bi ostatistics : 
Bi ostatistics & Data Ma na ge me nt 
De part me nt  
P ers o n res p o nsi ble f or q ualit y ma na ge me nt:  
 De vel o p me nt F u ncti o n 
Pers o n res p o ns i ble f or safet y i nf or mati o n a n d strate g y (strate g y): 
 P har mac o vi gila nce De part me nt 
Pers o n res p o nsi ble f or safet y i nf or mati o n a n d strate g y ( assess me nt ): 
 P har mac o vi gila nce De part me nt 
Pers o n res p o nsi ble f or ge n o mic a n d ge netic a nal ysis:  
 Bi o mar ker De part me nt 
Pers o n res p o nsi ble f or ba n ki n g  of ge netic a nal ysis s peci me ns : 
 Bi o mar ker De part me nt 
Office f or e n q uiries a b o ut ba n ki n g  of ge netic a nal ysis s peci me ns : 
Bi o mar ker De part me nt  
1 -2 -5 8 Hir o mac hi, S hi na ga w a-k u, To k y o 1 4 0 -8 7 1 0  
 
1 5. 1 2. 2  Me dic al E x perts  
 T he Car di o vasc ular I nstit ute 
3 -2 -1 9 Nis hi -Aza b u, Mi nat o -k u, To k y o 1 0 6 -0 0 3 1  
 
 De part me nt of Geriatric Me di ci ne, Gra d uate Sc h o ol of 
Me dici ne, T he U ni versit y of To k y o  
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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7 4  
De part me nt  
Ka ya bac h o First B uil di n g, 1 -1 7 -2 1, S hi n ka wa, C h u o -k u, To k y o 1 0 4 -0 0 3 3  
R ole:  To perf or m m o nit ori n g acti vities acc or di n g t o t he S p o ns or ’s sta n dar d o perati n g 
pr oce d ure s, base d o n a n o uts o urci n g c ontract.  
 
1 5. 1 2. 7  St u d y Sites a n d I n vesti g at ors  
T he a d dresses a n d tele p h o ne n u m bers of t he st u d y sites a n d t he na mes a n d j o b titles of 
t he i n vesti gat ors are as s h o w n i n Attac h me nt 1. 
R ole:  Base d o n disc ussi o n wit h t he S p o ns or, t o a gree o n t he pr ot oc ol, pre pare a n d 
a me n d t he i nf or me d c o nse nt f or m, select s u bjects a n d o btai n c o nse nt, i nstr uct a n d 
o versee t he s u bi n vesti gat ors a n d st u d y staff, pr o vi de d oc u me nts a n d i nf or mati o n, 
c o o perate wit h m o nit ori n g a n d a u diti n g, re p ort de viati o ns fr o m or c ha n ges t o t he 
pr ot oc ol, re p ort a d verse e ve nts, pre pare case re p ort f or ms, a n d st ore d oc u me nt s or  
rec or ds relati n g t o t he cli nical st u d y. 
 
1 5. 1 2. 8  C o or di n ati n g C o m mittee  
C hair of C o or di nati n g C o m mittee:  
, A d va nce d Arrh y t h mia T hera peutic Bra nc h, 
Di visi o n o f Car di ol o g y, Saisei kai K u ma m ot o H os pital  
5 -3 -1 C hi ka mi, Mi na mi -k u, K u ma m ot o Cit y, K u ma m ot o 8 6 1 -4 1 9 3  
 
C o or di nati n g C o m mittee  Me m bers  
 Tosei Ge neral H os pital 
1 6 0 Nis hi oi wa ke -c h o, Set o Cit y, Ai c hi 4 8 9 -8 6 4 2  
 
 K y ot o Me dical Ce nter, Nati o nal H os pital 
Or ga nizati o n  
1 -1 F u ka k usa M u kai hatac h o, F us hi mi -k u, K y ot o Cit y, K y ot o 6 1 2 -8 5 5 5  
 
 Osa ka Ge neral Me dical Ce nter, Osa ka Prefect ural H os pital 
Or ga nizati o n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
7 5  
3 -1 -5 6 Ba n dai Hi gas hi, S u mi y os hi -k u, Osa ka Cit y 5 5 8 -8 5 5 8  
 
 De part me nt of Car di o vasc ular Me dici ne, Gra d uate Sc h o ol of 
Ni p p o n Me dical Sc h o ol  
1 -1 -5 Se n da gi, B u n k y o -k u, To k y o 1 1 3 -8 6 0 3  
 
 De part me nt of Car di ol o g y, Na ha Cit y H os pital 
2 -3 1 -1 F ur uji ma, Na ha -s hi, O ki na wa 9 0 2-8 5 1 1  
 
R ole:  Has res p o nsi bilit y f or c o or di nati n g wit h i n vesti gat ors at st u d y sites t o c o n d uct t he 
st u d y.  C o n d ucts c oor di nati o n w he n t here are q uesti o ns at st u d y sites a b o ut t he 
i nter pretati o n of details s uc h as t he met h o d of c o n d uct or assess me nt i n t he 
pr ot oc ol.  
 
1 5. 1 2. 9  I n de pe n de nt Bi ost atistici a n 
P A R E X E L I nf or matics  
Pers o n res p o nsi ble: 
 Se ni or Statistical Desi g n & Trial S u p plies 
C o ns ulta nt  
Castle W harf, 4 Ca nal Street, N otti n g ha m, N G 1 7 E H, U K  
R ole:  To pre pare a n d ma na ge t he ra n d o mizati o n sc he d ule f or assi g ni n g s u bjects base d 
o n t he s pecificati o ns i n t he pr ot oc ol.  
 
1 5. 1 2. 1 0  Ce ntr al L a b or at or y  
1 5. 1 2. 1 0. 1  Dr u g C o nc e ntr ati o n Me as ure me nt  
Q 2 S ol uti o ns  
Pers o n res p o nsi ble: 
St u d y Direct or Bi oa nal ysis  
1 9 Br o w n R oa d It haca, N Y 1 4 8 5 0, U S A  
R ole:  To meas ure a n d st ore  s peci me ns se nt b y S R L, I nc., base d o n a c o ntract wit h t he 
S p o ns or.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
7 6  
1 5. 1 2. 1 0. 2  L a b or at or y Me as ure me nts, Me as ure me nt of P h ar m ac o d y n a mic 
I n dic at ors a n d C ollecti o n a n d Me as ure me nt of Bi o m ar ker S peci me ns, 
a n d C ollecti o n of S peci me ns f or Pl as m a Dr u g C o nce ntr ati o n 
Me as ure me nt a n d Cli nic al S peci me n s f or Ge n o mic a n d Ge netic A n al ysis 
C o ntract or: S R L Me disearc h I nc.  
Pers o n res p o nsi ble: 
 De vel o p me nt B usi ness Di visi o n  
1 0 F S hi nj u k u -I-La n d To wer, 6 -5 -1 Nis hi S hi nj u k u, S hi nj u k u -k u, To k y o 1 6 3 -1 3 1 0  
 
Testi n g la b orat or y: S R L, I nc. 
Pers o n res p o nsi ble: 
 Testi n g Di visi o n  
2 -1 -1 Nis hi S hi nj u k u, S hi nj u k u -k u, To k y o 1 6 3 -0 4 0 9  
R ole:  To c ollect, se n d, st ore, a n d meas ure s peci me ns pr o vi de d b y  st u d y sites, base d o n a 
c o ntract wit h t he S p o ns or.  
 
1 5. 1 2. 1 0. 3  C o ntr act or f or St or a ge a n d M a n a ge me nt of Cli nic al S peci me ns f or 
Ge n o mic a n d Ge netic A n al ysis  
S R L Me disearc h I nc.  
Pers o n res p o nsi ble:  
 Cli nical St u d y S u p p ort De part me nt 
1 0 F, S hi nj u k u I -L a n d -To wer, 6 -5 -1 Nis hi S hi nj u k u, S hi nj u k u -k u, To k y o 1 6 3 -1 3 1 0  
R ole:  To perf or m tas ks s uc h as e xtracti n g D N A fr o m cli nical s peci me ns (s uc h as bl o o d) 
f or ge n o mic a n d ge netic a nal ysis a n d ma na gi n g t he st ora ge ( ba n ki n g) of 
s peci me ns, a n d dis p osi n g of t he m  
 
1 5. 1 2. 1 1  Cli nic al Effic ac y E ve nt C o m mittee  
 K y us h u U ni versit y Fac ult y of Me dical Scie nces 
3 -1 -1 Mai das hi, Hi gas hi -k u, F u k u o ka Cit y, F u k u o ka 8 1 2 -8 5 8 2  
 
 Ce nter of Car di o vasc ul ar Disease , K ur u me U ni versit y 
H os pital  
6 7 Asa hi mac hi, K ur u me Cit y, F u k u o ka 8 3 0 -0 0 1 1  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
7 7  
 
R ole:  To ma ke a fi nal assess me nt o n efficac y e ve nts acc or di n g t o a pr oce d ure s pecifie d 
se paratel y, as c o m mittee me m bers w h o are i n de pe n de nt fr o m t he S p o n s or, 
i n vesti gat or, or c o or di nati n g i n vesti gat ors. 
 
1 5. 1 2. 1 2  Cli nic al Blee di n g E ve nt C o m mittee  
 I nter nati o nal U ni versit y of Healt h a n d Welfare 
Sa n n o H os pital, 8 -1 0 -1 6 A kasa ka, Mi nat o -k u, To k y o 1 0 7 -0 0 5 2  
 
 To k y o Wo me n’s 
Me dical U ni versit y H os pital  
8 -1 Ka wa d ac h o, S hi nj u k u -k u, To k y o 1 6 2 -8 6 6 6  
 
R ole:  To ma ke a fi nal assess me nt o n blee di n g  e ve nts acc or di n g t o a pr oce d ure s pecifie d 
se paratel y, as c o m mitt ee me m bers w h o are i n de pe n de nt fr o m t he S p o ns or, 
i n vesti gat or, or c o or di nati n g i n vesti gat ors. 
 
1 5. 1 2. 1 3  S afet y D at a M o nit ori n g C o m mittee  
Saisei kai To ya ma H os pita l 
3 3 -1 K us u n o ki, To ya ma Cit y, To ya ma 9 3 1 -8 5 3 3  
 
 Osa ka Nati o nal H os pital, Nati o nal H os pital Or ga nizati o n 
2 -1 -1 4 H oe nza ka, C h u o -k u, Osa ka Cit y 5 4 0 -0 0 0 6  
 
De part me nt of Cere br o vasc ular Me dici ne a n d Ne ur ol o g y, 
K y us h u Me dical Ce nter , Nati o nal H os pital Or ga nizati o n  
1 -8 -1 Ji g y o ha ma, C h u o -k u, F u k u o ka Cit y, F u k u o ka 8 1 0 -8 5 6 3  
 
 Bi ostatistics a n d Cli nical E pi de mi ol o g y , U ni versit y of 
To ya ma Gr a d uate Sc h o ol of Me dici ne a n d P har mace utical Scie nces  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
7 8  
2 6 3 0 S u gita ni, To ya m a Cit y 9 3 0 -0 1 9 4  
 
R ole:  To m o nit or safet y data as necessar y, c o nsi der matters s uc h as w het her t he cli nical 
st u d y ca n be c o nti n ue d a n d t he nee d f or c ha n ges t o t he st u d y pr ot oc ol, a n d ma ke 
rec o m me n dati o ns t o t he S p o ns or, acc or di n g t o a pr oce d ure s pecifie d se paratel y, 
wit h c o m mittee me m bers w h o are i n de pe n de nt fr o m t he S p o ns or, i n vesti gat or, or 
c o or di nati n g i n vesti gat ors.  
 
1 5. 1 2. 1 4  De p art me nt Res p o nsi ble f or A u dit  
R & D & P V Q ualit y Ass ura nce De part me nt , Q ualit y & Safet y Ma na ge me nt Di visi o n, 
Daiic hi Sa n k y o C o., Lt d.  
Pers o n res p o nsi ble: 
 
1 -2 -5 8 Hir o mac hi, S hi na ga wa -k u, To k y o 1 4 0 -8 7 1 0  
R ole:  To perf or m G C P a u dits.  
 
1 5. 1 3  E mer ge nc y C o nt act I nf or m ati o n  
Daiic hi Sa n k y o E mer ge nc y Ce nter, 2 4 h o urs a da y, 3 6 5 da ys a year  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
7 9  
1 6.  R E F E R E N C E S  
1)   
G o A S, H yl e k E M, P hilli ps K A, et al. Pre vale nce of dia g n ose d atrial fi brillati o n i n 
a d ults: nati o nal i m plicati o ns f or r h yt h m ma na ge me nt a n d str o ke pre ve nti o n: t he 
A n Tic oa g ulati o n a n d Ris k Fact ors i n Atrial Fi brillati o n ( A T RI A) St u d y.  J A M A. 
2 0 0 1; 2 8 5( 1 8): 2 3 7 0 -5.  
2)   
Wolf P A, A b b ott R D, Ka n nel W B. Atrial fi brillati o n as a n i n de pe n de nt ris k fact or 
f or str o ke: t he Fra mi n g ha m S t u d y. Str o ke. 1 9 9 1; 2 2( 8): 9 8 3-8.  
3)   
Ga ge B F, Water ma n A D, S ha n n o n W, et al.  Vali dati o n of cli nical classificati o n 
sc he mes f or p re dicti n g str o ke: res ults fr o m t he Nati o nal Re gistr y of Atrial 
Fi brillati o n. J A M A. 2 0 0 1; 2 8 5( 2 2): 2 8 6 4 -7 0.  
4)   
Ca m m AJ, Li p G Y, De Cateri na  R, et al.  2 0 1 2 f oc use d u p date of t he E S C 
G ui deli nes f or t he ma na ge me nt of atrial fi brillati o n: a n u p date of t he 2 0 1 0 E S C 
G ui deli nes f or t he ma na ge me nt of atrial fi brillati o n . De vel o pe d wit h t he s pecial 
c o ntri b uti o n of t he E ur o pea n Heart R h yt h m Ass ociati o n.  E ur Heart J. 
2 0 1 2; 3 3( 2 1): 2 7 1 9 -4 7.  
5)   
I n o ue H, F uji ki A, Ori gasa H, et al. Pre vale nce of atrial fi brillati o n i n t he ge ner al 
p o p ulati o n of Ja pa n: a n a nal ysis base d o n peri o dic healt h e xa mi nati o n. I nt J Car di ol. 
2 0 0 9; 1 3 7( 2): 1 0 2 -7.  
6)   
T he Ja pa nese Circ ulati o n S ociet y et al. G ui deli nes  f or Dia g n osis  a n d  Treat me nt  of  
Car di o vasc ular  Diseases  ( 2 0 1 2 J oi nt Wor ki n g Gr o u ps Re p ort). G ui del i nes f or 
P har mac ot hera p y of Atrial Fi brillati o n  ( 2 0 1 3 Re visi o n); 2 0 1 3. 
7)   
Ja n uar y C T, Wa n n L S, Al pert J S, et al. 2 0 1 4 A H A/ A C C/ H R S g ui deli ne f or t he 
ma na ge me nt of patie nts wit h atrial fi brillati o n: a re p ort of t he A merica n C olle ge of 
Car di ol o g y/ A merica n Heart Ass ociati o n Tas k F orce o n practice g ui deli nes a n d t he 
Heart R h yt h m S ociet y. Circ ulati o n. 2 0 1 4; 1 3 0( 2 3):e 1 9 9 -2 6 7.  
8)   
A ka o M, C h u n Y H, Wa d a H, et al. C urre nt stat us of cli nical bac k gr o u n d of patie nts 
wit h atrial fi brillati o n i n a c o m m u nit y -base d s ur ve y: t he F us h i mi A F Re gistr y. J 
Car di ol. 2 0 1 3; 6 1( 4): 2 6 0 -6.  
9)   
Ya mas hita Y, Ha mata ni Y, Esat o M, et al. Cli nical c haracteristics a n d o utc o mes i n 
e xtre me  el derl y (a ge ≥8 5) Ja pa nese patie nts wit h atrial fi brillati o n: T he F us hi mi A F 
Re gistr y.  C H E S T -1 5 -1 0 9 5.  
1 0)  M o nte S, Macc hia A, Pelle gri ni F, et al. A ntit hr o m b otic treat me nt is str o n gl y 
u n der use d des pite re d uci n g o verall m ortalit y a m o n g hi g h -ris k el derl y patie nts 
h os pitalize d wit h atrial fi brillati o n. E ur Heart J. 2 0 0 6; 2 7( 1 8): 2 2 1 7 -2 3.  
1 1)  H yle k E M, D’ A nt o ni o J, E va ns -M oli na C, et al. Tra nslati n g t he res ults of 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
8 0  
ra n d o mize d trials i nt o cli nical practice: t he c halle n ge of warfari n ca n di dac y a m o n g 
h os pitalize d el derl y pat ie nts wit h atrial fi brillati o n. Str o ke. 2 0 0 6; 3 7( 4): 1 0 7 5-8 0.  
1 2)  Ba hri O, R o ca F, Lec ha ni T, et al. U n der use of oral a ntic oa g ulati o n f or i n di vi d uals 
wit h atrial fi brillati o n i n a n ursi n g h o me setti n g i n Fra nce: c o m paris o ns of resi de nt 
c haracteristics a n d p h ysic ia n attit u de. J A m Geriatr S oc. 2 0 1 5; 6 3( 1): 7 1-6.  
1 3)  Hart R G, Di e ner H C, Ya n g S, et al. I ntracra nial he m orr ha ge i n atrial fi brillati o n 
patie nts d uri n g a ntic oa g ulati o n wit h warfari n or da bi gatra n: t he R E -L Y trial. Str o ke. 
2 0 1 2; 4 3( 6): 1 5 1 1 -7.  
1 4)  Patel M R, Ma haffe y K W, Gar g J, et al. Ri var o xa ba n vers us warfari n i n n o n val v ular 
atrial fi brillati o n. N E n gl J Me d. 2 0 1 1 ; 3 6 5: 8 8 3-9 1 . S u p ple me ntar y A p pe n di x; 
p. 1 -2 3.  
1 5)  Gr a n ger C B, Al e xa n der J H, Mc M urra y JJ, et al. A pi xa ba n vers us warfari n i n 
patie nts wit h atrial fi brillati o n. N E n gl J Me d. 2 0 1 1; 3 6 5( 1 1): 9 8 1 -9 2.  
1 6)  C o n n oll y SJ, Ei kel b o o m J, J o y ner C, et al. A pi xa ba n i n patie nts wit h atrial 
fi brillati o n. N E n gl J Me d. 2 0 1 1; 3 6 4( 9): 8 0 6-1 7.  
1 7)  Gi u glia n o R P, R uff C T, Bra u n wal d E, et al. E d o xa ba n vers us warfari n i n patie nts 
wit h atrial fi brill ati o n. N E n gl J Me d. 2 0 1 3 ; 3 6 9: 2 0 9 3-1 0 4 . S u p ple me ntar y 
A p pe n di x; p. 1 -3 3.  
1 8)  Yo u JJ, Si n ger D E, H o war d P A, et al. A ntit hr o m b otic thera p y f or atrial fi brillati o n: 
antit hr o m b otic thera p y a n d p re ve nti o n of thr o m b osis, 9t h e d: A merica n C olle ge of 
C hest P h ysicia ns E vi de nce -Base d Cli nical Practice G ui deli nes. C hest. 2 0 1 2; 1 4 1( 2 
S u p pl):e 5 3 1 S -7 5 S.  
1 9)  Ga ge B F, Ya n Y, Milli ga n P E, et al. Cli nical classificati o n sc he mes f or pre dicti n g 
he m orr ha ge:  res ults fr o m t he Nati o nal Re gistr y of Atrial Fi brillati o n ( N R A F). A m 
Heart J. 2 0 0 6; 1 5 1 ( 3): 7 1 3-9.  
2 0)  Fa n g M C, G o A S, C ha n g Y, et al. A ne w ris k sc he me t o pre dict warfari n -ass ociate d  
he m orr ha ge:  t he A T RI A (a ntic oa g ulati o n a n d ris k fact ors i n atrial fi brillati o n) st u d y. 
J A m C oll Car di ol. 2 0 1 1; 5 8 ( 4): 3 9 5-4 0 1.  
2 1)  Li p G Y, Fris o n L, Hal peri n J L, et  al. C o m parati ve vali dati o n of a n o vel ris k sc ore 
f or pre dicti n g blee di n g ris k i n a ntic oa g ulate d patie nts wit h atrial fi brillati o n: t he 
H A S -B L E D  ( h y perte nsi o n, a b n or mal re nal/li ver f u ncti o n, str o ke, blee di n g hist or y 
or  pre dis p ositi o n, la bile  I N R, el derl y, dr u gs/alc o h ol c o nc o mita ntl y) sc ore. J A m 
C oll Car di ol. 2 0 1 1; 5 7 ( 2): 1 7 3-8 0.  
2 2)  La ne D A, Li p G Y. U se of C H A 2D S 2-V A Sc a n d H A S -B L E D sc ore t o ai d decisi o n 
ma ki n g f or t hr o m b o pr o p h yla xis i n n o n val v ular atrial fi brillati o n. Circ ulati o n. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a


 
   
Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
Versi o n 0 1 .0 8 . 0 0 0, 1 7  Ma y  2 0 1 9  
C o nfi de ntial  
8 1  
2 0 1 2 ; 12 6( 7) :8 6 0 -5 . 
2 3)  Ke nji To ba, Jir o O k oc hi, Tai Ta ka has hi. De vel o p me nt of a p orta ble fall ris k i n de x 
f or el derl y pe o ple li vi n g i n t he c o m m u nit y. Ja pa nese J o ur nal of Geriatrics. 
2 0 0 5; 4 2: 3 4 6 -5 2.  
2 4)  Researc h F u n di n g f or L o n ge vit y Scie nces fr o m Nati o nal Ce nter f or Geriatrics a n d 
Ger o nt ol o g y : 2 0 1 4 ge neral re p ort : Researc h i nt o fact ors relati n g t o t he pr o gressi o n 
of frailt y. ( 2 5 -1 1) [I nter net]. 2 0 1 6 J u n [cite d 2 0 1 6 J u n]. Availa ble fr o m:  
htt p:// w w w. nc g g. g o.j p/ nc g g -ke n k y u/ ka dai 2 6. ht ml  
2 5)  H y u ma Ma kiza k o, Hir o y u ki S hi ma da, et al. I m pact of p h ysical frailt y o n disa bilit y  
i n c o m m u nit y-d welli n g ol der a d ults:a pr os pecti ve c o h ort st u d y. B MJ O p e n 
2 0 1 5; 5:e 0 0 8 4 6 2. d oi: 1 0. 1 1 3 6/ b mj o pe n -2 0 1 5 -0 0 8 4 6 2 . 
2 6)  Mi nistr y of E d ucati o n, C ult ure, S p orts, Scie nce, a n d T ec h n ol o g y. O ver vie w of 
res ults of 2 0 14  s ur ve y of stre n gt h a n d m ot or a bilit y. T he relati o ns hi p of A D L 
(acti vities of dail y life tests), stre n gt h a n d m ot or a bilit y t o s p orts a n d e xercise 
ha bits  i n el derl y pe o ple (a ge d 6 5 t o 7 9 years) [I nter net]. 2 0 1 5 Oct [cite d 2 0 1 6 J u n]. 
Availa ble fr o m: 
htt p:// w w w. me xt. g o.j p/c o m p o ne nt/ b _ me n u/ ot her/ _ _ics Files/afiel dfile/ 2 0 1 5/ 1 0/ 2 2/ 1
3 6 2 6 8 7 _ 0 7. p df  
2 7)  Mi nistr y of E d ucati o n, C ult ure, S p orts, Scie nce a n d Tec h n ol o g y , Mi nistr y of Healt h, 
La b o ur a n d Welfare, a n d Mi nistr y of Ec o n o m y, Tra de a n d I n d ustr y. Et hical 
G ui deli nes f or H u ma n Ge n o me/ Ge ne A nal ysis Researc h  ( pre pare d o n 2 9 Mar 2 0 0 1, 
f ull y re vise d o n 2 8 Dec 2 0 0 4, partiall y re vise d o n  2 9  J u n 2 0 0 5, partiall y re vise d o n 
0 1 Dec 2 0 0 8, f ull y re vise d o n 0 8 Fe b 2 0 1 3 , a n d partiall y re vise d o n 25 N o v 2 0 1 4 ). 
2 8)  Mi nistr y of E d ucati o n, C ult ure, S p orts, Scie nce a n d Tec h n ol o g y a n d Mi nistr y of 
Healt h, La b o ur a n d Welfare . Et hical G ui deli nes f or Me dical a n d Healt h Researc h 
I n v ol vi n g H u ma n S u bjects ( pre pare d o n 2 2 Dec 2 0 1 4 ). 
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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A T T A C H M E N T  
Attac h me nt  1 List of St u d y Sites a n d I n vesti gat ors  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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A P P E N DI C E S  
A p pe n di x 1 Falli n g Ris k  
A p pe n di x 2 Falli n g Sc ores  
A p pe n di x 3 Frailt y Assess me nt  
A p pe n di x 4 O ne -le g S ta n di n g T est wit h E yes O pe n  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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A p pe n di x 1 Falli n g Ris k  
S ur ve y t he f oll o wi n g ite ms a n d e nter t he m o n t he case re p ort f or m . 
 
1.  Hist or y of falli n g  
2.  L o wer li m b stre n gt h  
3.  P o or bala nce  
4.  Re d uce d c o g niti ve f u ncti o n  
5.  Ort h ostatic h y p ote nsi o n  
6.  Use of ps yc h otr o pic dr u gs  
7.  Se vere art hritis  
8.  Di zzi ness  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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A p pe n di x 2 Falli n g Sc ore 2 3)  
S ur ve y t he f oll o wi n g  ite ms a n d e nter t he m o n t he case re p ort f or m. 
 
1.  Has t he s u bject falle n i n t he past year? ( yes/ n o)  
If s o, h o w ma n y ti mes? (    ti mes/ year) 
2.  D oes t he s u bject s o meti mes tri p or st u m ble? ( yes/ n o)  
3.  Ca n t he s u bject asce n d or desce n d stairs wit h o ut h ol di n g a ha n dra il? ( yes/ n o) 
4.  Has t he s u bject ’s wal ki n g s pee d decrease d? ( yes/ n o) 
5.  Ca n t he s u bject fi nis h cr ossi n g t he r oa d at a pe destria n cr ossi n g w hile t he si g nal is 
gree n? ( yes/ n o)  
6.  Ca n t he s u bject c o nti n ue wal ki n g f or a b o ut 1 kil o meter wit h o ut a brea k?  ( yes/ n o) 
7.  Ca n t he s u bject sta n d o n o ne le g f or a b o ut 5 sec o n ds?  ( yes/ n o) 
8.  D oes t he s u bject use a ca ne?  ( yes/ n o) 
9.  Ca n t he s u bject wri n g o ut a t o wel?  ( yes/ n o) 
1 0.  D oes t he s u bject ha ve dizzi ness or fai nt ness? ( yes/ n o)  
1 1.  D oes t he s u bject ha ve a st o o pe d or r o u n de d bac k? ( yes/ n o)  
1 2.  D oes t he s u bject ha ve k nee pai n?  ( yes/ n o) 
1 3.  D oes t he s u bject ha ve vis ual dist ur ba nce?  ( yes/ n o) 
1 4.  D oes t he s u bject ha ve heari n g dist ur ba nce? ( yes/ n o)  
1 5.  D oes t he s u bject ha ve f or getf ul ness t hat c o ncer ns hi m/ her?  ( yes/ n o) 
1 6.  Is t he s u bject a n xi o us a b o ut t he p ossi bilit y of falli n g?  ( yes/ n o) 
1 7.  D oes t he s u bject recei ve 5 or m ore dr u gs e ver y da y?  ( yes/ n o) 
1 8.  D oes t he s u bject e x perie nce a se nsati o n of dar k ness at h o me?  ( yes/ n o) 
1 9.  Ar e t here o bstacles t hat t he s u bject m ust a v oi d i n t he c orri d or, li vi n g r o o m or 
e ntr y wa y? ( yes/ n o)  
2 0.  Ar e t here  ste ps i n t he s u bject’s h o use? ( yes/ n o) 
2 1.  D oes t he s u bject ha ve t o use ste ps? ( yes/ n o)  
2 2.  D oes t he s u bject wal k al o n g stee p sl o pes near t o his/ her h o me i n his/ her dail y life? 
( yes/ n o) 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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A p pe n di x 3 Frailt y Assess me nt 2 4) ,2 5) 
S ur ve y t he f oll o wi n g ite ms a n d e nter t he m o n t he case re p ort f or m . 
 
Ite m 
Details  
Wei g ht l oss 
If t he s u bject a ns wers “yes ” t o t he q uesti o n “Ha ve y o u ( u ni nte nti o nall y) 
l ost 2 t o 3 k g or m ore  i n t h e p ast 6 m o nt hs? ” 
E x ha usti o n  
If t he s u bject a ns wers “yes ” t o t he q uesti o n “I n t he last 2 wee ks, h a v e 
y o u felt tire d f or n o reas o n? ” 
A cti vit y  le vel 
If t he s u bject a ns wers “I d o n ot d o e xercise” t o b ot h of t h e f oll o wi n g 
q uesti o n s: 
A p pr o xi matel y h o w ma n y da ys per wee k  d o y o u  e n g a ge i n l o w le vels of 
p h ysical e xercise  (i ncl u di n g far m w or k)? 
A p pr o xi matel y h o w ma n y da ys per wee k d o y o u  e n g a ge i n m o derate 
le vels of p h ysical e xercise or s p orts (i ncl u di n g far m w or k)? 
Gri p stre n gt h  
( Meas ure d i n  t he d o mi n a nt h a n d) < 2 6 k g f or me n  or < 1 8 k g f or w o me n 
C o mf orta bl e  wal ki n g 
s pee d 
( Meas ure t h e ti me ta ke n t o wal k a meas ure me nt secti o n wit h a le n gt h of 
5 m, wit h a lea d -i n secti o n of 1 m bef ore a n d after t h e meas ure d 
secti o n.)  If t h e s pe e d is < 1 m/s.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol n u m ber: D U 1 7 6 b -C -J3 1 6  
 
   
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A p pe n di x 4 O ne -le g S ta n di n g T est wit h E yes O pe n 2 6) 
C o n d uct a test acc or di n g t o t he f oll o wi n g pr oce d ure, a n d e nter t he res ults of t he test o n 
t he case re p ort f or m. 
 
1.  Pre parati o n  
St o p watc h  
 
2.  Met h o d  
I. 
T he s u bject is t o ta ke t he test i n bare feet.  
II. T he s u bject places b ot h ha n ds o n his/ her hi ps, a n d sta n ds o n o ne le g at a ti me, 
tr yi n g eac h le g t o c hec k w hic h o ne is easiest t o sta n d o n. 
III. W he n t he s u bject has c h ose n a le g t o sta n d o n, he/s he p uts his/ her ha n ds o n 
his/ her hi ps, a n d u p o n bei n g t ol d t o “raise o ne le g, ” ass u mes a o ne -le g ge d sta nce. 
 
3.  Rec or ds  
I. 
Meas ure t he d urati o n of t he ti me f or w hic h t he s u bject mai ntai ns t he o ne -le g ge d 
sta nce. E n d t he test if t he s u bject c o nti n ues t o mai ntai n t he o ne -le g ge d sta nce f or 
1 2 0 sec o n ds.  
II. Rec or d ti mes i n sec o n ds, r o u n di n g d o w n fracti o ns of a sec o n d.  
III. C o n d uct t he test t wi ce a n d rec or d t he better sc ore o ut of t he t w o tests. (If t he first 
res ult is 1 2 0 sec o n ds, d o n ot c o n d uct t he test a sec o n d ti me.) 
 
4.  Preca uti o ns a b o ut c o n d ucti n g t he test.  
I. 
C o n d uct t he test o n a n o n -sli p flo or.  
II. D o n ot place o bjects near t he s u bject u n der g oi n g t he test. Av oi d l ocati o ns wit h 
stairs or sl o pes. 
III. Bef ore t he test, i nf or m t he s u bject u n der g oi n g t he test of t he f oll o wi n g.  
A)  T he tas k i n t his test is t o sta n d o n o ne le g f or as l o n g as p ossi ble.  
B)  T he sta nc e f or sta n di n g o n o ne le g is t o kee p t he k nee of t he s u p p orti n g le g 
strai g ht, a n d raise t he ot her le g u p s o t hat it d oes n ot t o uc h t he s u p p orti n g le g.  
C)  T he c o n diti o ns f or e n di n g t he test are:  
i. 
If t he le g bei n g lifte d u p t o uc hes t he gr o u n d or t he s u p p orti n g le g 
ii. If t he p ositi o n of t he s u p p orti n g le g s hifts 
iii. If t he s u bject ta kes o ne or b ot h ha n ds off his/ her hi ps. 
D)  Si nce sa yi n g “start” is e n o u g h t o ma ke s o me pe o ple l ose t heir bala nce, it is 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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better t o start b y sa yi n g “raise o ne le g” a n d meas ure t he ti me starti n g fr o m 
w he n t he s u bject sta n ds o n o ne le g.  
E)  T he pers o n d oi n g t he meas ure me nt will be rea d y t o s u p p ort t he s u bject 
u n der g oi n g t he test i m me diatel y if he/s he l oses his/ her bala nce.  
F)  T he c o n diti o ns f or e n di n g t he tests will be strictl y a d here d t o. It is a d visa ble 
to all o w t he s u bject u n derta ki n g t he test t o practice first.  
 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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