Conditions: Diabetic Peripheral Neuropathic Pain
Keywords: Diabetic Peripheral Neuropathic Pain
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 854
Healthy volunteers: no

Brief summary:
Investigate the efficacy and safety of DS-5565 in subjects with Diabetic Peripheral Neuropathic Pain (DPNP) in comparison to placebo

Detailed description:
\[Double Blind Phase\] The primary objective is to compare change in the Average Daily Pain Score(ADPS) from baseline to Week 14 in Asian subjects with DPNP receiving DS-5565 versus placebo.

\[Open Extension Phase\] The objective is to assess the long-term safety and efficacy of DS-5565 in subjects with DPNP.

Arms:
arm 1: placebo group (14 weeks) arm 2: DS-5565 15 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks fixed dose arm 3: DS-5565 20 mg, oral administration, Treatment period; 1-week titration and 13-weeks fixed dose arm 4: DS-5565 30 mg, oral administration, Treatment period; 2-weeks titration and 12-weeks fixed dose

Interventions: intervention 1: DS-5565 intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A N A SI A N, P H A S E 3 , M U L TI C E N T E R, 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 1 4 -W E E K S T U D Y O F 
D S -5 5 6 5 I N P A TI E N T S WI T H DI A B E TI C P E RI P H E R A L N E U R O P A T H I C 
P AI N  F O L L O W E D B Y A 5 2 -W E E K O P E N -L A B E L E X T E N SI O N  
 
 
 -F or D o u bl e -Bli n d St u d y -  
D S 5 5 6 5 - A-J 3 0 3 
 
 
V E R SI O N 6 . 0, 1 8 A pr  2 0 1 6 
 
 
D AII C HI S A N K Y O  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
I nf or m ati o n c o nt ai n e d i n t his d o c u m e nt is pr o prietar y t o D aii c hi S a n k y o.    T h e 
i nf or m ati o n is pr o vi d e d t o y o u i n c o nfi d e n ce, w hi c h is re q u est e d u n d er a n a gree d u p o n 
a n d si g n e d C o nfi d e nti alit y a n d Dis cl os ure A gree me nt.    D o n ot gi v e t his d o c u m e nt or 
a n y c o p y of it or r e v eal a n y pr o pri et ar y i nf or m ati o n c o nt ai n e d i n it t o a n y t hir d part y 
( ot h er t h a n t h os e i n y o ur or ga niz ati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d 
b y t h e C o nfi d e nti alit y a n d Discl os ur e A gree m e nt) wit h o ut t h e pri or writt e n p er missi o n of 
a n a ut h oriz e d r e pr es e nt ati v e o f D aii c hi S a n k y o.




Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
Versi o n  6. 0, 1 8  A pr  2 0 1 6 
Pa ge 3 of 1 0 1 
I N V E S TI G A T O R A G R E E M E N T 
 
A N A SI A N, P H A S E 3, M U L TI C E N T E R, 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 1 4 -W E E K S T U D Y O F D S - 5 5 6 5   
I N P A TI E N T S WI T H DI A B E TI C P E RI P H E R A L N E U R O P A T HI C P AI N 
F O L L O W E D B Y A 5 2 -W E E K O P E N -L A B E L E X T E N SI O N  
S p o ns or A p pr o v al: 
T his cli nical st u d y pr ot oc ol has bee n  re vie we d a n d a p pr o ve d b y t he Daiic hi Sa n k y o 
re pres e ntati ve liste d bel o w. 
    
 
  
 
 
 
 Pri nt N a me  / Si g n at ure   
 Pri nt N a me  / Si g n at ure 
 Pri nt N a me / Si g n at ure  
 
 
Cli nical St u d y Lea d, Cli nical 
De vel o p me nt De p art me nt, R & D 
Di visi o n, Daiic hi Sa n k y o C o., Lt d  
 
 
 
Vice Presi d e nt, Cli nical De vel o p me nt 
De p art me nt, Daiic hi Sa n k y o C o., Lt d   
Vice Presi d e nt, Asia  De vel o p me nt 
De p art me nt, Daiic hi Sa n k y o C o., Lt d   
 Title  
 Title  
 Title  
 
  
 
  
  
 
 
 D ate ( D D M M M Y Y Y Y)  
 D ate  ( D D M M M Y Y Y Y) 
 D ate ( D D M M M Y Y Y Y)  
 
I n vesti g at or’s Si g n at ure: 
I h a ve f ull y disc usse d t he o bjecti ves of t his st u d y a n d t he c o nte nts of t his pr ot oc ol wit h a 
S p o ns or’s re pres e ntati ve. 
I u n d ersta n d t hat i nf or m ati o n c o ntai ne d i n or pertai ni n g t o t his pr ot oc ol is c o nfi de ntial 
a n d s h o ul d n ot be discl ose d, ot her t ha n t o t h ose directl y i n v ol ve d i n t he e x ec uti o n or t he 
et hical re vie w of t he st u d y, wit h o ut writte n a ut h ori zati o n fr o m t he S p o ns or.    It is, 
h o we ver, p er missi ble t o pr o vi de i nf or mati o n t o a s u bject i n or der t o o btai n c o nse nt. 
I a gree t o c o n d uct t his st u d y acc or di n g t o t his pr ot oc ol a n d t o c o m pl y wit h its 
re q uire me nts, s u bject t o et hical a n d safet y c o nsi d erati o ns a n d g ui deli nes, a n d t o c o n d uct 
t he st u d y i n acc or d a nce wit h t he Declarati o n of H elsi n ki, I nter nati o nal C o nfere n ce o n 
Har m o nizati o n g ui deli nes o n G o o d Cli nical Practice (I C H E 6), a n d a p plica ble re gi o nal 
re g ulat or y r e q uire me nts. 
I a gree t o ma ke a vaila ble t o S p o ns or pers o n nel, t heir re prese ntati ves, a n d rele va nt 
re g ulat or y a ut h orities, m y s u bjects’ st ud y rec or ds i n or der t o verif y t h e data t hat I h a ve 
e ntere d i nt o t he case r e p ort f or ms.    I a m a ware of m y res p o nsi bilities as a Pri nci pal 
I n v esti gat or as pr o vi de d b y t he S p o ns or. 
I u n d ersta n d t hat t he S p o ns or ma y d eci de t o s us pe n d or pre mat urel y t er mi n ate t he st u d y 
at a n y ti me f or w h ate ver reas o n; s uc h a decisi o n will be c o m m u nicate d t o me i n writi n g.   
C o n versel y, s h o ul d I deci de t o wit h dra w fr o m e x ec uti o n of t he st u d y, I will c o m m u nicate 
m y i nte nti o n i m me diatel y i n writi n g t o t he S p o ns or.  
  
  
 
 
Pri nt N a me  
 
Si g n at ure  
 
  
  
 
 
Title  
 
D ate ( D D M M M Y Y Y Y)  
 
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 of 1 0 1 
P R O T O C O L S Y N O P SI S  
 
Pr ot o c ol N u m b er:  
D S 5 5 6 5 -A -J3 0 3  
I n v esti gati o n al Pr o d u ct: D S -5 5 6 5  
A cti v e 
I n gr e di e nt(s)/I N N: 
[( 1 R, 5 S, 6 S)-6 -(ami n o met h yl) -3 -et h yl bi c ycl o[ 3. 2. 0] h e pt -3 - 
e n -6 -yl] aceti c aci d m o n o b e nz e n es ulf o n at e  
St u d y Titl e:  
A n Asi a n, p h as e 3 , m ulti ce nt er, ra n d o miz e d, d o u bl e-bli n d, 
pl ace b o -c o ntr oll e d 1 4 -w ee k st u d y of D S- 5 5 6 5 i n pati e nts 
wit h di a b eti c p eri p h eral ne ur o p at h i c p ai n ( D P N P) f oll o w e d 
b y a 5 2 -w ee k o p e n -l a b el e xt e nsi o n 
St u d y P h as e:  
P h as e 3  
I n di cati o n U n d er 
I n v esti gati o n: 
D P N P  
St u d y O bj ecti v es:  
Pri m ar y o bj ecti v e:  
To c o m p are c h a n ge i n t h e Av era ge D ail y P ai n S c ore ( A D P S) 
fr o m bas eli n e t o Wee k 1 4 i n Asi a n s u bj ects wit h D P N P 
r ecei vi n g 1 0 m g BI D a n d 1 5 m g BI D of D S -5 5 6 5 vers us 
pl ace b o  
 
Sec o n dar y o bj ecti v es:  
• 
To c o m p are c h a n ge i n t h e A D P S fr o m b as eli n e t o Wee k 
1 4 i n Asi a n s u bj ects wit h D P N P recei vi n g 1 5 m g Q D of 
D S - 5 5 6 5 v ers us  pl ace b o  
• 
To c o m p are t h e A D P S  res p o n der rat e ( pr o p orti o n of 
s u bj ects wit h ≥ 3 0 %, a n d ≥ 5 0 % re d u cti o n fr o m b as eli n e 
t o Wee k 1 4) b et w ee n eac h ar m  of D S -5 5 6 5 a n d pl ace b o  
• 
To e v al u at e t h e effect of D S -5 5 6 5 o n a d diti o n al p ai n 
q u esti o n n aires, i n cl u di n g t h e S h ort -F or m M c Gill Pai n 
Q u esti o n n aire ([ S F -M P Q]: s e ns or y, affecti v e a n d t ot al 
s u bs cal es, Vis u al A n al o g S cal e [ V A S], a n d pres e nt p ai n 
i nt e nsit y) a n d t h e m o difi e d Bri ef P ai n I n v e nt or y ( S h ort 
F or m) ([ B PI-S F ]: p ai n i nte nsit y, f u n cti o n alit y, a n d 
i m p act of p ai n) 
• 
To ass ess t h e effect of D S -5 5 6 5 o n q u alit y of life  ( Q O L), 
m o o d a n d sl ee p, p ati e nt i m pressi o ns i n p ai n , a n d 
s y m pt o ms 
• 
To c oll ect bl o o d s a m pl es f or p h ar m ac o ki n eti c a n al ys es  
• 
To c h aract eriz e t h e s afet y a n d t ol era bilit y of D S - 5 5 6 5, 
bas e d o n t h e i nci d e n ce of a d v e rse e v e nts ( A Es), 
dis c o nti n u ati o ns d ue t o A Es, c h a n ges i n p h ysi cal 
fi n di n gs, a n d res ults of s afet y m o nit ori n g 
St u d y D esi g n:  
M ul ti n ati o n al, ra n d o miz e d, d o u bl e-bli n d, pl ace b o -c o ntr oll e d , 
par all el - gr o u p st u d y 
 
T h e t ot al st u d y d urati o n will b e a p pr o xi m at el y 1 6  w ee ks, 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 of 1 0 1 
c o nsist i n g of  1 -w ee k o bs er v ati o n p eri o d, 1 4 -w ee k treat m e nt 
peri o d a n d 1- w ee k f oll o w -u p p eri o d aft er l ast d ose.    Aft er 
c o m pl eti o n of t h e o bs er v ati o n  p eri o d,  t h e eli gi bl e s u bj ects 
will b e r a n d o miz e d i nt o o n e of 4 ar ms, pl ace b o, D S - 5 5 6 5 
1 5 m g Q D, D S -5 5 6 5 1 0 m g BI D, or D S -5 5 6 5 1 5 m g BI D at 
t h e r ati o of 2: 1: 1: 1, res p ecti v el y.  T h e titrati o n p eri o d will 
be a p plie d at t h e first wee k of 1 0 m g BI D, a n d at t h e first 2 
w ee ks of 1 5 m g Q D a n d 1 5 m g BI D .    Aft er t h e titrati o n 
peri o d , t he dr u g will b e a d mi nist ered f or 1 2 or 1 3  w ee ks at 
t h e assi g n e d d os e.    A n y s u bj ects w h o h a v e b ee n ta ki n g 
pr o hi bit e d c o n c o mit a nt dr u gs will u n d er g o a w as h o ut p eri o d 
of 7 d a ys or m ore, pri or t o t h e s cree ni n g. 
St u d y D ur ati o n  
(fr o m F PI t o L P L V): 
St u d y d urati o n: J a n u ar y 2 0 1 5 t o M a y 2 0 1 7  
St u d y Sites a n d 
L o cati o n:  
A p pr o xi m atel y 2 0 0  st u d y sit es i n J a p a n, K orea, Tai w a n  a n d 
Mal a ysi a  
Pla n n e d Sa m pl e Size:  
A p pr o xi m atel y 7 5 0 s u bj ects will b e ra n d o miz e d i n t h e st u d y. 
S u bject Eli gi bilit y 
Crit eri a:  
I n cl usi o n Crit eri a: 
S u bjects m ust s atisf y all of t h e f oll o wi n g crit eri a t o be 
i n cl u d e d i n t h e st u d y. 
1)  A ge ≥ 2 0 years at i nf or m e d c o ns e nt 
2)  A ble t o gi v e writt e n i nf or m e d c o nse nt f or st u d y 
parti ci p ati o n , u n d erst a n d pr o ce d ure s of t his st u d y, a n d 
c o m pl et e p ati e nt -re p ort e d q u esti o n n aires a d e q u at el y 
3)  Ty p e 1  or t y p e 2 di a b et es m ellit us at s cree ni n g  
4)  Pai nf ul dist al s y m m etri c p ol y n e ur o p at h y, di a g n os e d at 
least 6 m o nt hs pri or t o s cree ni n g  (s ee Pr o ce d ures 
ma n u al f or t h e Di a g n osis of Di a b eti c P eri p h eral 
N e ur o p at h y a n d N e ur ol o gi cal E x a mi n ati o n f or d etails)  
5)  At s cree ni n g, a pai n s cal e of ≥ 4 0 m m o n V A S of 
S F -M P Q  
6)  At r a n d o mizati o n, a p ai n s cal e of ≥ 4 0 m m o n V A S of 
S F -M P Q , a n d c o m pl eti o n of at l east 4  d a ys of dail y p ai n 
di ari es wit h a n A D P S  of ≥ 4 o v er t h e p ast 7  d a ys o n t h e 
1 1 - p oi nt N u m eric al R ati n g S cal e  ( N R S) 
 
E x cl usi o n Crit eri a:  
S u bjects w h o m eet a n y of t h e f oll o wi n g crit eri a will b e 
e x cl u d e d fr o m p arti ci p ati o n i n t h e st u d y.  
1)  At s cree ni n g, a p ai n s cal e of ≥ 9 0 m m o n V A S of 
S F -M P Q  
2)  At r a n d o mizati o n, a p ai n s cal e of ≥ 9 0 m m o n V A S of 
S F -M P Q , or at l east a dail y p ai n s c ore  of ≥ 9 d uri n g 
o bser v ati o n p eri o d  
3)  H b A 1c ( Nati o n al Gl yc o h e m o gl o bi n St a n d ar diz ati o n 
Pr o gra m ) > 1 0 . 0 % at scree ni n g  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 of 1 0 1 
4)  U n c o ntr olle d bl o o d gl u c os e at s cree ni n g or 
r a n d o miz ati o n t h at m a y r e q uire c h a n ges i n di a b et es 
tr eat m e nt ( n o n-i ns uli n dr u g t h era p y, e x ercise t h era p y, 
di et t h era p y) d uri n g st u d y  
5)  Ot her s e v ere p ai n at s cree ni n g or ra n d o miz ati o n, 
u nr el at e d t o dia b eti c p eri p h eral n e ur o p at h y ( D P N ), t h at 
ma y c o nf o u n d t he ass ess me nt of D P N P 
6)  N e ur ol o gi c dis or d ers  at s cree ni n g or ra n d o miz ati o n, 
u nr el at e d t o D P N , t h at m a y c o nf o u n d t h e ass ess m e nt of 
D P N P 
7)  Maj or ps yc hi atri c dis or d ers  at s cree ni n g or 
r a n d o miz ati o n 
8)  A m p ut ati o n of l o w er li m b parts, ot her t h a n t o es , pri or t o 
scr ee ni n g or ra n d o miz ati o n 
9)  Us e of pr o hi bit e d c o n c o mit a nt dr u gs wit hi n 7 d a ys or  
c h a n ge of restri ct e d c o nc o mit a nt dr u gs wit hi n 3 0 da ys 
pri or t o s cree ni n g  
1 0)  S ki n c o n diti o ns t h at c o ul d c o nf o u n d t h e assess m e nt of 
D P N P  
1 1)  Pr e vi o us a d mi nistrati o n  of pre ga b ali n  ≥ 3 0 0 m g/ da y or 
ga b a p e nti n ≥ 1 2 0 0 m g/ d a y, decl are d  l ac k of effect 
1 2)  Cr eati ni n e cleara n ce ( usi n g t h e C o c k croft -G a ult 
e q u ati o n) < 6 0 m L/ mi n  at s cree ni n g  
1 3)  M ali g n a n c y ot h er t h a n b as al cell carci n o m a wit hi n t h e 
past 2 years  pri or t o s cree ni n g 
1 4)  Cli ni call y si g nifi ca nt u nsta bl e n e ur ol o gic, 
o p ht h al m ol o gi c, h e p at o bili ar y , res pirat or y, h e mat ol o gi c 
ill n ess or u nst a bl e car di o vas c ul ar dis eas e ( e g, s e v ere 
h y p ot e nsi o n, u n c o ntr oll e d car diac arr h yt h mi a, or 
m y o car di al i nfarcti o n ) wit hi n 1 2 m o nt hs pri or t o 
scr ee ni n g  
1 5)  Cli ni call y si g nifi ca nt fi n di n gs o n el ectr o car di o gr a m 
(E C G ) at s cree ni n g  
1 6)  Hist or y of p er ni ci o us a n e mia, u ntreat e d h y p ot h yr oi dis m,   
or h u m a n i m m u n o d efi cie nc y vir us i nfecti o n 
1 7)  K n o w n hist or y of p ositi v e H e p atitis B a nti ge n or 
H e p atitis C a nti b o d y 
1 8)  Pr e g n a n c y, p ot e nti al pre g n a n c y, breast fee di n g, or 
s u bj ect u n willi n g t o t a k e reli a bl e c o ntrace pti v e m eas ures 
d uri n g t h e st u d y  or  f or 4 w ee ks aft er st u d y c o m pl eti o n 
1 9)  K n o w n h y p ers e nsiti vit y t o pre ga b ali n  or ga b a p e nti n  
2 0)  Partici p ati o n i n a n ot her cli ni cal st u d y, eit h er c urre ntl y or 
wit hi n 3 0 d a ys pri or t o pr o vi di n g of i nf or m e d c o nse nt 
2 1)  E x p eri e n ce of p arti ci p ati n g  D S - 5 5 6 5 cli ni cal st u d y an d 
r eceivi n g i n v esti gati o n al pr o d u ct  
2 2)  A b us e of illi cit dr u gs or al c o h ol wit hi n o n e year pri or t o 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 of 1 0 1 
scr ee ni n g 
2 3)  Res p o ns e of “ yes ” t o a n y of t h e q u esti o ns o n t h e 
C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e ( C -S S R S) at 
scr ee ni n g or ra n d o miz ati o n i n rel ati o n t o e v e nts 
occ urri n g wit hi n t he past 1 2 m o nt hs  
2 4)  Pr e vi o us treat m e nt wit h dr u gs t h at c o ul d ca us e 
irr e v ersi bl e reti n al d e ge n erati o n 
2 5)  At s cree ni n g, c li ni cal la b orat or y v al u es e x cee di n g li mits 
list e d i n Ta bl e 4- 1  (s ee S ecti o n 4. 1. 3 ) 
2 6)  T h e s u bj ect w h o is c o nsi dere d i n a p pr o pri at e f or t he 
st u d y at t h e dis creti o n of t h e i n v esti gat or or 
s u b-i n v esti gat or 
2 7)  Res p o ns e of “ yes ” t o t h e s ui ci dalit y q u esti o n (c urre nt or 
past) o n t h e M aj or D e pressi v e E pis o d e M o d ul e ( M o d ul e 
A) or res p o ns e of “ yes ” t o a n y q u esti o n of B 1 b, B 3 
t hr o u g h B 1 1 c, B 1 3, or B 1 4 i n t h e S ui ci d alit y M o d ul e 
( M o d ul e B) o n t h e Mi ni -i nt er n ati o n al Ne ur o ps yc hi atri c 
I nt er vi e w ( MI NI) I nt er vi e w ( Versi o n 6. 0) at s cree ni n g  
D os a ge F or m, D os e , 
a n d R o ut e of 
A d mi nistr ati o n:  
F or t h e fi x e d-d os e  p eri o d , D S-5 5 6 5 at a t ot al dail y d ose of 
1 5 m g ( 1 5 m g Q D), 2 0 m g  ( 1 0 m g BI D ) a n d 3 0 m g ( 1 5 m g 
BI D ), f or m ul at e d i n 5 m g , 1 0 m g a n d 1 5 m g t a bl ets, O R 
matc hi n g pl ace b o will b e a d mi nist ere d orall y, t wi ce d ail y (i n 
t h e m or ni n g a n d at b e dti me ). 
 
F or t h e titrati o n p eri o d , D S-5 5 6 5  will b e a d mi nistere d wit h 
1 0 m g ( 5 m g BI D ) d uri n g t h e first w ee k f or 1 0 m g BI D a n d 
1 5 m g BI D treat m e nt gr o u p, a n d f oll o w e d b y 2 0 m g ( 1 0 m g 
BI D ) d uri n g t h e s ec o n d w ee k f or 1 5 m g BI D treat m e nt 
gr o u p .  F or 1 5 m g Q D treat m e nt gr o u p , D S-5 5 6 5 will b e 
a d mi nist ere d wit h 5 m g ( 5 m g Q D) d uri n g t h e first wee k a n d 
f oll o w e d b y 1 0 m g ( 1 0 m g Q D) d uri n g t h e s ec o n d w ee k. 
St u d y E n d p oi nts:  
Pri m ar y e n d p oi nt:  
• 
C h a n ge i n A D P S  fr o m b as eli n e t o Wee k 1 4, rati n g 
a v er a ge d d ail y p ai n s c ore o v er a 7 -d a y p eri o d, b ase d o n 
e ntri es i n p at i e nts’ d ail y pai n di ari es  
 
Sec o n dar y e n d p oi nts  
• 
A D P S Res p o n d er rat e d efi n e d as t h e pr o p orti o n of 
s u bj ects wit h ≥ 3 0 %, a n d ≥ 5 0 % re d u cti o n fr o m b as eli n e 
t o Wee k 1 4 
• 
C h a n ge fr o m b as eli n e i n para m et ers ass ess e d usi n g 
S F -M P Q  
• 
C h a n ge fr o m b as eli n e i n para m et ers ass ess e d usi n g t h e 
m o difi e d B PI -S F  ( m eas ure m e nts of p ai n i nt e nsit y, 
f u n cti o n alit y, a n d i m p act of p ai n) 
• 
Pati e nt Gl o b al I m pressi o n of C h a n ge ( P GI C)  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 of 1 0 1 
• 
C h a n ge fr o m b as eli n e i n a v era ge d ail y sl ee p -i nt erfere n ce 
sc or e ( A D SI S) 
• 
C h a n ge fr o m b as eli n e i n Me di cal O ut c o m es St u d y  
( M O S) sl ee p s cal e 
• 
C h a n ge fr o m b as eli n e i n t h e H os pit al A n xiet y a n d 
D e pr essi o n S cal e ( H A D S)  
• 
C h a n ges fr o m b aseli n e i n Q O L , usi n g t h e S F-3 6  
• 
E v al u ati o n of S y m pt o m s 
St atisti cal A n al ys es:  
T h e m o difi e d i nte nt -t o-treat (mI T T) a n al ysis set  will b e us e d 
as a pri m ar y a n al ysis set f or all effi cac y a n al ys es.  
 
O bs er v e d A D P S a n d c h a n ge fr o m b as eli n e will b e 
s u m m arize d b y treat m e nt a n d w ee k (i n cl u di n g Wee k 1 4/last 
o bser v ati o n carri e d f or w ar d [ L O C F] a n d Wee k 1 4/ b as eli n e 
o bser v ati o n carri e d f or w ar d [ B O C F]).  
 
Mea n c h a n ge fr o m b as eli n e i n A D P S will b e c o m pare d 
bet w ee n eac h D S -5 5 6 5 ar m a n d pl ace b o at Wee k 1 4 usi n g 
t h e f oll o wi n g m ulti pl e i m p ut ati o n ( MI) met h o d a n d 
mi x e d -effect m o d el f or re p eate d m eas urem e nt s ( M M R M). 
 
T h e pri mar y i m p ut ati o n will b e b as e d o n “ n o nf ut ure 
de p e n d e n ce" m o d el 2 9  - 3 1 usi n g t h e p att er n mi xt ure a p pr o ac h 
wit h s hifti n g p ara m et ers u n der t h e missi n g n ot at ra n d o m 
( M N A R) m ec h a nis m f or t h e missi n g w ee kl y A D P S d ata.   
Reas o n f or dr o p o ut t o get her wit h t h e ti m e of dr o p o ut will b e 
us e d f or c o nstr u cti n g t h e missi n g d at a p att er n.    T h e 
st atisti cal m o d el us e d f or t h e MI d at a ge n erati o n will b e t h e 
Mar k o v C h ai n M o nt e C arl o ( M C M C) m et h o d wit h 
a dj ust m e nt f or c o v ari at es (e g , treat m e nt gr o u p, a ge, s e x) t o 
pr o d u ce a m o n ot o n e p at t er n first, a n d t h e n t h e i m p ut ati o n 
will c o nti n u e usi n g t h e R e gressi o n wit h Pre di cti v e M ea n 
Mat c hi n g ( R E G P M M) m et h o d f or t h e m o n ot o n e patt er n wit h 
t h e s a m e s et of c o v ari at es.  E ac h c o m pl et e i m p ute d d at as et 
will b e a n al yz e d usi n g t h e M M R M wit h treat me nt, w e e k, 
tr eat m e nt-b y -w ee k as t h e fi x e d effects, w ee k as t h e re p eat e d 
meas ur e, a n d b as eli n e A D P S as t h e c o v ari at e.    T h e res ults 
of M M R M a n al ysis fr o m eac h c o m pl et e i m p ute d dat as et will 
be c o m bi n e d usi n g R u bi n’s r ul e.  
 
All r eas o ns f or dis c o nti n uati o n will b e cat e g oriz e d, t o t h e 
e xt e nt p ossi bl e, i nt o eit h er lac k of effi cac y ( L O E) or a d v erse 
e v e nt ( A E) b as e d o n d et ail s p ecifi e d i n t he C as e R e p ort 
F or m.    O nl y reas o ns t h at ca n n ot be cl assifi e d i nt o t h e a b o v e 
t w o cat e g ori es will b e c o nsi d ere d as “all ot h er reas o ns 
( A OR) ”   T h e pri m ar y s hifti n g p ara m et er v al u es 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 of 1 0 1 
c orr es p o n di n g t o t h e t hree cate g ori es i n t h e p att er n mi xt ure 
m o d el ( P M M) will b e c h os e n as (1. 0 , 1. 0, 0. 5) f or dr o p o uts 
d u e t o A E, L O E a n d A O R, res p ecti v el y, a n d t h e 
c orr es p o n di n g s hifti n g a m o u nt of t h e w ee kl y A D P S i m p ut e d 
at first missi n g w ee k is gi v e n b y ( 1. 0, 1. 0, 0. 5) * R S D * U( 0, 1) 
w h er e U( 0, 1) is a ra n d o m v ari a bl e fr o m a u nif or m 
distri b uti o n wit h a ra n ge of 0 t o 1, a n d R S D is t h e resi d u al 
st a n d ar d d e vi ati o n at first missi n g w ee k aft er i m p ut ati o n. 
 
T h e t y p e I err o r rat e will b e c o ntr oll e d at l ess t h a n 0. 0 5 f or 
t h e m ulti pl e c o m p aris o ns of t h e pri m ar y effi cac y a n al ys es 
usi n g c o m bi n ati o n a p pr o ac h of B o nferr o ni -H ol m met h o d 
a n d gat e - kee pi n g pr o ce d ure ( S ee S ecti o n 1 1. 5. 1 f or d et ail). 
 
Se nsiti vit y a n al ys es will i n cl u d e f o ll o wi n g:    
• 
T h e a b o v e pri mar y “ n o nf ut ure d e p e n d e n ce” M N A R 
m o d el wit h differe nt s hift p ara m eters i n cl u di n g ( 0, 0, 0)  
• 
Place b o m ulti pl e i m p ut ati o n 2 7 , 28 
• 
M M R M usi n g o b ser v e d dat a o nl y 
• 
A n al ysis of c o v ari a n ce ( A N C O V A) usi n g B O C F  
• 
A N C O V A usi n g L O C F  
• 
T h e a b o v e pri mar y “ n o nf ut ure d e p e n d e n ce” M N A R 
m o d el wit h t h e s a m e s hift p ara m eters as t h e pri m ar y 
a n al ysis (i.e., ( 1. 0 , 1. 0., 0. 5) usi n g p er- pr ot o c ol s et 
[ P P S]) 
 
Res p o ns e rat e, d efi n e d as t h e pr o p orti o n of s u bj ects wit h ≥ 
3 0 %, a n d ≥ 5 0 % re d u cti o n fr o m b as eli ne i n A D P S , will b e 
c o m p ar e d bet w ee n eac h D S -5 5 6 5 ar m a n d pl ace b o, usi n g 
l o gisti c r e gressi o n m o d el.    T h e c u m ul ati v e distri b uti o n f or 
r e d u cti o n fr o m b as eli n e i n A D P S will be pr o vi d e d as a 
c o nti n u o us res p o n d er a n al ysis 2 5. 
 
F or t h e s afet y e n d p oi nts, A E s, cli ni cal l a b orat or y t est res ults, 
vit al si g ns (i n cl u di n g b o d y w ei g ht), E C G , p h ysi c al fi n di n gs, 
C- S S R S , a n d H A D S will b e s u m m ariz e d f or t he s afet y 
a n al ysis s et.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 0 of 1 0 1 
T A B L E O F C O N T E N T S  
I M P O R T A N T 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 ................................... 2 
I N V E S TI G A T O R A G R E E M E N T .................................................................................... 3 
P R O T O C O L S Y N O P SI S ................................................................................................... 4 
T A B L E O F C O N T E N T S  ................................................................................................. 1 0 
LI S T O F I N -T E X T T A B L E S  .......................................................................................... 1 6 
LI S T O F A B B R E VI A TI O N S  .......................................................................................... 1 7 
1. I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N ............................... 2 0 
1. 1 D at a S u m m ar y  ............................................................................................................ 2 0 
1. 1. 1 
I n v esti gati o n al Pr o d u ct(s) ...................................................................................... 2 0 
1. 1. 1. 1 
N a m e  .................................................................................................................. 2 0 
1. 1. 1. 2  
D es cri pti o n ......................................................................................................... 2 0  
1. 1. 1. 3 
I nt e n d e d Us e U n d er I n v esti gati o n ..................................................................... 2 0 
1. 1. 1. 4 
N o n cli ni cal St u di es  ............................................................................................ 2 0 
1. 1. 1. 5 
Cli ni cal E x p eri e nce  ............................................................................................ 2 0 
1. 2 St u d y R ati o nal e  .......................................................................................................... 2 2 
1. 3 Ris ks a n d Be n efits f or St u d y S u bj ects  ....................................................................... 2 3 
2. S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  ........................................................ 2 4 
2. 1 St u d y O bj ecti v es  ........................................................................................................ 2 4 
2. 1. 1 
Pri m ar y O bj ecti v e  .................................................................................................. 2 4 
2. 1. 2 
Sec o n dar y O bj ecti v es  ............................................................................................. 2 4 
2. 2 St u d y H y p ot h esis  ....................................................................................................... 2 4 
3. S T U D Y  D E SI G N  ........................................................................................................ 2 5 
3. 1 O v er all Pla n  ................................................................................................................ 2 5 
3. 1. 1 
St u d y Ty p e  .............................................................................................................. 2 5 
3. 1. 2 
St u d y S c h e me  ......................................................................................................... 2 5 
3. 1. 3 
St u d y E n d p oi nts  ..................................................................................................... 2 6 
3. 1. 3. 1 
Pri m ar y E n d p oi nt  ............................................................................................... 2 6 
3. 1. 3. 2 
Sec o n dar y E n d p oi nts  .......................................................................................... 2 6 
3. 1. 4 
D ur ati o n of S u bj ect P arti ci p ati o n  .......................................................................... 2 7 
3. 2 Disc ussi o n of St u d y D esi g n  ....................................................................................... 2 7 
3. 2. 1 
D os a ge of D S - 5 5 6 5 ................................................................................................ 2 7 
3. 2. 2 
D ur ati o n of St u d y Tr eat me nt  ................................................................................. 2 8 
3. 2. 3 
C o ntr ol Tr eat m e nt  .................................................................................................. 2 8 
3. 2. 4 
St u d y E n d p oi nts  ..................................................................................................... 2 8 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 1  of 1 0 1 
4. S T U D Y P O P U L A TI O N  ............................................................................................. 2 9 
4. 1 E nr o ll m e nt .................................................................................................................. 2 9 
4. 1. 1 
Pr oce d ur es f or S u bj ect E nr oll m e nt  ........................................................................ 2 9 
4. 1. 2 
I n cl usi o n Crit eri a .................................................................................................... 2 9 
4. 1. 3 
E x cl usi o n Crit eri a  .................................................................................................. 3 0 
4. 2 S u bject Wit h dr a w al  .................................................................................................... 3 3 
4. 2. 1 
Wit h dr a w al Criteria  ................................................................................................ 3 3 
4. 2. 2 
Reas o ns f or Wit h dr a wal  ......................................................................................... 3 3 
4. 2. 3 
Wit h dr a w al Pr o ce d ur es  .......................................................................................... 3 4 
4. 2. 4 
St o p pi n g R ul es f or t h e St u d y  ................................................................................. 3 5 
5. T R E A T M E N T A D MI NI S T E R E D  ............................................................................ 3 6 
5. 1 I n v esti gati o n al Pr o d u cts ............................................................................................. 3 6 
5. 1. 1 
St u d y Tr eat m e nts  .................................................................................................... 3 6 
5. 1. 1. 1 
I n v esti gati o n al Pr o d u ct ...................................................................................... 3 6 
5. 1. 1. 2 
I n v esti gati o n al Pr o d u ct Place b o ......................................................................... 3 6 
5. 1. 2 
D osi n g R e gi m e ns f or t h e St u d y  ............................................................................. 3 6 
5. 1. 3 
Met h o d of Assi g ni n g S u bj ects t o Treat m e nts a n d Bli n di n g  .................................. 3 7 
5. 1. 3. 1 
Met h o d of Assi g ni n g t h e I n v esti gati o nal Pr o d u ct t o S u bjects  .......................... 3 7 
5. 1. 3. 2 
Bli n di n g  .............................................................................................................. 3 7 
5. 1. 3. 3 
Pr e p ar ati o n a n d M a n a ge me nt of E m er ge n c y C o d es  .......................................... 3 8 
5. 1. 3. 4 
Pr oce d ur es f or E m er ge n c y U n bli n di n g .............................................................. 3 8 
5. 1. 3. 5 
S u bject R e pl ace m e nt  .......................................................................................... 4 0 
5. 1. 4 
Met h o d of Ass essi n g Tr e at me nt C o m pli a n ce  ........................................................ 4 0 
5. 1. 5 
La b eli n g a n d P ac k a gi n g  ......................................................................................... 4 0 
5. 1. 6 
St or a ge  .................................................................................................................... 4 2 
5. 1. 7 
Dr u g A cc o u nt a bilit y  ............................................................................................... 4 2 
5. 2 C o n c o mit a nt M e di cati o ns a n d Treat m e nts  ................................................................ 4 2 
5. 2. 1 
Pr o hi bit e d C o n c o mit a nt Me di cati o ns  .................................................................... 4 2 
5. 2. 2 
Restri ct e d C o nc o mit a nt Me di cati o ns  ..................................................................... 4 4 
5. 2. 3 
Resc u e M e di cati o ns  ............................................................................................... 4 4 
5. 2. 4 
Pr o hi bit e d C o n c o mit a nt T h era pi es  ........................................................................ 4 4 
5. 2. 5 
Ot her  ....................................................................................................................... 4 4 
6. S T U D Y P R O C E D U R E S  ............................................................................................ 4 5 
6. 1 Scr ee ni n g ( Visit  1, 7 d a ys pri or t o ra n d o miz ati o n)  ................................................... 4 5 
6. 2 Ra n d o miz ati o n ( Visit  2, D a y 1)  ................................................................................. 4 6 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 2 of 1 0 1 
6. 3 Tr eat m e nt P eri o d  ........................................................................................................ 4 6 
6. 3. 1 
Visit  3 a n d Visit  4 ................................................................................................... 4 6 
6. 3. 2 
Visit  5, Visit 6, Visit 7, Visit 8, a n d Visit 9  ............................................................ 4 7 
6. 4 E n d of Tr eat m e nt/ E arl y Ter mi nati o n ( Visit  1 0) ......................................................... 4 8 
6. 5  P ost- tr eat m e nt F oll o w-u p ( Visit  1 1, 7 da ys aft er t he c o m pleti o n of a d mi nistrati o n)  4 9 
7. E F FI C A C Y A S S E S S M E N T S  .................................................................................... 5 0 
7. 1 Pri m ar y Effi cac y Vari a bl e(s)  ...................................................................................... 5 0 
7. 2 Sec o n dar y Effi cac y Vari a bl e(s) .................................................................................. 5 0 
8. P H A R M A C O KI N E TI C A N D BI O M A R K E R A S S E S S M E N T S  .......................... 5 4 
8. 1 P h ar m ac o ki n eti c Vari a bl e(s)  ...................................................................................... 5 4 
8. 2 Bi o m ar k er Vari a ble(s)  ................................................................................................ 5 4 
9. S A F E T Y A S S E S S M E N T S  ......................................................................................... 5 5 
9. 1 A d v ers e E ve nts  .......................................................................................................... 5 5 
9. 1. 1 
D efi niti o n of A d v ers e E v e nt  .................................................................................. 5 5 
9. 1. 2 
It e ms t o Be I n v esti gat e d C o n cer ni n g A d v ers e E v e nts .......................................... 5 6 
9. 1. 3 
D efi niti o n of A d v ers e Dr u g R eacti o n  .................................................................... 5 8 
9. 1. 4 
A cti o ns t o Be Ta k e n W h e n A d v ers e E v e nts O cc ur  ............................................... 5 8 
9. 2 A cti o ns t o Be Ta k e n W h e n S eri o us A d v ers e E v e nts O cc ur  ...................................... 5 9 
9. 3 E x p os ur e I n Ut er o D uri n g Cli ni cal St u di es  ............................................................... 5 9 
9. 4 Cli ni cal La b or at or y E v al uati o ns  ................................................................................ 6 0 
9. 5  Vit al Si g ns .................................................................................................................. 6 4  
9. 6 El ectr o c ar di o gr a ms .................................................................................................... 6 4  
9. 7 P h ysi cal Fi n di n gs  ....................................................................................................... 6 4 
9. 7. 1 
B o d y H ei g ht a n d Wei g ht  ........................................................................................ 6 4 
9. 7. 2 
P h ysi cal E x a mi n ati o ns  ........................................................................................... 6 4 
9. 7. 3 
E v al u ati o n of E d e m a  .............................................................................................. 6 4 
9. 8 Ot her S af et y Ass ess m e nts  .......................................................................................... 6 5 
9. 8. 1 
N e ur ol o gi cal E x a mi n ati o n  ..................................................................................... 6 5 
9. 8. 2 
O p ht h al m ol o gi c E x a mi n ati o n  ................................................................................ 6 5 
9. 8. 3  C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e 1 4 ............................................................ 6 5 
9. 8. 4 
H os pit al A n xi et y a n d D e pr essi o n S cal e 1 2 .............................................................. 6 6 
9. 8. 5 
Pr e g n a n c y t est  ........................................................................................................ 6 6 
1 0. O T H E R A S S E S S M E N T S  .......................................................................................... 6 7 
11.  S T A TI S TI C A L M E T H O D S  ...................................................................................... 6 8 
1 1. 1  O bjecti ve  .................................................................................................................... 6 8 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 3 of 1 0 1 
1 1. 2  G e n er al S t atisti cal C o nsi der ati o ns ............................................................................. 6 8 
1 1. 3  A n al ysis S ets  .............................................................................................................. 6 9 
1 1. 4  St u d y P o p ul ati o n D at a  ............................................................................................... 6 9 
1 1. 5  Effi cac y A n al ys es  ....................................................................................................... 6 9 
1 1. 5. 1 Pri m ar y Effi cac y A n al ys es  ..................................................................................... 6 9 
1 1. 5. 2 Sec o n dar y Effi cac y A n al ys es  ................................................................................. 7 1 
1 1. 5. 2. 1  Res p o n d er R at e f or Av er a ge d D ail y P ai n S c ore  ................................................ 7 1 
1 1. 5. 2. 2  S h ort -F or m M c Gill P ai n Q u esti o n n aire ............................................................. 7 1 
1 1. 5. 2. 3  M o difi e d Bri ef P ai n I n v e nt or y ( S h ort F or m)  .................................................... 7 2 
1 1. 5. 2. 4  Pati e nt Gl o b al I m pr essi o n of C h a n ge  ................................................................ 7 2 
1 1. 5. 2. 5  Slee p -I nt erf er e n ce Sc or e .................................................................................... 7 2 
1 1. 5. 2. 6  Me di cal O ut c o m es St u d y Slee p Scal e  ............................................................... 7 2 
1 1. 5. 2. 7  H os pit al A n xi et y a n d D e pr essi o n S cal e  ............................................................. 7 2 
1 1. 5. 2. 8  S F - 3 6 .................................................................................................................. 7 2 
1 1. 5. 2. 9  E v al u ati o n of S y m pt o ms  .................................................................................... 7 3 
1 1. 6  P h ar m ac o ki n eti c/ Bi o m ar ker A nal ys es  ....................................................................... 7 3 
1 1. 6. 1 P h ar m ac o ki n eti c A n al ys es  ..................................................................................... 7 3 
1 1. 6. 2 Bi o m ar k er A n al ys es  ............................................................................................... 7 3 
1 1. 7  Saf et y A n al ys es  .......................................................................................................... 7 3 
1 1. 7. 1 A d v ers e E ve nt A n al ys es  ........................................................................................ 7 3 
1 1. 7. 2 Cli ni cal La b or at or y E v al uati o n A n al ys es  .............................................................. 7 4 
1 1. 7. 3 Vit al Si g n A n al ys es  ................................................................................................ 7 4 
1 1. 7. 4 El ectr o car di o gr a m A n al yses  .................................................................................. 7 4 
1 1. 7. 5 P h ysi cal Fi n di n g A n al ys es  ..................................................................................... 7 4 
1 1. 7. 6  C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e  .............................................................. 7 5 
1 1. 7. 7 H os pit al A n xi et y a n d D e pr essi o n S cal e  ................................................................. 7 5 
1 1. 7. 8 Ot her S af et y A n al ys es  ............................................................................................ 7 5 
1 1. 8  Ot her A n al ys es  ........................................................................................................... 7 5 
1 1. 9  D at a Saf et y M o nit ori n g B o ar d  ................................................................................... 7 5 
1 1. 1 0  H e p ati c A dj u di cati o n C o m mittee  ........................................................................... 7 6 
1 1. 1 1  Sa m pl e Siz e D et er mi n ati o n  .................................................................................... 7 6 
1 2. D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ............................................. 7 8 
1 2. 1 M o nit ori n g a n d I ns p ecti o ns  ....................................................................................... 7 8 
1 2. 2 D at a C oll ecti o n  .......................................................................................................... 7 9 
1 2. 2. 1 St yl e of Dat a C oll ecti o n  ......................................................................................... 7 9 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 4 of 1 0 1 
1 2. 2. 1. 1 Case R e p ort F or m  .............................................................................................. 7 9 
1 2. 2. 1. 2 El ectr o ni c D ail y Di ar y  ....................................................................................... 7 9 
1 2. 2. 1. 3  Ot her R e p orts ..................................................................................................... 8 0  
1 2. 2. 2 Pr e p ar ati o n of C as e R e p ort F or ms a n d D ail y Di ari es  ........................................... 8 0 
1 2. 2. 3 Si g nat ur es or S eals o n t h e C as e R e p ort F or m  ....................................................... 8 0 
1 2. 2. 4 D at a C orr ecti o n  ...................................................................................................... 8 0 
1 2. 3 D at a M a n a ge m e nt  ...................................................................................................... 8 1 
1 2. 4 St u d y D o c u m e ntati o n a n d St or a ge ............................................................................. 8 1 
1 2. 4. 1 D efi niti o n of S o ur ce D o c u m e nts  ........................................................................... 8 1 
1 2. 4. 2 St or a ge  .................................................................................................................... 8 2 
1 2. 5 Rec or d K ee pi n g  .......................................................................................................... 8 2 
1 3. FI N A N CI N G A N D I N S U R A N C E  ............................................................................ 8 3 
1 3. 1 Fi n a n ces  ...................................................................................................................... 8 3 
1 3. 2 Rei m b urs e m e nt, I n d e m nit y, a n d I ns ura n ce  ............................................................... 8 3 
1 4. P U B LI C A TI O N P O LI C Y  ......................................................................................... 8 4 
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  ..................................................... 8 5 
1 5. 1 C o m pli a n ce St at e m e nt, Et hi cs, a n d R e g ul at or y C o m pli a n ce  .................................... 8 5 
1 5. 2 S u bject C o nfi d e nti alit y  .............................................................................................. 8 5 
1 5. 3 I nf or m e d C o nse nt Pr o ce d ur es .................................................................................... 8 5 
1 5. 4 Re g ulat or y C o m pli a n ce  ............................................................................................. 8 6 
1 5. 5 Pr ot o c ol D e vi ati o ns .................................................................................................... 8 7  
1 5. 6 S u p pl y of N e w I nf or m ati o n Affecti n g t he C o n d u ct of t he St u d y ............................. 8 7  
1 5. 7 D ur ati o n of t h e St u d y  ................................................................................................. 8 7 
1 5. 8 Pr ot o c ol A m e n d m e nts  ................................................................................................ 8 8 
1 5. 9 St u d y  Dis c o nti n u ati o n or S us p e nsi o n  ........................................................................ 8 8 
1 5. 1 0  Or ga niz ati o n ........................................................................................................... 8 9  
1 5. 1 0. 1  S p o ns or ............................................................................................................... 8 9  
1 5. 1 0. 1. 1 S p o ns or’s R es p o nsi bl e Me di cal E x pert ............................................................. 8 9  
1 5. 1 0. 1. 2 S p o ns or’s R es p o nsi bl e Me di cal A d vis er  ........................................................... 8 9 
1 5. 1 0. 1. 3 S p o ns or’s Cli ni cal St u d y Lea d ........................................................................... 8 9  
1 5. 1 0. 1. 4 S p o ns or’s D eli v er y Lea d .................................................................................... 8 9  
1 5. 1 0. 2 
A ca d e mi c R es ear c h Or g a niz ati o n  ...................................................................... 9 0 
1 5. 1 0. 3 
C o or di n ati n g I n v esti gat or  .................................................................................. 9 0 
1 5. 1 0. 3. 1 C o or di n ati n g I n v esti gat or i n J a p a n  .................................................................... 9 0 
1 5. 1 0. 3. 2 C o or di n ati n g I n v esti gat or i n K orea  ................................................................... 9 0 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 5 of 1 0 1 
1 5. 1 0. 3. 3 C o or di n ati n g I n v esti gat or i n Tai wa n  ................................................................. 9 0 
1 5. 1 0. 4 
C o ntr act R es ear c h Or ga nizati o n  ........................................................................ 9 0 
1 5. 1 0. 4. 1 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of M o nit ori n g i n J a p a n  ................. 9 0 
1 5. 1 0. 4. 2 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of M o nit ori n g i n K orea  ................ 9 1 
1 5. 1 0. 4. 3 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of M o nit ori n g i n Tai w a n  ............... 9 1 
1 5. 1 0. 4. 4 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of M o nit ori n g i n M al a ysi a ............ 9 1 
1 5. 1 0. 4. 5 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of I nt eracti v e We b R es p o ns e S yst e m 9 1  
1 5. 1 0. 4. 6 C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of E m er ge n c y C o ntact  .................. 9 1 
1 5. 1 0. 4. 7 Ra n d o miz ati o n m a n a ger  .................................................................................... 9 2 
1 5. 1 0. 5 
Ce ntr al La b or at or y  ............................................................................................. 9 2 
1 5. 1 0. 5. 1 Bi o a nal yti cal La b or at or y  ................................................................................... 9 2 
1 5. 1 0. 5. 2 Ce ntr al La b or at or y M a n a ge m e nt  ....................................................................... 9 2 
1 5. 1 0. 5. 3 Ce ntr al La b or at or y i n J a pa n  ............................................................................... 9 2 
1 5. 1 0. 5. 4 Ce ntr al La b or at or y M a n a ge m e nt i n K orea  ........................................................ 9 2 
1 5. 1 0. 5. 5 Ce ntr al La b or at or y i n K or ea  .............................................................................. 9 3 
1 5. 1 0. 5. 6 Ce ntr al La b or at or y i n Tai w a n  ............................................................................ 9 3 
1 5. 1 0. 5. 7 Ce ntr al La b or at or y i n Si n ga p ore  ........................................................................ 9 3 
1 5. 1 0. 6 
D at a Saf et y M o nit ori n g B o ar d  ........................................................................... 9 3 
1 5. 1 0. 7 
C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of D at a S afet y M o nit ori n g B o ar d 
C o or di n ati o n ........................................................................................................... 9 4  
1 5. 1 0. 8 
H e p ati c A dj u di cati o n C o m mittee  ....................................................................... 9 4 
1 5. 1 0. 9 
C o ntr act R es ear c h Or ga nizati o n i n C h ar ge of H e p atic A dj u di cati o n C o m mitt ee 
C o or di n ati o n ........................................................................................................... 9 4  
1 5. 1 0. 1 0 E D C S yst e m D e v el o p m e nt  ................................................................................ 9 5 
1 5. 1 0. 1 1  E D C S yst e m S u p p ort ......................................................................................... 9 5  
1 5. 1 0. 1 2 e P R O s yst e m D e v el o p m e nt a n d S u p p ort  ........................................................... 9 5 
1 6. R E F E R E N C E S  ........................................................................................................... 9 6 
1 7. A P P E N DI C E S  ............................................................................................................ 9 8 
1 7. 1 Sc he d ul e of E v e nts  ..................................................................................................... 9 8 
1 7. 2 Pr ocessi n g of Bl o o d S a m pl es f or P h ar m ac o ki n etic A nal ys es  ................................. 1 0 1 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 6 of 1 0 1 
LI S T O F I N -T E X T T A B L E S  
Ta bl e 4 -1   He m at ol o g y/ Bl o o d  C h e mistr y  Li mits  ............................................................ 3 2 
Ta bl e 5 - 1    M et h o d of A d mi nistrati o n D uri n g t he Treat m e nt Peri o d  ............................... 3 7 
Ta bl e 5 - 2    Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 1) ......................... 4 1 
Ta bl e 5 - 3    Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 2) ......................... 4 1 
Ta bl e 5 -4    Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 3 t o Wee k 1 4)  ...... 4 2 
Ta bl e 9 -1    It e ms t o b e I n v esti gat e d f or A d v ers e E v e nt  ................................................... 5 7 
Ta bl e 9 -2    La b or at or y P ar a m et ers t o b e Ass ess e d, a n d Ti m e of Ass ess m e nt .................. 6 1 
Ta bl e 1 1 -1    St atisti cal p o w ers ( %) of D S -5 5 6 5 1 5 m g Q D, 1 0 m g BI D, a n d 1 5 m g BI D 
bei n g s u p eri or o v er pl ace b o  ............................................................................. 7 7 
Ta bl e 1 2 -1    El ectr o nic D at a C a pt ur e S yst e m  ................................................................... 7 9 
Ta bl e 1 2 -2    El ectr o nic Pati e nt R e p ort O ut c o m e S yst e m  ................................................. 7 9 
Ta bl e 1 7 -1    St u d y Visits  ................................................................................................... 9 8 
Ta bl e 1 7 -2    Effi cac y Assess me nt b y Visit  ..................................................................... 1 0 0 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 7 of 1 0 1 
LI S T O F A B B R E VI A TI O N S  
 
A B B R E VI A TI O N  
D E FI NI TI O N  
A D P S  
Av er a ge D ail y P ai n S c ore  
A D R  
A d v ers e Dr u g R eacti o n  
A D SI S  
Av er a ge D ail y Sl ee p I nt erfere n ce S c ore  
A E  
A d v ers e E ve nt  
A/ G r ati o  
Al b u mi n/ Gl o b uli n rati o  
A L P  
Al kali n e P h os p h at as e  
A L T  
Al a ni n e A mi n otra nsferas e  
A M A  
a nti -mit o c h o n drial a nti b o d y  
A N A  
a nti -n u cl ear a nti b o d y  
A N C O V A  
A n al ysis of C o v ari a n ce  
A N O V A  
A n al ysis of Varia n ce  
A S M A  
a nti -s m o ot h m us cle a nti b o d y 
A S T  
As p art at e A mi n otra nsferas e  
B O C F  
Baseli n e O bs er v ati o n C arri e d F or w ar d  
B PI -S F  
Bri ef P ai n I n v e nt or y  ( S h ort F or m) 
B U N  
Bl o o d Ur ea Nitr o ge n  
C M V  
C yt o m e gal o vir us  
C N S  
Ce ntr al N er v o us S yst e m  
C R F  
Case R e p ort F or m  
C R O  
C o ntr act R es earc h Or ga nizati o n  
C R P  
C -R eacti v e Pr ot ei n  
C -S S R S  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S cal e  
DI LI  
Dr u g -I n d uce d Li ver I nj ur y 
D S M B  
Data Saf et y M o nit ori n g B o ar d  
D P N  
Di a b eti c P eri p h eral N e ur o p at h y  
D P N P  
Di a b eti c P eri p h eral N e ur o p at hi c P ai n  
E B V  
E pst ei n -Barr Vir us  
e C R F  
El ectr o ni c C as e R e p ort F or m  
E C  
I n d e p e n d e nt Et hi cs C o m mitt ee 
E C G  
El ectr o car di o gra m  
E D C  
El ectr o ni c D at a C a pt ure  
e -DI S H  
E v al u ati o n of dr u g -i n d u ce d s eri o us h e p at ot o xi cit y 
EI U  
E x p os ur e I n Ut er o  
E M A  
E ur o p ea n M e di ci n es A ge nc y  
e P R O  
El ectr o ni c P ati e nt R e p ort O ut c o m e  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 8 of 1 0 1 
A B B R E VI A TI O N  
D E FI NI TI O N  
F D A  
F o o d Dr u g  A d mi nistrati o n  
F M  
Fi br o m yal gi a  
F PI  
First P ati e nt I n  
G C P  
G o o d Cli nical Practi ce (refers t o I C H a n d C F R)  
γ-G T( γ-G T P)  
ga m m a -Gl ut a m yl Tra ns p e pti d as e  
G O T  
Gl ut a mi c O x al o aceti c Tra ns a mi n as e  
G P T  
Gl ut a mi c P yr u vi c Tra ns a mi n ase  
H A C  
He p atic A dj u dicati o n C o m mittee  
H A D S  
H os pit al A n xi et y a n d D e pressi o n S cal e  
I C F 
I nf or m e d C o nse nt F or m 
I C H 
I nt er n ati o nal C o nfere nce o n H ar m o niz ati o n 
I N N 
I nt er n ati o nal N o n pr o pri etar y N a m es 
I R B 
I nstit uti o n al R e vi e w B o ar d 
I S F L B 
I n d e p e n d e nt S u b-F u n cti o n al Lea d of Bi ost atisti cs  
I W R S 
I nt er acti v e We b R es p o ns e S yst e m 
L D H  
Lact at e D e h y dr o ge n as e  
L F T  
Li v er F u n cti o n Test  
L O C F  
Last O bser v ati o n C arri e d F or w ar d  
L O E  
Lac k of Effi cac y  
L P L V  
Last P ati e nt Last Visit  
M A R  
Missi n g at Ra n d o m  
M C M C  
Mar k o v C h ai n M o nt e C arl o  
Me d D R A  
Me di cal Di cti o nar y f or Re g ulat or y A cti viti es  
MI  
M ulti pl e I m p ut ati o n  
MI NI  
Mi ni -i nter n ati o n al N e ur o ps yc hi atri c I nt er vi e w 
mI T T  
M o difi e d I nt e nt -To -Treat  
M M R M  
Mi x e d -Eff ects M o d el f or R e p eat e d M eas ure m e nts  
M N A R  
Missi n g N ot At R a n d o m  
M O S  
Me di cal O ut c o m es St u d y  
N A S H  
N o n al c o h oli c St eat o h e p atitis  
N M D A  
N -m et h yl -D -as p art at e rece pt or  
N R S  
N u m eri cal Rati n g S cal e  
P A P  
P K A n al ysis Pl a n  
P GI C  
Pati e nt Gl o b al I m pressi o n of C h a n ge  
P H N  
P ost -H er p eti c N e ural gi a  
P K  
P h ar m ac o ki n eti cs  
P M M  
Patt er n M i xt ure M o d el  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 1 9 of 1 0 1 
A B B R E VI A TI O N  
D E FI NI TI O N  
P P S  
Per -Pr ot o c ol S et  
P T  
Pr ot hr o m bi n Ti m e  
Q O L  
Q u alit y of Life  
R B C  
Re d Bl o o d C ell  
R E G P M M  
Re gr essi o n wit h Pre di cti ve M ea n M at c hi n g  
S A E  
Seri o us A d vers e E v e nt  
S A P  
St atisti cal A n al ysis Pl a n  
S D  
St a n d ar d D e vi ati o n  
S F -M P Q  
S h ort -F or m M c Gill P ai n Q u esti o n n aire  
T E A E  
Tr eat m e nt -E m er ge nt A d vers e E v e nt  
T -Bil  
Tot al bilir u bi n  
U L N  
U p p er Li mit of N or m al  
V A S  
Vis u al A nal o g S cal e  
W B C  
W hit e Bl o o d C ell  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 0 of 1 0 1 
1.  
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N 
1. 1  
D at a S u m m a r y  
1. 1. 1  
I n v esti g ati o n al Pr o d u ct(s) 
1. 1. 1. 1  
N a me  
D S -5 5 6 5  
 
1. 1. 1. 2  
D es cri pti o n  
D S -5 5 6 5 bi n ds wit h hi g h affi nit y t o t h e α 2δ s u b u nit of v olt a ge -d e p e n d e nt Ca 2 + c h a n n els. 
T h e α 2δ s u b u nit is e x pr ess e d i n t h e n e ural s y n a ps es, a n d a n al gesi c acti o n a p p ears t o b e 
elicit e d w h e n D S - 5 56 5 bi n ds t o t his s u b u nit.  
 
1. 1. 1. 3  
I nte n d e d Us e U n d er I n vesti g ati o n 
D i a b eti c p eri p h er al n e ur o p at hi c p ai n ( D P NP) 
 
1. 1. 1. 4  
N o ncli nic al St u dies  
E vi d e n ce fr o m n o n cli ni cal st u di es s u g gests t h at n e ur o p at hi c p ai n s y m pt o ms m a y b e d u e 
t o c h a n ges i n t h e pr otei n c o nt e nt of m e m bra n es of i nj ure d ne ur o ns (“ m e m bra n e 
r e m o d eli n g”).    T his pr o cess ca n l o w er t h e t hres h ol d f or acti o n p ot e nti al ge n erati o n, 
r es ulti n g i n a b n or m al a n d s p o nt a n e o us firi n g i n p eri p h eral a n d pri m ar y aff ere nt a n d 
d ors al r o ot ga n gli o ni c n e ur o ns.    Tr eat m e nt wit h a n α 2δ l i ga n d is re p ort e d t o re d u ce t h e 
cal ci u m i o n ( C a 2 +) i nfl u x t hr o u g h v olta ge-d e p e n d e nt Ca 2 + c h a n n els, a n d t h eref ore t o 
r e d u ce t h e s u bs e q u e nt r elease of e x cit at or y n e ur otra ns mitt ers s u c h as gl ut a m at e, 
n or e pi n e p hri n e, a n d s u bsta n ce  P.1 , 2, 3,4 
 
I n n o n cli ni cal e x peri m e nts, D S -5 5 6 5 s h o w e d p ot e nt a n d hi g hl y s p ecifi c bi n di n g affi nit y 
t o t h e α2δ s u b u nit.    D S -5 5 6 5 als o d e m o nstrat e d a str o n ger a n al gesi c effect t h a n 
pr e ga b ali n i n r o d e nt m o d els of n e ur o p at hi c p ai n.    A d diti o n al i nf or m ati o n o n n o n cli nical 
st u di es ca n b e f o u nd i n t he I n v esti gat or’s Br oc h ure.  
 
1. 1. 1. 5  
Cli ni c al E x p eri e n ce  
T h e effi cac y, s af et y, a n d t ol er a bilit y of D S - 5 5 6 5 w ere  e v al u at e d i n 2 P h as e 2 st u di es i n 
s u bj ects wit h D P N P i n t h e U S a n d Asi a. 
 
1. 1. 1. 5. 1  
P h as e 2 S t u d y i n t h e U S  
T his w as a r a n d o miz e d, d o u bl e-bli n d, pl ace b o - a n d acti ve -c o ntr olle d st u d y i n s u bj ects 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 1 of 1 0 1 
wit h D P N P i n t h e U S . 
 
I n t his st u d y, gr eat er m ea n decr eases fr o m b as eli n e t o e n d-of -treat m e nt ( Wee k 5) i n 
a v er a ge d ail y p ai n s c or e ( A D P S ) w ere o bs er v e d i n t h e D S - 5 5 6 5 treat m e nt gr o ups t h a n i n 
t h e pl ace b o  gr o u p.   T h e m ea n c h a n ges fr o m bas eli n e t o Wee k 5 ( wit h last o bser v ati o n 
carri e d for w ar d ( L O C F ) i m p ut e d f or missi n g v al u es) i n A D P S w ere - 2. 0, - 2. 3, - 2. 7, -2. 6, 
a n d -2. 8 f or t h e D S -5 5 6 5 5 m g Q D, 1 0 m g Q D, 1 5 m g Q D, 1 0 m g BI D, a n d 1 5 m g BI D 
tr eat m e nt gr o u ps, r es p ecti v el y.  B y c o m p aris o n, pl ace b o a n d pre ga b ali n s h o w e d m ea n 
c h a n ges of -1. 9 a n d -1. 8, r es p ecti v el y.  
 
T h e pri mar y a n al ysis w as a n a n al ysis of c o v ari a n ce ( A N C O V A) o n Wee k 5 L O C F d at a. 
T h e L S m ea n diff er e n ces v ers us place b o i n c h a n g e i n A D P S fr o m b aseli ne t o Wee k 5 
w er e -0. 2 2, -0. 5 3, -0. 9 4, -0. 8 8, a n d -1. 0 1 f or t he D S -5 5 6 5 5 m g Q D, 1 0 m g Q D, 1 5 m g 
Q D, 1 0 m g BI D, a n d 1 5 m g BI D tr eat m e nt gr o u ps, res p ecti v el y.  T h ese L S m ea n 
diff er e n ces w er e st atisti call y si g nifi ca nt at t h e D S -5 5 6 5 1 5  m g Q D ( P  = 0. 0 1 3 7), 1 0 m g 
BI D ( P  = 0. 0 1 7 1), a n d 1 5 m g BI D ( P  = 0. 0 0 6 0) d os e l e v els.  
 
I n t his st u d y, all D S-5 5 6 5 d ose l e v els w ere ge n erall y w ell t olerate d.  
 
At l east 1 tr eat m e nt -e m er ge nt a d v ers e e v e nt ( T E A E ) w as re p ort e d i n 5 2. 7 % of s u bj ects 
r ecei vi n g D S- 5 5 6 5 5 m g Q D, 5 0. 0 % of s u bj ects recei vi n g D S- 5 5 6 5 1 0 m g Q D, 5 6. 6 % of 
s u bj ects r ecei vi n g D S-5 5 6 5 1 5 m g Q D, 5 8. 9 % of s u bj ects recei vi n g D S -5 5 6 5 1 0 m g BI D, 
6 3. 2 % of s u bj ects r ecei vi n g D S -5 5 6 5 1 5 m g BI D, 4 4. 4 % of s u bj ects recei vi n g pl ace b o, 
a n d 6 0. 0 % of s u bj ect s r ecei vi n g pr e ga b ali n.   C o m m o n T E A Es (i e, t h os e re p ort e d i n ≥ 
5 % of s u bjects recei vi n g D S -5 5 6 5) w ere dizzi n ess ( 9. 4 %), h ea d ac h e ( 6. 1 %), a n d 
s o m n ol e n ce ( 6. 1 %).  M ost T E A Es w ere mil d or m o d erat e i n s e v erit y, a n d all s e v ere 
T E A Es r es ol v e d e x ce pt f or 1 e v e nt eac h of h e p ati c cirr h osis a n d ost e o art hritis.  At l east 
1 T E A E of s p eci al i nt er est ( e g, ce ntral n er v o us s yst e m ( C N S )-rel at e d e v e nts, e d e m a, 
vis u al dis or d ers, h e p ati c -r el at e d e v e nts, car di ac-relate d e v e nts, e v e nts rel at e d t o a b us e 
p ot e nti al) w as r e p orte d i n 1 0. 9 % of s u bj ects recei vi n g D S -5 5 6 5 5 m g Q D, 1 9. 6 % of 
s u bj ects r ecei vi n g D S-5 5 6 5 1 0 m g Q D, 2 6. 4 % of s u bj ects recei vi n g D S - 5 5 6 5 1 5 m g Q D, 
1 9. 6 % of s u bj ects r ecei vi n g D S -5 5 6 5 1 0 m g BI D, 2 8. 1 % of s u bj ects recei vi n g D S - 5 5 6 5 
1 5 m g BI D, 7. 4 % of s u bj ects r ecei vi n g pl ace b o, a n d 2 8. 0 % of s u bj ects recei vi n g 
pr e ga b ali n. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 2 of 1 0 1 
1. 1. 1. 5. 2  
P h as e 2 S t u d y i n Asi a 
T his w as a r a n d o miz e d, d o u bl e -bli n d, pl ace b o - a n d acti ve -c o ntr olle d st u d y i n s u bj ects 
wit h D P N P i n Asi a . 
 
T h e pri mar y e n d p oi nt w as t h e c h a n ge fr o m bas eli n e i n A D P S  t o Wee k 7 (wit h L O C F 
i m p ut e d f or missi n g v al u es).    F or t h e pri m ar y a n al ysis, a n A N C O V A w as perf or m e d 
usi n g tr eat m e nt as t h e f act or a n d b as eli ne A D P S as t h e c o v ari at e t o c o m p are t h e m ea n 
c h a n ge fr o m b as eli n e t o Wee k 7/ L O C F  b et w ee n eac h D S -5 5 6 5 treat m e nt gr o u p a n d 
pl ac e b o, b et w ee n eac h D S - 5 5 6 5 tr eat m e nt gr o u p a n d pre ga b ali n, a n d b et w ee n pre ga b ali n 
a n d pl ace b o.   T h e m ea n c h a n ges fr o m b as eli n e t o Wee k 7 ( wit h L O C F i m p ut e d f or 
missi n g v al u es) i n A D P S w er e - 1. 9, -1. 8, a n d -1. 7 f or  D S -5 5 6 5 5 m g BI D, 1 0 m g BI D, 
a n d 1 5 m g BI D  tr eat m e nt gr o u ps.    B y c o m p aris o n, pl ace b o a n d pre ga b ali n s h o w e d 
mea n c h a n ges of -1. 5 a n d -1. 4, r es p ecti v el y.  T h e pri m ar y a n al ysis w as a n A N C O V A o n 
Wee k 7 L O C F d at a. 
 T h e L S m ea n differe n ces v ers us place b o i n c h a n ge i n A D P S fr o m 
bas eli n e t o Wee k 7 wer e - 0. 4 2, -0. 3 7, a n d - 0. 3 0 f or t h e D S-5 5 6 5 5 m g BI D, 1 0 m g BI D, 
a n d 1 5 m g BI D tr eat m e nt gr o u ps, r es p ecti v el y.  T h es e L S mea n differe n ces w ere 
n u m eri call y l o wer t h a n t hat i n t h e pl ace b o gr o u p, alt h o u g h t h e re d u cti o n w as n ot 
st atisti call y si g nifica nt f or a n y tr ea t m e nt gr o u ps. 
 
All D S -5 5 6 5 d os e le v els w er e ge n er all y w ell t ol erat e d.    Bas e d o n d os e l e vel, at l east 1 
T E A E w as e x p eri e n ce d b y 4 8 . 9 % of s u bj ects i n t he D S - 5 5 6 5 5 m g BI D gr o u p , 6 3. 4 % of 
s u bj ects i n t h e D S-5 5 6 5 1 0 m g BI D gr o u p , 7 3. 3 % of s u bj ects i n t h e D S- 5 56 5 1 5 m g BI D 
gr o u p , 5 8. 1 % of s u bj ects r ecei vi n g p re ga b ali n 1 5 0 m g BI D, a n d 5 3. 4 % of s u bj ects 
r ecei vi n g pl ace b o. T h e m ost c o m m o n T E A Es (i e, t h os e re p ort e d i n ≥ 5 % of s u bj ects 
r ecei vi n g D S- 5 5 6 5) e x p eri e nce d b y s u bj ects t a ki n g D S -5 5 6 5 w ere: s o m n ol e n ce ( 1 4. 7 %) , 
dizzi ness  ( 1 1. 0 %), n as o p har y n gitis ( 8. 4 %). 
 
1. 2  
St u d y R ati o n al e  
C urr e ntl y a v aila bl e α 2δ li ga n ds, ga b a p e nti n a n d pre ga b ali n, are est a blis h e d as effecti v e 
first-li n e tr eat m e nts f or p ai n ass o ci at e d wit h di a b eti c p eri p h eral n e ur o p at h y ( D P N).2, 3  
H o w e v er, t h e d os a ge, a n d t h us effi cac y, of t h es e a ge nts is li mit e d b y fre q ue nt a n d 
si g nifi ca nt C N S-r el at e d si d e eff ects, i n cl u di n g di zzi n ess a n d s o m n ol e n ce; ass o ci at e d 
w ei g ht gai n a n d p eri p h er al e d e m a ca n als o b e pr o bl e m ati c.    As a res ult, a l ar ge 
pr o p or ti o n of p ati e nts wit h D P N P are l eft wit h i ns uffi ci e nt p ai n reli ef, a n d ne w treat m e nt 
o pti o ns ar e n ee d e d.   


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 3 of 1 0 1 
 
D S -5 5 6 5 is a n or al a n al g esi c dr u g bei n g d e v el o p e d f or D P N P a n d ot h er i n di cati o ns.   
D S -5 5 6 5 is a n a nt a g o nist t o t h e α 2δ s u b u nit of v olta ge -d e p e n d e nt C a 2 + c h a n n els, t h e m ai n 
tar get m ol ec ul e f or t h e a nal gesi c eff ect of pre ga b ali n a n d ga b a pe nti n.    N o n cli ni cal 
( S ecti o n 1. 1. 1. 4 ) a n d cli ni cal ( S ecti o n 1. 1. 1. 5 ) d ata s u p p ort t h e pr o gress of D S- 5 5 6 5 i nt o 
P h as e 3 st u di es i n D P N P t o e v al u at e t h e effect of D S -5 5 6 5 o n A D P S as c o m p are d t o 
pl ace b o d uri n g t h e c o urs e of a 1 4 w ee k (i n cl u di n g titrati o n  p eri o d) d o u bl e- bli n d 
tr eat m e nt p eri o d. 
 
1. 3  
Ris ks a n d B e n efits f o r St u d y S u bjects  
T h e r es ults fr o m n o ncli nical st u di es s u g gest t h at s u bj ects treat e d wit h D S - 5 5 6 5 m a y 
e x p eri e n ce i m pr o v e m e nt i n D P N P, p ost- h er p eti c ne ural gi a ( P H N ), a n d fi br o m yal gi a 
(F M ).   T h e cli ni cal effi cac y of D S -5 5 6 5 has b ee n e v al u at e d i n 2 P has e 2, m ulti -ce nt er, 
r a n d o miz e d, d o u bl e- bli n d, pl ace b o- a n d acti v e -c o m p arat or c o ntr oll e d a d a pti v e st u d y i n 
s u bj ects wit h D P N P.    I n D S 5 5 6 5- A-U 2 0 1 c o n d u ct e d i n t h e U S, D S -5 5 6 5 1 5 m g Q D, 
1 0 m g BI D, a n d 1 5 m g BI D tr eat m e nt gr o u ps d e m o nstrat e d st atisti call y si g nifi ca nt m ea n 
r e d u cti o ns i n A D P S fr o m b as eli n e t o e n d-of -treat m e nt c o m p are d t o pl ace b o.    I n 
D S 5 5 6 5 - A-J 2 0 2 c o n d u ct e d i n Asi a n c o u ntri es, D S-5 5 6 5 5 m g  BI D , 1 0 m g BI D, a n d 
1 5 m g BI D s h o we d n u m eri call y m ea n re d ucti o ns i n A D P S, alt h o u g h t h e re d u cti o n w as 
n ot st atisti call y si g nifi ca nt.    T hes e d at a pr o vi d e pr o of - of-c o n ce pt f or D S - 5 5 6 5 as a 
tr eat m e nt f or D P N P a n d s u g gest t h at D S-5 5 6 5 m a y h a v e utilit y i n ot h er c hr o ni c  p ai n 
c o n diti o ns s u c h as P H N a n d F M . 
 
A nti ci p at e d ris ks of D S -5 5 6 5 i n cl u d e t h e o cc urre nce of a d v ers e reacti o ns rel at e d t o C N S 
de pr essi o n, s u c h as dizzi ness a n d s o m n ol e n ce, as w ell as p eri p h eral e d e m a.   Ot h er  
n ot a bl e T E A Es t h at h a v e b ee n o bs er v e d i n P h as e 1  a n d P h ase 2 st u di es i n cl u d e el e v ati o ns  
of h e p ati c tr a ns a mi n as es a n d s ui ci de.   F or t h e a p pr o v e d α 2δ li ga n ds, i n a d diti o n t o 
dizzi ness, s o m n ol e n ce, a n d p eri p h er al e d e m a, certai n a d vers e reacti o ns re q uiri n g ca uti o n 
ha v e als o b ee n r e p ort e d, i n cl u di n g b ut n ot li mit e d t o: w ei g ht gai n, o p ht h al m ol o gic 
dis or d ers, s ui ci d al b e h a vi or a n d i deati o n, a n gi o e d e m a, h y p ers e nsiti vit y, a br u pt or ra pi d 
dis c o nti n u ati o n, a b us e p ot e nti al, c o n gesti v e h eart fail ure, re n al fail ure, a n d creati n e 
ki n as e el e v ati o ns.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 4 of 1 0 1 
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  
2. 1  
St u d y O bj ecti v es  
2. 1. 1  
Pri m a r y O bj ecti ve  
T h e pri mar y o bj ecti v e is t o c o m p ar e c h a n ge i n t h e A D P S fr o m b as eli n e t o Wee k 1 4 i n 
Asia n s u bj ects wit h D P N P  r ecei vi n g 1 0 m g BI D a n d 1 5 m g BI D of D S -5 5 6 5 v ers us 
pl ace b o . 
 
2. 1. 2  
S ec o n d a r y O bj ecti v es  
• 
To c o m p ar e c h a n ge i n t h e A D P S fr o m b as eli n e t o Wee k 1 4 i n Asi a n s u bj ects wit h 
D P N P r ecei vi n g 1 5 m g Q D of D S-5 5 6 5 v ers us  place b o  
• 
To c o m p ar e t h e A D P S  r es p o n der rat e ( pr o p orti o n of s u bj ects wit h ≥ 3 0 %, a n d ≥ 5 0 % 
r e d u cti o n fr o m b as eli n e t o Wee k 1 4) b et w ee n eac h  ar m of D S -5 5 6 5 a n d pl ace b o  
• 
To e v al u at e t h e effect of D S -5 5 6 5 o n a d diti o n al p ai n q u esti o n n aires, i n cl u di n g t h e 
S h ort -F or m M c Gill P ai n Q u esti o n n aire ([ S F -M P Q]: s e ns or y, affecti v e , a n d t ot al 
s u bs cal es, Vis u al A n al o g S cal e [ V A S], a n d pres e nt p ai n i nt e nsit y) a n d t he m o difi e d 
Bri ef P ai n I n v e nt or y ( S h ort F or m) ([ B PI-S F ]: pai n i nt e nsit y, f u n cti o n alit y, a n d 
i m p act of p ai n) 
• 
To ass ess t h e eff ect of D S -5 5 6 5 o n q u alit y of life ( Q O L), m o o d a n d sl ee p, pati e nt 
i m pr essi o ns i n p ai n, a n d s y m pt o ms 
• 
To c oll ect bl o o d s a m pl es f or  ph ar m ac o ki n eti c an al ys es  
• 
To c h ar act eriz e t h e s af et y a n d t ol era bilit y of D S -5 5 6 5, b as e d o n t h e i n ci d e n ce of 
a d v ers e e v e nts ( A Es), disc o nti n u ati o ns d u e t o A Es, c h a n ges i n p h ysi cal fi n di n gs, a n d 
r es ults of s af et y m o nit ori n g 
 
2. 2  
St u d y H y p ot h esis 
T h e pri mar y h y p ot h esis of t his P h as e 3 d o u bl e -bli n d st u d y is t h at at l east o n e of t h e d os e 
ar m  of D S -5 5 6 5 1 0 m g BI D a n d 1 5 m g BI D will b e s u p eri or t o pl ace b o i n m a n a gi n g 
D P N P as m eas ur e d b y A D P S a n d will b e ge n erall y w ell t ol erat e d.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 5 of 1 0 1 
3.  
S T U D Y D E SI G N  
3. 1  
O v er all Pl a n  
3. 1. 1  
St u d y Ty p e  
T his is a m ulti n ati o n al, r a n d o miz e d, d o u bl e -bli n d, pl ace b o -c o ntr oll e d , p arallel - gr o u p 
st u d y f or tr eat m e nt of D P NP. 
 
St u d y sit es: A p pr o xi m at el y 2 0 0 st u d y sit es i n J a pa n, K orea, Tai w a n  a n d M al a ysi a . 
Pla n n e d s a m pl e siz e:  A p pr o xi m at el y 7 5 0 s u bj ects will b e ra n d o mize d i n t h e st u d y. 
 
3. 1. 2  
St u d y S c h e me  
T h e t ot al st u d y d ur ati o n (f or a n i n di vi d u al s u bj ect’s p arti ci p ati o n) is a p pr o xi mat el y 1 6 
w ee ks, c o nsist i n g of a n o bs er v ati o n p eri o d  ( 1 w ee k), a titrati o n p eri o d  ( 1 t o 2 w ee ks) , a 
fi x e d-d os e p eri o d  ( 1 2 t o 1 3 w ee ks) , a nd a f oll o w - u p p eri o d ( 1 w ee k) ( S ee st u d y s c h e m e 
bel o w). 
 
If pr o hi bit e d c o n c o mit a nt m e di cati o ns are use d wit hi n 7 d a ys pri or t o o bt ai ni n g writt e n 
i nf or m e d c o ns e nt, s cr ee ni n g will f oll o w a w as h o ut p eri o d of at l east 7 d a ys pri or t o 
scr ee ni n g.    I nf or m e d c o ns e nt m ust b e o bt ai n e d b ef ore i niti ati n g w as h o ut or s cree ni n g .   
E nr oll m e nt will b e li mit e d t o s u bj ects w h o m eet t he i n cl usi o n/ e x cl usi o n crit eri a d es cri be d 
i n Secti o n 4. 1. 2  a n d 4. 1. 3 .  S u bj ect s will b e ra n d o miz e d t o pl ace b o or o ne of 3 differe nt 
ar ms  of D S - 5 5 6 5 ( D S- 5 5 6 5 1 5 m g Q D, 10 m g BI D, or 1 5 m g BI D) wit h ra n d o miz ati o n 
r ati o of 2: 1: 1: 1 i n a d o u ble-bli n d f as hi o n at ra n do mizati o n ( Visit  2).   I n creasi n g t h e 
pr o p orti o n of pl ace b o ar m is e x p ect e d t o mi ni mi ze t h e pl ace b o res p o ns e b y re d u ci n g t h e 
e x p ect ati o ns of s u bj ects assi g n e d t o acti v e dr u g.   Aft er t h e c o m pl eti o n of a d mi nistrati o n, 
s u bj ects will b e m o nit or e d f or a n a d diti o n al f oll o w-u p o bs er v at i o n peri o d of 1 w ee k.   
F oll o w- u p o bs er v ati o n is n ot r e q uir e d f or s u bj ects w h o are e nr oll e d i n a n o pe n- l a bel 
e xt e nsi o n st u d y. 
F urt h er d et ails of t h e st u d y pr o ce d ur es are pr o vi d e d i n t h e S c h e d ul e of E v e nts 
( S ecti o n 1 7. 1 ) a n d St u d y Pr o ce d ur es ( S ecti o n 6 ). 




 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 7 of 1 0 1 
a v er a ge ti m e t o f all asl ee p, a v er a ge sl ee p ti m e p er ni g ht , a n d t h e 5- p oi nt s cal es 
r el at ed t o sl ee p dist ur b a n ce  
• 
C h a n ge fr o m b as eli n e i n t h e H os pit al A n xiet y a n d D e pressi o n S cale ( H A D S ) 
i n cl u di n g 7 it e ms t o s c or e d e pr essi o n ( 4- p oi nt s cale) a n d 7 it e ms t o s c ore a n xiet y 
( 4-p oi nt s cale)  
• 
C h a n ges fr o m b aseli n e i n Q O L , usi n g t h e S F- 3 6 i n cl u di n g p h ysi cal f u n cti o ni n g, 
r ol e-p h ysi cal, s o ci al f u n cti o ni n g, b o dil y p ai n, m e ntal h ealt h, r ol e -e m oti o n al, vit alit y, 
a n d ge n er al p er ce pti o n of h ealt h  
• 
E v al u ati o n of S y m pt o m s, ass ess e d o n a 4 - p oi nt s cal e 
 
3. 1. 4  
D u r ati o n of S u bj ect P a rti ci p ati o n  
T h e d ur ati o n of s u bj ect p arti ci p ati o n will b e a p pr o xi mat el y 1 6 w ee ks, i n cl u di n g a n 
o bser v ati o n p eri o d,  a titr ati o n p eri o d,  a fi x e d -d os e p eri o d, a n d a f oll o w - u p p eri o d .  N o 
f oll o w- u p o bs er v ati o n is r e q uir e d f or s u bj ects e nr oll e d i n a n o pe n-l a bel e xte nsi o n st u d y. 
 
3. 2  
Dis c ussi o n of St u d y D esi g n  
3. 2. 1  
D os a g e of D S- 5 5 6 5  
It is e x p ect e d t h at, i n p ost-m ar k eti n g, t h e d os e of D S - 5 5 6 5 will b e a dj uste d u p or d o w n 
de p e n di n g o n t h e p ati e nt’s s y m pt o ms.    T h eref ore, t o i d e ntif y m ulti pl e rec o m m e n d e d 
cli ni cal d oses, t h e f oll o wi n g 3 d o s es of D S-5 5 6 5 w ere s el ect e d i n t h e st u d y f or t h e 
fi x e d-d os e p eri o d: 1 5 m g Q D, 1 0 m g BI D, a n d 1 5 m g BI D.    T h e d os es w ere s el ect e d 
bas e d o n t h e res ults of t h e 2 P h ase 2 st u di es of D S -5 5 6 5 i n pati e nts wit h D P N P.  
 
I n t h e Asi a n P h as e 2 st u d y ( D S 5 5 6 5 - A-J 2 0 2), DS- 5 5 6 5 s h o w e d n u m eri call y greater 
i m pr o v e m e nt i n A D P S at d os es of 5 m g BI D, 1 0 m g BI D, a n d 1 5 m g BI D t h a n pl ace b o, 
alt h o u g h t hes e diff er e n ces v ers us pl ace b o w ere n ot st atisti call y si g nifi ca nt.    D S - 5 5 6 5 
als o s h o w e d st atisti call y si g nifi ca nt i m pr o v e m e nt i n A D P S at d os es of 1 5 m g Q D, 1 0 m g 
BI D, a n d 1 5 m g BI D t h a n pl ace b o i n t h e U S P h as e 2 st u d y ( D S 5 5 6 5 - A-U 2 0 1).   I n  
a d diti o n, t h e r es ults f or t he s ec o n d ar y effi cac y e n d p oi nts i n t h e Asi a n P h ase 2 st u d y 
s u g gest e d a d os e-d e p e n d e nt tr eat m e nt effect of D S -5 5 6 5.   S afe t y a n al ysis i n t h e Asi a n 
P h as e 2 st u d y s h o w e d t h at D S -5 5 6 5 w as t ol erat e d at d os es of 5 m g BI D, 1 0 m g BI D, a n d 
1 5 m g BI D, alt h o u g h t h er e w er e s o m e A Es t hat s h o ul d b e m o nit ore d i n f ut ure cli ni cal 
st u di es of D S- 5 5 6 5. 
 
O n t h e b asis of t h e r es ults i n t h e Asi a n P h as e 2 st u d y, 1 0 m g BI D is e x p ecte d t o ac hi e v e a 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 8 of 1 0 1 
g o o d b al a n ce b et w ee n effi cac y a n d s afet y.    I n a d diti o n, 1 5 m g BI D is e x p ect e d t o s h o w 
a b etter effi cac y pr ofil e t ha n 1 0 m g BI D, alt h o u g h 1 5 m g BI D res ult e d i n a s o m e w h at 
hi g h er i n ci d e n ce of T E A Es.    T h e r es u lts i n t h e U S P h as e 2 st u d y s u g geste d t h at 1 5 m g 
Q D m a y b e t h e mi ni m u m eff ecti ve d ose.    H o w e v er, t h e Asi a n P h as e 2 st u d y di d n ot 
i n cl u d e t h e d os e of 1 5 m g Q D.    T h eref ore, i n t his Asi a n P h as e 3 st u d y i n pati e nts wit h 
D P N P, 1 0 m g BI D a n d 1 5 m g BI D w ere s el ec t e d as pri m ar y d os es, a n d 1 5 m g Q D as a 
sec o n d ar y d os e. 
 
T h e d os e of D S -5 5 6 5 will b e l o w er d uri n g t h e titrati o n p eri o d t h a n t h e fi x e d -d os e p eri o d 
f or s u bject s af et y. 
 
3. 2. 2  
D u r ati o n of St u d y Tre at me nt  
I n t h e d o u bl e- bli n d st u d y, t h e effi cac y of D S-5 5 6 5 vers us pl a ce b o i n n e ur o p at hi c p ai n 
will b e e v al u at e d.    T h e E ur o p ea n M e di ci n es A ge nc y ( E M A) g ui d eli n e 5 rec o m m e n ds 
t h at t h e tr eat m e nt d ur ati o n f or fi x e d d os e p eri o d b e 1 2 w ee ks or l o n ger.    T h eref ore, t h e 
st u d y will h a v e 1 2 t o 1 3 w ee ks of fi x e d-d os e p eri o d.    I n a d diti o n, t a ki n g i nt o 
c o nsi d er ati o n f or s u bj ect s af et y, t h e st u d y will h a ve 1 t o 2 w ee ks of titrat i o n p eri o d b ef ore 
t h e fi x e d-d os e p eri o d.    T h e d os e of D S -5 5 6 5 will b e l o w er d uri n g t h e titrati o n p eri o d 
t h a n t h e fi x e d-d ose p eri o d.  
 
3. 2. 3  
C o nt r ol Tre at me nt  
Place b o will be us e d as t he c o ntr ol treat m e nt i n t he st u d y.    I n cl usi o n of place b o is 
r e q uir e d i n t h e E M A g ui deli n e 5. 
 
3. 2. 4  
St u d y E n d p oi nts  
I n acc or da n ce wit h rec o m m e n d ati o ns fr o m t h e E M A g ui d eli n e, t h e pri m ar y e n d p oi nt w as 
sel ect e d as i nt er gr o u p c o m p aris o n of t h e a m o u nt of c h a n ge i n fi n di n gs o n a n 1 1 - p oi nt 
pai n s cal e.    P atie nts wit h ne ur o p at hi c p ai n ca n e x peri e nce  s eri o usl y d ecreas e d Q O L, n ot 
o nl y fr o m p ai n b ut als o fr o m f act ors s u c h as p o or sl ee p.    To ass ess t h es e fact ors, 
sec o n d ar y e n d p oi nts wer e s el ect e d i n areas s u c h as sl ee p a n d Q O L.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 2 9 of 1 0 1 
4.  
S T U D Y P O P U L A TI O N  
4. 1  
E n r oll me nt  
S u bjects ar e t o b e e nr oll e d i n t his st u d y usi n g t h e I nt eracti v e We b R es p o nse S yst e m 
(I W R S) i n acc or d a n ce wit h t he pr o ce d ures s p ecifi e d b el o w.   I n v esti gat ors will assi g n 
eac h c o ns e nti n g s u bj ect a u ni q u e s u bj ect i d e ntifi cati o n c o d e , a n d t h at i d e ntifi cati o n co d e 
will b e r ec or d e d  i n a s u bject i d e ntifi cati o n l o g. 
 
4. 1. 1  
Pr o ce d u res f o r S u bj ect E nr oll me nt  
T h e  i n v esti gat or or s u b-i n v esti gat or will p erf or m a m a n d at or y i nter vi e w t o ass ess t h e 
eli gi bilit y of s u bj ects f or t h e st u d y, aft er o bt ai ni n g eac h s u bj ect’s writt e n i nfor m e d 
c o ns e nt, a n d will m a k e n ecess ar y e ntri es i n t h e I W R S at s cree ni n g.   A n y s u bj ects w h o 
ha v e b ee n t a ki n g pr o hi bite d c o n c o mit a nt dr u gs will u n d er g o a w as h o ut p eri o d of 7 d a ys 
or m ore, pri or t o t h e o bs er v ati o n  p eri o d.  Aft er t he s cree ni n g visit ( Visit 1), a 7-d a y 
o bser v ati o n p eri o d will b e i m pl e m e nt e d b ef ore ra n d o miz ati o n. 
 
At r a n d o mizati o n ( Visit 2), aft er c o m pl eti o n of t h e o bs er v ati o n  p eri o d, t h e i n v esti gat or or 
s u b-i n v esti gat or will a gai n p erf or m a m a n d at or y i nt er vi e w t o ass ess t h e eli gi bilit y of 
s u bj ects f or t h e st u d y a n d will ma k e n ecess ar y e ntri es i n t he s u bj ect re gistrati o n s yst e m.  
 
If t h e e nr oll e d s u bj ect is c o nfir m e d t o b e eli gi bl e, t h e i n v esti gat or or s u b-i n vesti gat or will 
be n otifi e d of t h e st u d y dr u g i d e ntifi er assi g n e d t o t h e s u bj ect b y t h e IW R S .   T h e  
i n v esti gat or or s u b-i n vesti gat or will c o nfir m t h e re p ort e d st u d y dr u g i d e ntifi er, a n d will 
assi g n t he i n v esti gati o n al pr o d u cts l a b el e d wit h t he st u d y dr u g i d e ntifi er f or t h e s u bj ect. 
 
If t h e s u bj ect is c o nsi d er e d i n eli gi bl e f or t h e st u d y, t h e i n vesti gat or or s u b-i n v esti gat or 
will i nf or m t h e s u bj ect, a n d will pr o vi d e st a n d ar d care.  
 
4. 1. 2  
I n cl usi o n C rit eri a 
S u bjects m ust s atisf y all of t h e f oll o wi n g crit eri a t o be i n cl u d e d i n t h e st u d y . 
1)  A ge ≥ 2 0 years at i nf or m e d c o ns e nt  
2)  A ble t o gi v e writt e n i nf or m e d c o nse nt f or st u d y p arti ci p ati o n, u n d erst a n d pr o ce d ure s 
of t his st u d y, a n d c o m pl ete p ati e nt -re p ort e d q u esti o n naires a d e q u at el y  
3)  Ty p e 1 or t y p e 2 di a b et es m ellit us at s cree ni n g  
4)  Pai nf ul dist al s y m m etri c p ol y n e ur o p at h y,  di a g n ose d  at l east 6 m o nt hs pri or t o 
scr ee ni n g (s ee Pr oce d ur es m a n u al f or t he Di a g n osis of Di a b eti c P eri p h eral 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 0 of 1 0 1 
N e ur o p at h y a n d N e ur ol o gi cal E x a mi n ati o n  f or d etails) 
5)  At s cr ee ni n g, a pai n s cal e of ≥ 4 0 m m o n V A S of S F -M P Q  
6)  At r a n d o mizati o n, a p ai n s cal e of ≥ 4 0 m m o n V A S of S F - M P Q, a n d c o m pleti o n of at 
least 4 d a ys of d ail y p ai n di ari es wit h a n A D P S of ≥ 4 o ver t h e p ast 7 d a ys o n t h e 
1 1 - p oi nt N R S  
 
Rati o n al e  
1)  
P h as e 1 a n d P h as e 2 st u dies i n el d erl y s u bj ects s h o w e d n o n ot a bl e differe n ces 
fr o m t h e r es ults o bt ai n e d i n n o n-el d erl y s u bj ects wit h re gar d  t o s afet y, 
t ol er a bilit y, a n d p h ar m ac o ki n eti cs ( P K ).   T h us, n o u p p er li mit w as pl ace d o n 
a ge i n t his st u d y.    Beca us e t h e P K a n d s afet y of t his dr u g h a v e n ot b ee n 
est a blis h e d i n c hil dr e n, a n d i n or d er t o o bt ai n a p pr o pri at e i nf or m e d c o ns e nt fr o m 
t h e s u bj ects t h e ms el v es, t h e l o w er a ge li mit w as s et at 2 0 years of a ge. 
2) 
T h e st u d y will b e c o n d u ct e d i n acc or d a n ce wit h G o o d Cli nical P racti ce ( G C P ). 
3), 4)  
T h e st u d y will i n v esti gat e D P N P. 
5), 6)  
I n or d er t o ass ess t h e effi cac y of t he i n v esti gati o n al pr o d u ct a p pr o pri at el y, t h e 
st u d y will b e li mit e d t o s u bj ects w h o e x p eri e n ce pai n of m o d erat e or greater 
i nt e nsit y. 
 
4. 1. 3  
E x cl usi o n C rit eri a  
S u bjects w h o m eet a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m p artici p ati o n i n t h e 
st u d y. 
1)  At s cr ee ni n g, a pai n s cal e of ≥ 9 0 m m o n V A S of S F -M P Q  
2)  At r a n d o mizati o n, a p ai n s cal e of ≥ 9 0 m m o n V A S of S F -M P Q, or at l east a d ail y 
pai n s c ore of ≥ 9 d uri n g o bser v ati o n p eri o d  
3)  H b A 1c ( Nati o n al Gl yc o h e m o gl o bi n St a n d ar diz ati o n Pr o gra m) > 1 0. 0 % at scree ni n g  
4)  U n c o ntr olle d bl o o d gl u c os e at s cree ni n g or ra n d o mizati o n t h at ma y re q uire c h a n ges 
i n di a b et es tr eat m e nt ( n o n-i ns uli n dr u g t h era p y, e x ercis e t h era p y, di et t h era p y) d uri n g 
t h e st u d y 
5)  Ot her s e v er e p ai n at s cr ee ni n g or ra n d o miz ati o n, u nrel at e d t o D P N , t h at m a y 
c o nf o u n d t h e assess m e nt of D P N P 
6)  N e ur ol o gi c dis or d ers at s cr ee ni n g or ra n d o miz ati o n, u nrel at e d t o D P N , t h at m a y 
c o nf o u n d t h e assess m e nt of D P N P 
7)  Maj or ps yc hi atri c dis or d ers  at s cree ni n g or  ran d o mizati o n  
8)  A m p ut ati o n of l o w er li m b parts, ot her t h a n t o es, pri or t o  s cree ni n g or ran d o miz ati o n  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 1 of 1 0 1 
9)  Us e of pr o hi bit e d c o n c o mit a nt dr u gs wit hi n 7 d a ys or  c h a n ge of restri ct e d 
c o n c o mit a nt dr u gs wit hi n 3 0 d a ys pri or t o s cree ni n g  
1 0)  S ki n c o n diti o ns t h at c o ul d c o nf o u n d t h e assess m e nt of D P N P  
1 1)  Pr e vi o us a d mi nistr ati o n  of pr e ga b ali n  ≥ 3 0 0 m g/ da y or ga b a p e nti n  ≥ 1 2 0 0  m g/ d a y , 
decl ar e d  l ac k of eff ect 
1 2)  Cr eati ni n e clear a n ce ( usi n g t h e C o c k cr oft -G a ult e q u ati o n) < 6 0 m L/ mi n  at scree ni n g  
1 3)  M ali g n a n c y ot h er t h a n b as al cell carci n o m a wit hi n t h e p ast 2 years  pri or t o s cree ni n g  
1 4)  Cli ni call y si g nifi ca nt u nsta bl e n e ur ol o gic, o p ht h al m ol o gic, h e p at o bili ar y , r es pirat or y, 
he m at ol o gi c ill n ess  or  u nst a ble car di o v as c ul ar dis eas e ( e g, s e v ere h y p ote nsi o n, 
u n c o ntr oll e d car di ac arr h yt h mi a, or m y o car di al i nfarcti o n ) wit hi n 1 2 m o nt hs pri or t o 
scr ee ni n g 
1 5)  Cli ni call y si g nifi ca nt fi n di n gs o n el ectr o car di o gr a m ( E C G ) at s cree ni n g  
1 6)  Hist or y of p er ni ci o us a n e mia, u ntreat e d h y p ot h yr oi dis m, or h u m a n 
i m m u n o d efi ci e n c y vir us i nf ecti o n 
1 7)  K n o w n hist or y of p ositi v e H e p atitis B a nti ge n or H e p atitis C a nti b o d y  
1 8)  Pr e g n a n c y, p ot e nti al pr e g n a n c y, breast fee di n g, or s u bj ect u n willi n g t o t a k e reli a ble 
c o ntr ace pti ve m eas ur es  d uri n g t h e st u d y or  f or 4 w ee ks aft er st u d y c o m pl eti o n   
1 9)  K n o w n h y p ers e nsiti vit y t o pr e ga b ali n  or ga b a p e nti n  
2 0)  Partici p ati o n i n a n ot her cli ni cal st u d y, eit h er c urre ntl y or wit hi n 3 0 d a ys pri or t o 
pr o vi di n g of i nf or m e d c o ns e nt 
2 1)  E x p eri e n ce of p arti ci p ati n g D S -5 5 6 5 cli ni cal st u d y  a n d recei vi n g i n v esti gati o n al 
pr o d u ct 
2 2)  A b us e of illi cit dr u gs or al c o h ol wit hi n o n e  year  pri or t o s cree ni n g 
2 3)  Res p o ns e of “ yes ” t o a n y of t h e q u esti o ns o n t h e  C ol u m bi a-S ui ci d e S e v erit y R ati n g 
Scal e ( C -S S R S) at s cree ni n g or ra n d o miz ati o n i n relati o n t o e ve nts o cc urri n g wit hi n 
t h e p ast 1 2 m o nt hs 
2 4)  Pr e vi o us tr eat m e nt wit h dr u gs t h at c o ul d ca us e irre v ersi bl e reti n al d e ge n erati o n  
2 5)  At s cr ee ni n g, c li ni cal la b or at or y v al u es e x cee di n g li mits list e d i n Ta bl e 4- 1  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 2 of 1 0 1 
Ta bl e 4- 1   He m at ol o g y/ Bl o o d C h e mistr y Li mits  
H e m at ol o g y  
H e m o gl o bi n  
< 1 0 g/ d L Fe m al es  
< 1 2 g/ d L M al es  
H e m at o crit  
< 3 2 % Fe m al es  
< 3 5 % M al es  
Plat el et C o u nt  
< 1 0 0  0 0 0 /m m 3 
W B C  
< 2 5 0 0/ m m 3 
A bs ol ut e Ne utr o p hil C o u nt  
< 1 5 0 0/ m m 3 
Bl o o d C h e mistr y  
A S T ( G O T)  
> 2. 0 ×  U L N  
A L T ( G P T)  
> 2. 0 ×  U L N  
A L P  
> 1. 5 ×  U L N  
T -Bil  
> 1. 2 a ×  U L N  
B U N   
> 1. 5 ×  U L N  
Cr eati n e Ki n as e  
> 3. 0 ×  U L N  
Ser u m Cr eati ni n e  
> 1. 6 m g/ d L ( > 1 4 1. 4 m ol/ L)  
a：If a s u bject has t otal bilir u bi n 1. 2 > U L N: u nc o nj u g ate d a n d c o nj u gate d bilir u bi n fr acti o ns s h o ul d 
be a nal yz e d a n d o nl y s u bje cts d o c u me nte d t o ha ve Gil bert’s s y n dr o me ma y be e nr olle d.  
 
2 6)  T h e s u bj ect w h o is c o nsi der e d i n a p pr o pri at e f or t he st u d y at t h e dis creti o n of t h e 
i n v esti gat or or s u b-i n vesti gat or 
2 7)  Res p o ns e of “ yes ” t o t h e s ui ci dalit y q u esti o n (c urre nt or past) o n t h e M aj or 
D e pr essi v e E pis o d e M o d ul e ( M o d ul e A) or res p o ns e of “ yes ” t o a n y q u esti o n  of  B 1 b, 
B 3 t hr o u g h B 1 1 c , B 1 3, or B 1 4 i n t h e S ui ci dalit y M o d ul e ( M o d ul e B) o n t he 
Mi ni -i nter n ati o n al N e ur o ps yc hi atri c I nt er vi e w ( MI NI) I nt er vi e w ( Versi o n 6. 0) at 
scr ee ni n g 
 
Rati o n al e  
1) , 2) T h es e crit eri a w er e s el ect e d s o t h at effi cac y c o ul d n ot b e a p pr o pri at el y ass ess e d i n 
t h es e s u bj ects, b eca us e r e p orti n g e xtre m e p ai n m a y refl ect ps yc h os o ci al distress, 
a n d m a y r efl ect p ati e nts’ lac k of c o m pre h e nsi o n t o acc urat el y rat e t h eir p ai n.  
3) , 4), 5), 6), 7), 8), 9), 1 0) T h ese crit eri a w ere s el ect e d s o t h at effi cac y  a n d s afet y c o ul d 
be a p pr o pri at el y ass ess e d i n s u bj ects.  
1 1 ), 2 1) T h es e crit eri a w er e s el ect e d o ut of c o nsi derati o n f or effi cac y ass ess m e nt i n  
s u bj ects. 
1 2), 1 3 ), 1 4), 1 5), 1 6), 1 7), 1 8), 1 9), 2 0), 2 2), 2 3), 2 4), 2 5), 26), 2 7)  T h es e crit eri a w ere 
sel ect e d o ut of c o nsi d erati o n 
f or t he s afet y of s u bj ects. 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 3 of 1 0 1 
 
4. 2  
S u bj ect Wit h d r a w al  
D at a fr o m all r a n d o miz e d s u bj ects ar e i m p ort a nt t o ac hi e v e st u d y o bj ecti v es, a n d s u bj ects 
s h o ul d b e e n c o ur a ge d t o a d h er e t o pr ot o c ol i nstr u cti o ns a n d visit s c h e d ul es.    H o w e v er, 
i n acc or d a n ce wit h t h e D ecl ar ati o n of H elsi n ki a n d ot h er a p pli ca bl e re g ul ati o ns, a s u bj ect 
has t h e ri g ht t o wit h dr a w fr o m t h e st u d y at a n y ti me a n d f or a n y reas o n wit h o ut prej u di ce 
t o his or h er f ut ur e m e di cal car e b y t h e st u d y p h ysi ci a n or at t h e st u d y sit e.    T h e 
i n v esti gat or is als o fr ee t o t er mi n at e a s u bj ect’s i n v ol v e m e nt i n t h e st u d y at a n y ti m e if 
t h e s u bj ect’s cli ni cal c o n diti o n w arr a nts s u c h acti o n.    T h e s p o ns or or re g ul at or y 
a ut h orities als o m a y r e q u est ter mi n ati o n of t h e st u d y at a n y ti m e d u e t o safet y iss u es or 
c o n cer ns r el at e d t o st u d y c o n d uct.  
 
4. 2. 1  
Wit h d r a w al C rit eri a  
If a s ubj ect m eets t h e f oll o wi n g wit h dra w al criteria, t h at s u bj ect s h o ul d b e wit h dra w n 
fr o m t h e st u d y. 
• 
Diffi c ult y of c o nti n ui n g t he st u d y d u e t o A E  
• 
A E  r el at e d t o s ui ci de (if t h ere are a n y “ yes ” res p o ns es t o a n y of t h e q u esti o ns i n t h e 
C- S S R S)  
• 
S u bjects wit h a n y of t h e f oll o wi n g el e v ati o ns i n cli ni cal l a b orat or y v al u e s 
• 
I n cr eas e i n al a ni n e a mi n otr a nsferas e ( A L T) or as partat e a mi n otra nsferas e ( A S T) 
≥ 5 x u p p er li mit of n or mal ( U L N)  
• 
A L T or A S T ris es t o ≥ 3 x U L N a n d p ersists f or m ore t h a n 2 w ee ks  
• 
C o n c urr e nt i ncr eases i n A L T or A S T ≥ 3 x U L N a n d t ot al bilir u bi n  ( T-Bil ) ≥ 2 x 
U L N  
• 
A L T or A S T ≥ 3 x U L N ass o ciat e d wit h a cli ni cal pres e nt ati o n s u g gesti v e of 
li v er i nj ur y (i e, i n cl u di n g t h e a p p eara n ce of fati g u e, n a us ea, v o miti n g, j a u n di ce, 
ri g ht u p p er q u a dra nt p ai n or t e n d er n ess, fe v er, ras h, a n d/ or e osi n o p hili a)  
• 
Wit h dr a w al b y su bj ect (i e, wit h dra w al of c o ns e nt)  
• 
Maj or d e vi ati o n fr o m st u d y pr o ce d ure  
 
4. 2. 2  
R e as o ns f o r Wit h d r a w al  
If a s u bj ect dis c o nti n u es fr o m t h e st u d y treat m e nt f or a n y reas o n, t h e d at e a n d t h e reas o n 
f or dis c o nti n u ati o n m ust be r ec or de d o n t h e El ectr o ni c C as e R e p ort F or m ( e C R F ) usi n g 
t h e f oll o wi n g crit eri a. 
F or s u bj ects wit h dr a w n pri or t o r a n d o miz ati o n b ut aft er si g ni n g i nf or m e d c o ns e nt  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 4 of 1 0 1 
• 
S cr ee n f ail ur e  
• 
Wit h dr a w al b y s u bj ect ( e g, A E , Lac k of effi cac y [L O E ], Ot h er) 
• 
P h ysi ci a n d ecisi o n  
• 
Ot her  
 
F or s u bj ects wit h dr a w n aft er r a n d o miz ati o n b ut b ef ore c o m pl eti n g t h e st u d y as p er 
pr ot o c ol 
• 
A E  
• 
D eat h  
• 
L O E  
• 
L ost t o f oll o w-u p  
• 
Pr ot o c ol vi ol ati o n 
• 
Pr e g n a n c y  
• 
St u d y ter mi n at e d b y s p o ns or 
• 
Wit h dr a w al b y su bj ect ( e g, A E , L O E , Ot h er)  
• 
Ot her  
 
If a s u bj ect is wit h dr a w n d ue t o n ee d  f or a pr o hi bit e d m e di cati o n, t h e reas o n m a y b e 
r ec or de d as L O E , as a p pr o pri at e.  R eas o ns rec or de d u n d er “ Pr ot o c ol vi ol ati o n ” m a y 
i n cl u d e f ail ur e t o c o m pl y wit h pr ot o c ol re q uire m e nts or st u d y pr o ce d ures. 
 
F or all s u bj ects w h o wit h dr a w fr o m t h e st u d y, t h e i n v esti gat or m ust c o m plete a n d re p ort  
perti n e nt o bs er v ati o ns as t h or o u g hl y as p ossi bl e u p t o t h e d at e of wit h dra w al , i n cl u di n g 
t h e d at e of l ast tr eat m e nt a n d t h e r eas o n f or wit h dra w al. 
 
If a s u bj ect is wit h dr a w n d u e t o a n A E, t h e in v esti gat or s h o ul d f oll o w t h e s u bj ect u ntil  t h e 
A E h as r es ol v e d or st a bilize d.  
 
All s u bj ects w h o ar e wit h dr a w n fr o m t h e st u d y s h o ul d c o m plet e pr ot o c ol -s p ecifi e d 
wit h dr a w al pr oce d ur es (s ee S ecti o n 4. 2. 3  a n d S ecti o n 6. 4 ). 
 
4. 2. 3  
Wit h d r a w al Pr o ce d u res  
If a s u bj ect wit h dr a ws or is wit h dr a w n fr o m t h e st u d y b ef ore t h e c o m pl eti o n of 
i n v esti gati o n al pr o d u ct a d mi nistrati o n, a p pr o pri at e m eas ures will b e i m pl e me nt e d.    I n 
a d diti o n, t o t h e e xte nt t h at t h e s u bj ect ’s c o o p erati o n ca n b e o bt ai ne d, all o bs er v ati o ns a n d 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 5 of 1 0 1 
tests s c h ed ul e d f or t h e E n d of Tr eat m e nt / E arl y Ter mi n ati o n Visit (Visit 1 0 ) will b e 
c o n d u ct e d , assess m e nts will b e m a d e at t h at ti m e p oi nt , all o bs er v ati o ns a n d t ests 
sc h e d ul e d f or t h e P ost-tr eat m e nt F oll o w- u p Visit ( Visit 1 1) will b e c o n d u cte d , a n d 
ass ess m e nts will b e m a d e 5 t o 1 4 d a ys  aft er t he  l ast d os e.    T his will b e d o ne f or all 
s u bj ects w h o w er e tr eat e d wit h e v e n o n e d os e of t he i n v esti gati o n al pr o d u ct .    If t h e 
wit h dr a w al w as d u e t o A Es, t h e o ut c o me f or t hat s u bj ect will b e rec or d e d t o t h e e xte nt 
p ossi bl e i n t h e C as e R e p ort F or m ( C R F ) (s ee S ecti o n 9. 1. 4 ).   If th e wit h dra w al w as d u e 
t o s ui ci d al b e h a vi or a n d/ or s ui ci d al i deati o n, a p pr o pri at e m eas ures will b e i m pl e m e nt e d 
s u c h as r ef erri n g t h e s u bj ect t o a s p ecialist. 
 
4. 2. 4  
St o p pi n g R ul es f o r t h e St u d y  
Cir c u mst a n ces u n d er w hic h t h e st u d y m a y b e st o p p e d bas e d u p o n i n d e p e n d e nt  D at a 
Saf et y M o nit ori n g B o ar d ( D S M B)  r ec o m m e n d ati o n are s p ecifi e d i n S ecti o n 1 1. 9. 
S p ecifi c st o p pi n g crit eri a h a v e b ee n s et u p re gar di n g 2 p ot e nti al s afet y c o n cer ns ( he p ati c 
e v e nts a n d s ui ci d e) as f oll o ws:  
He p ati c e v e nts st u d y st o p pi n g r ul es : 
If t h er e is o ne a dj u di cat e d H y’s l a w cas e o n D S - 5 5 6 5 i n a n y of t h e P h as e 3 st u di es a n d/or 
t h e e ntir e P h as e 3 pr o gr a m. 
S ui ci d e st u d y st o p pi n g r ul es:  
If 4 or m or e c o m pl et e d s ui ci d es ar e ass ess e d b y t he D S M B t o b e rel at e d t o D S- 5 5 6 5 
( wit h a n i m b al a n ce of 2 m or e cas es v ers us pl ace b o) i n a n y of t h e P has e 3 stu di es  a n d/ or 
t h e e ntir e P h as e 3 pr o gr a m. 
I n a d diti o n, t h e st u d y m a y b e t er mi n at e d at a n y ti me at t h e s p o ns or’s dis creti o n.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 6 of 1 0 1 
5.  
T R E A T M E N T A D MI NI S T E R E D  
5. 1  
I n v esti g ati o n al Pr o d u cts 
T h e in v esti gat or m ust e ns ur e t h at t h e i n v esti gati o nal pr o d u ct will b e us e d o nl y i n 
acc or d a n ce wit h t h e pr ot oc ol.  
 
5. 1. 1  
St u d y Tre at me nts  
F or det ails a n d h a n dli n g of t h e i n vesti gati o n al pr o d u ct, refer t o t h e I n v esti gat or ’s 
Br oc h ur e a n d t h e m a n u al f or ma n a ge m e nt of t h e i n v esti gati o n al pr o d u ct . 
 
5. 1. 1. 1  
I n v esti g ati o n al Pr o d u ct  
I n v esti gati o n al pr o d u ct c o d e: D S -5 5 6 5  
C h e mi cal  n a m e: [( 1 R, 5 S, 6 S)- 6-( ami n o m et h yl )- 3-et h yl bi c ycl o[ 3. 2. 0] h e pt- 3-e n - 6-yl] 
aceti c aci d m o n o b e nz e n es ulf o n at e  
C o nt e nt a n d d os a ge f or m:  
 
Na me of  
i n vesti g ati o nal pr o d u ct  
C o nte nt a n d d osa g e f or m  
D S - 5 5 6 5 Ta blets 5 m g  
W hite fil m -c oate d ta blet c o ntai ni n g 5 m g of t he free f or m of D S - 5 5 6 5 
D S - 5 5 6 5 Ta blets 1 0 m g  W hite fil m -c oate d ta blet c o ntai ni n g 1 0 m g of t he fre e f or m of D S - 5 5 6 5 
D S - 5 5 6 5 Ta blets 1 5 m g   W hite fil m -c oate d ta blet c o ntai ni n g 1 5 m g of t he fre e f or m of D S - 5 5 6 5 
 
5. 1. 1. 2  
I n v esti g ati o n al Pr o d u ct Pl a ce b o  
C o nt e nt a n d d os a ge f or m:  
Na me of  
i n vesti g ati o nal pr o d u ct  
C o nte nt a n d d osa g e f or m  
D S - 5 5 6 5 Ta blets Pla ce b o 3  
W hite fil m -c oate d matc hi n g pla ce b o ta blet f or D S -5 5 6 5 Ta blets 5 m g  
D S - 5 5 6 5 Ta blets Pla ce b o 4 
W hite fil m -c oate d matc hi n g pla ce b o ta blet  f or D S -5 5 6 5 Ta blets 1 0 m g  
a n d D S -5 5 6 5 Ta blets 1 5 m g  
 
5. 1. 2  
D osi n g Re gi me ns f o r t h e St u d y  
T h e d ur ati o n of i n v esti gati o n al pr o d u ct a d mi nistrati o n will b e 1 4 w ee ks, c o nsisti n g of a 
titr ati o n p eri o d a n d a fi x e d- d os e p eri o d.  As Ta ble 5- 1  s h o ws, t h e treat m e nt p eri o d will 
be gi n at b e dti m e  o n Da y 1 ( Visit 2 ) a n d will c o nti n u e u ntil t h e m or ni n g of D a y 9 9  ( Visit 
1 0).   D uri n g t h e tr eat m e nt p eri o d , 1 t a bl et eit h er  D S - 5 5 6 5 or  m at c hi n g  pl ace b o  will b e 
a d mi nist er e d or all y t wi ce d ail y (i n t h e m or ni n g a n d at b e dti m e ).   T h e s u bj ect m ust 
sel ect t h e a d mi nistr ati o n ti mi n g, eit h er fast e d or fe d i n t h e m or ni n g at ra n do miz ati o n  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 7 of 1 0 1 
( Visit 2), a n d it will b e f oll o w e d d uri n g t h e treat me nt peri o d. 
 
Ta bl e 5- 1   M et h o d of A d mi nistrati o n D uri n g t he Treat m e nt  Peri o d  
Gr o u p  
D a y 1  
D a y 2 t o 7  
D a y 8  
D a y 9 t o 1 4  
D a y 1 5  
D a y 1 6 t o 9 8  
D a y 9 9  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
M or ni
n g  
Be dti
me  
D S -5 5 6 5  
1 5 m g  Q D  
— 
5 
0 
5 
0 
1 0  
0 
1 0  
0 
1 5  
0 
1 5  
0 
— 
D S -5 5 6 5  
1 0 m g  BI D 
— 
5 
5 
5 
5 
1 0  
1 0  
1 0  
1 0  
1 0  
1 0  
1 0  
1 0  
— 
D S -5 5 6 5  
1 5 m g BI D  
— 
5 
5 
5 
5 
1 0  
1 0  
1 0  
1 0  
1 5  
1 5  
1 5  
1 5  
— 
Plac e b o  
—  
0  
0  
0  
0  
0  
0  
0  
0  
0  
0  
0  
0  
—  
 
5. 1. 3  
Met h o d of Assi g ni n g S u bj ects t o Tre at me nts a n d Bli n di n g  
5. 1. 3. 1  
Met h o d of Assi g ni n g t h e I n vesti g ati o n al Pr o d u ct t o S u bjects 
T h e s u bj ects w h o are c o nsi d ere d t o b e eli gi bl e f or p arti ci p ati o n i n t h e st u d y, o n t he b asis 
of e v al u ati o ns  pri or t o r a n d o miz ati o n , will be ra n d o ml y assi g n e d t o pl ace b o, or o n e of t h e 
D S -5 5 6 5 ar ms ( 1 5 m g Q D, 1 0 m g BI D, or 1 5 m g BI D) wit h ra n d o mizati o n rati o of 
2: 1: 1: 1  i n acc or da n ce wit h t h e I W R S.  T h e ra n d o miz ati o n will b e stratifi e d wit h t h e 
f act ors of b as eli n e  A D P S ( < 6. 0 or ≥ 6. 0) .   T h e ra n d o miz ati o n s c h e d ul e f or t h e I W R S 
will b e ge n er at e d b y t he i n d e p e n d e nt bi ost atisti ci a n. 
 
Aft er o btai ni n g writt e n i nf or m e d c o ns e nt, t h e i n v esti gat or or s u b-i n v esti g at or will access 
t h e I W R S t o r e gist er t h e s u bj ect a n d i n p ut t he s u bject’s i nf or m ati o n.  At t he 
r a n d o miz ati o n visit, t h e i n v esti gat or or s u b-i n v esti gat or will e nt er t h e eli gi bilit y crit eri a 
dat a t o o bt ai n a u ni q u e st u d y dr u g i d e ntifi er t h at will b e assi g n e d t o t he s u bj ect. 
 
T h e i n v esti gat or or s u b-i n v esti gat or will dis p e nse t h e i n v esti gati o n al pr o d uct t o eac h 
s u bj ect i n acc or d a n ce wit h t h e i n di vi d u al st u d y dr u g i d e ntifi er fr o m t h e I W R S.   T h e  
i n v esti gati o n al pr o d u ct f or eac h st u d y dr u g i d e ntifi er will b e dis p e ns e d s p ecifi call y t o 1 
s u bj ect, a n d will n ot b e use d b y a n y ot h er s u bj ects.  
 
5. 1. 3. 2  
Bli n di n g  
T h e st u d y is a d o u bl e- bli n d st u d y usi n g D S - 5 5 6 5 a n d pl ace b o , w hi c h will be pre p are d t o 
be i n disti n g uis ha bl e i n a p p ear a n ce fr o m t h e i n v esti gati o n al pr o d u ct .  T h e s t ud y will b e 
bli n d e d f or t h os e w h o will b e i n v ol v e d i n t h e stu d y (s u bj ects, i n v esti gat ors, 
s u b-i n v esti gat ors, ot her staff m e m b ers rel at e d t o t he cli ni cal st u d y, t he s p o ns or, etc.), wit h 
t h e e x ce pti o n of t h e i n d e pe n d e nt bi ost atisti ci a n, t he i n d e p e n d e nt s u b-f u n cti o n al l ea d of 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 8 of 1 0 1 
bi ost atisti cs  (I S F L B), a n d st aff m e m b ers rel at e d t o pac k agi n g o p erati o n a n d q u alit y 
ass ur a n ce . 
 
Ra n d o miz ati o n s c h e d ule will b e ge n erat e d b y t he i n d e p e n d e nt bi ost atisti ci a n a n d 
a p pr o v e d b y t h e I S F L B.   Th e i n d e p e n d e nt bi ost atisti ci a n  will s h are t h e ra n d o miz ati o n 
sc h e d ul e wit h  pers o n n el s p ecifi e d i n  t h e ra n d o mi zati o n s c h e d ul e re q u est f or m f or t h e 
i n v esti gati o n al pr o d u ct assi g n me nt a n d k ee p i n g it stri ctl y c o nfi d e nti al u ntil t h e st u d y is 
u n bli n d e d. 
 
U ntil t he st u d y is u n bli n de d, t h e p ers o n res p o nsi bl e f or i n v esti gati o n al pr o d uct 
m o nit ori n g at t h e dr u g c o n ce ntrati o n m o nit ori n g facilit y will us e a differe nt i d e ntifi cati o n 
n u m b er fr o m t h e s u bj ect i d e ntifi cati o n c o d e a n d t he st u d y dr u g i d e ntifi er t o m ai nt ai n 
bli n d e d m a n n er w h e n r e p orti n g t h e o ut c o m e of meas ure m e nts t o t h e s p o ns or. 
 
5. 1. 3. 3  
Pre p a r ati o n a n d M a n a ge me nt of E mer g e n c y C o d es    
I n d e p e n d e nt bi ost atisti ci a n or I S F L B will pre p are e m er ge n c y c o d es t h at ca n be u n bli n d e d 
b y t h e st u d y dr u g i de ntifier, s o t h at a d mi nist ere d treat m e nt of t h e pati e nt ca n b e i d e ntifi e d 
i n cas e of e m er ge n c y. 
 
T h e e m er ge n c y c o d es will b e r et ai n e d i n d e dicat e d I W R S m a n a ge d b y Bell M e di cal 
S ol uti o ns, I n c.  
 
T h e e m er ge n c y c o d es m ust n ot b e u n bli n d e d f or t he cas es ot h er t h a n t h e st at es of S ecti o n 
5. 1. 3. 4 . 
 
5. 1. 3. 4  
Pr o ce d u res f o r E mer g e nc y U n bli n di n g  
1)  If em er ge n c y u n bli n di n g is d ee m e d n ecess ar y b y t h e i n v esti gat or or s u b -i n vesti gat or: 
• 
W he n it is d ee me d n ecessar y t o u n bli n d t h e treat me nt assi g n m e nts t o treat A E s, t h e 
i n v esti gat or or s u b-i n vesti gat or will re q u est t h e s p o ns or t o d et er mi n e t h e 
a p pr o pri at e n ess of t h e e mer ge n c y u n bli n di n g aft er e x plai ni n g t h e reas o n t hr o u g h 
t h e I W R S. 
• 
T h e s p o ns or will d et er mi ne t h e a p pr o pri at e n ess of t h e e m er ge n c y u n bli n di n g i n 
c o ns ultati o n wit h m e di cal e x p ert as re q uire d.  
i. W h e n e mer g e n c y u n bli n di n g is d ee me d a p p r o p ri ate b y t h e s p o ns or  
• 
W he n u n bli n di n g is d ee me d a p pr o pri ate, t h e s p o ns or will n otif y t h e 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 3 9 of 1 0 1 
i n v esti gat or or s u b-i n vesti gat or of t h e fact a n d t h e reas o n t hr o u g h 
t h e I W R S. 
• 
T h e s p o ns or will re q u est t h e i n v esti gat or or s u b -i n v esti gat or t o 
pr e p are t h e C R F of t h e a p pr o pri at e p ati e nt.  
• 
T h e s p o ns or iss u es t h e p ass w or d f or c o nfir mi n g t he e m er ge n c y 
c o d e of t h e a p pr o priat e p atie nt o n t h e I W R S t hr o u g h t h e I W R S.  
• 
T h e i n v esti gat or or s u b -i n v esti gat or recei v e t h e p ass w or d, e nt er 
t h eir p ass w or ds t o l o gi n, a n d t h e n c o nfir m t h e e m er ge n c y c o d e of 
t h e a p pr o pri at e p ati e nt. 
• 
I nf or m ati o n a b o ut t h e treat me nt assi g n m e nt m ust be  restri ct e d t o 
o nl y d esi g n at e d st u d y sit e st aff/ p ers o n nel w h o are pr o vi di n g 
i m m e di at e care t o t h e s u bj ect. 
• 
A n y d o c u m e nt ati o n of t h e treat m e nt assi g n m e nt m ust b e 
mai nt ai n e d se p arat el y (i e, a s ec ure d file).    T h e i nf or m ati o n m ust 
n ot b e i n cl u d e d i n t h e s u bj ect’s s o urce fil es t o e ns ure t h e treat e me nt 
assi g n m e nt will re m ai n bli n d e d t o t h e st u d y mo nit or a n d ot h er 
st u d y p ers o n n el n ot i n v ol v e d wit h t h e s u bj ect’s i m m e di at e care. 
 
ii. W he n e mer g e n c y u n bli n di n g is n ot d ee me d a p p r o p ri ate b y t h e s p o ns o r 
• 
W he n u n bli n di n g is d et er mi n e d n ot a p pr o pri at e, t he s p o ns or will 
n otif y t h e i n v esti gat or or s u b -i n v esti gat or of t he fact a n d t h e reas o n 
t hr o u g h t h e I W R S. 
 
2)  W he n e m er ge nc y u n bli n di n g is d ee m e d n ecess ar y b y t h e s p o ns or  
• 
W he n e m er ge nc y u n bli n di n g is d ee m e d n ecess ar y i n c o ns ult ati o n wit h m e di cal 
e x p ert i n cas e of s u c h as occ urre n ce of a p ot e nti al s afet y pr o bl e m f o r t h e p atie nts, 
t h e s p o ns or will n otif y t h e i n v esti gat or or s u b-i n v esti gat or of t h e u n bli n di n g. 
• 
T h e s p o ns or will r e q u est t h e i n v esti gat or or s u b -i n v esti gat or t o pre p are a C R F of 
t h e a p pr o pri at e p ati e nt. 
• 
T h e s p o ns or r el i es t h e iss u a n ce of t h e p ass w or d f or co nfir mi n g t h e e m er ge n c y c o d e 
of t h e a p pr o pri at e p ati e nt o n t h e I W R S t o t h e i n v esti gat or or s u b-i n v esti gat or 
t hr o u g h t h e I W R S. 
• 
T h e s p o ns or r ecei v es t h e p ass w or d, e nt ers t h e p ass w or d t o l o gi n, a n d t he n c o nfir m 
t h e e mer ge n c y co d e of t h e a p pr o pri at e p ati e nt.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 0 of 1 0 1 
5. 1. 3. 5  
S u bj ect R e pl a ce me nt  
N o s u bj ects will b e r e pl ace d i n t his st u d y.  
 
5. 1. 4  
Met h o d of Assessi n g Tre at me nt C o m pli a n ce  
All s u bj ects i n t his st u d y will c o m m e n ce t h era p y as o ut p ati e nts, a n d t h e i n vesti gati o n al 
pr o d u ct will b e s elf -a d mi nist er e d or all y.    S u bj ects will b e s e nt h o m e wit h t h e 
i n v esti gati o n al pr o d u ct.    E ac h s u bj ect is t o ret ur n t h e i n v esti gati o n al pr o d u ct at e v er y 
visit.    C o m pli a n ce will be ass esse d b y ret ur n e d t a bl et c o u nt.    A d mi nistrati o n of t h e 
i n v esti gati o n al pr o d u ct will b e r ec or d e d i n t h e e C R F/ Dr u g A cc o u nt a bilit y R ec or d 
( nu m b er of ta bl ets ta k e n) at all tr eat m e nt visits .    If n o t a bl ets are ret ur n e d, t h e s u bj ect 
will b e as k e d w h et h er a n y w er e dis car d e d or t hr o w n a w a y, or if all of t h e t a bl ets w ere 
ta k e n or all y. 
 
5. 1. 5  
L a b eli n g a n d P a c k a gi n g  
D S - 5 5 6 5 a n d/or m at c hi n g pl ace b o , will b e p ac k a g e d i n al u mi n u m blist er pac ks.   
Pac k a ges f or t h e tr eat m e nt p eri o d will b e pre pare d f or t h e c o m bi n ati o ns s h o w n i n Ta bl e 
5- 2 , Ta ble 5- 3 , a n d Ta bl e 5- 4 .    O n e b o x will be pre p are d f or eac h s u bj ect.    E ac h b o x 
will c o nt ai n t h e  i n v esti gati o n al pr o d u ct f or t h at s u bj ect d uri n g t h e treat m e nt p eri o d.   T h e  
pac k a gi n g will b e cl earl y l a b ele d " F or Cli nical St u d y Us e O nl y," a n d will s h o w t h e 
dis pl a y n a m e of t h e i n v esti gati o n al pr o d u ct, t h e i n v esti gati o n al-pr o d u ct -ma n ufact uri n g 
c o d e, t h e st u d y dr u g i d e ntifi er, t h e n a me a n d a d dress of t h e s p o ns or, a n d t h e e x pire d d at e 
of t h e i n vesti gati o n al pr o d u ct i n acc or d a n ce wit h l ocal re g ul ati o ns.  Eac h w all et car d  of 
t h e i n v esti gati o n al pr o d u ct will c o nt ai n s uffi ci e nt e xtra d oses t o c o v er t h e per mitte d visit 
wi n d o w f or eac h s u bj ect.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 1 of 1 0 1 
 
Ta bl e 5- 2   Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 1) 
Treat me nt gr o u p  
I n vesti gati o nal pr o d uct c o m bi n ati o n   
M or ni n g 
Be dti me  
D S - 5 5 6 5 1 5 m g  Q D    
 
 
D S - 5 5 6 5 1 0  m g  BI D    
 
 
D S - 5 5 6 5 1 5  m g BI D  
 
 
Place b o    
 
 
 
 
 
 
 
Ta bl e 5- 3   Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 2) 
Treat me nt gr o u p  
I n vesti gati o nal pr o d uct c o m bi n ati o n   
M or ni n g 
Be dti me  
D S - 5 5 6 5 1 5 m g  Q D    
 
 
D S - 5 5 6 5 1 0  m g BI D  
 
 
 
D S - 5 5 6 5 1 5  m g BI D  
 
 
Place b o  
 
 
 
 
D S - 5 5 6 5 matc hi n g plac e b o ta blet  
 
D S - 5 5 6 5 1 0 m g ta blet  
 
 
D S - 5 5 6 5 matc hi n g plac e b o ta blet 
 
D S - 5 5 6 5 5 m g ta blet  
P 
 
5 
5 
5 
P 
P 
5 
 
P 
 
1 0  
1 0  
1 0  
1 0  
1 0  
P 
P 
5 
P 
5 
P 
1 0  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 2 of 1 0 1 
 
Ta bl e 5- 4   Dr u g C o m bi nati o ns D uri n g t h e Treat me nt P eri o d ( Wee k 3 t o Wee k 1 4)  
Treat me nt gr o u p  
I n vesti gati o nal pr o d uct c o m bi n ati o n   
M or ni n g 
Be dti me  
D S - 5 5 6 5 1 5 m g Q D  
 
 
D S - 5 5 6 5 1 0  m g BI D  
 
 
D S - 5 5 6 5 1 5  m g BI D  
 
 
Place b o  
 
 
 
 
D S - 5 5 6 5 matc hi n g plac e b o ta blet 
 
D S - 5 5 6 5 1 0 m g ta blet  
 
D S - 5 5 6 5 1 5  m g ta blet  
 
5. 1. 6  
St o r a g e  
U p t o 2 5° C; d o n ot fr eez e ( ex c ursi o n p er mitt e d u p t o 3 0° C ). 
 
5. 1. 7  
D r u g A cc o u nt a bilit y  
T h e s p o ns or will d eli v er t h e i n v esti gati o n al pr o d u ct as n ee de d t o t h e i n vesti gati o n al 
pr o d u ct a d mi nistr at or d esi g n at e d at t h e st u d y sit e.   T h e  a d mi nistrat or will st ore a n d 
ma n a ge t h e i n v esti gati o n al pr o d u ct b as e d o n t h e ma n u al f or m a na ge m e nt of 
i n v esti gati o n al pr o d u ct, a n d will m ai nt ai n rec or ds a n d pre p are re p orts as re q uire d. 
 
5. 2  
C o n c o mit a nt Me di c ati o ns a n d Tre at me nts  
A n y c o n c o mit a nt m e di cati o ns e x ce pt res c u e m e di cati o n (s ee S ecti o n 5. 2. 3 ) a n d a n y 
c o n c o mit a nt tr eat m e nts c o n d u ct e d t o  a s u bj ect d uri n g t h e p eri o d fr o m t h e ti me of 
o bt ai ni n g i nf orm e d c o ns e nt  u ntil Visit 1 1 , w h et h er p er mitt e d or n ot, will b e d o c u m e nt e d 
i n t h e C R F.    T h e r o ut e of a d mi nistr ati o n, t h e t ot al d ail y d os e, t h e d urati o n of us e, t h e 
i n di cati o n f or us e, a n d t h e cl assifi cati o n of t h era pi es will als o b e d o c u m e nt e d i n t h e C R F.  
 
5. 2. 1  
P r o hi bit e d C o n c o mit a nt Me di c ati o ns  
T h e f oll o wi n g dr u gs ar e pr o hi bit e d f or c o nc o mit a nt us e fr o m t h e scree ni n g ( Visit 1) 
t hr o u g h t h e p ost- tr eat m e nt f oll o w-u p  (Visit 1 1 ).   T h e p ati e nts  gi v e n dr u gs t h at c o ul d 
P 
 
1 0  
1 5  
1 0  
1 0  
1 5  
1 5  
P 
P 
1 5  
P 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 3 of 1 0 1 
ca us e irr e v ersi bl e r eti n al de ge n er ati o n m ust b e e x cl u d e d.   Aft er i nf or m e d c o ns e nt is 
o bt ai n e d, s u bj ects w h o ar e u n d er tr eat m e nt wit h t he f oll o wi n g pr o hi bit e d c o n c o mit a nt 
dr u gs will u n d er g o a w as h o ut p eri o d of 7 d a ys or m ore.    Visit 1 will o cc ur aft er 
c o m pl eti o n of t his w as h o ut p eri o d.  
1)  Pr e ga b ali n  
2)  A nti e pi l e pti cs (g a b a p e nti n, c ar b a m az e pi n e, et c.)  
3)  A nti d e pr ess a nts ( ot h er t h a n s el ecti v e s er ot o ni n re u pt a k e i n hi bit ors) 
4)  H y p n oti cs , a n xi ol yti cs ( ot h er t h a n ultras h ort acti n g dr u g [tri az ol a m, z o picl o n e, 
z ol pi d e m t artr at e] ) 
5)  O pi oi ds 
6)  Tr a m a d ol 
7)  N e ur otr o pi n ®  
8)  N- m et h yl - D-as p art at e r ece pt or ( N M D A)  a nt a g o nists ( d e xtr o m et h or p h a n, ket a mi n e, 
me ma nti n e, et c.)  
9)  N o n -st er oi d al a nti-i nfl a m m at or y dr u gs (e x ce pt t o pi cal pr o d u ct f or ot h er t ha n dis eas e 
sit e of D P N) 
1 0)  M us cl e r el a x a nts  
1 1)  To pi cal ca ps ai ci n  ( e x ce pt t o pical pr o d u ct f or ot h er t h a n dis eas e sit e of D P N)  
1 2)  L o cal a n est h eti cs ( li d o cai n e, et c.) (e x ce pt t o pi cal pr o d u ct f or ot h er t h a n diseas e sit e 
of D P N)  
1 3)  N a c h a n n el bl o c k ers ( m e xileti n e , et c.) 
1 4)  Ce ntr all y acti n g s y m p at h ol yti c a ge nts  (cl o ni di n e, et c.) 
1 5)  St er oi ds (e x ce pt t o pi cal pr o d u ct f or ot h er t h a n diseas e sit e of D P N) 
1 6)  cil ost az ol , pr ost a gl a n di n ( e x ce pt t o pi cal pr o d u ct f or ot h er t h a n dis eas e sit e of D P N) 
1 7)  C hi n es e h er b al m e di ci n es wit h a n al gesi c effects o n ne ur o p at hi c p ai n ( Life - pres er vi n g 
ki d n e y - qi pill, P e o n y a nd li c ori ce d ec o cti o n, Ei g ht -i n gre di e nt pill wit h re h m a n ni a, 
et c.)  
1 8)  Vit a mi ns B 1 a n d B 1 2  ( e x ce pt t o pi cal pr o d u ct f or ot h er t h a n dis ease sit e of D P N) 
1 9)  α -li p oi c aci d 
2 0)  γ -li no le ni c aci d ( e v e ni n g pri mr os e oil) 
2 1)  Al d ose r e d u ct as e i n hi bit ors  
2 2)  Dr u gs t h at c o ul d ca us e irr e v ersi bl e reti n al d e ge n erati o n ( p h e n ot hi azi n e 
a nti ps yc h oti cs, d ef er o x a mi n e, q ui ni n e, q ui ni di n e, et h a m b ut ol, v ori c o n az ol e , et c.) 
2 3)  Ot her i n v esti gati o n al pr o d u cts 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 4 of 1 0 1 
5. 2. 2  
R est ri ct e d C o n c o mit a nt Me di c ati o ns  
T h e f oll o wi n g dr u gs ar e per mitte d f or c o n c o mita nt us e if t h eir d os a ge h as n ot c h a n ge d 
f or 3 0 d a ys pri or t o Visit 1.    T h es e dr u gs m a y b e us e d c o n c o mit a ntl y fr o m t h e s cree ni n g 
( Visit 1) t hr o u g h t he p ost- tr eat m e nt f oll o w-u p ( Visit 1 1 ), b ut t he d os a ge m a y n ot b e 
c h a n ge d. 
1)  A nti di a b eti c dr u gs ot h er t h a n i ns uli n  
2)  Sel ecti v e s er ot o ni n r e u pt a k e i n hi bit ors (li mit e d t o t h e treat m e nt of d e pressi o n a n d 
a n xi et y)  
3)  H y p n oti cs ( o nl y ultr as h ort -acti n g dr u g s [tri az ol a m, zo pi cl o n e, zol pi d e m t artrat e] ) 
4)  a m eli or at or f or p eri p her al cir c ul ati o n  (e x ce pt f or cil ost az ol a n d pr ost a gl a n di n) 
5)  As piri n ( o nl y f or pre v e nti n g t hr o m b osis a n d e m b olis m [ e g , m y o car di al  i nfarcti o n 
a n d str o k e] , s h o ul d b e us e d acc or di n g t o t h e p ac ka ge i ns ert) 
 
5. 2. 3  
R es c u e Me di c ati o ns  
A cet a mi n o p he n will b e p er mitt e d as a "res c u e m e di cati o n ," t o b e us e d as n ee d e d o nl y, 
a n d n ot t o e x cee d t h e m a xi m u m d os e sti p ul at e d i n t h e p ac k a ge i ns ert.    E ac h s u bj ect 
s h o ul d r ec or d d os e(s) of  acet a mi n o p h e n us e d  i n t he el ectr o nic p ati e nt di ar y  fr o m Visit 1 
t o Visit 1 0 , if he/s h e t a k es acet a mi n o p h e n. 
 
5. 2. 4  
Pr o hi bit e d C o n c o mit a nt T h er a pi es  
C o n c o mit a nt us e of t h e f oll o wi n g t h era pi es is pr o hi bit e d fr o m t h e s cree ni n g ( Visit 1) 
t hr o u g h p ost- tr eat me nt f oll o w-u p ( Visit 1 1 ). 
1)  N er v e bl o c ks  
2)  Las er t h er a p y  
3)  A c u p u n ct ur e tr eat m e nt  
4)  S pi nal c or d sti m ul ati o n  
5)  S ur ger y  t h at mi g ht c o nf o u n d t h e ass ess m e nt of D P N P 
6)  E l ectri cal sti m ul ati o n t h er a p y 
7)  Ot her f or ms of p ai n r e d u cti o n t h era p y t h at mi g ht c o nf o u n d t h e assess m e nt of D P N P 
 
5. 2. 5  
Ot h er  
S u bjects s h o ul d be i nstr u ct e d t o a v oi d e x cessi v e c o ns u m pti o n of al c o h ol d uri n g t h e 
tr eat m e nt p eri o d, as t h e i n v esti gati o n al pr o d u ct m a y i n creas e si de effects of sl ee pi n ess 
a n d dizzi n ess a n d p ot e nti at e t he i m p air m e nt of m ot or s kills.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 5 of 1 0 1 
6.  
S T U D Y P R O C E D U R E S  
A st u d y visit s c h e d ul e i n ta b ul ar f or m at is pr o vi d e d i n  s ecti o n 1 7. 1 . 
 
I n pri n ci pl e, all of t h e acti viti es a n d/ or e x a mi n ati o ns will b e rec or d e d wit h t h e d at e i n t h e 
C R F.  
Missi n g visits ar e str o n gl y dis c o ur a ge d i n t his st u d y.    It is e x p ect e d t h at i n v esti gat or sit e 
st aff t h or o u g hl y e x pl ai n t h e visit s c h e d ul e wit h p ot e nti al s u bj ects.    If it is felt t h at a 
s u bj ect is n ot a bl e t o a d h er e t o t h e visit s c h e d ul e, t h e n t h at s u bj ect s h o ul d n ot b e 
r a n d o miz e d i nt o t h e st u d y.    A n y miss e d visit t h at o cc urs d uri n g t h e d o u bl e-bli n d 
tr eat m e nt p eri o d m ust b e r es c h e d ul e d wit hi n 1 w ee k.    
 
6. 1  
S cree ni n g ( Visit  1, 7 d a ys p ri o r t o ra n d o mi z ati o n ) 
Writt e n i nf or m e d c o ns e nt will be o bt ai n e d b ef ore scree ni n g.    If pr o hi bite d c o n c o mit a nt 
dr u gs ar e use d wit hi n 7 d a ys b ef or e o bt ai ni n g i nf or m e d c o nse nt, s cree ni n g acti viti es will 
f oll o w a w as h o ut p eri o d of at l east 7 d a ys.  T h eref ore, i n t his cas e, writt e n i nf or m e d 
c o ns e nt m ust b e o bt ai n e d bef or e e nt eri n g t h e was h o ut p eri o d.  T h e f oll o wi n g acti vities 
a n d/ or e x a mi n ati o n s will b e p erf or m e d at s cree ni n g. 
• 
E v al u at e i n cl usi o n crit eri a a n d e x cl usi o n crit eri a 
• 
Rec or d  d e m o gr a p hi cs ( birt h d at e, s e x, t y p e of di a bet es, d urati o n of di a b et es, d urati o n 
of D P N, d ur ati o n of D P N P) , m e di cal/s ur gi cal hist or y  rel at e d t o e x cl usi o n crit eri a a n d 
al c o h ol hist or y 
• 
Pr o vi d e e x pl a n ati o n r e gar di n g el ectr o ni c p ati e nt diar y, a n d pr o vi di n g of el ectr o ni c 
di ar y 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y h ei g ht a n d w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m f ull n e ur ol o gi cal e x a mi n ati o n  
• 
Perf or m o p ht h al m ol o gi c e x a mi nati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m 1 2 -l ea d E C G 
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 6 of 1 0 1 
• 
E v al u at e A Es  
• 
C o m pl et e C -S S R S  
• 
Perf or m p r e g n a n c y t est ( o nl y i n w o m e n of  c hil d b eari n g p ot e nti al)  
• 
E v al u at e pri or dr u g tr eat me nt, c o n c o mit a nt dr u gs, a n d c o nc o mit a nt t h era p y  
• 
C o m pl et e M o d ul e A a n d B o n MI NI  I nt er vi e w ( Versi o n 6. 0) 
 
6. 2  
R a n d o mi z ati o n ( Visit  2, D a y 1) 
S u bjects will b e r a n d o mi ze d t o tr eat m e nt gr o u ps aft er s cree ni n g.    T h e f oll o wi n g 
acti viti es a n d/ or e x a mi n ati o ns will b e p erf or m e d at ra n d o miz ati o n. 
• 
E v al u at e i n cl usi o n crit eri a a n d e x cl usi o n crit eri a 
• 
R e vi e w el ectr o ni c p ati e nt di ar y d at a  
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e t h e mo difi e d B PI -S F  
• 
C o m pl et e M O S sl ee p scal e  
• 
C o m pl et e H A D S  
• 
C o m pl et e 3 6 -it e m s h ort f or m h ealt h s ur ve y ( S F- 3 6) 
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m a b br e vi at e d n e ur ol o gi cal e x a mi n ati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mi t a nt dr u gs a n d c o nc o mit a nt t hera p y 
• 
C o nfir m eli gi bil it y a n d r a n d o miz ati o n 
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
• 
Sel ect a n d r ec or d t h e dr u g a d mi nistrati o n i n t h e m or ni n g (fast e d/ fe d) d uri n g t h e 
st u d y tr eat m e nt 
 
6. 3  
Tre at me nt Peri o d  
T h e tr eat m e nt p eri o d will b e 1 4 w ee ks i n d urati o n.  
 
6. 3. 1  
Visit  3 a n d Visit  4 
Fr o m V isit 2 t o V isit 4, s u bj ects will c o m e t o t h e st u d y sit e e v er y w ee k ( Visit 3, Visit 4).   
T h e i n v esti gat or or s u b-i n v esti gat or will  c o nfir m t ol era bilit y a n d re vi e w c o nti n u ati o n of 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 7 of 1 0 1 
t h e tr eat m e nt b ef or e iss ui n g t h e  n e w i n v esti gati o n al pr o d u ct.    T h e f oll o wi n g acti viti es 
a n d/ or e x a mi n ati o n s will b e p erf or m e d at Visit 3 a n d Visit 4. 
• 
R e vi e w el ectr o ni c p ati e nt di ar y d at a  
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m a b br e vi at e d n e ur ol o gi cal e x a mi n ati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
C oll ect bl o o d  a n d u ri n e s a m pl es f or l a b orat or y t ests 
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d a n d re vi e w dr u g -t a ki n g 
c o m pli a n ce  
• 
Rec or d t h e d ate  of t h e first d os e ta k e n 
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
• 
C oll ect bl o o d s a m ple f or P K a n al ysis  
 
6. 3. 2  
Visit  5, Visit 6, Visit 7, Visit 8, a n d Visit 9 
Fr o m V isit 4 t o V isit 9, su bj ects will c o m e t o t h e st u d y sit e o n ce e v er y 2 w ee ks  ( Visit 5, 
Visit 6, Visit 7, Visit  8, a n d Visit 9 ).   T he i n v esti gat or or s u b-i n v esti gat or will c o nfir m 
t ol er a bilit y a n d r e vi e w c o nti n u ati o n of t he treat m e nt b ef ore iss ui n g t h e n e w 
i n v esti gati o n al pr o d u ct.   T h e f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e p erf or me d 
at Visit 5 , Visit 6, Visit 7, Visit  8, a n d Visit 9. 
• 
R e vi e w el ectr o ni c p ati e nt di ar y d at a  
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m a b br e vi at e d n e ur ol o gi cal e x a mi n ati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or l a b orat or y t ests 
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  ( Visit 6 o nl y) 
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e  l e v els ( Visit 6 o nl y) 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 8 of 1 0 1 
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d a n d re vi e w dr u g -t a ki n g 
c o m pli a n ce  
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
• 
C oll ect b l o o d s a m ple f or P K a n al ysis ( Visit 6 a n d Visit 8 o nl y) 
 
6. 4  
E n d of Tre at me nt / E a rl y Ter mi n ati o n ( Visit 1 0 ) 
T h e tr eat m e nt p eri o d will b e c o m pl et e d at Visit  1 0 .    T h e f oll o wi n g acti viti es a n d/ or 
e x a mi nati o n s will b e p erf or m e d at t h e e n d of treat m e nt / earl y t er mi n ati o n. 
• 
C oll ect  a n d r e vi e w electr o ni c p ati e nt di ar y d ata, a n d c oll ecti n g el ect r o ni c di ar y 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e t h e mo difi e d B PI -S F  
• 
C o m pl et e P GI C  
• 
C o m pl et e M O S sl ee p scal e  
• 
C o m pl et e H A D S  
• 
C o m pl et e S F -3 6  
• 
C o m pl et e E v al u ati o n of S y m pt o ms  
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal  e x a mi n ati o n  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m f ull n e ur ol o gi cal e x a mi n ati o n  
• 
Perf or m o p ht h al m ol o gi c e x a mi nati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m  1 2 -l ea d E C G 
• 
C oll ect bl o o d  a n d u ri n e s a m pl es f or la b orat or y t ests  
• 
C oll ect bl o o d s a m ple f or e v al u a ti o n of H b A 1 c  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  
• 
C o m pl et e C -S S R S  
• 
Perf or m p r e g n a n c y t est ( o nl y i n w o m e n of c hil d b eari n g p ot e nti al)  
• 
E v al u at e A E s 
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d a n d re vi e w dr u g -t a ki n g 
c o m pli a n ce  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 4 9 of 1 0 1 
• 
Rec or d t h e d ate  of t h e l ast d os e ta k e n 
• 
C oll ect bl o o d s a m ple f or P K a n al ysis  
 
6. 5  
P ost -t re at me nt F oll o w-u p ( Visit  11, 7 d a ys after t h e c o m pl eti o n of 
a d mi nistr ati o n ) 
F oll o w- u p o bs er v ati o ns will b e c o n d u ct e d 7 d a ys after t h e c o m pl eti o n of a d mi nistrati o n 
( Visit 1 1 ).    T h e f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e p erf or m e d at 
p ost- tr eat m e nt f oll o w-u p .   N o f oll o w -u p o bser v ati o n is re q uire d f or s u bj ects e nr oll e d i n 
an o p e n -l a b el e xte nsi o n st u d y. 
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m a b br e vi at e d n e ur ol o gi cal e x a mi n ati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
E v al u at e A E s 
• 
C o m pl et e C- S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 0 of 1 0 1 
7.  
E F FI C A C Y A S S E S S M E N T S  
7. 1  
Pri m a r y Effi c a c y Va ri a ble(s)  
Pai n s c or e 7 
E ac h s u bj ect will r ec or d a p ai n s c or e i n t h e el ectr o ni c p ati e nt di ar y o n ce d ail y fr o m t h e 
da y aft er Visit  1 t hr o u g h Visit  1 0 .   E v er y m or ni n g u p o n a w a k e ni n g, pri or t o t a ki n g st u d y  
me di cati o n, t h e s u bj ect will s el ect t h e n u m b er t h at b est d es cri b es his or h er p ai n o v er t h e 
past 2 4 h o urs o n a s cal e of 0 ( n o p ai n) t o 1 0 ( w orst p ossi bl e p ai n).   A D P S is t h e w ee kl y 
a v er a ge  p ai n s c or e bas e d o n t h e p ai n s c ores fr o m t h e electr o ni c p ati e nt d ail y p ai n di ari es.  
 
7. 2  
S ec o n d a r y Effi c a c y Va ri a bl e(s)  
1)  
R es p o ns e r at e  
Res p o ns e r at e  is d efi n e d as t h e pr o p orti o n of s u bj ects wit h ≥ 3 0 % , a n d ≥ 5 0 %  re d u cti o n 
fr o m bas eli n e i n A D P S. 
 
2)  
S h ort -F or m M c Gill P ai n Q u esti o n n aire
8 
At Visit 1, Visit 2, Visit 3, Visit 4, Visit 5 , Visit 6, Visit 7, Visit 8, Visit 9,  a n d Visit 1 0 , 
s u bj ects will pr o vi d e a s elf-ass ess m e nt usi n g t h e S F- M P Q.   T h e S F -M P Q  c o nsists of 3 
parts: 
• 
Fift ee n p ai n d es cri pt ors t hat ar e gi v e n a s c ore of 0 ( n o n e) t o 3 (s e v ere) b as e d o n 
i nt e nsit y.    T h e s c ores ar e s u m m ariz e d as a s e ns or y s c ore of 1 1 d es cri pt ors, a n 
aff ecti v e s c or e of 4 d es cri pt ors, a n d a t ot al s c ore of 1 5 d es cri pt ors.  
• 
A V A S, i n w hi c h t he s u bject r at es p ai n i nt e nsit y o n a 1 0 0  m m -l o n g h oriz o nt al li n e, 
w h er e 0 m m = n o p ai n a n d  1 0 0 m m = w orst p ossi bl e p ai n. 
• 
A Pr es e nt Pai n I nt e nsit y i n d e x t h at  pr o vi d es  a s c ore of 0 t o 5 b ase d o n i nt e nsit y  
 
3)  
M o difi e d Bri ef P ai n I n v e nt or y ( S h ort F or m)9 
At Visit 2 a n d Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess me nt usi n g t h e m o difie d B PI-S F .   
T h e m o difi e d B PI -S F  will b e us e d t o ass ess t h e s e v erit y of p ai n a n d t h e i m p act of p ai n o n 
dail y f u n cti o n.    S u bj ects will s el ect t h e n u m b er t hat m ost cl os el y re pres e nts t h eir p ai n 
e x p eri e n ce o n a n 1 1 -p oi nt s cal e i n t w o cat e g ories: s e v erit y, s c ore d fr o m 0 ( n o p ai n) t o 1 0 
( p ai n as b a d as y o u ca n i ma gi n e), a n d i m p act o n dail y f u n cti o ns, sc ore d fr o m 0 ( d o es n ot 
i nt erf er e) t o 1 0 (c o m pl et el y i nt erf er es). 
 
Se verit y of p ai n  
• 
Worst p ai n i n t he l ast 2 4 h o urs 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 1 of 1 0 1 
• 
Least p ai n i n t h e  l ast 2 4 h o urs 
• 
Av er a ge p ai n  
• 
Pai n ri g ht n o w  
 
I m p act o n d ail y f u n cti o ns 
• 
G e n er al acti vit y  
• 
M o o d 
• 
Wal ki n g a bilit y 
• 
N or m al w or k (i n cl u d es b ot h w or k o utsi d e t h e h o me a n d h o us e w or k)  
• 
Rel ati o ns wit h ot h er p e o pl e  
• 
Slee p  
• 
E nj o y m e nt of lif e  
 
4)  
P ati e nt Gl o b al I m pr essi o n of C h a n ge 7 
At Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess m e nt i n c o m p aris o n t o Visit 2, usi n g t h e 
7- p oi nt scal e i n t h e P GI C . 
1: v er y m uc h i m pr o ve d  
2: m u c h i m pr o v e d 
3: mi ni m all y i m pr o v e d  
4: n o c h a n ge  
5: mi ni m all y w ors e  
6: m u c h w ors e  
7: v er y m uc h w ors e  
 
5)  
Slee p -i nt erf er e n ce S c or e 
T h e D ail y Sl ee p I nt erf er e n ce Di ar y c o nsists of a n 1 1 -p oi nt N R S w hi c h will b e us e d t o 
ass ess h o w p ai n h as i nt erf ere d wit h t h e s u bj ect’s slee p d uri n g t h e p ast 2 4 h o urs.   Eac h 
s u bj ect will rec or d a sl ee p-i nterf er e n ce s c ore i n t h e el ectr o nic p ati e nt di ar y o nce d ail y 
fr o m t h e d a y aft er Visit 1 t hr o u g h Visit 1 0 .   E v er y m or ni n g u p o n a w a k e ni n g, pri or t o 
ta ki n g st u d y m e dicati o n, t h e s u bj ect will s el ect t h e n u m b er t h at b est d es cri bes his or h er 
sl ee p i nt erf er e nce e x p eri e n ce d uri n g t h e p ast 2 4 h o urs o n a s cal e of 0 ( p ai n di d n ot 
i nt erf er e wit h sl ee p) t o 1 0 ( p ai n c o m pl etel y i nt erfere d wit h sl ee p).  T h e w ee kl y a v era ge  
sl ee p i nt erf er e nce s c or e is b as e d o n t h e sl ee p i nt erfere n ce s c ores fr o m t h e electr o ni c 
pati e nt d ail y p ai n di ari es . 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 2 of 1 0 1 
6)  
M e di cal  O utc o m es St u d y  sl ee p s cal e1 0, 1 1   
At Visit 2 a n d Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess me nt usi n g t h e M O S sl ee p s cal e.   
T h e M O S sl ee p scal e is bas e d o n q u esti o ns a b o ut sl ee p q u alit y d uri n g t h e past 4 wee ks, 
a n d c o nsists of 3 p arts : 
• 
T h e a v er a ge ti me r e q uir e d t o f all asl ee p  
  
0- 1 5 mi n ut es........................ 1 
  
1 6-3 0 mi n ut es...................... 2    
  
3 1-4 5 mi n ut es...................... 3  
  
4 6-6 0 mi n ut es...................... 4  
 
M or e t h a n 6 0 mi n ut es.......... 5  
• 
T h e a v er a ge h o urs of sl ee p p er ni g ht , gi v e n as n u m b er of h o urs p er ni g ht.  
• 
1 0 q u esti o n s t h at ar e gi v e n a s c ore of 1 (all of t h e ti m e) t o 5 ( n o ne of t h e ti me), b as e d 
o n sl ee p dist ur b a n ce i n t he f oll o wi n g areas: diffi c ult y i n falli n g asl ee p or re m ai ni n g 
asl ee p, diffi c ult y i n st a yi n g a w a k e d uri n g t h e d a y, diffic ult y i n breat h i n g, a n d s n ori n g 
d uri n g slee p. 
 
7)  
H os pit al A n xi et y a n d D e pr essi o n S cal e 1 2 
At Visit 2 a n d Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess me nt usi n g t he H A D S, w hi c h 
will b e a d o pt e d as effi cac y e v al u ati o n.  T h e H A D S  c o nsists of 7 it e ms t o s c ore 
de pr essi o n ( 4 -p oi nt s cal e) a n d 7 ite ms t o sc ore a n xiet y ( 4 -p oi nt s cal e).    T he s u bj ect will 
r es p o n d t o eac h it e m o n t he q u esti o n n aire. 
 
8)  
S F - 3 61 3 
At Visit 2 a n d Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess me nt usi n g t he S F-3 6.   T h e 
S F -3 6 q u esti o n n air e yi el ds a n 8 -s cal e pr ofil e of t he s u bj ect's s elf-assess e d Q O L  i n t h e 
f oll o wi n g cat e g ori es: P h ysi cal F u n cti o ni n g ( 3-p oi nt s cal e,  1 0 it e ms) , R ol e-P h ysi cal 
( 5- p oi nt s cale, 4 it e ms t o s c or e r ol e li mit ati o ns ca us e d b y p h ysi cal pr o bl e ms), B o dil y 
Pai n ( 6- p oi nt s cal e,  1 ite m ; 5-p oi nt s cal e, 1 it e m) , G e n eral P erce pti o n of H ealt h ( 5- p oi nt 
scale, 5 it e ms), Vit alit y ( 5- p oi nt scal e, 4 it e ms), S oci al F u n cti o ni n g  ( 5-p oi nt s cal e, 2 
it e ms), R ol e-E m oti o n al ( 5- p oi nt scal e, 3 it e ms t o sc ore r ol e li mit atio ns ca use d b y 
e m oti o n al pr o bl e ms ) a n d M e nt al H ealt h ( 5- p oi nt scale, 5 it e ms).   T h e s u bj ect will 
r es p o n d t o eac h it e m o n t he q u esti o n n aire. 
 
9)  
E v al u ati o n of S y m pt o m s6 
At Visit 1 0 , s u bj ects will pr o vi d e a s elf-ass ess m e nt of “ p ai n  e x ce pti n g ‘ti n gli n g’ a n d ‘ pi ns 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 3 of 1 0 1 
a n d n ee dl es ’ ”, “ ‘ti n gli n g’ or ‘ pi ns a n d nee dl es’ ”, a n d “ d ys est h esi a” i n t h eir feet i n 
c o m p aris o n t o b as eli n e , usi n g t h e f oll o wi n g 4-p oi nt s cal e.  
1: i m pr o v e d  
2: n o c h a n ge  
3: w ors e  
4: n o s y m pt o ms 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 4 of 1 0 1 
8.  
P H A R M A C O KI N E TI C  A N D BI O M A R K E R A S S E S S M E N T S  
8. 1  
P h a r m a c o ki n eti c  Va ri a ble(s)  
Bl o o d s a m pl es will b e ta ke n at t h e sit es ca p a ble of bl o o d s a m pli n g .   Bl o o d s a m ple will 
be c oll ect e d o n e ti me eac h at Tr eat m e nt P eri o d Visits ( Visit 3, Visit 4 , Visit 6, a n d Visit 8 ) 
a n d at E n d of Tr eat m e nt/ E arl y Ter mi n ati o n Visit ( Visit 1 0 ).   At l east o n e bl o o d s a m pl e 
m ust b e c oll ect e d wit hi n 4 h o ur aft er a d mi nistrati o n .   Bl o o d s a m pl es  will b e c ollect e d i n 
acc or d a n ce wit h t h e pr o ce d ur e s d escri b e d i n S ecti o n 1 7. 2 .   I n t h e C R F , t h e f oll o wi n g 
will b e r ec or d e d : 
• 
A d mi nistr ati o n/ N o a d mi nistr a ti o n i n t h e m or nin g o n t h e d a y b ef ore eac h visit  
• 
A d mi nistr ati o n/ N o a d mi nistr a ti o n at b e dti m e o n t he d a y b ef ore eac h visit 
• 
A d mi nistr ati o n/ N o a d mi nistr a ti o n i n t h e m or ni n g o n t h e d a y of eac h visit 
• 
D at e/ T i m e of t h e m or ni n g d ose o n t h e d a y b ef ore eac h visit  
• 
D at e/ T i m e of t h e b e dti m e d os e o n t h e d a y b ef ore eac h visit  
• 
D at e/ T i m e of t h e m or ni n g d ose o n t h e d a y of eac h visit 
• 
Ta ki n g/ N o t a ki n g brea kf ast o n t h e d a y of eac h  visit 
• 
D at e/ T i m e of br ea kf ast o n t h e d a y of eac h visit  
• 
D at e/ T i m e of bl o o d s a m pli n g 
 
Alt h o u g h P K s a m pl es will b e t a k e n f or all s u bj ects, dr u g c o n ce ntrati o n  will b e m eas ure d 
o nl y o n s u bj ects r ecei vi n g D S -5 5 6 5 . 
 
8. 2  
Bi o m a r k er Va ri a bl e(s)  
N o bi o m ar k er a n al ysis will b e p erf or m e d.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 5 of 1 0 1 
9.  
S A F E T Y A S S E S S M E N T S  
Saf et y e n d p oi nts will b e b o d y w ei g ht, A Es, l a b orat or y v al u es, vit al si g ns, 1 2 -l ea d E C G, 
fi n di n gs fr o m p h ysi cal e x a mi n ati o n, fi n di n gs fr o m n e ur ol o gi cal e x a mi n ati o n, C-S S R S, 
H A D S, e d e m a, a n d fi n di n gs fr o m o p ht h al m ol o gi c  e x a mi n ati o n . 
 
9. 1  
A d v ers e E v e nts  
9. 1. 1  
D efi niti o n of A d v ers e E ve nt 
A n A E  is a n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i ncl u di n g a n a b n or m al l a b orat or y v al u e 
or a b n or mal vit al si g n), s y m pt o m, or dis eas e t h at de v el o ps aft er t h e s u bj ect si g ns t h e 
I nf or m e d C o nse nt F or m (I C F) a n d u p t o 7 d a ys after t h e l ast d os e of st u d y me di cati o n 
( Visit 1 1 ), re gar dless of r el ati o ns hi p t o t h e i n v esti gati o n al pr o d u ct . 
 
A n y s y m pt o m t h at t h e i n vesti gat or or s u b-i n v esti gat or c o nsi d ers ass o ci at e d wit h D P N 
will b e e v al u at e d as a n effi cac y v aria bl e a n d will n ot b e re gar d e d as a n A E .    H o w e v er, if 
t h e s y m pt o m is c o nsi d er e d p ot e nti all y rel at e d t o t he i n v esti gati o n al pr o d u ct, s u c h 
s y m pt o m will b e r e gar d e d as a n A E.    If a n y pre-e xisti n g s y m pt o m or dis eas e is 
a g gr a v at e d d uri n g t h e st u d y p eri o d, t h e a g gra v ati o n will b e re p ort e d as a n A E , a n d t h e 
dat e of c o nfir mi n g t h e a g gr a v ati o n will b e c o nsi dere d t h e d at e of e v e nt o ns et.  
 
Dizzi n ess , s o m n ol e n ce, e de m a, a n d w ei g ht i n crease are c urre ntl y d efi n e d as “si g nifi ca nt 
A Es ”.  A n y ot h e r si g nifica nt A Es t o b e a d d e d will b e s p ecifi e d i n t he st atisti cal a n al ysis 
pl a n  ( S A P). 
 
All a ntie pile ptic dr u gs carr y a ris k of i ncrease d s uici dal be ha vi or a n d i deati o n.    F urt her m ore, 
i ncrease d h e patic tra nsa mi nases ha ve bee n o bser ve d i n t he D S- 55 6 5 de vel o p me nt pr o gr a m.   
T heref ore,  t he f oll o wi n g “s uici dal be ha vi or a n d i deati o n” a n d “li ver e n z y me ele vati o ns/li ver 
d ysf u ncti o n” will be treat e d as a d verse e ve nts of s p ecial i nterest.    
•  
I ncre ase i n A L T or A S T ≥ 5 x U L N 
•  
A L T or A S T rises t o ≥ 3 x U L N a n d persists f or m or e t ha n 2 wee ks  
•  
C o nc urre nt i n creases i n A L T or A S T ≥ 3 x U L N a n d T -Bil ≥ 2 x U L N  
•  
A L T or A S T ≥ 3 x U L N ass ociate d wit h a cli nical prese ntati o n s u g gesti ve of li ver i nj ur y 
(ie, i ncl u di n g t he a p peara nce of fati g ue, na usea, v o miti n g, ja u n dice, ri g ht u p per q ua dra nt 
pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia) 
•  
Seri o us he pat o biliar y a d v erse e ve nt 
•  
Se vere he pat o biliar y a d verse e ve nt  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 6 of 1 0 1 
•  
He pat o biliar y A d verse e ve nt lea di n g t o Disc o nti n uati o n  
•  
A n y tra nsa mi nase ele vati o n ass ociate d wit h a cli nical prese ntati o n s u g gesti ve of Li ver 
i nj ur y  
•  
A n ele vati o n of A L T or A S T > = 3 x U L N ( wit h o ut cli nical prese ntati o n s u g gesti ve of 
li ver i nj ur y) 
•  
A E relate d t o s uici de (if t h ere are a n y “ yes” res p o nses t o a n y of t he q uesti o ns i n t he 
C- S S R S)  
 
9. 1. 2  
It e ms t o B e I n v esti g at e d C o n cer ni n g A d v ers e E v e nts 
If a n A E  d e v el o ps d uri n g t h e cli ni cal st u d y, t he it e ms i n Ta bl e 9- 1  will b e i n v esti gat e d 
a n d t h e r es ults will b e r ec or d e d.   T h e s u bj ect s h o ul d b e q u esti o n e d i n a g e n eral w a y, 
wit h o ut as ki n g a b o ut t h e o cc urr e nce of a n y s p ecific s y m pt o ms.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 7 of 1 0 1 
Ta bl e 9- 1   It e ms t o b e I n v esti gat e d for A d v ers e E v e nt  
Ite ms re vie we d 
C o nte nt of r e vie w  
C o nte nt of A E  
Na me of A E , date of o ns et 
Acti o n ta k e n re gar di n g 
t he i n vesti g ati o nal 
pr o d uct 
N o ne  
N o c ha n ge i n i n vesti gati o nal pr o d u ct d osa ge was 
ma d e.  
Dis c o nti n u e d 
P er ma n e ntl y  
T he i n vesti g ati o nal pr o d u ct  was p er ma ne ntl y 
st o p p e d. 
I nterr u pte d 
T he i n vesti g ati o nal pr o d u ct was te m p oraril y 
st o p p e d. 
D ose R e d u ce d  
T he d os a ge of t he i n vesti gati o n al pr o d ucts was 
re d uce d. 
O utc o me  
Classificati o n of o utc o me, d ate of o utc o me ass ess me nt, date of r es ol uti o n  
 
Classificati o n 
of o utc o me  
Rec o ver e d/ Res ol ve d  
• 
T he s u bje ct f ull y re c o ver e d fr o m t he A E , 
wit h n o resi d ual effect s o bs er ve d.  
Rec o ver e d/ Res ol ve d 
wit h S e q u elae  
• 
T he resi d ual effects of t he A E  ar e still 
prese nt a n d o bs er va ble.  
• 
I de ntif y s e q uelae/resi d ual effects.  
N ot Re c o ver e d/ N ot 
Res ol ve d  
• 
T he A E  itself is still prese nt a n d o bs er va ble. 
Rec o veri n g/ R es ol vi n g  • 
T he A E  was al m ost f ull y res ol ve d, a n d t h e 
s u bje ct rec o vere d t o near-baseli ne stat us.  
U n k n o w n  
• 
N o i nf or mati o n a n d t h e o utc o me was 
u n k n o w n. 
Fatal  
 
Se verit y  
Mil d  
A war e ness of si g n or s y m pt o m, b ut easil y 
t olerate d, ie, d o es n ot i nterfere wit h s u bject’s 
us u al f u ncti o n  
M o derate  
Dis c o mf ort e n o u g h t o c a us e i nterfere n ce wit h 
us u al acti vit y  
Se vere  
I nc a pa citati n g wit h i na bilit y t o w or k or d o us ual 
acti vit y, ie, i nterf er es si g nifica ntl y wit h s u bject’s 
us u al f u ncti o n  
Seri o us n ess  
Seri o us ( acc or di n g t o t he f oll o wi n g defi niti o n of S A E s) / N ot s eri o us 
 
 
Defi niti o n of S A E  
1. Res ults i n deat h  
2. Lif e -t hr eate ni n g 
3. Re q uir es i n p atie nt h os pitalizati o n or pr ol o n g ati o n of e xisti n g 
h os pitaliz ati o n  
4. Res ults i n persiste nt or si g nific a nt disa bilit y/i nc a pa cit y  
5. A c o n ge nital a n o mal y/ birt h defe ct  
6. A n i m p orta nt me dic al e ve nt  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 8 of 1 0 1 
Ta bl e 9 -1   It e ms  t o b e I n v esti gat e d f or A d v ers e E v e nt (c o nt.) 
Ite ms re vie we d 
C o nte nt of r e vie w  
Relati o ns hi p t o t he 
i n vesti g ati o nal pr o d u ct 
Classificati o n of relati o ns hi p (i n a cc or d a nc e wit h t h e f oll o wi n g 
classific ati o ns of relati o ns hi p), r eas o n f or t hat assess me nt  
 
Classificati o n of 
relati o ns hi p 
Relate d  
• 
T he A E f oll o ws a r eas o n a ble te m p oral 
se q ue n ce fr o m i n vesti g ati o n al pr o d u ct 
a d mi nistr ati o n, a n d c a n n ot b e r eas o n a bl y 
e x plai n e d b y t h e s u bje ct’s cli nic al state or 
ot h er f act ors (e g, dise ase u n der st u d y, 
c o nc urre nt dis ea ses, c o n c o mita nt 
me dic ati o ns).  
• 
T he A E f oll o ws a r eas o n a ble te m p oral 
se q ue n ce fr o m i n vesti g ati o n al pr o d u ct 
a d mi nistr ati o n, a n d is a k n o w n re acti o n t o t he 
dr u g u n der st u d y or its c h e mic al gr o u p, or is 
pre dicte d b y k n o w n p h ar ma c ol o g y.  
 
 
N ot relate d  
• 
T he A E d oes n ot f oll o w a r e as o na ble 
te m p oral s e q ue nce fr o m i n vesti gati o n al 
pr o d uct a d mi nistrati o n, or c a n b e reas o na bl y 
e x plai n e d b y t h e s u bje ct’s cli nic al state or 
ot h er f act ors (e g, dise ase u n der st u d y, 
c o nc urre nt dis eases, c o n c o mita nt 
me dic ati o ns).  
Ot her acti o n ta ke n f or 
e ve nt  
N o ne  
N o tre at me nt was re q uire d.  
Me dic ati o n re q uir e d  
Prescri pti o n a n d/ or o ver -t h e-c o u nter me dicati o n 
was re q uir e d t o tr eat t h e A E.  
H os pitalizati o n or 
pr ol o n gati o n of 
h os pitaliz ati o n 
re q uire d 
H os pitalizati o n was re q uire d or pr ol o n ge d d u e t o 
t he A E, w het her or n ot me dicati o n was re q uire d. 
Ot her  
 
 
9. 1. 3  
D efi niti o n of A d v ers e D r u g R e a cti o n  
T h os e A E s f or w hi c h t h e r elati o ns hi p t o t h e i n vesti gati o n al pr o d u ct is c o nsi d ere d 
“ R el at e d ” will b e h a n dl e d as a d v ers e dr u g reacti o ns  ( A D Rs). 
 
9. 1. 4  
A cti o ns t o B e Ta k e n W he n A d v ers e E v e nts O cc u r  
W he n a n A E  o cc urs, t h e i n v esti gat or or s u b-i n vesti gat or will pr o vi d e a p pr o pri at e 
tr eat m e nt, will r e p ort t h e A E  t o t h e s p o ns or if n ecess ar y, a n d t o t h e e xte nt p ossi bl e will 
m o nit or pr o gr ess u ntil t h e s u bj ect r ec o v ers or t h e A E  is res ol v e d or reli e v e d.    If it 
a p p ears u nli k el y fr o m a me di cal p ers p ecti v e t h at t h e s u bj ect will rec o v er, t his will b e 
e x pl ai n e d t o t h e s u bj ect, a n d m o nit ori n g of t h e s u bj ect as a p art of t h e cli nical tri al will 
be c o n cl u d e d ( alt h o u g h t he tr eat me nt f or t h e A E  will b e c o nti n u e d).   I n a d diti o n, cli ni cal 
tri al f oll o w- u p will b e t er mi n at e d a n d t he cli ni cal tri al will b e c o n cl u d e d if  t h e 
i n v esti gat or or s u b-i n vesti gat or d eci d es f urt h er f oll o w-u p  is u n n ecess ar y f or t h e A E 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 5 9 of 1 0 1 
beca us e t her e is n o r el ati o ns hi p b et w ee n t h e A E a n d t h e i n v esti gati o n al pr o d uct, or if t h e 
s u bj ect r ef us es f urt h er f oll o w- u p. 
 
9. 2  
A cti o ns t o B e Ta k e n W he n S eri o us A d vers e E v e nts O cc u r  
If a s eri o us a d v ers e e v e nt (S A E ) o cc urs aft er o bt ai ni n g t he s u bj ect’s writt e n I C F  a n d u p 
t o Vis it 1 1 , t h e i n v esti gat or or s u b-i n v esti gat or will pr o vi d e a p pr o pri at e treat me nt f or t h e 
s u bj ect a n d will r e p ort t h e e v e nt vi a t h e e C R F  t o t he s p o ns or wit hi n 2 4 h o urs aft er 
bec o mi n g a w ar e of t h e e ve nt.    T h e i n v esti gat or will pr o m ptl y e ntr y a d et aile d 
i nf or m ati o n of t h e e v e nt t o t h e s p o ns or  i n t h e e C R F.   S A E  re p orts will b e pre p are d a n d 
s u b mitt e d t o t h e h ea d of t h e st u d y sit e or t o t h e I nstit uti o nal Re vi e w B o ar d (I R B), usi n g 
t h e f or m a n d pr o ce d ur es s p ecifi e d b y t h e st u d y sit e.    D et ail e d i nf or m ati o n re gar di n g th e 
pr o ce d ur es f or r e p orti n g S A E s is pr o vi d e d s e p arat el y, i n t he st a n d ar d o perati n g 
pr o ce d ur es f or S A Es.  
I n a d diti o n, t h e f oll o wi n g t y p es of e v e nts s h o ul d be re p ort e d t o t h e s p o ns or wit hi n 2 4 
h o urs aft er b ec o mi n g a w ar e of t h e e v e nt i n t h e d esi g n at e d f or m of t h e e C R F: 
• 
I n cr eas e i n A L T or A S T ≥ 5 x U L N 
• 
A L T or A S T ris es t o ≥ 3 x U L N a n d p ersists f or m ore t h a n 2 w ee ks  
• 
C o n c urr e nt i ncr eases i n A L T or A S T ≥ 3 x U L N a n d T -Bil ≥ 2 x U L N  
• 
A L T or A S T ≥ 3 x U L N ass o ciat e d wit h a cli ni cal pres e nt ati o n s u g gesti v e of li v er 
i nj ur y (i e, i ncl u di n g t he a p p ear a n ce of fati g u e, n a us ea, v o miti n g, ja u n di ce, ri g ht 
u p per q u a dr a nt p ai n or  t e n d er n ess, fe v er, ras h, a n d/ or e osi n o p hili a) 
• 
A E r el at e d t o s ui ci de (if t h ere ar e a n y “ yes ” res p o ns es t o a n y of t h e q u esti o ns i n t h e 
C- S S R S)  
T h e f oll o wi n g t y p es of e ve nts s h o ul d b e re p orte d t o t h e s p o ns or as pr o m ptl y as p ossi bl e 
aft er b ec o mi n g a w ar e of t h e e v e nt vi a t h e e C R F.  
•  
Se ver e h e p at o bili ar y a d v ers e e v e nt  
•  
H e p at o bili ar y A d v ers e e ve nt l ea di n g t o Dis c o nti n uati o n 
•  
A n y  tr a ns a mi n ase  el e v ati o n  ass o ci at e d  wit h  a  cli ni cal  pres e nt ati o n  s u g gesti ve  of  
Li v er i nj ur y  
•  
A n el e v ati o n of A L T or A S T > = 3 x U L N ( wit h o ut cl i ni cal pres e nt ati o n s u g gesti v e of 
li v er i nj ur y) 
 
9. 3  
E x p os u re I n Ut er o D u ri n g Cli ni c al St u di es  
D aii c hi S a n k y o m ust b e n otifi e d of a n y s u bj ect w h o b ec o m es pre g n a nt w hil e recei vi n g or 
at t h e ti m e of disc o nti n ui n g t h e i n v esti gati o n al pr o d uct.    All pre g n a n ci es m us t b e 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 0 of 1 0 1 
f oll o w e d t o c o ncl usi o n t o det er mi n e t h eir o ut c o m e.    T his i nf or m ati o n is i m p orta nt f or 
b ot h dr u g s afet y a n d p u bli c h ealt h c o n cer ns.    It is t h e res p o nsi bilit y of t h e in v esti gat or 
t o r e p ort a n y pr e g n a n c y i n a s u bj ect usi n g t h e E x p os ure I n Ut er o ( EI U) R e p orti n g f or m.   
T h e i n v esti gat or will c o ntact t h e st u d y m o nit or t o o bt ai n t h e EI U R e p orti n g F or m u p o n 
lear ni n g of a pr e g n a n c y.  If t h e o ut c o m e of t h e pre g n a n c y m eets t h e crit eri a f or 
i m m e di at e classifi cati o n as a S A E (i e, p ost-p art u m c o m pli cati o ns, s p o nt a ne o us a b orti o n, 
still birt h, n e o n at al d eat h, or c o n ge nit al a n o m al y, i ncl u di n g c o n ge nit al a n o mal y i n a n 
a b ort e d f et us), t h e in v esti gat or s h o ul d f oll o w t h e pr o ce d ures f or re p orti n g S A Es.  
 
9. 4  
Cli ni c al L a b o r at o r y E v al u ati o ns 
T h e st u d y site st aff will c oll ect bl o o d a n d uri n e s peci m e ns f or r o uti n e l a b orat or y t ests at 
s p ecifi e d ti m es.    S p eci me ns will b e st ore d u n der c o n diti o ns sti p ul at e d i n t h e S a m pl e 
H a n dli n g M a n u al u ntil t he y ar e tr a ns p ort e d f or meas ure m e nt.    S p eci m e ns will b e 
tr a ns p ort e d a n d m easur e d b y a ce ntral l a b orat or y.  Ta bl e 9- 2  s u m m ariz es t h e l a b orat or y 
par a m et ers t o b e assess e d a n d t h e ti m es of ass ess me nt.  
 
Res ults of all l a b or at or y tests will b e re p ort e d fr o m t h e ce ntral l a b orat ory t o t h e sit e. 
 
A v al u e or fi n di n g  t h at r e pr es e nts a cli ni call y si g nifi ca nt a b n or m al c h a n ge s h o ul d b e 
r e gar de d as a n A E , a n d s h o ul d b e d es cri b e d ( di a g n ose d) a p pr o pri atel y i n t he C R F. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 1 of 1 0 1 
Ta bl e 9- 2   La b or at or y P ar a m et ers t o b e Ass ess e d, a n d Ti m e of Ass ess m e nt  
 
Para m et ers  
Ti m e of ass ess m e nt  
He mat ol o g y  
W B C, R B C, h e m o gl o bi n, he mat ocrit, 
platelet c o u nt, differe ntial le u k oc yte 
( ne utr o p hil, e osi n o p hil, b as o p hil, 
m o n o c yte, l y m p h oc yte) c o u nts , r etic ul oc yte 
c o u nt 
Visit  1, Visit  2, Visit  3, 
Visit  4, Visit 5, Visit 6, 
Visit  7, Visit 8, Visit 9, 
Visit 1 0 , a n d Visit 1 1  
Bl o o d 
c he mistr y 
Total pr otei n, al b u mi n, A/ G rati o, T -Bil , 
A S T ( G O T), A L T ( G P T), A L P, γ-G T 
(γ-G T P), L D H, B U N, creati ni n e, uric a ci d, 
cre ati ne ki nase, t otal c h olester ol, 
tri gl yceri d es, Na, K, Cl , Ca, M g, i n or g a nic 
p h os p h or us, bicar b o nate, C R P  
Uri nal ysis  
Sta n d ar d uri n al ysis , i ncl u di n g micr osc o pic 
e xa mi nati o n 
S pecific gr a vit y, p H, pr otei n, gl u c os e, 
ket o nes, ur o bili n o ge n, o cc ult bl o o d , R B C, 
W B C, bilir u bi n  
H b A 1c 
H b A 1c 
Visit  1 , Visit 6 , a n d  
Visit  1 0  
Fasti n g bl o o d 
gl u c ose  
Fasti n g bl o o d gl uc ose le vel  
Visit  1 , Visit 6 , a n d 
Visit  1 0  
Pre g na n c y  
Q ualitati ve test ( uri ne)  
Visit  1  a n d Visit 1 0  
 
As d es cri b e d i n S ecti o n 4. 2. 1 , i ncr eases i n a mi n otrasferas es h a v e b ee n o bser v e d i n t h e 
D S -5 5 6 5 d e v el o p m e nt pr o gr a m t o dat e.  S p eci al m o nit ori n g of s u c h el e v ati o ns d uri n g 
P h as e 3 is d es cr ib e d b el o w.  T h e H e p ati c A dj u di cati o n C o m mitt ee ( H A C) c h art er  
i n cl u d es a pr o cess b y w hic h s el ect e d cas es will b e a dj u di cat e d b y a li v er diseas e 
s p eci alist ( S ecti o n 1 1. 1 0).  I n cases of li v er l a b orat or y a b n or m aliti es, it is i m p ort a nt t o 
e ns ur e t hat t h e n at ur e a n d t h e e xt e nt of li v e r i nj ur y is i d e ntifi e d a n d st u d y s u bj ects are 
m o nit or e d u ntil t h e li v er la b or at or y assess m e nts ret ur n t o n or m al.   S u bjects w h o h a v e 
a n y tr a nsa mi n as e el e v ati o n ass o ci at e d wit h a cli nical pres e nt ati o n s u g gesti v e of li v er 
i nj ur y (i e, i ncl u di n g t he a p p ear a n ce of fati g u e, n a us ea, v o miti n g, ja u n di ce, ri g ht u p p er 
q u a dr a nt p ai n or t e n der n ess, f e v er, r as h, a n d/ or e osi n o p hili a) or a n el e v ati o n of A L T or 
A S T ≥ 3 x U L N ( wit h o ut cli ni cal pr es e nt ati o n s u g gesti v e of li ver i nj ur y) at a n y visit 
s h o ul d b e m o nit or e d cl os el y, acc or di n g t o t h e f oll o wi n g:  
•  
Re p eat li v er t ests of at l east all f o ur of t h e us u al s er u m m eas ures ( A L T, A S T,  al k ali n e 
p h os p h at as e ( A L P), a n d t ot al bilir u bi n  at l east 2 ti mes w ee kl y (t h e first re p eat s h o ul d 
be wit hi n 4 8 t o 7 2 h o urs of i niti al a b n or m alit y) u nt il v al u es h a v e decreas e d t o < 2 x 
U L N, t h e n at l east e ver y 1 or 2 w ee ks u ntil res ol uti o n or ret ur n t o b as eli n e.    A n 
a d diti o n al s er u m s e p ar ati n g t u b e of bl o o d will b e c oll ect e d at ti m e of e v e nt a n d u ntil 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 2 of 1 0 1 
val u es r et ur n t o bas eli n e.  S a m pl es will b e st ore d f o r f urt h er a n al ysis, as re q uire d. 
•  
Re vi e w or o bt ai n a d et ail e d hist or y of s y m pt o ms a n d pri or or c o n c urre nt dis eas es . 
•  
Re vi e w or o bt ai n a hist or y of t h e us e of c o n c o mit a nt dr u gs, i n cl u di n g 
n o n pr es cri pti o n m e di cati o ns, h er b al a n d di et ar y s u p pl e m e nts, al c o h ol, r ecreati o n al 
dr u gs, a n d s p ecial di ets . 
•  
R ul e o ut al c o h oli c h e p atitis; n o n -alc o h oli c st eat o h e p atitis ( N A S H); h y p o xi c/is c h e mi c 
he p at o p at h y; a n d bili ar y tr act dis eas e . 
•  
O btai n a hist or y of e x p os ur e t o e n vir o n m e nt al c h e mical a ge nts . 
•  
Perf or m a d diti o n al li v er f u n ct i o n t ests ( L F Ts) (e g, s er u m l act at e d e h y dr o g e n as e 
( L D H), al kali n e p h os p h atas e ( A L P), ga m m a-gl ut a m yl tra ns p e pti d as e  (γ-G T [ γ-G T P ]), 
pr ot hr o m bi n ti m e  [ P T]), e v al u ati o ns f or p ot e nti al viral eti ol o gi es (i n cl u di n g he p atitis 
A, B, C, E; c yt o m e gal o vir us  [ C M V]; E pst ei n- Barr vir us  [ E B V]) a n d a ut oi m m u n e 
eti ol o gi es ( a nti -n u cl ear a nti b o d y  [ A N A], a nti-s m o ot h m us cl e a nti b o d y [ A S M A], 
a nti -mit o c h o n drial a nti b o d y  [ A M A]). 
 
C o m bi n e d el e v ati o ns of a mi n otr a nsf erases a n d bilir u bi n m eeti n g t h e crit eria of a 
p ot e nti al H y’s La w c as e [ A L T or A S T ≥ 3 x U L N wit h si m ult a n e o us t ot al bilir u bi n ≥ 2 x 
U L N],  eit h er s eri o us or n o n -s eri o us a n d w h et h er or n ot ca us all y rel at e d, s h o ul d al w a ys b e 
r e p ort e d t o t h e s p o ns or wit hi n 2 4 h o urs (refer t o Secti o n 9.2 ), wit h t h e i n vesti gat or’s 
ass ess m e nt o f seri o us n ess, ca us alit y, a n d a d et ail e d narrati v e.  ( F D A’s G ui d a n ce f or 
I n d ustr y: Dr u g-I n d u ce d Li v er I nj ur y: Pre m ar keti n g Cli ni cal E v al u ati o n; J ul y 2 0 0 9; 
htt p:// w w w.f d a. g o v/ d o w nl o a ds/ Dr u gs/ G ui d a nce/ U C M 1 7 4 0 9 0. p df ).  T hese e v e nts 
s h o ul d b e r e p ort e d as s o o n as p ossi ble f oll o wi n g t h e pr o ce d ures o utli n e d i n S ecti o n 9.2 
f or S A E re p orti n g. T h e s p o ns or will b e res p o nsi bl e f or re p orti n g t h e case(s) t o t he F D A. 
 
Crit eri a f or dis c o nti n ui n g s u bj ects bas e d o n tra ns a mi n as e i n creas es are pr o vi d e d i n 
Secti o n 4. 2. 1 . 
 
F or s u bj ects dis c o nti n u e d fr o m t h e st u d y d u e t o a n y tra ns a mi n as e i n creas e or h e p ati c 
e v e nt, t h e f oll o wi n g s h o ul d b e p erf or m e d:  
•  
G astr o e nter o l o g y or h e p at ol o g y c o ns ult ati o n 
•  
H e p at o bili ar y ultr as o u n d  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 3 of 1 0 1 
 
 
 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 4 of 1 0 1 
9. 5  
Vit al Si g ns  
Vit al si g ns will b e r ec or d e d at all visits a n d will i n cl u d e s u pi n e p uls e rat e a n d s u pi n e a n d 
ort h ost ati c bl o o d pr ess ur e.   F or m eas ure m e nt of s u pi n e bl o o d press ure, s u bj ects s h o ul d 
be i n a s u pi n e or s e mir ec u m b e nt p ositi o n f or at l e ast 5 mi n ut es b ef ore t h e bl o o d press ure 
meas ur e m e nt.    M eas ure me nt of ort h ost ati c bl o o d press ure s h o ul d f oll o w meas ure m e nt 
of s u pi n e bl o o d pr ess ur e.    S u bjects s h o ul d b e as k e d t o st a n d f or 3 mi n ut es b ef ore 
meas ur e m e nt of ort h ost ati c bl o o d pr ess ure.    M eas ure m e nt of bl o o d press ure s h o ul d b e 
c o n d u ct e d usi n g a cali br at e d ma n o m et er or a ut o mati c i nfl at a bl e c uff m o nit or; t h e bl o o d 
pr ess ure c uff s h o ul d b e k e pt i n pl ace b et w ee n s u pi n e a n d ort h ost ati c bl o o d press ure 
meas ur e m e nts.  R es ults will b e rec or d e d i n t h e C R F.  
 
9. 6  
El ect r o c a r di o g r a ms  
At t h e sti p ul ate d ti m es ( Visit  1 a n d Visit  1 0), 1 2-lea d E C G will b e p erf or me d .   Res ults  
(N or m al / A b n or m al, n ot cli ni call y si g nifi ca nt / A b n or m al, cli ni call y si g nifica nt ) will b e 
r ec or de d i n t h e C R F . 
 
9. 7  
P h ysi c al Fi n di n gs  
9. 7. 1  
B o d y H ei g ht a n d Wei g ht  
At S cr ee ni n g ( Visit 1) , b o d y h ei g ht will b e m eas ure d.    B o d y w ei g ht will be m eas ure d at 
eac h visit.    Res ults will be r ec or de d i n t h e C R F . 
 
9. 7. 2  
P h ysi c al E x a m i n ati o ns 
At S cr ee ni n g Visit ( Visit 1) a n d E n d of Treat m e nt/ E arl y Ter mi n ati o n Visit ( Visit 1 0 ), a 
c o m pl et e p h ysi cal e x a mi nati o n, wit h t h e e x ce pti o n of p el vis, breast , a n d rect u m i n  
w o m e n a n d t h e ge nit o uri nar y s yst e m a n d pr ost at e i n m e n, will b e p erf or m e d o n eac h  
s u bj ect. 
 
At Visit 2, Visit  3, Visit 4, Visit 5 , Visit 6, Visit 7, Visit 8, Visit 9, a n d V isit 1 1, th e 
e x a mi nati o n s h o ul d mi ni mall y i n cl u d e cli ni cal e v al u ati o ns of t h e h ea d, n ec k, t h yr oi d,  
e yes, ears, n ose, t hr o at, h eart, l u n gs, l y m p h n o d es, a b d o m e n, s ki n, e xtre mities, a n d  
m us c ul os kel et al s yst e m.  
Res ults will b e r ec or d e d i n t h e C R F.  
 
9. 7. 3  
E v al u ati o n of E d e m a  
At Visit 1 a n d Visit 1 0 , e val u ati o n of e d e m a will be p erf or m e d i ncl u di n g p h ysi cal 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 5 of 1 0 1 
e x a mi nati o n a n d/ or pitti n g .   R es ults  ( pres e n ce or a bs e n ce of e d e m a a n d e x pressi o n sit e) 
will b e r ec or d e d i n t h e C R F.  
 
9. 8  
Ot h er S af et y Ass ess me nts  
9. 8. 1  
N e u r ol o gi c al E x a mi n ati o n 
A f ull  n e ur ol o gi cal e x a mi n ati o n  will b e p erf or m e d at t h e sti p ulat e d ti m es ( Visit 1 a n d 
Visit 1 0 ).  A n a b br e vi at e d e x a mi n ati o n  will b e p erf or m e d at Visit 2, Visit 3, Visit 4, Visit  
5 , Visit 6, Visit 7, Visit 8, Visit 9, a n d Visit 1 1 . 
 
T h e  f ull n e ur ol o gi cal e x a mi n ati o n  will i n cl u d e t h e f oll o w i n g: a n kl e j er k , vi brator y 
se ns ati o n, pai n s e ns ati o n i n cl u di n g h y p eral gesi a, all o d y ni a, m us cl e stre n gt h ( 0-t o-5 
r ati n g; a n kle d orsifl e xi o n), a n d gait/st ati o n ( o bs er v ati o n of re g ul ar w al ki n g, h eel-t o-t oe 
[ta n d e m] w al ki n g, a n d R o m b er g t est, eac h ass ess e d as n or m al or a b n or m al).   T h e t ests 
of a n kl e j er k , vi br ator y s e ns ati o n , a n d pai n s e ns ati o n are d et ail e d i n t he Pr oce d ures 
ma n u al f or t h e Di a g n osis of Di a b eti c P eri p h eral N e ur o p at h y a n d N e ur ol o gi cal 
E x a mi n ati o n .   T he ass e ssm e nt o n p ai n s y m pt o m  will be rec ore d as “ P ai n e x ce pti n g 
ti n gli n g a n d pi ns & n ee dles”, “ Ti n gli n g or pi ns & n ee dl es” or “D ys est h esi a ”.  
 
T h e  a b br e vi at e d e x a mi n ati o n  will i n cl u de m us cl e stre n gt h  a n d gait/stati o n bas e d o n 
p h ysi cal e x a mi nati o n a n d  m e di cal i nt er vie w, eac h ass ess e d as n or m al or a b n or m al.  
Res ults will b e r ec or d e d i n t h e C R F . 
 
9. 8. 2  
O p ht h al m ol o gic E x a mi n ati o n  
T h e o p ht h al m ol o gi c e x a mi n ati o n  will b e p erf or m e d at Visit 1  (all o w e d t o Visit 2) a n d 
Visit 1 0  ( all o w e d t o 4 d a ys after).   T h e  e x a mi n at i o n i n cl u d es e x a mi n ati o n of vis u al 
ac uit y a n d f u n d us c o pi c e x a mi n ati o n.   F or a gi v e n s u bj ect, vis u al ac uit y s h o ul d b e 
e x a mi ne d u n d er t h e s a m e c o n diti o ns ( u n c orrect e d or c orrect e d) at b ot h visits , a n d 
f u n d us c o p y s h o ul d b e p erf or m e d wit h  t he s a m e d e vi ce .   R es ults of vis ual ac uit y will b e 
r ec or de d as v al u es, a n d r es ults of f u n d us c o pi c e x a mi n ati o n will b e rec or d e d as [ N or m al / 
A b n or m al, n ot cli ni call y si g nifi ca nt / A b n or m al, cli ni call y si g nifi ca nt] i n t he C R F.  
 
9. 8. 3  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e 1 4 
T h e C - SS R S is a t o ol d esi g n e d t o s yst e m ati call y ass ess a n d trac k s ui ci d al A E s ( b e h a vi or 
a n d i d eati o n).    T h e C -S S R S ass ess es lifeti m e s ui ci d alit y d uri n g a n i niti al bas eli n e 
e v al u ati o n usi n g st a n d ar diz e d q u esti o ns, a n d t h e n pr os p ecti v el y m o nit ors i d eati o ns a n d 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 6 of 1 0 1 
be h a vi ors at s u bs e q u e nt f oll o w -u p ass ess me nts t hr o u g h o ut t h e trial.    T he re vie w er is a n 
i n v esti gat or or s u b-i n vesti gat or w h o h as c o m pl et e d trai ni n g pri or t o t h e st u d y usi n g t h e 
tr ai ni n g D V D.   T h e C -S S R S will b e a d mi nist ere d b y t h e i n v esti gat or or s u b-i n v esti gat or 
at eac h  visit.  A ns wers t o all r el e v a nt q u esti o ns will b e rec or d e d i n t h e C R F.    If t h e 
s u bj ect is j u d ge d t o ha v e s ui ci dal b e h a vi or a n d/ or s ui ci dal i d eati o n, a p pr o pri at e m eas ures 
will b e i m pl e m e nt e d s uc h as r eferri n g t h e s u bj ect t o a s p eci alist  as d es cri b e d i n t h e 
wit h dr a w al pr oce d ur es  (s ee S ecti o n 4. 2. 3 ). 
 
9. 8. 4  
H os pit al A n xi et y a n d D e p ressi o n S c al e 1 2 
At eac h visit , s u bj ects will pr o vi d e a s elf-ass ess m e nt usi n g t h e H A D S.    T he H A D S 
c o nsists of 7 it e ms t o s c or e d e pr essi o n ( 4 -p oi nt s cal e) a n d 7 it e ms t o s c ore a n xi et y 
( 4-p oi nt s cale).    T h e s u bj ect will res p o n d t o eac h it e m o n t h e q u esti o n n aire.   Bas e d o n 
t h e r es ults, t h e i n v esti gat or will c hec k f or t h e pres e n ce or a bse n ce of d e pressi o n a n d/ or 
a n xi et y.  If t h e s u bj ect is j u d ge d t o h a v e a n A E , a p pr o pri at e m eas ures will b e 
i m pl e m e nt e d s u c h as r ef erri n g t h e s u bject t o a s p eci alist.  R es ults will b e rec or d e d i n t h e 
C R F.  
 
9. 8. 5  
Pre g n a n c y t est  
Pr e g n a n c y t ests ( uri n e t ests) will b e c o n d u ct e d at t h e sti p ul at e d ti m es ( Visit  1 a n d 
Visit  1 0 ), f or w o m e n of c hil d-b eari n g p ot e nti al  o nl y.   All fe m al e s u bj ects will b e 
c o nsi d er e d as w o m e n of c hil d-b eari n g  p ot e nti al u nl ess t h e y h a v e u n d er g o ne  s ur gi cal 
st eriliz ati o n ( wit h d o c u m e nt e d bil at eral o o p h orect o m y) or are p ost m e n o p a us al a n d h a v e 
e x p eri e n ce d n o m e ns es wit hi n t h e pre vi o us 6 m o nt hs.    T he s u bj ect is c o nsi d ere d t o b e 
p ost m e n o p a usal w he n 1 2 c o ns ec uti v e m o nt hs of a bs e n ce of m e nstr uati o n is c o n fir m e d 
wit h n o pat h ol o gi cal or p h ysi ol o gi cal fact ors.   R es ults will b e rec or d e d i n t h e C R F . 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 7 of 1 0 1 
1 0.  O T H E R A S S E S S M E N T S  
N o ot h er  ass ess m e nts will b e p erf or m e d.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 8 of 1 0 1 
1 1.  S T A TI S TI C A L M E T H O D S  
1 1. 1  O bj ecti v e  
T h e pri mar y o bj ecti v e is t o c o m p ar e t h e c ha n ge fr o m b as eli n e t o Wee k  1 4 ( Visit 1 0) i n 
A D P S f or 1 0 m g BI D a n d 1 5 m g BI D  of D S -5 5 6 5 a gai nst pl ace b o.    T h e sec o n d ar y 
o bj ecti v es ar e s h o w n i n s ecti o n 2. 1. 2 . 
. 
1 1. 2  Ge n er al St atistic a l C o nsi d er ati o ns 
T h e st atisti cal p ac k a ge S A S ®  ( Ve rs i o n 9. 2 or hi g h er) will b e us e d t o pr o d u ce t a bl es, 
fi g ur es, a n d listi n gs.     
T h e m o difi e d i nte nt- t o-tr eat ( mI T T) a n al ysis set will b e us e d as a pri m ar y effi cac y 
a n al ysis s et f or all effi cac y a n al ys es a n d t h e p er-pr ot o c ol s et  ( P P S) will b e us e d f or 
se nsiti vit y a n al ysis.    All s af et y a n al ys es a n d p h ar m ac o ki n eti c a n al yses will b e 
c o n d u ct e d f or t h e s af et y a n al ysis s et a n d P K a n al ysis s et, res p ecti v el y. 
T h e pri m ar y i m p ut ati o n will be b as e d o n “ n o nf ut ure d e pe n de n ce" m o d el usi n g t h e p att er n 
mi xt ur e a p pr o ac h u n d er t he missi n g n ot at ra n d o m ( M N A R) mec h a nis m f or t h e missi n g 
w ee kl y A D P S d at a 1 9 - 2 1.    R eas o n f or dr o p o ut t o get h er wit h t h e ti m e of dr o p o ut will be 
us e d f or c o nstr u cti n g t h e missi n g d at a p att er n.    D et ail wil l b e at S ecti o n 1 1. 5. 1  a n d i n 
t h e S A P. 
Ra w d at a will b e pr es e nt e d t o t h e e x act precisi o n at w hi c h t h e y w ere c oll ect e d.  
F or s u m m ar y st atisti cs, mea ns  a n d m e di a ns will be dis pl a ye d t o o n e m ore d eci mal pl ace 
t h a n w as d eter mi n e d f or r a w d at a, d is p ersi o n st atisti cs will h a ve t w o m ore deci m al pl aces, 
a n d t h e mi ni m u m a n d m a xi m u m will b e dis pl a ye d t o t h e s a m e n u m b er of deci m al places 
as t h e r a w d ata. 
Q u a ntit a ti v e d at a will b e t a b ul at e d wit h d es cri pti ve s u m mar y st atisti cs: arit h m eti c m ea n, 
st a n d ar d d e vi ati o n ( S D), me di a n, mi ni m u m a n d m a xi m u m v al u es, a n d n u m ber of 
o bser v ati o ns.   F or c ate g ori cal d at a , fre q u e n c y t a bl es will b e pr o vi d e d . 
All h y p ot h esis t esti n g will pr o vi d e t h e P  v al ues a n d t h eir c orres p o n di n g t w o -si d e d 9 5 % 
c o nfi d e n ce i nter v als if a p pli ca bl e.    T h e si g nifi ca n ce l e vel is 0. 0 5 (t w o -si de d) f or all 
h y p ot h esis t esti n g.    T h e t y p e I err or rat e will b e c o ntr oll e d at l ess t h a n 0. 0 5 f or t h e 
m ulti pl e c o m p aris o ns of t h e pri m ar y e n d p oi nt of A D P S at Wee k 1 4 b et w ee n eac h 
D S -5 5 6 5 ar m ( 1 5 m g Q D, 1 0 m g BI D, or 1 5 m g BI D) a n d pl ace b o, usi n g c o m bi n ati o n 
a p pr o ac h of B o nf err o ni -H ol m m et h o d a n d gat e -k ee pi n g pr o ce d ure (see S ecti o n 1 1. 5. 1 ).  
N o a dj ust m e nt f or m ulti pl e c o m paris o ns will b e ma d e f or t h e s ec o n d ar y effi cac y 
a n al ys es.  
A n al ysis f or t h e c h a n ge fr o m b as eli n e, i n cl u di n g t he s hift t a bl e, w ill b e c o n d uct e d f or t h e 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 6 9 of 1 0 1 
s u bj ects w h o h a v e a n a v aila bl e b as eli n e v al u e a n d at l east o n e p ost-ra n d o mizati o n v al u e. 
S u b gr o u p a n al ys es b y c o u ntr y ( e g, J a p a n, K orea, a n d Tai w a n) will b e c o n d u ct e d f or s o m e 
of effi cac y a n d s af et y a n al ys es s p ecifi e d i n t he S A P.  
P K a n al ysis will b e d et aile d i n t h e P K a n al ysis pl a n ( P A P).  
A d etail e d S A P a n d P A P des cri bi n g t h e m et h o d ol o g y t o b e us e d i n t h e fi n al a n al ysis will 
be pr e p are d b ef or e d at a u n bli n di n g.    A c h a n ge i n t h e pl a n n e d st atisti cal a n al ysis will 
r e q uir e a pr ot oc ol a m en d me nt o nl y if it s u bst a nti v el y alt ers t h e pri n ci p al feat ures of t h e 
pr ot o c ol.    A n y d e vi ati o ns fr o m t h e pl a n n e d st atisti cal a n al ys es i n t h e pr ot o c ol will b e 
f ull y d es cri be d i n t h e S A P a n d P A P. 
 
1 1. 3  A n al ysis S ets 
T h e r a n d o mize d a n al ysis s et will i n cl u d e all s u bj ects w h o si g n e d t h e I C F a n d w ere 
r a n d o miz e d i nt o t h e st u d y. 
T h e s af et y a n al ysis s et will i n cl u de all s u bj ects w h o si g n e d t h e I C F a n d recei v e d at l east 
o n e d os e of st u d y m e di cati o n.  
T h e mI T T a n al ysis s et will i n cl u de all s u bj ects i n t h e ra n d o miz e d a nal ysis set w h o 
r ecei v e d at l east o n e d os e of st u d y m e di cati o n.    T h e mI T T  a n al ysis s et will b e us e d f or 
pri m ar y a n d s ec o n d ar y effi cac y a n al ys es.  
T h e  P P S will i n cl u d e all s u bj ects i n t h e ra n d o mize d a n al ysis s et w h o recei ve d at least o n e 
d ose of st u d y m e di cati o n , a n d w h o w ere s uffi ci e ntl y c o m plia nt wit h t h e pr ot o c ol, 
acc or di n g t o pr e -s p ecifi e d crit eri a t h at will b e fi n alize d pri or t o d at a bas e l oc k.    T h e P P S 
will b e us e d f or s e nsiti vit y a n al ys es.  
 
T h e P K a n al ysis s et will i n cl u d e all s u bj ects w h o si g n e d t h e I C F a n d recei ve d a d os e of 
D S -5 5 6 5 a n d h a d at l east o ne P K s a m pl e c oll ect e d.  
 
1 1. 4  St u d y P o p ul ati o n D at a 
D e m o gr a p hi c a n d b as eli ne c h ar act eristi cs will b e s u m m ariz e d f or t h e ra n d o miz e d, s afet y, 
mI T T, P P S, a n d P K a n al ysis s ets.  
 
1 1. 5  Effi c a c y A n al ys es  
1 1. 5. 1  Pri m a r y Effi c a c y A n al ys es  
T h e pri mar y effi cac y a n al ysis will b e p erf or me d usi n g t h e mI T T a n al ysis s et.    
O bs er v e d A D P S a n d c h a n ge fr o m b as eli n e will b e s u m m ariz e d b y treat m e nt a n d w ee k  
(i n cl u di n g Wee k 1 4/ L O C F a n d Wee k 1 4/ b as eli n e o bs er v ati o n carri e d f or w ar d [ B O C F]).  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 0 of 1 0 1 
Mea n c h a n ge fr o m b as eli n e i n A D P S will b e c o m pare d b et w ee n eac h D S -5 5 6 5 ar m a n d 
pl ace b o at Wee k 1 4 usi n g t h e f oll o wi n g m ulti pl e i m p ut ati o n ( MI) m et h o d a n d 
mi x e d -eff ect m o d el f or r e p eate d m eas urem e nt s ( M M R M)1 7, 1 8 acc or di n g t o t h e 
pr e- s p ecifi e d t est pro ce d ur e d es cri b e d lat er i n t his s ecti o n.  
T h e pri mar y i m p ut ati o n will b e b as e d o n “ n o nf ut ure d e p e n d e n ce" m o d el  19 - 2 1 usi n g t h e 
patt er n mi xt ur e a p pr o ac h wit h s hifti n g p ara m et ers u n d er t h e M N A R  m ec h a nis m f or t h e 
missi n g w ee kl y A D P S d at a.    R eas o n f or dr o p o ut  t o get h er wit h t h e ti m e of dr o p o ut will 
be us e d f or c o nstr u cti n g t h e missi n g d at a p att er n.    T h e st atisti cal m o d el use d f or t h e MI 
dat a ge n er ati o n will b e t he M ar k o v C h ai n M o nt e Carl o ( M C M C) m et h o d wit h a dj ust m e nt 
f or c o v ari at es ( e g, tr eat m e nt gr o u p, a ge, s e x) t o pr o d uce a m o n ot o n e p att er n first, a n d 
t h e n t h e i m p ut ati o n will c o nti n u e usi n g t h e R e gressi o n wit h Pre di cti v e M ea n M at c hi n g 
( R E G P M M) m et h o d f or t h e m o n ot o ne patt er n wit h t h e s a m e s et of c o v ariates.   T h e 
i m p ut e d v al u e will b e s et as 1 0 (t h e m a xi m al A D P S s c ore) w h e n t h e i m p ut e d v al u e of 
A D P S s c or e is o v er 1 0.    A d diti o n all y, f or dr o p o uts d u e t o L O E, t he i m p ut e d v al u es will 
be b o u n d s o t h at a s u bj ect’s i m p ute d w ee kl y A D P S aft er dis c o nti n u ati o n ca n n ot b e b ett er 
t h a n t h at s u bj ect’s b aseli ne A D P S.   E ac h c o m p l et e i m p ut e d d at as et will be a n al yz e d 
usi n g t h e M M R M wit h tr eat m e nt, w ee k, treat m e nt -b y -w ee k as t h e fi x e d effects, w ee k as 
t h e r e peat e d m eas ur e, a n d bas eli n e A D P S as t h e c o v ari at e.   T h e res ults of M M R M 
a n al ysis fr o m eac h c o m plete i m p ut e d d at as et will be c o m bi n e d usi n g R u bi n’s r ul e.   All 
r eas o ns f or dis c o nti n u ati o n will b e cat e g oriz e d, t o t h e e xt e nt p ossi bl e, i nt o eit h er L O E or 
A E b as e d o n d et ail s p ecifi e d i n t h e C as e R e p ort F or m.    O nl y reas o ns t h at ca n n ot b e 
cl assifi e d i nt o t h e a b o v e t w o cat e g ori es will b e c o nsi d ere d as “all ot h er reas o ns ( A O R)”.  
T h e pri mar y s hifti n g p ar a m et er v al u es c orres p o n di n g t o t h e t hree cat e g ori es i n t h e p att er n 
mi xt ur e m o d el ( P M M) will b e c h os e n as ( 1. 0, 1. 0, 0. 5 ) f or dr o p o uts d u e t o A E, L O E a n d 
A O R, r es p ecti v el y, a n d t he c orr es p o n di n g s hifti n g a m o u nt of t h e w ee kl y A D P S i m p ut e d 
at first missi n g w ee k is gi v e n b y ( 1. 0, 1. 0, 0. 5) * R S D * U( 0, 1) w h ere U( 0, 1) is a ra n d o m 
varia bl e fr o m a u nif or m distri b uti o n wit h a ra n ge of 0 t o 1, a n d R S D is t h e resi d u al 
st a n d ar d d e vi ati o n at first missi n g w eek aft er i m p ut ati o n.  
 
T h e t y p e I err or r at e will b e c o ntr oll e d at l ess t h a n 0. 0 5 f or t h e m ulti pl e c o m p aris o ns of 
t h e pri m ar y effi cac y a n al ys es i n t h e f oll o wi n g m ulti pl e test pr o ce d ure. 
1)  D S -5 5 6 5 1 0  m g BI D a n d 1 5  m g BI D will be t est e d a gai nst pl ace b o usi n g 
B o nf err o ni -H ol m m et h o d at si g nifi ca n ce l e vel of 0. 0 5.  
2)  T h e f oll o wi n g st atisti cal test will b e p erf or m e d acc or di n g t o t h e res ult of 1) . 
• 
If b ot h of ar ms ar e st atisticall y si g nifi ca nt, D S -5 5 6 5 1 5 m g Q D ar m will b e 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 1 of 1 0 1 
test e d at l e v el of 0. 0 5. 
• 
If n eit h er of t h e ar ms is statisti call y si g nifi ca nt, D S-5 5 6 5 1 5 m g Q D ar m will n ot 
be t est e d.  
• 
If eit h er D S -5 5 6 5 1 0 m g BI D or D S -5 5 6 5 1 5 m g BI D is st atisti call y si g nifica nt , 
D S -5 5 6 5 1 5 m g Q D ar m will b e t est e d at l e v el of 0. 0 2 5. 
 
Se nsiti vit y a n al ys es will i n cl u d e f oll o wi n g:  
• 
T h e a b o v e pri mar y “ n o nf ut ur e d e p e n d e n ce” M N A R m o d el wit h differe nt s hift 
par a m et ers i n cl u di n g ( 0, 0, 0)  
• 
Place b o m ulti pl e i m p ut ati o n 1 7, 1 8  
• 
M M R M usi n g o b ser v e d dat a o nl y 
• 
A N C O V A usi n g B O C F  
• 
A N C O V A usi n g L O C F  
• 
T h e a b o v e pri mar y “ n o nf ut ur e d e p e n d e n ce” M N A R m o d el wit h t h e s a m e s hift 
par a m et ers as t h e pri mar y a n al ysis (i. e., ( 1. 0, 1. 0, 0. 5) usi n g P P S ). 
 
1 1. 5. 2  S ec o n d a r y Effic a c y A n al ys es  
Sec o n dar y effi cac y a n al yses will b e p erf or m e d usi n g t h e mI T T  a n al ysis s et .   F or  all  
sec o n d ar y e n d p oi nts, t h e s u m m ar y st atisti cs or fre q u e n c y t a bl es will b e creat e d b y 
tr eat m e nt gr o u p f or eac h w ee k or s c h e d ul e d visit.    T h e s ec o n d ar y e n d p oi nts f or eac h 
D S -5 5 6 5 ar m will b e c o m p are d wit h t h at f or pl ace b o wit h n o a dj ust m e nt of m ulti pl e 
c o m p aris o ns.  
 
1 1. 5. 2. 1  
R es p o n d er R at e f o r Av er a g e d D ail y P ai n S c o re  
A D P S r es p o n d er r at e, d efi n e d as t h e pr o p orti o n of s u bj ects wit h ≥ 3 0 % , a n d ≥ 5 0 % 
r e d u cti o n fr o m b as eli n e t o Wee k 1 4, will b e cal c ulate d b y treat m e nt gr o u p.   A D P S 
r es p o n d er r at e of eac h ar m of D S-5 5 6 5 will b e c o m p are d wit h t h at of pl ace b o usi n g 
l o gisti c r e gr essi o n m o d el.    T h e c u m ul ati v e distri b uti o n of re d u cti o n fr o m b as eli n e i n 
A D P S will b e pr o vi d e d as a c o nti n u o us res p o n d er a n al ysis 1 5. 
 
1 1. 5. 2. 2  
S h o rt -F o r m Mc Gill P ai n Q u esti o n n ai re  
F or t h e s e ns or y s c or e, aff ecti v e s c or e, t ot al s c ore, V A S, a n d t h e pres e nt p ai n i nte nsit y 
i n d e x, t h e m eas ur e d val u e a n d t h e c h a n ge fr o m b aseli ne will b e s u m m ariz e d at eac h 
sc h e d ul e d visit.    T h e c h a n ge fr om b as eli n e i n t h e p ara m et ers a b o v e will be c o m p are d 
bet w ee n eac h ar m of D S -5 5 6 5 a n d pl ace b o.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 2 of 1 0 1 
 
1 1. 5. 2. 3  
M o difi e d B ri ef P ai n I n ve nt o r y ( S h ort F o r m) 
F or t h e p ara m et ers rel at e d t o s e v erit y of p ai n a n d i m p act o n d ail y f u n cti o ns, t h e m eas ure d 
val u e a n d t h e c h a n ge fr o m b a s eli n e will b e s u m m ariz e d at eac h s c h e d ul e d visit.    T h e 
c h a n ge fr o m b as eli n e i n t h e p ara m et ers a b o v e will b e c o m p are d b et w ee n eac h ar m of 
D S -5 5 6 5 a n d pl ace b o.  
 
1 1. 5. 2. 4  
P ati e nt Gl o b al I m p ressi o n of C h a n g e  
P GI C s c or e ( 1 t o 7 o n a 7 -p oi nt scal e) will b e d es cri be d as fre q u e nc y t a ble a n d will b e 
c o m p ar e d bet w ee n eac h ar m of D S -5 5 6 5 a n d pl ace b o.  
 
1 1. 5. 2. 5  
Slee p -I nt erf ere nce S c o re 
T h e s u m m ar y statisti cs will b e c o m p ut e d f or t h e A D SI S  a n d t h eir c h a n ge fr o m b as eli n e at 
eac h wee k.    T h e c ha n ge fr o m b as eli ne i n sl ee p i nterfere n ce s c ore will b e c o m p are d 
be t w ee n eac h ar m of D S-5 5 6 5 a n d pl ace b o.  
 
1 1. 5. 2. 6  
M e di c al O ut c o mes S t u d y Sl ee p S c al e 
F or t h e s u bs cal es of sl ee p dist ur ba n ce, s n ori n g, a w a k e ni n g s h ort of breat h or wit h a 
hea d ac h e, s o m n ol e n ce, slee p a d e q u ac y, sl ee p pr o bl e ms i n d e x, a n d q u a ntit y of sl ee p, t h e 
meas ur e d v al u e a n d t h e c ha n ge fr o m b as eli n e will b e s u m m ariz e d at eac h s c h e d ul e d visit.   
T h e c h a n ge fr o m b as eli n e i n t h e s u bs cal es a b o ve will be c o m p are d b et w ee n eac h ar m of 
D S -5 5 6 5 a n d pl ace b o.  
F or t h e o pti m al sl ee p w hic h is di c h ot o miz e d v ersi o n of o pti m al sl ee p fi n di n gs, t h e 
s u m m ar y will b e pr o vi d e d as fr e q ue n c y t a bl es a n d t h e p ara m et er will b e c o m p are d 
bet w ee n treat m e nts.  
 
1 1. 5. 2. 7  
H os pit al A n xi et y a n d  D e p ressi o n S c al e  
F or t h e s u bs cal es of a n xiet y a n d d e pressi o n, t h e meas ure d v al u e a n d t h e c ha n ge fr o m 
bas eli n e will b e s u m m ari ze d at b aseli ne a n d Visit 1 0.    T h e c h a n ge fr o m b as eli n e i n t h e 
s u bs cal es a b o v e will b e c o m p ar e d bet w ee n eac h ar m of D S-5 5 6 5 a n d pl ace b o.  
 
1 1. 5. 2. 8  
S F -3 6  
F or t h e ei g ht- s cal e pr ofil e of p h ysi cal f u n cti o ni n g, r ol e-p h ysi cal, b o dil y p ai n, ge n eral 
per ce pti o n of h ealt h, vit alit y, s o ci al f u n cti o ni n g, r ol e -e m oti o n al, a n d m e nt al h ealt h, t h e 
tr a nsf or me d s c or e a n d t h eir c h a n ge fr o m b as eli n e will b e d es cri b e d as s u m mar y st atisti cs 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 3 of 1 0 1 
at eac h s c h e d ul e d visit.    T h e c ha n ge fr o m bas eli n e will b e c o m p are d b et w ee n eac h ar m 
of D S -5 5 6 5 a n d place b o f or eac h s cal e pr ofil e a b o v e.  
 
1 1. 5. 2. 9  
E v al u ati o n of S y m pt o m s 
T h e e v al u ati o n of s y m pt o ms (f o ur cat e g ori es of “i m pr o v e d ”, “ n o c h a n ge”, “ w ors e”, “ n o 
s y m pt o ms ”) will b e d es cri b e d as fr e q u e n c y t a bl e a n d will b e c o m p are d b et w ee n eac h ar m 
of D S -5 5 6 5 a n d place b o.  
 
1 1. 6  P h a r m a c o ki n eti c/ Bi o m ar ker A n al ys es  
1 1. 6. 1  P h a r m a c o ki n eti c A n al yses  
Scatt er pl ot ill ustr ati n g t he p h ar m ac o ki n eti c rel ati o ns hi p b et w ee n ti m e aft er d os e a n d 
pl as ma c o n ce ntr ati o n b y tr eat m e nt f or eac h visit will b e creat e d, usi n g t h e P K a n al ysis s et.   
T h e p o p ul ati o n P K a n al ysis will b e r e p ort e d s e p arat el y fr o m t h e cli ni cal st u d y re p ort (i. e. 
n ot i n t h e cli ni cal st u d y r e p ort).  
 
1 1. 6. 2  Bi o m a r k er A n al ys es 
N ot a p pli ca bl e.  
 
1 1. 7  S af et y A n al ys es  
All s af et y a n al ys es will be p erf or m e d o n a b y -treat me nt b asis, u nl ess ot her wis e s p ecifi e d, 
usi n g t h e s af et y a n al ysis set.  
 
1 1. 7. 1  A d vers e E v e nt A n al ys es  
A n y A E s t h at a p p ear aft er t h e first a d mi nistrati o n, or t h at w orse n relati v e t o t h e 
pr e- tr eat m e nt st at e, ar e c o nsi d er e d as T E A Es.    T E A Es will b e c o d e d usi n g t h e M e dical 
Di cti o n ar y f or R e g ul at or y A cti viti es ( M e d D R A).  
 
T h e n u m b er a n d p erce nt a ge of s u bjects re p orti n g T E A Es will b e cal c ul at e d f or t h e 
cat e g ori es liste d b el o w b y  tr eat m e nt a n d all-D S -5 5 6 5 treat m e nt.    T h e n u m b er a n d 
per ce nt a ge of s u bjects r e p orti n g T E A Es a n d A D R s will b e s u m m ariz e d b y s yst e m or ga n 
cl ass, pr eferr e d t er m, a n d tr eat m e nt a n d all -D S -5 5 6 5 treat m e nt.  
• 
T E A E  
• 
A D R  
• 
Seri o us T E A E  
• 
Seri o us A D R  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 4 of 1 0 1 
• 
Se ver e T E A E  
• 
Se ver e A D R 
• 
Si g nifi ca nt T E A E  
• 
Si g nifi ca nt A D R  
• 
T E A E l ea di n g t o tr eat m e nt dis c o nti n u ati o n  
• 
A D R  lea di n g t o tr eat m e nt dis c o nti n u ati o n 
 
Ti m e t o first T E A E, d efi ne d as t h e d urati o n fr o m first a d mi nistrati o n of i n vesti gati o n al 
pr o d u ct t o t h e first T E A E, will b e s u m m ariz e d b as e d o n t h e K a pl a n-M ei er pr o d u ct li mit 
met h o d b y tr eat m e nt a n d all -D S -5 5 6 5 treat m e nt.  
 
1 1. 7. 2  Cli ni c al L a b o r at o r y E v al u ati o n A n al ys es  
F or t h e h e m at ol o g y a n d bl o o d c h e mistr y t est p ara meters, s u m m ar y st atisti cs will b e 
cal c ul at e d f or t h e m eas ur e d v al u es a n d c h a n ge fr o m b as eli n e at eac h s c h e d ul e d visit.    A 
s hift t a bl e will b e cr eate d bas e d o n t h e cat e g ori es of “a b n or m al l o w ”, “ n or mal”, a n d 
“a b n or mal hi g h ” b et w ee n bas eli n e a n d eac h s c h e d ul e d visit . 
 
A d diti o n all y, f or A L T, A S T, T- Bil , a n d A L P, t h e n u m b er a n d p erce nt a ge of s u bj ects w h o 
meet t h e crit eri a s p ecifi e d i n F o o d Dr u g A d mi nistrati o n  (F D A ) Dr u g -I n d u ce d Li v er 
I nj ur y ( DI LI) g ui d eli n e 1 6 a n d e v al u ati o n of dr u g -i n d uce d s eri o us he p at ot o xicit y (e- DI S H ) 
pl ot will b e pr o vi d e d.    F or t h e uri nal ysis para m et ers e x ce pti n g s p eci fi c gra vit y, t h e 
n u m b er a n d p er ce nt a ge of s u bj ects will b e pr o vi d e d at eac h visit.    S u m m ar y statisti cs 
will b e t a b ul at e d f or t he s p ecifi c gr a vit y.    A s hift t a bl e will b e creat e d bas e d o n t h e 
cat e g ori es of “ n or m al ” a n d “a b n or m al ” b et w ee n bas eli n e a n d eac h s c he d ule d visit.  
 
1 1. 7. 3  Vit al Si g n A n al ys es  
S u m m ar y st atisti cs will be cal c ul at e d f or m eas ure d v al u es a n d c h a n ges fr o m b as eli n e i n 
t h e s u pi n e a n d ort h ost ati c bl o o d pr ess ure, a n d s u pi n e p uls e rat e at eac h sc he d ul e d visit. 
 
1 1. 7. 4  El ect r o c a r di o g r a m A n al ys es  
A s hift t a bl e will b e pr o vi d e d f or E C G e v al u ati o n bet w ee n b as eli n e a n d Visit 1 0.  
 
1 1. 7. 5  P h ysi c al Fi n di n g A n al yses  
S u m m ar y st atisti cs will be cal c ul at e d f or m eas ure d v al u es a n d c h a n ges fr o m b as eli n e i n 
b o d y w ei g ht at eac h s c h e d ul e d visit.    F or t h e e val u ati o n of e d e ma, t h e res ults ( pres e n ce 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 5 of 1 0 1 
or a bs e n ce) will b e t a b ul at e d f or eac h e x pressi o n sit e.    
 
1 1. 7. 6  C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e  
T h e d at a c oll ect e d fr o m C -S S R S will b e t a b ul at e d.  
 
1 1. 7. 7  H os pit al A n xi et y a n d D e p ressi o n S c al e  
T h e s u bscal es of a n xi et y a n d de pr essi o n f or H A D S will b e s u m m ariz e d at eac h s c h e d ul e d 
visit.  
 
1 1. 7. 8  Ot h er S af et y A n al ys es  
T h e d at a c oll ect e d fr o m t he o p ht h al m ol o gi c e x a mi n ati o n will b e t a b ul at e d at eac h 
sc h e d ul e d visit. 
 
1 1. 8  Ot h er A n al ys es  
N ot a p pli ca bl e.  
 
1 1. 9  D at a S af et y M o nit o ri n g B o a r d  
A n i n d e p e n de nt D S M B  will b e r es p o nsi ble f or re vi e wi n g u n bli n d e d s afet y d at a i n a n  
o n g oi n g m a n n er a n d f or m o nit ori n g a n d ass uri n g o v erall s afet y of t h e st u d y s u bj ects.  I n 
acc or d a n ce wit h a n a gr ee d -u p o n c h art er, t h e D S M B  will m eet p eri o di call y, o n a re g ul ar  
a n d/ or a d h o c b asis, t o disc uss a n d a d dress a n y e mer gi n g s afet y or t ol era bilit y iss u es,  
i n cl u di n g S A Es, dis c o nti n u ati o ns d u e t o A Es, et c, as w ell as ot h er rel e v a nt st u d y 
i nf or m ati o n, s u c h as r ecr uit m e nt st at us, i neli gi bilit y rat es, a n d d at a q ualit y.  Bas e d o n 
a n y f or m al D S M B  r e vi e w m eeti n g w h ere bli n d e d or u n bli n d e d s afet y d at a are re vi e w e d 
a n d dis c uss e d, t h e D S M B  will r ec o m m e n d t o t h e s p o ns or o n e of t h e f oll o wi n g:  
 
C o nti n u e t h e st u d y wit h o ut m o difi cati o n  
 
C o nti n u e t h e st u d y b ut m o dif y t h e pr ot oc ol a n d/ or I C F  
 
S us p e n d t h e st u d y ( or a c o h ort) u ntil f urt h er n otice, wit h rec o m m e n d ati o ns f or 
f urt h er acti o n t o a d dr ess s p ecifi c iss u es a n d a p pr o pri at el y m a n a gi n g acti v e st u d y  
s u bj ects 
 
Ter mi nat e t h e st u d y ( or a c o h ort) wit h pr o visi o ns f or or d erl y dis c o nti n u ati o n i n 
acc or d a n ce wit h G C P.  
M o difi cati o n, s us p e nsi o n or t er mi n ati o n ma y b e ma d e f or a n y of t h e f oll o wi n g reas o ns:  
 
C o n cer n a b o ut dr u g -i n d u ce d li v er i nj ur y 
 
C o n cer n a b o ut s ui ci d e  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 6 of 1 0 1 
 
A n y ot h er saf et y c o n cer n  
T h e a p pr o ac h t o st u d y ( or c o h ort) m o difi cati o n, s us pe nsi o n, or t er mi n ati o n will b e  
des cri b e d i n t h e D S M B c harter.  
T h e s p o ns or ( Hea d of Cli ni cal S af et y a n d P h ar m ac o vi gil a n ce) will b e n otifie d of t h e  
D S M B  d ecisi o n b y t he D S M B  c h air m a n wit hi n 3 da ys aft er t h e m eeti n g.  Mi n ut es of all  
f or m al D S M B  m eeti n gs a n d dis c ussi o ns will b e mai nt ai n e d b y t he i n d e p e n d e nt 
st atisti cia n, i n a s ec ure l o cati o n, u ntil c o m pl eti o n or t er mi n ati o n of t h e st u d y, at w hi c h 
p oi nt t he y will b e f or w ar de d t o D aii c hi Sa n k y o f or arc hi vi n g.  
 
1 1. 1 0  H e p ati c A dj u di c ati o n C o m mittee  
T h e H A C will c o m pris e at l east t w o q u alifi e d he p at ol o gists, w h o are n ot i n vesti gat ors i n 
t h e st u d y a n d n ot ot h er wis e dir ectl y ass o ci at e d wit h t h e s p o ns or.  T h e H A C will f oll o w 
its o w n c h art er f or pr o cessi n g a n d a dj u di cati n g h e p ati c e v e nts.  T h e H A C will 
a dj u di cat e h e p ati c e v e nts i n a bli n de d m a n n er.  T his a d j u di cati o n will b e i n d e p e n d e nt of 
t h e i n v esti gat ors.  T h e H A C will c o m pl et e assess m e nts o n a n o n g oi n g b asis.  
A dj u di cati o n of h e p ati c e v e nts will b e b as e d o n e val u ati o n of e C R Fs a n d s o urce 
d o c u m e nts, as a v ail a bl e, i n cl u di n g b ut n ot li mit e d t o h os pital disc h ar ge s u m m ari es, 
di a g n osti c i m a gi n g, hist o pat h ol o g y, c o ns ult ati o n, a n d l a b orat or y re p orts.   S u c h p ati e nt’s 
r el e v a nt r ec or ds will b e pr o vi d e d t o t h e H A C fr o m t h e st u d y sit es acc or di n g t o H A C 
r e q u est. 
 
1 1. 1 1  S a m ple Si ze Det er mi n ati o n  
A p pr o xi m atel y 7 5 0 s u bj ects wil l b e ra n d o miz e d t o o n e of pl ace b o ( 3 0 0 s u bj ects), 
D S -5 5 6 5 1 5 m g Q D ( 1 5 0 s u bj ects), D S -5 5 6 5 1 0 m g BI D ( 1 5 0 s u bj ects), or D S - 5 5 6 5 
1 5 m g BI D ( 1 5 0 s u bj ects) acc or di n g t o t h e ra n d o mizati o n rati o of 2: 1: 1: 1.  
 
T his s a m pl e siz e pr o vi d es ar o u n d 9 0 % statisti cal p o w e r w hi c h is t h e pr o b a bilit y of 
D S -5 5 6 5 1 5 m g BI D ( or D S -5 5 6 5 1 0 m g BI D) s u peri orit y o v er t h e pl ace b o u n d er t h e 
ass u m pti o n of 0. 6 diff er e nce ( vs pl ace b o) i n c h a n ge fr o m bas eli n e i n A D P S ( Δ A D P S) f or 
all D S -5 5 6 5 ar ms a n d c o m m o n S D f or Δ A D P S of 1. 8 u nits.    T h e st atisti cal p o wer is 
bas e d o n A n al ysis of Varia n ce ( A N O V A ) usi n g c o m bi n ati o n a p pr o ac h of 
B o nf err o ni- H ol m m et h o d a n d gat e -kee pi n g pr o ce d ure (s ee S ecti o n 1 1. 5. 1) t o c o ntr ol t h e 
t y p e I err or r at e at l ess t h a n 0. 0 5.    T h e st atisti cal p o w er s h o w n i n Ta bl e 1 1 - 1 is 
si m ul ati o n-b asis ( 1 0 0, 0 0 0 r e p etiti o ns).  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 7 of 1 0 1 
Ta bl e 1 1 - 1  St atisti cal p o w ers ( %) of D S -5 5 6 5 1 5 m g Q D, 1 0 m g BI D, a n d 1 5 m g BI D 
bei n g s u p eri or  o v e r pl ace b o 
Diff er e n ce ( 1 5 m g Q D, 1 0 m g 
BI D, 1 5 m g BI D) a n d S D  
1 5 m g 
Q D  
1 0 m g 
BI D  
1 5 m g 
BI D  
Diff =( 0. 6, 0. 6, 0. 6), S D = 1. 8  
8 7. 0 %  
8 9. 5 %  
8 9. 3 %  
Diff =( 0. 4, 0. 6, 0. 6), S D = 1. 8  
5 6. 9 %  
8 7. 7 %  
8 7. 5 %  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 8 of 1 0 1 
1 2.  D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  
T h e i n v esti gat or/st u d y site will p er mit st u d y-rel at e d m o nit ori n g, a u dits, I R B/i n d e p e n d e nt 
et hi cs c o m mitt ee ( E C ) r e vi e w, a n d r e g ul at or y i ns p ecti o ns b y pr o vi di n g direct access t o 
s o ur ce d at a/ d o c u m e nts.    Dir ect access i n cl u d es per missi o n t o e x a mi ne, a nal yz e, v erif y, 
a n d r e pr o d u ce a n y r ec or ds a n d r e p orts t h at are i m p orta nt t o t h e e v al u ati o n of a cli ni cal 
st u d y. 
 
1 2. 1  M o nit o ri n g a n d I ns p ecti o ns 
T h e m o nit or a n d r e g ul at or y a ut h orit y i ns pect ors are res p o nsi ble f or c o nt acti n g a n d 
visiti n g t h e in v esti gat or f or t h e p ur p ose of i ns p ecti n g t h e faciliti es a n d, u p o n re q u est, 
i ns p ecti n g t h e v ari o us rec or ds of t h e st u d y (e g, C R F s, s o urce d at a, a n d ot her p erti n e nt 
d o c u m e nts).  
 
T h e m o nit or is res p o nsi ble f or visiti n g st u d y sit e(s) at re g ul ar i nt er v als t hr o u g h o ut t h e 
st u d y t o v erif y a d h er e n ce t o t h e pr ot o c ol; c o m pl ete n ess, acc urac y, a n d c o nsiste n c y of t h e 
dat a; a n d a d h er e n ce t o I nter nati o n al C o nfere n ce o n H ar m o niz ati o n (I C H) G C P a n d l o cal 
r e g ul ati o ns o n t h e c o n d u ct of cli ni cal res earc h.    T h e m o nit or is res p o nsi ble f or 
i ns p ecti n g t h e C R F s a n d e ns uri n g c o m pl et e n ess of t h e ess e nti al st u d y d o c u m e nts.   T h e  
m o nit or s h o ul d h a v e access t o s u bject m e di cal rec or ds a n d ot h er st u d y -rel at e d rec or ds 
nee d e d t o v erif y t he e ntri es in t h e C R F s. 
 
T h e m o nit or will c o m m u ni cat e d e vi ati o ns fr o m t h e pr ot o c ol, st a n d ar d pr o ce d ure s, G C P, 
a n d a p pli ca bl e r e g ul ati o ns t o t h e in vesti gat or a n d will e ns ure t h at a p pr o pri at e acti o n 
desi g n e d t o pr e v e nt r ec urr e n ce of t h e d et ecte d d e vi ati o ns is t a k e n a n d d o c u m e nt e d.  
 
T h e in v esti gat or a gr ees t o c o o per ate wit h t h e m o nit or t o e ns ure t h at a n y pr o bl e ms 
det ect e d i n t h e c o urs e of t h es e m o nit ori n g visits are a d dress e d a n d d o c u m e nt e d.  
 
I n acc or da n ce wit h I C H G C P a n d t h e s p o ns or’s a u dit pl a ns, t his st u d y m a y b e s el ect e d 
f or a udit b y r e pr es e nt ati v es fr o m t h e s p o ns or.    I ns p ecti o n of sit e faciliti es (e g, p h ar m ac y, 
dr u g st or a ge ar eas, l a b or at ori es , etc .) a n d re vi e w of st u d y-rel at e d rec or ds will b e 
perf or m e d i n or d er t o e v al u at e t h e c o n d u cti n g of t h e  st u d y a n d c o m plia n ce wit h t h e 
pr ot o c ol, I C H G C P, a n d a p pli ca bl e re g ul at or y re q uire m e nts.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 7 9 of 1 0 1 
1 2. 2  D at a C oll ecti o n 
1 2. 2. 1  St yl e of D at a C ollecti o n 
1 2. 2. 1. 1  
C as e R e p o rt F o r m  
T his st u d y will us e a n El ectr o ni c Dat a C a pt ure ( E D C) s yst e m  (Ta bl e 1 2 - 1) t o ge n erat e 
C R F s, s o t h e C R F s will be e nt er e d el ectr o ni call y.   C R F s (i n cl u di n g a u dit trails) will b e 
pr e p are d f or eac h s u bj ect.   T h e e C R F will b e c o m pl et e d, re vi e w e d , a n d e -si g n e d b y t h e 
i n v esti gat ors.   T h e E D C s yst e m will b e v ali d at e d pri or t o us e.  
 
Ta bl e 1 2 - 1  El ectr o nic D at a C a pt ure S yst e m  
Na me of E D C s yste m  
Me di data Ra ve
Ⓡ 
E D C s yste m de vel o p er  
Me di data S ol uti o ns I nc.  
E ntr y met h o d  
We b -base d data e ntr y  
I n p ut ter mi n al 
Des kt o p c o m p uter at t he st u d y site 
I nc o m p ati ble o perati n g 
s yste ms 
N o ne  
Rec o m me n de d br o wsers  
T he M e di data Ra ve Ⓡ s u p p orts a n y br o ws er w hi c h is H T M L 4, H T M L 5, 
a n d C S S 2 c o m pli a nt. Br o ws ers m ust ha ve J a va Scri pt e na ble d.  
Scr ee n Res ol uti o n  
T he mi ni m u m scre e n res ol uti o n r e q uire d t o pr o perl y dis pla y M e di data 
Ra ve a p plic ati o ns is 1 0 2 4 x 7 6 4.  
C o n necti o n S pee d  
1 2 8 k b ps is t he mi ni m u m c o n necti o n s pe e d re c o m me n de d f or usi n g 
Me di data Ra ve.  
Ot her  
A d o be Flas h Pla yer : ver. 1 0 or a b o ve is r e q uire d 
 
1 2. 2. 1. 2  
El ect r o ni c D ail y Di a r y  
T his st u d y will us e a n El ectr o ni c P ati e nt R e p ort O utc o m e (e P R O) s yst e m ( Ta bl e 1 2 - 2) t o 
c oll ect pati e nt d ail y di ar y d at a.    T h e d e vi ce f or el ectr o nic dail y di ari e s (i ncl u di n g a u dit 
tr ails) will b e pr e p ar e d f or eac h s u bj ect.    T h e el ectr o ni c d ail y di ari e s will b e c o m pl et e d 
b y t h e p ati e nt a n d re vi e w e d b y t h e i n v esti gat ors.    T h e e P R O s yst e m will b e v ali d at e d 
pri or t o us e.  
 
Ta bl e 1 2 -2    El ectr o nic Pati e nt R e p ort O ut c o m e S yst e m  
E D C s yste m de vel o p er  
e Res earc h Te c h n ol o g y, I n c  
E ntr y met h o d  
P atie nt -re p orte d o utc o mes; Ha n d-hel d de vice  
I n p ut ter mi n al 
DI A R Ypr o ®  M o bile  
I nc o m p ati ble o perati n g 
s yste ms 
N o ne  
Rec o m me n de d br o wsers  
 
DI A R Ypr o ®  M o bil e is a pr o prietar y s yst e m t hat r u ns o n a Wi n d o ws 
platf or m.  
Wi n d o ws O S a n d I nter net E x pl or er 7. 0. 8. 0 or 9. 0  
Scr ee n Res ol uti o n  
N/ A, as s oft ware is pr o gr a m me d t o fit o n t he DI A R Ypr o m o bile de vice.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 0 of 1 0 1 
1 2. 2. 1. 3  
Ot h er R e p o rts  
Res ults of p h ar m ac o ki n eti c t est a n d l a b orat or y t ests are re p ort e d b y ce ntral l a b orat or y, 
se p ar at el y. Pr o ce d ur e f or t h es e r e p orts are s et s e p arat el y.  
 
1 2. 2. 2  Pre p a r ati o n of C as e R e p o rt F o r ms  a n d D ail y Di ari e s 
All p ers o ns w h o m a k e e ntri es a n d/ or c orrecti o ns o n C R F s or dail y di ari e s s h o ul d b e 
tr ai n e d a n d s h o ul d b e assi g n e d t h eir o w n acc o u nts t o us e t h e E D C or e P R O s yst e m. T h e 
tr ai ni n g r ec or d is r e gar d e d as a si g n at ure s h eet.   
1)  C R F s will b e cr eat e d f or s u bj ects w h o si g n t h e I C F f or t h e st u d y, a n d el ectr o ni c d ail y 
di ari es  will be cr eat e d f or s u bj ects w h o are c o n d u ct e d  s cree ni n g visit f or t he st u d y. 
2)  T h e i n v esti gat or or s u b-i n v esti gat or will pre p are t he C R F  i n acc or d a nce wit h C R F 
c o m pl eti o n g ui d eli n es  t h at ar e pr o vi d e d b y t he s p o ns or.  
3)  If st u d y st aff assists i n t h e pr e p arati o n of t h e C R F , t h e y will d o s o u n d er t h e directi o n 
of t h e i n vesti gat or or s u b-i n v esti gat or. 
4)  T h e i n v esti gat or will s u b mit t h e C R F  t o t h e s p o ns or, a n d will k ee p a c o p y. 
5)  If t h er e is a c o ntr a di cti o n b et w ee n s o m e of t h e d at a t h at is e nt ere d i n t h e C R F  a n d t h e 
s o ur ce d o c u m e nts, t he i n vesti gat or will pre p are a se p arat e rec or d t h at e x pl ai ns t he 
r eas o n(s) f or t his dis cr e p a n c y, a n d will s u b mit t h at rec or d t o t h e s p o ns or.  
6)  S u bject will r ecei v e t h e de vi ce f or t h e el ectr o ni c dail y di ar i es a n d a ns w er t o th e 
q u esti o n. 
7)  T h e d e vi ce f or t h e el ectr o ni c d ail y di ari es s h o ul d be c oll ect e d w h e n s u bj ect t er mi n at e 
t h e st u d y. 
 
1 2. 2. 3  Si g n at u res o r S e als o n t he C as e R e p o rt F o r m  
T h e i n v esti gat or will c o nfir m all of t h e C R F s t h at are pre p are d at t h at st u d y sit e, a n d will 
e nt er his or h er el ectr o ni c si g n at ur e i n t h e fil e.  
T h e i n v esti gat or will als o c o nfir m all of t h e el ectr o ni c d ail y di ari e s t h at are pre p are d at 
t h at st u d y site. 
 
1 2. 2. 4  D at a C orrecti o n  
1)  T h e i n v esti gat or, s u b-i n v esti gat or, or st u d y st aff will c orrect t h e d at a i n  t h e C R F  in 
acc or d a n ce wit h t h e C R F  c o m pl eti o n gui d eli n e s t h at are pr o vi d e d b y t h e s p o ns or.  
2)  T h e i n v esti gat or will b e r es p o nsi bl e f or t h e c o nt e nt of e ntri es i n t h e C R F . 
3)  Pr oce d ur e f or d at a c orr ecti o n of t h e electr o ni c d ail y diari ys will s et s e p aratel y.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 1 of 1 0 1 
1 2. 3  D at a M a n a g e me n t 
E ac h s u bj ect will b e i d e ntifi e d i n t h e d at a bas e b y a u ni q u e s u bj ect i d e ntifi er as d efi n e d b y 
t h e s p o ns or. 
 
To e ns ur e t h e q u alit y of cli ni cal dat a acr oss all s u bj ects a n d  st u d y sit es, a Cli ni cal D at a 
Ma n a ge me nt r e vi e w will b e p erf or m e d o n s u bj ect d at a acc or di n g t o s pecifi cati o ns gi v e n 
t o D aii c hi S a n k y o .    D at a will b e v ett e d el ectr o ni call y a n d/ or m a n u all y as a p pr o pri at e.   
D uri n g t his r e vi e w, s u bj ect d ata will b e c hec k e d f or c o nsist e n c y, o missi o ns, a n d a n y 
a p p ar e nt dis cr e p a n ci es.    I n a d diti o n, d at a will b e re vi e w e d f or a d h ere n ce t o t h e pr ot o c ol 
a n d G C P.    F or e C R Fs  a n d e P R O d at a will b e el ectr o ni call y v ett e d b y pr o gra m m e d d at a 
r ul es wit hi n t h e a p pli cati o n.    Q u eri es ge n erat e d b y r ul es a n d rais e d b y re vi e w ers will b e 
ge n er at e d wit hi n t h e E D C or e P R O a p pli cati o ns a n d als o res ol v e d wit hi n t h e 
a p pli cati o n s. 
 
D at a r ecei v e d fr o m e xter nal s o ur ces s u c h as ce ntral l a bs will b e rec o n cil e d t o t h e cli nical 
dat a b ase.  
 
S A E s i n t h e cli ni cal d at a bas e will b e rec o n cil e d wit h t h e s afet y d at a b as e.  
 
All A E s will b e c o d e d usi n g M e d D R A. 
 
1 2. 4  St u d y D o c u me nt ati o n a n d St or a ge  
1 2. 4. 1  D efi niti o n  of S o u rce D o c u me nts  
S o ur ce d o c u m e nts ar e ori gi n al d o c u m e nts, d at a, a n d rec or ds fr o m w hi c h t he s u bj ect’s 
C R F d at a ar e o bt ai n e d.    T h es e i n cl u d e b ut are n ot li mit e d t o h os pit al rec or ds, cli ni cal 
a n d offi ce c h arts, l a b or at or y a n d p h ar m ac y rec or ds, el ectr o ni c di ari es, mi cr ofi c h es,  
X- r a ys, a n d c orr es p o n d e nce. 
 
If t h e f oll o wi n g it e ms ar e e nt er e d directl y i nt o t h e C R F , t h e c o nt e nt of t h ose C R F e ntri es 
ar e d efi nit e d as s o ur ce d at a . 
1)  Dir ect e ntr y of s p ecifi c it e ms (i n t h e C o m m e nts c ol u m n, et c.)  
2)  E ntri es s u c h as " N o n e" or " U n k n o w n" f or s p e cifi c it e ms  
3)  Reas o ns f or us e of c o nc o mit a nt dr u gs  
4)  La b or at or y v al u es t h at d e vi at e d fr o m t h e refere n ce ra n ge, if a n y, a n d reas o n f or 
de vi ati o n. 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 2 of 1 0 1 
5)  D es cri pti o ns of A E s 
6)  A E s, if a n y, na m e of A E , s e v erit y, s eri o us n ess, o utc o m e, rel ati o ns hi p t o t h e 
i n v esti gati o n al pro d u ct  
7)  W het h er tr eat m e nt w as dis c o nti n u e d, a n d reas o n f or dis c o nti n u ati o n  
 
1 2. 4. 2  St o r a g e  
All ori gi n al s o ur ce d o c u me nts s u p p orti n g e ntries i n t h e e C R Fs a n d el ectr o ni c d ail y di ar y 
m ust b e m ai nt ai n e d a n d be r ea dil y a v ail a ble.  
 
All ess e nti al d oc u m e nt ati o n will b e r et ai n e d b y t h e i nstit uti o n f or at l east 1 0  years aft er 
c o m pl eti o n of t h e st u d y (f or a l o n ger p eri o d if n ee de d t o c o m pl y wit h ot h er a p pli ca bl e 
r e q uir e m e nts), or u ntil t h e i nstit uti o n is i nstr u ct e d ot h er wis e b y t h e sp o ns o r. 
 
N o st u d y d o c u m e nt s h o ul d b e d estr o ye d wit h o ut pri or writt e n a gree m e nt bet w ee n t h e 
sp o ns or a n d t h e i n vesti g at or .   S h o ul d t he i n v esti gat or wis h t o assi g n t h e st u d y rec or ds t o 
a n ot h er p art y or m o v e t h e m t o a n ot h er l o cati o n, h e/s h e m ust n otif y t h e s p o ns or i n writi n g 
of t h e n e w r es p o nsi bl e p ers o n a n d/ or t h e n e w l o cati o n.  
 
1 2. 5  R ec o r d Kee pi n g  
Rec or ds of s u bj ects, s o ur ce d o c u m e nts i n cl u di n g el ectr o nic dail y di ar y, m o nit ori n g visit 
l o gs, d at a c orr ecti o n f or ms, C R Fs, i n v e nt or y of i n v esti gati o n al pr o d u ct, re g ul at or y 
d o c u m e nts ( e g, pr ot oc ol a n d a m e n d m e nts, I R B/ E C c orres p o n d e n ce a n d a p pr o v als, 
a p pr o v e d a n d si g n e d I C Fs, I n v esti gat or’s A gree m e nt, cli ni cal s u p pli es recei pts, 
distri b uti o n a n d r et ur n r ec or ds), a n d ot h er s p o ns or c orres p o n d e n ce p ert ai ni n g t o t h e st u d y 
m ust b e k e pt i n a p pr o pri at e st u d y fil es at t h e st u d y sit e. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 3 of 1 0 1 
1 3.  FI N A N CI N G A N D I N S U R A N C E  
1 3. 1  Fi n a n ces  
Pri or t o st arti n g t h e st u d y, t h e Pri n ci p al I n vesti gat or a n d/ or i nstit uti o n will si g n a cli ni cal 
st u d y a gr ee m e nt wit h D aii c hi S a n k y o or t h e c o ntract res earc h or ga niz ati o n ( C R O ) i n 
c h ar ge of m o nit ori n g i n eac h c o u ntr y.    T his a gre e m e nt will i ncl u d e t h e fi na n ci al 
i nf or m ati o n a gr ee d u p o n b y t h e p arti es. 
 
1 3. 2  R ei m b u rs e me nt, I n d e m nit y, a n d I ns u r a n ce  
Rei m b urs e m e nt, i n d e m nit y , a n d i ns ura n ce s h all b e a d dress e d i n a s e p arat e a gree m e nt o n 
ter ms a gr ee d u p o n b y t he p arti es. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 4 of 1 0 1 
1 4.  P U B LI C A TI O N P O LI C Y  
 
   
 
    
 
 
 
   
 
 
   
 
 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 5 of 1 0 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  
1 5. 1  C o m pli a n ce St at e me nt, Et hi cs , a n d Re g ul at o r y C o m pli a n ce  
T his st u d y will b e c o n d u ct e d i n c o m pli a n ce wit h t h e pr ot o c ol, t h e et hi cal pri n ci pl es t h at 
ha v e t h eir ori gi n i n t h e D ecl ar ati o n of H elsi n ki, t h e I C H c o ns oli d at e d G ui d eli n e E 6 f or 
G C P ( C P M P/I C H/ 1 3 5/ 9 5), a n d  a p plica bl e re g ul at or y re q uire m e nts . 
 
1 5. 2  S u bj ect C o nfi d e nti alit y  
T h e in v esti gat ors a n d t h e sp o ns or will pres er v e t h e c o nfi d e nti alit y of all s u bj ects t a ki n g 
part i n t h e st u d y, i n acc or d a n ce wit h G C P a n d l o cal re g ul ati o ns.  
 
T h e in v esti gat or m ust e ns ur e t h at t h e  s u bj ect’s a n o n y mit y is m ai nt ai n e d.    O n t h e C R Fs 
or ot h er d oc u m e nts s u b mitt e d t o t h e sp o ns or or a C R O, s u bjects s h o ul d be i d e ntifi e d b y a 
u ni q u e s u bj ect i d e ntifi er as d esi g n at e d b y t h e sp o ns or.    D o c u m e nts t h at are n ot f or 
s u b missi o n t o t h e sp o ns or or t h e C R O (e g, si g n e d I C F s) s h o ul d b e k e pt i n stri ct 
c o nfi d e n ce b y t h e in v esti gat or.  
 
I n c o m pli a n ce wit h I C H G C P G ui d eli n es, it is re q uire d t h at t h e i n v esti gat or a n d 
i nstit uti o n p er mit a ut h ori ze d r e pr es e nt ati v es of t h e c o m p a n y, t h e re g ul at or y a ge n c y(i es), 
a n d t h e  I R B/ E C dir ect access t o r e vi e w t h e s u bj ect’s ori gi n al m e di cal rec or ds f or 
verifi cati o n of st u d y- r el ate d pr o ce d ures a n d d at a.    T h e i n v esti gat or is o bli gat e d t o 
i nf or m t he s u bj ect t h at his/ h er st u d y-rel at e d rec or ds will b e re vi e w e d b y t h e a b o v e-n a m e d 
r e pr ese nt ati v es wit h o ut vi ol ati n g t h e c o nfi d e nti alit y of t h e s u bj ect.  
 
1 5. 3  I nf or me d C o ns e nt Pr o ce d u res 
Bef or e a s u bj ect’s p arti ci pati o n i n t h e st u d y, it is t he in v esti gat or’s res p o nsi bilit y t o 
o bt ai n fr eel y gi v e n c o ns e nt, i n writi n g, fr o m t h e s u bj ect aft er a d e q u at e e x pla n ati o n of t h e 
ai ms, m et h o ds, a nti ci p at e d b e n efits, a n d p ot e nti al h az ar ds of t h e st u d y a n d b ef ore a n y 
pr ot o c ol- s p ecific pr o ce d ur es or a n y i n v esti gati o n al pr o d u cts are a d mi nist ere d.    T h e 
writte n I C F s h o ul d b e pr e p ar e d i n t h e l o cal l a n g u a ge(s) of t h e p ote ntial s u bj ect 
p o p ul ati o n. 
 
I n o bt ai ni n g a n d d o c u m e nti n g i nf or m e d c o ns e nt, t he i n v esti gat or s h o ul d c o m pl y wit h t h e 
a p pli ca bl e re g ul at or y r e q uir e m e nts, a n d s h o ul d a d here t o G C P a n d t o t h e et hi cal 
pri n ci pl es t h at h a v e t h eir ori gi n i n t h e D ecl arati o n of H elsi n ki.    T h e c o ns e nt f or m a n d 
a n y r e visi o n(s) s h o ul d b e a p pr o v e d b y t h e E C or I R B pri or t o b ei n g pr o vi d e d t o p ot e nti al 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 6 of 1 0 1 
s u bj ects. 
 
T h e s u bj ect’s writt e n i n f or m e d c o ns e nt s h o ul d b e d oc u m e nt e d i n t h e s u bject’s m e dical 
r ec or ds.    T h e I C F s h o ul d be si g n e d a n d p ers o n all y d at e d b y t he s u bj ect a n d b y t h e 
pers o n w h o c o n d u ct e d t h e i nf or m e d c o ns e nt dis c ussi o n ( n ot n ecess aril y t h e i n v esti gat or).   
T h e ori gi n al si g n e d I C F  s h o ul d b e r et ai n e d i n acc or d a n ce wit h i nstit uti o nal p olic y, a n d a 
c o p y of t h e si g n e d c o ns e nt f or m s h o ul d b e pr o vi d e d t o t h e s u bj ect.    T h e d at e a n d ti m e 
(if a p pli ca bl e) t h at i nf or me d c o ns e nt w as gi v e n s h o ul d b e rec or d e d o n t h e C R F. 
 
S u g gest e d m o d el t e xt f o r t h e I C F f or t h e st u d y is pr o vi d e d i n t h e s p o ns or’s I C F t e m pl at e 
f or t he in v esti gat or t o pr e p ar e t h e d o c u m e nts t o b e us e d at his or h er sit e.    U p d ates t o 
a p pli ca bl e f or ms will b e c o m m u ni cate d fr o m t h e s p o ns or. 
 
1 5. 4  R e g ul at o r y C o m pli a n ce  
T h e st u d y pr ot o c ol, s u bj ect i nf or m ati o n a n d c o ns e nt f or m, t h e I n v esti gat or ’s Br o c h ure, 
a n y writt e n i nstr u cti o ns t o be gi v e n t o t he s u bj ect s, a v ail a bl e s afet y i nf or mati o n, s u bj ect 
r ecr uit m e nt pr o ce d ur es ( e g, a d v ertis e me nts), i nf or m ati o n a b o ut p a y m e nts a n d 
c o m p e ns ati o n a v ail a bl e t o t h e s u bj ects, a n d d o c u me nt ati o n e vi d e n ci n g t he in v esti gat or’s 
q u alifi cati o ns s h o ul d b e s u b mitt e d t o t h e E C or I R B f or et hi cal re vi e w a n d a p pr o v al 
acc or di n g t o l o cal r e g ul ati o ns, pri or t o t h e st u d y start.    T h e writt e n a p pr o val s h o ul d 
i d e ntif y all d o c u m e nts r e vi e w e d b y n a m e a n d v ersi o n.  
 
C h a n ges i n t h e c o n d u ct of t h e st u d y or pl a n n e d a nal ysis will b e d o c u m e nt e d i n a pr ot oc ol 
a m e n d me nt a n d/ or t h e S A P. 
 
T h e in v esti gat or m ust s u b mit a n d, w h ere n ecess ar y, o bt ai n a p pr o v al fr o m t he E C or I R B 
f or all s u bs eq u e nt pr ot o c ol a m e n d m e nts a n d c ha n ges t o t h e I C F.    T h e in v esti gat or 
s h o ul d n otif y t h e E C or I R B of d e vi ati o ns fr o m t h e pr ot o c ol or S A Es o cc urri n g at t h e 
st u d y sit e a n d ot h er A E r e p orts r ecei v e d fr o m t h e sp o ns or/ C R O, i n acc or d a nce wit h l o cal 
pr o ce d ur es.  
 
As  re q uir e d b y l o cal re g ul ati o ns, t h e s p o ns or’s l o cal R e g ul at or y Affairs gr o u p or 
r e pr es e nt ati v e t o w h o m t his r es p o nsi bilit y h as b ee n del e gat e d will e ns ure t hat all l e gal 
as p ects ar e c o v er e d , t h at a p pr o v al fr o m t h e a p pr o pri at e re g ul at or y b o di es is o bt ai n e d 
p ri or t o st u d y i nitiati o n, a n d t h at c ha n ges t o t h e i niti al pr ot o c ol a n d ot h er rel e v a nt st u d y 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 7 of 1 0 1 
d o c u m e nts ar e i m pl e m e nte d o nl y aft er a p pr o v al b y t h e rel e v a nt re g ul at or y b o di es.  
 
1 5. 5  Pr ot o c ol D e vi ati o ns  
T h e in v esti gat or s h o ul d c o n d u ct t h e st u d y i n c o m pli a n ce wit h t h e pr ot o c ol, w hi c h w as  
a gr ee d t o b y t h e sp o ns or a n d, if re q uire d, b y t he re g ul at or y a ut h orit y(i es), a n d w hi c h w as 
a p pr o v e d or gi v e n a f a v or a ble o pi ni o n b y t h e I R B/ E C. 
 
A d e vi ati o n t o eli mi n at e a n a p p ar e nt i m m e di at e h az ar d t o o n e or m ore s u bjects m a y b e 
i m pl e m e nt e d i m m e di at el y.    T h e sp o ns or a n d t h e I R B/ E C m ust b e n otifi e d.  
T h e in v esti gat or, or pers o n d esi g n at e d b y t h e in v esti gat or, s h o ul d d o c u m e nt a n d e x pl ai n 
a n y d e vi ati o n fr o m t h e a p pr o v e d pr ot o c ol.  
 
T h e in v esti gat or s h o ul d n otif y t h e I R B of d e vi ati o ns fr o m  t h e pr ot o c ol i n acc or d a n ce 
wit h  l o cal pr o ce d ures. 
 
1 5. 6  S u p pl y of N e w I nf o r m ati o n Affecti n g t h e C o n d uct of t h e St u d y  
W he n n e w i nf or m ati o n b ec o m es a v aila bl e t hat m a y a d v ers el y affect t h e s afet y of s u bj ects 
or t h e c o n d u ct of t h e st u d y, t h e sp o ns or will i nf or m all in v esti gat ors i n v ol ve d i n t h e 
cli ni cal st u d y, E Cs/I R Bs, a n d r e g ul at or y a ut h oriti es of t h at i nf or m ati o n, a n d w h e n n ee d e d, 
will a m e n d t h e pr ot o c ol a n d/ or s u bj ect i nf or m ati o n.  
 
T h e in v esti gat or s h o ul d i m m e di at el y i nf or m t h e s u bj ect orall y w h e n e v er n e w i nf or mati o n 
bec o m es a vail a bl e t h at ma y b e r el e v a nt t o t h e s u bj ect’s c o ns e nt or m a y i nfl u e n ce t h e 
s u bj ect’s willi n g n ess t o c o nti n u e p arti ci p ati o n i n t he st u d y.    T he c o m m u nicati o n s h o ul d 
b e d o c u m e nte d i n t h e  m e di cal r ec or ds, f or e x a m pl e, a n d t h e s u bject’s willi n g ness t o 
r e m ai n i n t he st u d y s h o ul d b e c o nfir m e d. 
 
If t h e s u bj ect i nf or m ati o n is r e vis e d, it m ust b e re-a p pr o v e d b y t h e E C/I R B.    T h e 
in v esti gat or s h o ul d o bt ai n writte n i nf or m e d c o ns e nt t o c o nti n u e p arti ci p ati o n wit h t h e 
r e vis e d writte n i nf or m ati o n e v e n if s u bj ects w ere alrea d y i nf or m e d of t h e rel e v a nt 
i nf or m ati o n  or all y.   T h e  s u bj ect a n d t h e in v esti g at or or ot h er res p o nsi bl e pers o n n el w h o 
pr o vi d e d e x pla n ati o ns s h o ul d  si g n a n d d at e t h e re vis e d I C F. 
 
1 5. 7  D u r ati o n of t h e St u d y  
St u d y d ur ati o n:  J a n u ar y 2 0 1 5 t o M a y 2 0 1 7  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 8 of 1 0 1 
 
1 5. 8  Pr ot o c ol A me n d me nts  
A n y a m e n d m e nts t o t h e st u d y pr ot o c ol t h at s ee m t o b e a p pr o pri ate as t h e st u d y 
pr o gr ess es will b e c o m m u ni cate d t o t h e i n v esti gat or b y D aii c hi S a n k y o.    Als o, th e 
sp o ns or will ass ur e t h e ti mel y s u b missi o n of a m e n d m e nts t o re g ulat or y a ut h oriti es.  
 
A gl o b al pr ot o c ol a m e n d me nt will affect st u d y c o n d uct at all sit es i n all re gi o ns of t h e 
w orl d.    S u c h a m e n d m e nts will be i n c or p orat e d i nt o a re vis e d pr ot o c ol d o c u m e nt.   
C h a n ges m a d e b y s u c h a me n d m e nts will b e d oc u me nt e d.    T h es e pr ot o c ol a m e n d m e nts 
will u n d er g o t h e s a m e re vi e w a n d a p pr o v al pr o cess as t h e ori gi n al pr ot o c ol.  
 
A l o cal pr ot o c ol a m e n d me nt will affect st u d y c o n d uct at a p arti c ul ar st u d y sit e(s) a n d/ or 
i n a p artic ul ar re gi o n/ c o u ntr y.    S u c h a m e n d m e nts ge n erall y will n ot b e i n c or p orat e d i nt o 
a r e vis e d pr ot o c ol d o c u me nt.    C h a n ges ma d e b y s u c h a m e n d me nts will be cl earl y st at e d 
i n a d o c u m e nt s e p arat e fr o m t h e pr ot o c ol.    S p o ns or a p pr o v al of l o cal a m e n d m e nts will 
be cl ea rl y d o c u m e nt e d. 
 
A pr ot o c ol a m e n d m e nt ma y b e i m pl e m e nt e d aft er it h as b ee n a p pr o v e d b y t h e I R B/ E C, 
u nl ess i m m e di at e i m ple me nt ati o n of t h e c h a n ge is n ecess ar y f or s u bj ect s afet y.   I n t h e 
cas e of i m me di ate i m pl e me nt ati o n,  t he sit uati o n m ust b e d o c u m e nt e d a n d re p ort e d t o t h e 
I RB/ E C wit hi n fi v e w or ki n g d a ys.  
 
1 5. 9  St u d y Dis c o nti n u ati o n o r S us p e nsi o n  
T h e s p o ns or will i m m e di at el y s us p e n d p art of t h e st u d y or t h e e ntire st u d y if a n y of t h e 
f oll o wi n g e v e nts m a k es t he s p o ns or c o nsi der it diffi c ult t o c o nti n u e t h e st u d y: 
1)  A n y n e w saf et y or S A E  i nf or m ati o n b ec o m es a v aila bl e o n t h e i n v esti gati o n al 
pr o d u cts. 
2)  T h e s p o ns or, t h e st u d y site, or t h e i n v esti gat or h as i m pl e m e nt e d a n y si g nifi ca nt G C P 
n o n- c o m pli a n ce or a n y si g nifi ca nt pr ot o c ol de vi at i o n. 
3)  A n y ot h er i nf or m ati o n is o bt ai n e d d uri n g t h e st u d y.  
 
T h e s p o ns or will d eci d e o n w h et h er t o pre m at urel y t er mi n at e p art of t h e st u d y or t h e 
e ntir e st u d y a n d will d o c u m e nt t h e d ecisi o n.  
 
If t he s p o ns or deci des t o pre mat urel y ter mi nate part of t he st u d y or t he e ntire st u d y after 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 8 9 of 1 0 1 
c o ns ulti n g wit h me dical e x perts a n d ot her desi g nate d pe o ple, t he s p o ns or will pr o m ptl y 
n otif y t he st u d y site a n d t he i n vesti gat or i n writi n g of ter mi nati o n a n d t he reas o n f or t he 
acti o n.    If t he st u d y is pre mat urel y ter mi nate d or s us pe n de d f or a n y reas o n, t he 
i n vesti gat or will pr o m ptl y i nf or m t he s u bjects partici pati n g i n t he st u d y a n d will pr o vi de 
a p pr o priate tr eat me nts a n d f oll o w- u p f or t he s u bjects t o c o nfir m t hei r safet y. 
 
1 5. 1 0  O r g a ni z ati o n  
1 5. 1 0. 1  S p o ns o r  
1 5. 1 0. 1. 1  S p o ns o r’s R es p o nsi bl e Me di c al E x p ert  
 
 
 
 
 
1 5. 1 0. 1. 2  S p o ns o r’s R es p o nsi bl e Me di c al A d vis er  
 
 
 
 
 
 
1 5. 1 0. 1. 3  S p o ns o r’s Cli ni c al St u d y L e a d 
 
Cli ni cal D e vel o p m e nt D e p art m e nt, R & D Di visi o n, D aii c hi S a n k y o C o., Lt d.  
1- 2- 5 8, Hir o mac hi, S hi n a ga w a- k u, To k y o, 1 4 0 - 8 7 1 0, J a pa n 
 
 
 
1 5. 1 0. 1. 4  S p o ns o r’s D eli v er y L e a d  
 
Cli ni cal D e vel o p m e nt D e p art m e nt, R & D Di visi o n, D aii c hi S a n k y o C o., Lt d.  
1- 2- 5 8, Hir o mac hi, S hi n a ga w a- k u, To k y o , 1 4 0 - 8 7 1 0, J a pa n 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 0 of 1 0 1 
 
Asia D e v el o p m e nt D e p art m e nt, R & D Di visi o n, D aii c hi S a n k y o C o., Lt d.  
1- 2- 5 8, Hir o mac hi, S hi n a ga w a- k u, To k y o , 1 4 0 - 8 7 1 0, J a pa n 
 
 
 
1 5. 1 0. 2  A c a d e mi c R es e a rc h O r g a niz ati o n  
N ot a p pli ca bl e  
 
1 5. 1 0. 3  C o o r di n ati n g In v esti g at o r  
1 5. 1 0. 3. 1  C o o r di n ati n g In v esti g at o r  i n J a p a n 
 
 
 
 
 
 
1 5. 1 0. 3. 2  C o o r di n ati n g In v esti g at o r  i n K o re a 
 
 
 
 
 
 
1 5. 1 0. 3. 3  C o o r di n ati n g In v esti g at o r  i n Tai w a n 
 
 
 
 
 
1 5. 1 0. 4  C o nt r a ct R es e a rc h O r g a ni z ati o n  
1 5. 1 0. 4. 1  C o nt r a ct R es e a rc h O r g a ni z ati o n i n C h a r g e of M o nit o ri n g i n J a p a n 
C MI C C o., Lt d.  
1- 1- 1, S hi b a ur a, Mi n at o -k u, To k y o, 1 0 5 - 0 0 2 3, J a pa n   
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 1 of 1 0 1 
 
 
1 5. 1 0. 4. 2  C o nt r a ct R es e a rc h O r g a ni z ati o n i n C h a r g e of M o nit o ri n g i n K o re a 
Q ui ntil es Tr a ns n ati o n al K or ea C o., Lt d . 
1 3t h Fl o or, Worl d To w er B uil di n g, 5 5 8 S o n g p a -d aer o, S o n g p a - g u, S e o ul, K orea , 1 3 8- 7 3 1 
 
 
 
1 5. 1 0. 4. 3  C o nt r a ct R es e a rc h O r g a ni z ati o n  i n C h a r g e of M o nit o ri n g i n Tai w a n 
Q ui ntil es Tai w a n Lt d.  
8 F, N o. 1 3 4, S ec. 3, Mi n S h e n g E ast R o a d, Tai p ei, 1 0 5, Tai w a n, R. O. C.  
 
 
 
1 5. 1 0. 4. 4  C o nt r a ct R es e a rc h O r g a ni z ati o n i n C h a r g e of M o nit o ri n g i n M al a ysi a  
Q ui ntil es M al a ysi a S d n. B h d. 
S uit e D- 0 8- 0 2 Pl az a M o nt Ki ar a, N o. 2 J al a n Ki ara, M o nt Ki ara, 5 0 4 8 0 K ual a L u m p ur,  
M A L A Y S I A  
 
 
 
1 5. 1 0. 4. 5  C o nt r a ct R es e a rc h O r g a ni z ati o n  i n C h a r g e of I nter a cti v e We b R es p o ns e 
S yst e m   
 
Bell M e di cal S ol uti o ns. I nc. 
To k y u Bl d g . East N o. 3,  2- 1 6- 8 Mi na mi-Ik e b u k ur o, Tos hi ma -k u, To k y o, 1 7 1 -0 0 2 2 , J a p a n 
 
  
 
 
  
 
 
  
 
 
 
1 5. 1 0. 4. 6  C o nt r a ct R es e a rc h O r g a ni z ati o n  i n C h a r g e of E mer g e n c y C o nt a ct  
Bell M e di cal S ol uti o ns. I nc. 
To k y u Bl d g. East N o. 3, 2- 1 6- 8 Mi na mi -Ik e b u k ur o, Tos hi ma -k u, To k y o, 1 7 1 -0 0 2 2 , J a p a n 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 2 of 1 0 1 
 
 
1 5. 1 0. 4. 7  R a n d o mi z ati o n m a n a g er  
 
Bell M e di cal S ol uti o ns. I nc. 
To k y u Bl d g . East N o. 3, 2- 1 6- 8, Mi n a mi -Ik e b u k ur o, Tos hi m a- k u, To k y o, 1 7 1 -0 0 2 2, J a p a n  
 
 
 
1 5. 1 0. 5  C e nt r al L a b o r at o r y  
1 5. 1 0. 5. 1  Bi o a n al yti c al L a b o r at o r y  
Cel eri o n  
6 2 1 R os e Str eet, Li n c ol n, N E 6 8 5 0 2 U S A  
 
 
 
1 5. 1 0. 5. 2  C e nt r al L a b o r at o r y M a n a g e me nt  
S R L M e dis ear c h I n c.  
6- 5- 1, Nis his hi nj u k u, S hi nj u k u -k u, To k y o  1 6 3-1 3 1 0 , J a p a n 
 
 
 
1 5. 1 0. 5. 3  C e nt r al L a b o r at o r y i n J a p a n  
S R L, I n c.  
2- 1- 1, Nis his hi nj u k u , S hi nj u k u-k u , To k y o 16 3 -0 4 0 9 , J a p a n 
 
 
 
1 5. 1 0. 5. 4  C e nt r al L a b o r at o r y M a n a g e me nt i n K o re a  
Me ditr ee C o., Lt d.  
# 5 0 1, 3 8 - 3, Ba u m o er o 4 1 - gil, Se o c h o - g u, Se o ul, 1 3 7-8 8 6, K orea  
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D




 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 4 of 1 0 1 
 
   
 
 
   
 
 
 
 
 
 
 
 
 
1 5. 1 0. 7  C o nt r a ct R es e a rc h O r g a ni z ati o n  i n C h a r g e of D at a S af et y M o nit o ri n g 
B o a r d  C o o r di n ati o n  
M M S H ol di n gs, I n c.  
6 8 8 0 C o m m er ce Bl v d, C a nt o n, MI 4 8 1 8 7 , U S A 
 
 
 
1 5. 1 0. 8  H e p ati c A dj u di c ati o n C o m mittee  
  
 
 
 
 
 
 
 
 
1 5. 1 0. 9  C o nt r a ct R es e a rc h O r g a ni z ati o n i n C h a r g e of He p ati c A dj u di c ati o n 
C o m mitt ee C o o r di n ati o n  
M M S H ol di n gs, I n c.  
6 8 8 0 C o m m er ce Bl v d, C a nt o n, MI 4 8 1 8 7, U S A  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 5 of 1 0 1 
 
 
 
1 5. 1 0. 1 0  E D C S yst e m D e v el o p me nt  
Me di d at a S ol uti o ns, I n c.  
Pers o n R es p o nsi bl e: Tar e k S h erif, C h air m a n a n d C hi ef E x ec uti v e Offi cer  
3 5 0 H u ds o n Str eet, 9t h Fl o or , N e w Yor k, N Y 1 0 01 4 , U S A 
 
 
R ol e: T h e y will b e r es p o nsi bl e f or t h e o p erati o n ma n a ge m e nt a n d mai nte na n ce of t h e  
E D C s yst e m i n acc or d a n ce wit h a b usi ness tr ust a gree m e nt.  
 
1 5. 1 0. 1 1  E D C S yst e m S u p p o rt  
F ujits u S yst e ms E ast Li mit e d  
Pers o n R es p o nsi bl e: M a na b u Ya m a m ot o  
S hi na ga w a s eas o n t err ace 1 - 2- 7 0 K o na n, Mi n at o-k u, To k y o 1 0 8 - 0 0 7 5,, 
J a p a n 
 
 
R ol e: T h e y will b e r es p o nsi bl e f or t h e E D C S yst e m S u p p ort i n acc or d a n ce wit h a 
b usi n ess tr ust a gr ee m e nt.  
 
1 5. 1 0. 1 2  e P R O s yst e m D e v el o p me nt a n d S u p p o rt  
e R es ear c h Tec h n ol o g y, I n c  
Pers o n R es p o nsi bl e: Sat os hi Az ut a  
 
 
R ol e: T h e y will b e r es p o nsi bl e f or t h e o p erati o n ma n a ge m e nt, mai nt e n a n ce of t h e  e P R O 
s yst e m a n d e P R O S yst e m S u p p ort i n acc or d a n ce wit h a b usi n ess tr ust a gree m e nt.  
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 6 of 1 0 1 
1 6.  R E F E R E N C E S  
1)  
Li C Y, Z h a n g X L, M att h e ws E A, et al. C alci u m c ha n n el α 2δ 1 s u b u nit m e di at es 
s pi n al h y p er e x cit a bilit y i n pai n m o d ul ati o n. P ai n. 2 0 0 6; 1 2 5( 1-2): 2 0 - 3 4. 
2)  
Ta yl or C P. M ec h a nis ms of a n al gesi a b y ga b a p e nti n a n d pre ga b ali n – C al ci u m 
c h a n n el α 2-δ [ C a vα 2-δ] li ga n ds. P ai n. 2 0 0 9; 1 4 2( 1 - 2): 1 3-6.  
3)  
Fi el d MJ, Li Z, S c h w artz J B. C a 2 + c h a n n el α 2-δ li ga n ds f or t h e treat m e nt of 
ne ur o p at hi c p ai n. J M e d C h e m. 2 0 0 7; 5 0( 1 1): 2 5 6 9-7 5 . 
4)  
Fi el d MJ, C o x PJ, St ott E, et al. I d e ntifi cati o n of t h e α2-δ -1 s u b u nit of 
v olt a ge- d e p e n d e nt cal ci u m c h a n n els as a m ol ec ul ar tar get f or p ai n m e di ati n g t h e 
a n al gesi c acti o ns of pr e ga b ali n. Pr o c N atl Aca d S ci  U S A. 2 0 0 6; 1 0 3( 4 6): 1 7 5 3 7 -4 2.  
5)  
E ur o p ea n M e di ci n es A ge nc y ( E M E A), C o m mitt ee f or M e di ci n al Pr o d u cts f or 
H u m a n Us e ( C H M P), G ui d eli n e o n Cli ni cal M e dici n al Pr o d u cts I nt e n d e d f or t he 
Tr eat m e nt of N e ur o p at hi c Pai n . J ul y, 2 0 0 7. 
6)  
Sat o h J, Ya gi h as hi S, Ba ba M . Effi cacy a n d s afet y of pre ga b ali n f or treati n g 
ne ur o p at hi c p ai n ass o ci ate d wit h dia b etic p eri p h eral n e ur o p at h y: a 1 4  w ee k, 
r a n d o miz e d, d o u bl e- bli n d, pl ace b o-c o ntr oll e d tri al. Di a b M e d. 2 0 1 1; 2 8( 1): 1 0 9 - 1 6. 
7)  
Farr ar J T, Y o u n g J P Jr, La M or ea u x L, et al.  Cli nical i m p ort a n ce of c h a n ges i n 
c hr o ni c p ai n i nt e nsit y m eas ur e d o n a n 1 1 -p oi nt n u m eri cal p ai n rati n g s cal e. P ai n. 
2 0 0 1; 9 4( 2): 1 4 9- 5 8. 
8)  
Melzac k R. T h e S h ort - F or m M c Gill P ai n Q u esti o n naire. P ai n. 1 9 8 7; 3 0( 2): 1 9 1-7.  
9)  
Zel m a n D C, G or e M, D u kes E, et al . Vali d ati o n of a m o difi e d v ersi o n of t h e Bri ef 
Pai n I n v e nt or y f or p ai nf ul di a b eti c p eri p h eral n e ur o p at h y. J Vas c N urs 2 0 0 5; 
2 3 ( 3): 9 7- 1 0 4 
1 0)  Vi al a -D a nte n M, M arti n S, G uill e mi n I, et al. E v al u ati o n of t h e reli a bilit y a n d 
vali dit y of t h e M e di cal O utc o m e St u d y sl ee p s cale i n p ati e nts wit h p ai nf ul di a b eti c 
peri p h er al n e ur o p at h y d uri n g a n i nt er n ati o n al cli nical tri al. H ealt h Q u al Life 
O utc o m es 2 0 0 8; 6: 1 1 3 -2 5  
1 1)  H a ys R D, St e w art A L. Sl ee p m eas ures. I n: M eas uri n g F u n cti o ni n g a n d Well -Bei n g. 
St e w art A L, War e J E  Jr e dit ors. D ur h a m a n d L o n d o n: D u k e U ni v ersit y Press; 
1 9 9 2; 2 3 5- 2 5 9.  
1 2)  Bjell a n d I, D a hl A A, H a u g T T, et al. T h e v ali dit y of t h e H os pital A n xi et y a n d 
D e pr essi o n S cal e. A n u p dat e d lit erat ure re vi e w. J Ps yc h os o m R es . 
2 0 0 2; 5 2 ( 2): 6 9- 7 7. 
1 3)  War e J E Jr, S h er b o ur n e C D. T h e M O S 3 6- it e m sh ort -f or m healt h s ur v e y ( S F-3 6):  I. 
C o n ce pt u al fr a m e w or k a n d it e m  s el ecti o n. M e d C are 1 9 9 2; 3 0( 6): 4 7 3- 8 3. 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0 1 8 A pr  2 0 1 6 
Pa ge 9 7 of 1 0 1 
1 4)  O q u e n d o M A, H al berst a m B , Ma n n JJ. Ris k fact ors f or s ui ci d al b e h a vi or: utilit y 
a n d li mit ati o ns of r es ear c h i nstr u m e nts. I n : First M B , e dit or.  St a n d ar diz e d 
E v al u ati o n i n Cli ni cal Pr acti ce  Arli n gt o n: A m eri ca n Ps yc hi atri c P u blis hi n g, I n c;  
2 0 0 3; 1 0 3- 1 3 0.  
1 5)  Ki m Y. Missi n g d at a h a n dli n g i n c hr o ni c p ai n tri als, J Bi o p h ar m St at. 
2 0 1 1; 2 1( 2): 3 1 1 - 2 5.   
1 6)  U. S. D e p art m e nt of H ealt h a n d H u m a n Ser vi ces . F o o d a n d Dr u g  A d mi nistrati o n . 
Ce nt er f or Dr u g E v al u ati o n a n d R es earc h ( C D E R) . C e nt er f or Bi ol o gi cs E val u ati o n 
a n d R es ear c h ( C B E R) . G ui d a n ce f or I n d ustr y Dr u g -I n d u ce d Li v er I nj ur y: 
Pr e m ar k eti n g Cli ni cal E val u ati o n . J ul y 2 0 0 9, Dr u g S afet y  
1 7)  Malli n c kr o dt C H , Li n Q, Li p k o vi c h , et al. A str u ct ure d a p pr o ac h t o c h o osi n g 
esti m a n ds a n d esti m at ors i n l o n git u di n al cli ni cal tri als. P har m St at, 
2 0 1 2; 1 1 ( 6): 4 5 6-6 1  
1 8)  Malli n c kr o dt C H , Li n Q, M ol e n b er g hs G . A str u ct ure d fra m e w or k f or ass essi n g 
se nsiti vit y t o missi n g d at a ass u m pti o ns i n l o n git u di n al cli ni cal tri als. P h ar m St at, 
2 0 1 3; 1 2 ( 1): 1- 6 
1 9)  N ati o n al A ca d e m y of S ci e n ce . T h e Pre ve nti o n a n d Treat m e nt of Missi n g D at a i n 
Cli ni cal Tri als. Was hi n gt o n: N ati o n al A ca de mi es Press; 2 0 1 0    
2 0)  Littl e R J, D’ A g osti n o R, C o h e n M L, et al. T h e Pre v e nti o n a n d Treat m e nt of 
Missi n g D ata i n Cli ni cal Tri als.    N E n g J M e d  2 0 1 2; 3 6 7(1 4 ):1 3 5 5- 6 0  
2 1)  K e n w ar d M G, M ol e n b er g hs G, T hijs H. P att er n mi xt ure m o d els wit h pr o per ti m e 
de p e n d e n ce. Bi o m etri ka . 2 0 0 3;9 0( 1) :5 3 - 7 1. 
 


Pr o t oc ol D S 5 5 6 5- A-J 3 0 3 
Ve r s i o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 9 8 of 1 0 1 
1 7.  A P P E N DI C E S  
1 7. 1  S c h e d ul e of E v e nts  
Ta bl e 1 7 - 1  St u d y Visits  
 
Scree ni n g  
R a n d o miz ati o n  
T re at me nt peri o d  
E n d of Tre at me nt  
P ost -tre at me nt 
f oll o w-u p d)  
E arl y 
Ter  mi n ati o n  
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
11  
 
Wee k  
−1  
0  
1  
2  
4  
6  
8  
1 0  
1 2  
1 4  
1 5  
 
D a y  
≤ −7  
1 
8 
1 5  
2 9  
4 3  
5 7  
7 1  
8 5  
9 9  
D a y 7 
p ost -l ast-d ose  
 
Visit wi n d o w 
( d a ys) 
−7 t o −1 4  
－ 
6 t o 
1 0  
1 3 t o 
1 7  
2 6 t o 
3 2  
4 0 t o 
4 6  
5 4 t o 
6 0  
6 8 t o 
7 4  
8 2 t o 
8 8  
9 6 t o 1 0 2  
D a y 5 t o 1 4 
p ost -l ast-d ose  
 
I nf or m e d c o ns e nt 
X a) 
 
 
 
 
 
 
 
 
 
 
 
I n cl usi o n/ e xcl usi
o n crit eria  
X 
X 
 
 
 
 
 
 
 
 
 
 
D e m o gra p hic 
i nf or mati o n 
X 
 
 
 
 
 
 
 
 
 
 
 
Me dical  
/s ur gical hist or y 
X 
 
 
 
 
 
 
 
 
 
 
 
Efficac y 
p ara m et er(s)  
- s ee n e xt ta ble 
f or d etails 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
B o d y h ei g ht a n d 
wei g ht  
X 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
X b) 
P h ysical 
e xa mi n ati o n  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
E val u ati o n of 
e d e m a  
X 
 
 
 
 
 
 
 
 
X 
 
X 
F ull n e ur ol o gical 
e xa mi n ati o n  
X 
 
 
 
 
 
 
 
 
X 
 
X 
A b br e viat e d 
n e ur ol o gical 
e xa mi n ati o n  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
O p ht h al m ol o gic 
e xa mi n ati o n  
X  c) 
 
 
 
 
 
 
 
 
X 
 
X 
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -lea d E C G 
X  
 
 
 
 
 
 
 
 
X  
 
X  


 
 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
 
A N A SI A N, P H A S E 3, M U L TI C E N T E R, 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 1 4 -W E E K S T U D Y O F 
D S -5 5 6 5 I N P A TI E N T S WI T H DI A B E TI C P E RI P H E R A L N E U R O P A T HI C 
P AI N F O L L O W E D B Y A 5 2 -W E E K O P E N -L A B E L E X T E N SI O N  
 
 
  -F or O p e n -La bel E xte nsi o n st u d y -   
D S 5 5 6 5 - A-J 3 0 3 
 
 
V E R SI O N 6 . 0, 1 8 A pr  2 0 1 6 
 
 
D AII C HI S A N K Y O  
 
C O N FI D E N TI A LI T Y S T A T E M E N T  
I nf or m ati o n c o nt ai n e d i n t his d o c u m e nt is pr o prietar y t o D aii c hi S a n k y o.    T h e 
i nf or m ati o n is pr o vi d e d t o y o u i n c o nfi d e n ce w hic h is re q u est e d u n d er a n a gree d u p o n 
a n d si g n e d C o nfi d e nti alit y a n d Dis cl os ure A gree me nt.    D o n ot gi v e t his d o c u m e nt or 
a n y c o p y of it or r e v eal a n y pr o pri et ar y i nf or m ati o n c o nt ai n e d i n it t o a n y t hir d part y 
( ot h er t h a n t h os e i n y o ur or ga niz ati o n w h o are assisti n g y o u i n t his w or k a n d are b o u n d 
b y t h e C o nfi d e nti alit y a n d Discl os ur e A gree m e nt) wit h o ut t h e pri or writt e n p er missi o n of 
a n a ut h oriz e d r e pr es e nt ati v e of D aii c hi S a n k y o.


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 of 5 0 
I M P O R T A N T 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 
 
S p o ns or   
D aii c hi S a n k y o C o. , Lt d.  
3- 5- 1, Ni h o n b as hi -h o n c h o, C h u o -k u, To k y o 
1 0 3- 8 4 2 6, J a p a n  
T E L: s ee S ecti o n 1 5. 1 0  
F A X: s ee S ecti o n 1 5. 1 0  
C o ntr act R es ear c h Or ga nizati o n 
(J a p a n):  
C MI C C o., Lt d.  
1- 1- 1, S hi b a ura, Mi n at o - k u, To k y o, 1 0 5-0 0 2 3, 
J a p a n  
 
 
C o ntr act R es ear c h Or ga nizati o n 
( K or ea):  
Q ui ntil es Tra ns n ati o n al K orea C o., Lt d.  
1 3t h Fl o or, Worl d To w er B uil di n g, 5 5 8 
S o n g p a- daer o, S o n g p a - g u, S e o ul, K orea 1 3 8-7 3 1  
 
 
C o ntr act R es ear c h Or ga nizati o n 
( Tai w a n):  
Q ui ntil es Tai w a n Lt d.  
8 F, N o. 1 3 4, S ec. 3, Mi n S h e n g E ast R o a d, 
Tai p ei, 1 0 5, Tai w a n, R. O. C.  
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 of 5 0 
P R O T O C O L S Y N O P SI S  
 
Pr ot o c ol N u m b er:  
D S 5 5 6 5 -A -J3 0 3  
I n v esti gati o n al Pr o d u ct: D S -5 5 6 5  
A cti v e 
I n gr e di e nt(s)/I N N: 
[( 1 R, 5 S, 6 S)-6 -(ami n o met h yl) -3 -et h yl bi c ycl o[ 3. 2. 0] h e pt -3 - 
e n -6 -yl] aceti c aci d m o n o b e nz e n es ulf o n at e  
St u d y Titl e:  
A n Asi a n, p h as e 3, m ulti ce nt er, ra n d o miz e d, d o u bl e -bli n d, 
pl ace b o -c o ntr oll e d 1 4 -w ee k st u d y of D S - 5 5 6 5 i n pati e nts 
wit h di a b eti c p eri p h eral ne ur o p at hi c p ai n ( D P N P) f oll o w e d 
b y a 5 2 -w ee k o p e n -l a b el e xt e nsi o n 
St u d y P h as e:  
P h as e 3  
I n di cati o n U n d er 
I n v esti gati o n: 
D P N P  
St u d y O bj ecti v es:  
To ass ess t h e l o n g -t er m safet y a n d effi cac y of D S-5 5 6 5 f or a 
fl e xi bl e d osi n g of 1 0 m g BI D  a n d 1 5  m g  BI D  i n s u bj ects 
wit h D P N P  
St u d y D esi g n:  
O p e n -l a bel, l o n g-t er m st u d y 
T h e s t u d y d urati o n is ap pr o xi m at el y 5 3 w ee ks, i ncl u di n g a 
tr eat m e nt p eri o d of 5 2 w ee ks wit h a f oll o w -u p p eri o d of 1 
w ee k.  After t h e treat m e nt p eri o d of t h e d o u bl e- bli n d st u d y, 
t h e first 2 w ee k s will b e t h e titrati o n p eri o d wit h 
a d mi nistrati o n of 5 m g BI D .   F or t h e s ec o n d 2 w ee k s, t h e 
i n v esti gati o n al pr o d u ct is a d mi nist ere d at a d os a ge of 1 0 m g 
BI D .   Fr o m t he fift h w ee k , if t h ere are n o c o n cer n s i n 
saf et y, a d mi nistrati o n will b e i n creas e d t o 1 5 m g BI D.   F or 
t h e f oll o wi n g visits, t h e d osa ge m a y c h a n ge  t o eit her 1 0 m g 
BI D  or 1 5 m g BI D  d e p e n di n g o n s afet y fi n di n gs. 
St u d y D ur ati o n  
(fr o m F PI t o L P L V ) :  
St u d y d urati o n: J a n u ar y 2 0 1 5  t o M a y 2 0 1 7  
St u d y Sites a n d 
L o cati o n:  
A p pr o xi m atel y 2 0 0  st u d y sit es i n J a p a n, K orea a n d  Tai w a n  
Pla n n e d Sa m pl e Size:  
A p pr o xi m atel y 4 0 0 s u bj ects will b e e nr oll e d i n t he st u d y.  
S u bject Eli gi bilit y 
Crit eri a:  
I n cl usi o n Crit eri a:  
S u bjects m ust s atisf y all of t h e f oll o wi n g crit eri a t o be 
i n cl u d e d i n t h e st u d y. 
1)  C o m pl et e d 1 4 w ee ks of a d mi nistrati o n i n t h e 
d o u bl e- bli n d st u d y 
2)  A ble t o gi v e writt e n i nf or m e d c o nse nt f or st u d y 
parti ci p ati o n , u n d erst a n d pr o ce d ure s of t his st u d y, a n d 
c o m pl et e p ati e nt -re p ort e d q u esti o n n aires a d e q u at el y  
 
E x cl usi o n Crit eri a:  
S u bjects w h o m eet a n y of t h e f oll o wi n g crit eri a will b e 
e x cl u d e d fr o m p arti ci p ati o n i n t h e st u d y.  
1)  Dr u g c o m pli a nce <  8 0 %  i n t h e d o u bl e -bli n d st u d y 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 of 5 0 
2)  Cr eati ni n e cleara n ce  ( usi n g t h e C o c k cr oft -G a ult 
e q u ati o n) < 6 0 m L/ mi n at Visit 9 of t h e d o u bl e- bli n d 
st u d y 
3)  E x p eri e n ce d  criti cal s afet y iss u e i n t h e d o u bl e- bli n d 
st u d y 
4)  K n o w n hist or y of p ositi v e H e p atitis B a nti ge n or 
H e p atitis C a nti b o d y  
5)  Pr e vi o us treat m e nt wit h dr u gs t h at c o ul d ca us e 
irr e v ersi bl e reti n al d e ge n erati o n 
6)  Pr e g n a n c y, p ot e nti al pre g n a n c y, breast fee di n g, or 
s u bj ect u n willi n g t o t a k e reli a bl e c o ntrace pti v e m eas ures 
d uri n g t h e st u d y or f or 4 w ee ks aft er st u d y c o m pl eti o n  
7)  T h e s u bj ect is c o nsi d ere d i n a p pr o pri at e f or t h e st u d y at 
th e discreti o n of t h e i n v esti gat or or s u b-i n v esti gat or 
D os a ge F or m, D os e , 
a n d R o ut e of 
A d mi nistr ati o n:  
D S -5 5 6 5 is a d mi nist ere d orall y t wi ce d ail y.  T h e first 2 
w ee k s of t h e titrati o n p eri o d , t h e i n v esti gati o n al pr o d u ct is 
a d mi nist ere d at a d os a ge of 5 m g BI D .  F or t h e s ec o n d 2 
w ee ks, t h e d os a ge will b e 1 0 m g BI D .   Fr o m t h e fift h w ee k , 
if t her e are n o c o n cer n s i n s afet y, a d mi nistrati o n will b e 
i n creas e d t o 1 5 m g BI D.   F or t h e f oll o wi n g visits, t h e 
d osa ge m a y c h a n ge  t o eit her 1 0 m g BI D  or 1 5 m g BI D  
de p e n di n g o n s afet y fi n di n gs at t h e ti m e of eac h visit . 
St u d y E n d p oi nts:  
Saf et y:  
• 
A d v ers e E ve nts ( A Es) 
• 
cli ni cal l a b orat or y e v al u ati o ns 
• 
vit al si g n  
• 
1 2- l ea d el ectr o car di o gra m ( E C G ) 
• 
b o d y w ei g ht  
• 
p h ysi cal e x a mi nati o ns  
• 
e d e m a  
• 
ne ur ol o gi cal e x a mi n ati o ns  
• 
o p ht h al m ol o gi c e x a mi n ati o n  
• 
C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e ( C -S S R S)  
• 
H os pit al A n xi et y a n d D e pressi o n S cal e ( H A D S)  
 
Effi cac y : 
• 
S h ort -F or m M c Gill P ai n Q u esti o n n aire ( S F -M P Q ) 
St atisti cal A n al ys es:  
T h e s af et y a n al ysis s et will b e us e d f or all safet y a n al ys es  
a n d efficac y a n al ys es .   A E s, cli ni cal l a b orat or y t est res ults, 
vit al si g ns (i n cl u di n g b o d y w ei g ht), 1 2 -l ea d-E C G s, p h ysi cal 
fi n di n gs, C-S S R S a n d H A D S  will b e s u m m ariz e d.   Effi cac y 
e n d p oi nts will b e d es cri b e d as s u m m ar y st atisti cs.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 5 of 5 0 
T A B L E O F C O N T E N T S  
I M P O R T A N T 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 ................................... 2 
P R O T O C O L S Y N O P SI S ................................................................................................... 3 
T A B L E O F C O N T E N T S  ................................................................................................... 5 
LI S T O F I N -T E X T T A B L E S  ............................................................................................ 9 
LI S T O F A B B R E VI A TI O N S  .......................................................................................... 1 0 
1. I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N ............................... 1 2 
1. 1 D at a S u m m ar y  ............................................................................................................ 1 2 
1. 2 St u d y R ati o nal e  .......................................................................................................... 1 2 
1. 3 Ris k s a n d Be n efits f or St u d y S u bj ects ....................................................................... 1 2 
2. S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  ........................................................ 1 3 
2. 1 St u d y O bj ecti v es  ........................................................................................................ 1 3 
2. 2 St u d y H y p ot h esis  ....................................................................................................... 1 3 
3. S T U D Y D E SI G N  ........................................................................................................ 1 4 
3. 1 O v er all Pla n  ................................................................................................................ 1 4 
3. 1. 1 
St u d y Ty p e  .............................................................................................................. 1 4 
3. 1. 2 
St u d y S c h e me  ......................................................................................................... 1 4 
3. 1. 3 
St u d y E n d p oi nts  ..................................................................................................... 1 4 
3. 1. 3. 1 
Saf et y  .................................................................................................................. 1 4 
3. 1. 3. 2 
Effi cac y  .............................................................................................................. 1 5 
3. 1. 4 
D ur ati o n of S u bj ect P arti ci p ati o n  .......................................................................... 1 5 
3. 2 Disc ussi o n of St u d y D esi g n  ....................................................................................... 1 5 
4. S T U D Y P O P U L A TI O N  ............................................................................................. 1 6 
4. 1 E nr oll m e nt  .................................................................................................................. 1 6 
4. 1. 1 
Pr oce d ur es f or S u bj ect E nr oll m e nt  ........................................................................ 1 6 
4. 1. 2 
I n cl usi o n Crit eri a .................................................................................................... 1 6 
4. 1. 3 
E x cl usi o n Crit eri a  .................................................................................................. 1 6 
4. 2 S u bject Wit h dr a w al  .................................................................................................... 1 7 
4. 2. 1 
Wit h dr a w al Criteria  ................................................................................................ 1 7 
4. 2. 2 
Reas o ns f or Wit h dr a wal  ......................................................................................... 1 7 
4. 2. 3 
Wit h dr a w al Pr o ce d ur es  .......................................................................................... 1 8 
4. 2. 4 
St o p pi n g R ul es f or t h e St u d y  ................................................................................. 1 8 
5. T R E A T M E N T A D MI NI S T E R E D  ............................................................................ 1 9 
5. 1 I n v esti gati o n al Pr o d u cts ............................................................................................. 1 9 
5. 1. 1 
St u d y Tr eat m e nts  .................................................................................................... 1 9 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 6 of 5 0 
5. 1. 1. 1 
I n v esti gati o n al Pr o d u ct ...................................................................................... 1 9 
5. 1. 2 
D osi n g R e gi m e ns f or t h e St u d y  ............................................................................. 1 9 
5. 1. 3 
Met h o d of Ass essi n g Tr e at me nt C o m pli a n ce  ........................................................ 1 9 
5. 1. 4 
La b eli n g a n d P ac k a gi n g  ......................................................................................... 2 0 
5. 1. 5 
St or a ge  .................................................................................................................... 2 0 
5. 1. 6 
Dr u g A cc o u nt a bilit y  ............................................................................................... 2 0 
5. 2 C o n c o mit a nt M e di cati o ns a n d Treat m e nts  ................................................................ 2 0 
5. 2. 1 
Pr o hi bit e d C o n c o mit a nt Me di cati o ns  .................................................................... 2 0 
5. 2. 2 
Ot her  ....................................................................................................................... 2 1 
6. S T U D Y P R O C E D U R E S  ............................................................................................ 2 2 
6. 1 Visit  1 0  ....................................................................................................................... 2 2 
6. 2 Visit  1 1  ....................................................................................................................... 2 2 
6. 3 Visit 1 2  ....................................................................................................................... 2 3 
6. 4 Visit  1 3 t o Visit  2 3 ..................................................................................................... 2 4 
6. 5 E n d of Tr eat m e nt/ E arl y Ter mi nati o n ( Visit  2 4) ......................................................... 2 4 
6. 6  P ost- tr eat m e nt F oll o w-u p ( Visit  2 5, 7 d a ys aft er t he c o m pleti o n of a d mi nistrati o n)  2 5 
7. E F FI C A C Y A S S E S S M E N T S  .................................................................................... 2 6 
8. P H A R M A C O KI N E TI C A N D BI O M A R K E R  A S S E S S M E N T S  .......................... 2 7 
8. 1 P h ar m ac o ki n eti c Vari a bl e(s)  ...................................................................................... 2 7 
8. 2 Bi o m ar k er Vari a ble(s)  ................................................................................................ 2 7 
9. S A F E T Y A S S E S S M E N T S  ......................................................................................... 2 8 
9. 1 A d v ers e E ve nts  .......................................................................................................... 2 8 
9. 1. 1 
D efi niti o n of A d v ers e E v e nt  .................................................................................. 2 8 
9. 1. 2 
It e ms t o Be I n v esti gat e d C o n cer ni n g A d v ers e E v e nts .......................................... 2 9 
9. 1. 3 
D efi niti o n of A d v ers e Dr u g R eacti o n  .................................................................... 3 1 
9. 1. 4 
A cti o ns t o Be Ta k e n W h e n A d v ers e E v e nts O cc ur  ............................................... 3 1 
9. 2 A cti o ns t o Be Ta k e n W h e n S eri o us A d v ers e E v e nts O cc ur  ...................................... 3 2 
9. 3 E x p os ur e I n Ut er o D uri n g Cli ni cal St u di es  ............................................................... 3 2 
9. 4 Cli ni cal La b or at or y E v al uati o ns  ................................................................................ 3 3 
9. 5  Vit al Si g ns .................................................................................................................. 3 7  
9. 6 El ectr o car di o gr a ms  .................................................................................................... 3 7 
9. 7 P h ysi cal Fi n di n gs  ....................................................................................................... 3 7 
9. 7. 1 
B o d y Wei g ht  ........................................................................................................... 3 7 
9. 7. 2 
P h ys i cal E x a mi n ati o ns ........................................................................................... 3 7 
9. 7. 3 
E v al u ati o n of E d e m a  .............................................................................................. 3 7 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 7 of 5 0 
9. 8 Ot her S af et y Ass ess m e nts  .......................................................................................... 3 7 
9. 8. 1 
N e ur ol o gi cal E x a mi n ati o n  ..................................................................................... 3 7 
9. 8. 2 
O p ht h al m ol o gi c E x a mi n ati o n  ................................................................................ 3 8 
9. 8. 3  C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e 2 4 ............................................................ 3 8 
9. 8. 4 
H os pit al A n xi et y a n d D e pr essi o n S cal e 2 2 .............................................................. 3 8 
9. 8. 5 
Pr e g n a n c y t est  ........................................................................................................ 3 9 
1 0. O T H E R A S S E S S M E N T S  .......................................................................................... 4 0 
11.  S T A TI S TI C A L M E T H O D S  ...................................................................................... 4 1 
1 1. 1  O bjecti ve  .................................................................................................................... 4 1 
1 1. 2  G e n er al St atisti cal C o nsi der ati o ns  ............................................................................. 4 1 
1 1. 3  A n al ysis S ets  .............................................................................................................. 4 1 
1 1. 4  St u d y P o p ul ati o n D at a  ............................................................................................... 4 2 
1 1 . 5 Effi cac y A n al ys es  ....................................................................................................... 4 2 
1 1. 6  P h ar m ac o ki n eti c/ Bi o m ar ker A nal ys es  ....................................................................... 4 2 
1 1. 7  Saf et y A n al ys es  .......................................................................................................... 4 2 
1 1. 7. 1 A d v ers e E ve nt A n al ys es  ........................................................................................ 4 2 
1 1. 7. 2 Cli ni cal La b or at or y E v al uati o n A n al ys es  .............................................................. 4 3 
1 1. 7. 3 Vit al Si g n A n al ys es  ................................................................................................ 4 3 
1 1. 7. 4 El ectr o car di o gr a m A n al yses  .................................................................................. 4 3 
1 1. 7. 5 P h ysi cal Fi n di n g A n al ys es  ..................................................................................... 4 3 
1 1. 7. 6  C ol u m bi a- s ui ci de S e verit y R ati n g S cal e ............................................................... 4 3 
1 1. 7. 7 H os pit al A n xi et y a n d D e pr essi o n S cal e  ................................................................. 4 3 
1 1. 7. 8 Ot her S af et y A n al ys es  ............................................................................................ 4 3 
1 1. 8  Ot her A n al ys es  ........................................................................................................... 4 4 
1 1. 9  D at a Saf et y M o nit ori n g B o ar d  ................................................................................... 4 4 
1 1. 1 0  H e p ati c A dj u di cati o n C o m mittee  ........................................................................... 4 4 
1 1. 1 1  Sa m pl e Siz e D et er mi n ati o n  .................................................................................... 4 4 
1 2. D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  ............................................. 4 5 
1 2. 1 M o nit ori n g a n d I ns p ecti o ns  ....................................................................................... 4 5 
1 2. 2 D at a C oll ecti o n  .......................................................................................................... 4 5 
1 2. 3 D at a M a n a ge m e nt  ...................................................................................................... 4 5 
1 2. 4 St u d y D o c u m e ntati o n a n d St or a ge ............................................................................. 4 5 
1 2. 5 Rec or d K ee pi n g  .......................................................................................................... 4 5 
1 3. FI N A N CI N G A N D I N S U R A N C E  ............................................................................ 4 6 
1 3. 1 Fi n a n ces  ...................................................................................................................... 4 6 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 8 of 5 0 
1 3. 2 Rei m b urs e m e nt, I n d e m nit y, a n d I ns ura n ce  ............................................................... 4 6 
1 4. P U B LI C A TI O N P O LI C Y  ......................................................................................... 4 7 
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  ..................................................... 4 8 
1 5. 1 C o m pli a n ce St at e m e nt, Et hi cs,  a n d R e g ul at or y C o m pli a n ce .................................... 4 8 
1 5. 2 S u bject C o nfi d e nti alit y  .............................................................................................. 4 8 
1 5. 3 I nf or m e d C o nse nt Pr o ce d ur es .................................................................................... 4 8 
1 5. 4 Re g ulat or y C o m pli a n ce  ............................................................................................. 4 8 
1 5. 5 Pr ot o c ol D e vi ati o ns .................................................................................................... 4 8  
1 5. 6 S u p pl y of N e w I nf or m ati o n Affecti n g t he C o n d u ct of t he St u d y ............................. 4 8  
1 5. 7 D ur ati o n of t h e St u d y  ................................................................................................. 4 8 
1 5. 8 Pr ot o c ol A m e n d m e nts  ................................................................................................ 4 8 
1 5. 9 St u d y Dis c o nti n u ati o n or S us p e nsi o n  ........................................................................ 4 8 
1 5. 1 0  Or ga niz ati o n ........................................................................................................... 4 8  
1 6. R E F E R E N C E S  ........................................................................................................... 4 9 
1 7. A P P E N DI C E S  ............................................................................................................ 5 0 
1 7. 1 Sc he d ul e of E v e nts  ..................................................................................................... 5 0 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 9 of 5 0 
LI S T O F I N -T E X T T A B L E S  
Ta bl e 9 -1    It e ms t o b e I n v esti gat e d f or A d v ers e E v e nt  ................................................... 3 0 
Ta bl e 9- 2    La b or at or y P ar a m et ers t o b e Ass ess e d, a n d Ti m e of Ass ess m e nt .................. 3 4 
Ta bl e 1 7 -1    St u d y Visits  ................................................................................................... 5 0 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 0 of 5 0 
LI S T O F A B B R E VI A TI O N S  
 
A B B R E VI A TI O N  
D E FI NI TI O N  
A D R   
A d v ers e Dr u g R eacti o n  
A E  
A d v ers e E ve nt  
A/ G r ati o  
Al b u mi n/ Gl o b uli n rati o  
A L P  
Al kali n e P h os p h at as e  
A L T  
Al a ni n e A mi n otra nsferas e  
A M A  
a nti -mit o c h o n drial a nti b o d y  
A N A  
a nti -n u cl ear a nti b o d y  
A S M A  
a nti -s m o ot h m us cle a nti b o d y 
A S T  
As p art at e A mi n otra nsferas e  
B U N  
Bl o o d Ur ea Nitr o ge n  
C M V  
C yt o m e gal o vir us  
C N S  
Ce ntr al N er v o us S yst e m  
C R F  
Case R e p ort F or m  
C R P  
C -R eacti v e Pr ot ei n  
C -S S R S  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S cal e  
DI LI  
Dr u g -I n d uce d Li ver I nj ur y 
D S M B  
D at a Saf e t y M o nit ori n g B o ar d 
D P N  
Di a b eti c P eri p h eral N e ur o p at h y  
D P N P  
Di a b eti c P eri p h eral N e ur o p at hi c P ai n  
E B V  
E pst ei n -Barr Vir us  
e C R F  
El ectr o ni c C as e R e p ort F or m  
E C  
I n d e p e n d e nt Et hi cs C o m mitt ee 
E C G  
El ectr o car di o gra m  
e -DI S H  
E v al u ati o n of D r u g-In d u ce d S eri o us H e p at ot o xi cit y 
EI U  
E x p os ur e I n Ut er o  
e P R O  
El ectr o ni c  P ati e nt R e p ort O ut c o m e  
F D A  
F o o d Dr u g A d mi nistrati o n  
F PI  
First P ati e nt I n  
G C P  
G o o d Cli nical Practi ce (refers t o I C H a n d C F R) 
γ-G T( γ-G T P)  
ga m m a -Gl ut a m yl Tra ns p e pti d as e  
G O T  
Gl ut a mi c O x al o aceti c Tra ns a mi n as e  
G P T  
Gl ut a mi c P yr u vi c Tra ns a mi n ase  
H A C  
H e p ati c A dj u di cati o n C o m mittee  
H A D S  
H os pit al A n xi et y a n d D e pressi o n S cal e  
I C F 
I nf or m e d C o nse nt F or m 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 1  of 5 0 
A B B R E VI A TI O N  
D E FI NI TI O N  
I C H 
I nt er n ati o nal C o nfere nce o n H ar m o niz ati o n 
I N N 
I nt er n ati o nal N o n-pr o pri et ar y N a m e  
I R B 
I nstit uti o n al R e vi e w B o ar d 
I W R S 
I nt er acti v e We b R es p o ns e S yst e m 
L D H  
Lact at e D e h y dr o ge n as e  
L F T  
Li v er F u n cti o n Test  
L O E  
Lac k of Effi cac y  
L P L V  
L ast P ati e nt L ast V isit 
Me d D R A  
Me di cal Di cti o nar y f or Re g ulat or y A cti viti es  
N A S H  
N o n al c o h oli c S t eat o h e p atitis 
P T  
P r ot hr o m bi n T i m e 
R B C  
Re d Bl o o d C ell  
S A E  
Seri o us A d vers e E v e nt  
S A P  
St atisti cal A n al ysis Pl a n  
S D  
St a n d ar d D e vi ati o n  
S F -M P Q  
S h ort -F or m M c Gill P ai n Q u esti o n n aire  
T E A E  
Tr eat m e nt -E m er ge nt A d vers e E v e nt  
T -Bil  
T ot al bilir u bi n  
U L N  
U p p er Li mit of N or m al  
V A S  
Vis u al A nal o g S cal e  
W B C  
W hit e Bl o o d C ell  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 2 of 5 0 
1.  
I N T R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N 
1. 1  
D at a S u m m a r y  
Ref er t o S ecti o n 1. 1  of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3).   
 
1. 2  
St u d y R ati o n al e  
C urr e ntl y a v aila bl e α 2δ li ga n ds, ga b a p e nti n a n d pre ga b ali n, are est a blis h e d as effecti v e 
first-li n e tr eat m e nts f or p ai n ass o ci at e d wit h di a b eti c p eri p h eral n e ur o p at h y ( D P N).2, 3  
H o w e v er, t h e d o s a ge, a n d t h us effi cac y, of t h es e a ge nts is li mit e d b y fre q ue nt a n d 
si g nifi ca nt ce ntr al n er v o us s yst e m ( C N S )-rel at e d si d e effects, i n cl u di n g di zzi n ess a n d 
s o m n ol e n ce; ass o ci ate d w ei g ht gai n a n d p eri p h eral e d e m a ca n als o b e pr o bl e m ati c.    As 
a r es ult, a lar g e pr o p orti o n of p ati e nts wit h di a b eti c p eri p h eral n e ur o p at hi c pai n ( D P N P ) 
ar e l eft wit h i ns uffi ci e nt pai n r eli ef, a n d n e w treat me nt o pti o ns are n ee d e d.  
 
D S -5 5 6 5 is a n or al a n al g esi c dr u g bei n g d e v el o p e d f or D P N P a n d ot h er i n di cati o ns.   
D S -5 5 6 5 is a n a nt a g o nist t o t h e α 2δ s u b u nit of v olta ge -d e p e n d e nt C a 2 + c h a n n els, t h e m ai n 
tar get m ol ec ul e f or t h e a nal gesi c eff ect of pre ga b ali n a n d ga b a pe nti n.    N o n cli ni cal 
( S ecti o n 1. 1. 1. 4 of d o u bl e -bli n d st u d y i n t he pr ot oc ol [D S 5 5 6 5 - A-J 3 0 3]) a n d cli ni cal 
( S ecti o n 1. 1. 1. 5 of d o u bl e -bli n d st u d y i n t he pr ot oc ol [D S 5 5 6 5 - A-J 3 0 3]) dat a s u p p ort t h e 
pr o gr ess of D S- 5 5 6 5 i nt o P h as e 3 st u di es i n D P N P. 
 
D S -5 5 6 5 is b ei n g de v el o pe d f or c hr o ni c us e i n D P N P a n d ot h er i n di cati o ns.    T h eref ore, 
t his l o n g-t er m st u d y will b e c o n d uct e d t o e val u at e t h e l o n g-t er m s afet y a n d effi cac y of 
D S -5 5 6 5 d uri n g t h e c o urse of a 5 2 wee k (i n cl u di n g titrati o n p eri o d) o p e n treat m e nt 
peri o d. 
 
1. 3  
Ris ks a n d B e n efits f o r St u d y S u bjects  
Ref er t o S ecti o n 1. 3  of d o u bl e - bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 3 of 5 0 
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S  
2. 1  
St u d y O bj ecti v es  
T h e o bj ecti v e is t o  ass ess t h e l o n g -t er m s afet y a n d effi cac y of D S-5 5 6 5 f or a fl e xi ble 
d osi n g of 1 0 m g BI D a n d 1 5 m g BI D i n s u bjects wit h D P N P. 
 
2. 2  
St u d y H y p ot h esis 
T h e h y p ot hes is of t h e l o n g-t er m st u d y is t h at D S- 5 5 6 5 will b e ge n erall y w ell t ol erat e d 
w h e n a d mi nist er e d wit h a fle xi bl e d osi n g of 1 0 m g BI D  a n d 1 5 m g BI D  f or u p t o 5 2 
w ee ks . 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 4 of 5 0 
3.  
S T U D Y D E SI G N  
3. 1  
O v er all Pl a n  
3. 1. 1  
St u d y Ty p e  
T his is a m ulti n ati o n al , o pe n-l a bel, l o n g-t er m st u d y f or treat m e nt of D P NP. 
 
St u d y sit es: A p pr o xi m at el y 2 0 0 st u d y sit es i n J a pa n, K orea a n d  Tai w a n . 
Pla n n e d s a m pl e siz e  is a p pr o xi mat el y 4 0 0 s u bj ects w h o will b e e nr oll e d i n t h e st u d y.  
 
3. 1. 2  
St u d y S c h e me  
T h e t ot al st u d y d ur ati o n is a p p r o xi m at el y 53 w ee ks, i n cl u di n g a treat m e nt p eri o d of 5 2 
w ee ks wit h a f oll o w -u p peri o d of 1 w ee k.  Aft er t h e treat m e nt p eri o d of t he 
d o u bl e- bli n d st u d y, t h e first 2 w ee k s will b e t h e titrati o n p eri o d wit h a d mi ni strati o n of 
5 m g BI D .  F or t h e sec o n d 2 w ee k s, t h e i n v esti gati o n al pr o d u ct is a d mi nist ere d at a d os e 
of 1 0 m g BI D .   Fr o m t h e fift h wee k, if t h ere are  n o c o ncer n s i n safet y, a d mi nistrati o n 
will b e i n cr eas e d t o 1 5 m g BI D .  F or t h e f oll o wi n g visits, t h e d os a ge m a y c h a n ge t o 
eit h er 1 0 m g BI D or 1 5 m g BI D  d e p e n di n g o n safet y fi n di n gs at t h e ti m e of e ac h visit. 
 
O n e v al u ati o n of ris k a n d be n efit b y t h e s p o ns or, if it is n ot t h e p ositi v e res ult as 
c o m p ar e d wit h pl ace b o ar m i n 1 0  m g BI D ar m or 1 5  m g BI D ar m of D S -5 5 6 5 of 
d o u bl e- bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3), t h e d os a ge i n t his st u d y will b e 
c h a n ge d t o t h e o pti m al d os e of D S - 5 5 6 5. 
 
F urt h er d et ails of t h e st u d y pr o ce d ur es are pr o vi d e d i n t h e S c h e d ul e of E v e nts 
( S ecti o n 1 7. 1 ) a n d St u d y Pr o ce d ur es ( S ecti o n 6 ). 
 
3. 1. 3  
St u d y E n d p oi nts  
3. 1. 3. 1  
S af et y  
• 
A d v ers e E ve nts ( A Es) 
• 
cli ni cal l a b or at or y e v al u ati o ns  
• 
vit al si g n  
• 
1 2- l ea d el ectr o car di o gr a m ( E C G ) 
• 
b o d y w ei g ht  
• 
p h ysi cal e x a mi nati o ns  
• 
e d e m a  
• 
ne ur ol o gi cal e x a mi n ati o ns  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 5 of 5 0 
• 
o p h t h al m ol o gi c e x a mi n ati o n 
• 
C ol u m bi a- S ui ci d e S e v erit y R ati n g S cal e ( C- S S R S ) 
• 
H os pit al A n xi et y a n d D e pr essi o n S cal e ( H A D S ) 
 
3. 1. 3. 2  
Effi c a c y  
• 
S h ort -F or m M c Gill P ai n Q u esti o n n aire ( S F -M P Q ) 
 
3. 1. 4  
D u r ati o n of S u bj ect P a rti ci p ati o n  
T h e d ur ati o n of s u bj ect p arti ci p ati o n will b e a p pr o xi mat el y 5 3 w ee ks, i n cl u di n g a 2 
w ee k s of titr ati o n p eri o d,  a 5 0  w ee k s of d os a ge a dj ust m e nt  p eri o d,  a n d a 1- w ee k 
f oll o w- u p p eri o d . 
 
3. 2  
Dis c ussi o n of St u d y D esi g n  
I n acc or da n ce t o I nt er n ati o n al C o nf ere n ce o n H ar m o niz ati o n (I C H) -E 1 g ui d eli n e, 
D S -5 5 6 5 will b e a d mi nister e d f or 5 2 w ee ks t o e v al u at e t h e l o n g -t er m s afet y.    It is 
e x p ect e d t h at, i n p ost -mar k eti n g, t h e d os e of D S -5 5 6 5 will b e a dj ust e d u p or d o w n 
de p e n di n g o n t h e p ati e nt’s s y m pt o ms.    T h eref ore, 1 0 m g BI D a n d 1 5 m g BI D, w hi c h are 
me di u m a n d hi g h est d os e i n t h e d o u ble -bli n d st u d y, w ere s el ect e d a n d t h e d os e of 
D S - 5 5 6 5 will b e a dj uste d i n t h e l o n g-t er m st u d y.    I n t h e P h as e 2 st u di es i n p ati e nts wit h 
D P N P ( D S 5 5 6 5 - A-U 2 0 1 a n d D S 5 5 6 5 - A-J 2 0 2), D S- 5 5 6 5 w as ge n erall y t ol era bl e at d os es 
of 1 0 m g BI D a n d 1 5 m g BI D.    T h e l o w est d os e i n t h e d o u bl e - bli n d st u d y ( 1 5 m g Q D) 
w as n ot s el ect e d.    F or s u bj ect s af et y, 5 m g BI D, w hic h is l o w er t ha n 1 0 m g BI D or 1 5 
m g BI D, w as s elect e d as a n i niti al d ose of D S -5 5 6 5 a n d will b e a d m i nist ere d f or first 2 
w ee ks of t h e st u d y tr eat me nt.  
 
T h e s af et y e n d p oi nts w er e s el ect e d t o e v al u at e t h e l o n g -ter m s afet y of D S-5 5 6 5.   A E s, 
cli ni cal l a b or at or y e v al u ati o ns, p h ysi cal e x a mi n ati o ns, E C G s, a n d vit al si g n are 
c o m m o nl y e v al u at e d f or saf et y ass ess m e nt i n cli nical st u di es.    B o d y w ei g ht w as 
sel ect e d t o e val u ate e d e ma, w hi c h is a k n o w n a d vers e reacti o n of D S-5 5 6 5.   
Ass ess m e nts b y H A D S a n d C -S S R S were s el ecte d t o e v al u at e t h e ris k of a n xi et y, 
de pr essi o n, or s ui ci d al t e n d e n c y.    N e ur ol o gi cal e x a mi n ati o n w as s el ect e d t o e v al uat e 
gait/st ati o n a n d m us cl e str e n gt h.    I n a d diti o n, t h e efficac y of D S -5 5 6 5 will b e als o 
e v al u at e d wit h S F -M P Q, w hi c h ca n e v al u at e affecti v e or s e ns or y s c ore, as w ell as p ai n 
i nt e nsit y. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 6 of 5 0 
4.  
S T U D Y P O P U L A TI O N  
4. 1  
E n r oll me nt  
S u bject s will b e c o nsi d er e d e nr oll e d u p o n si g n at ure of t h e I nf or m e d C o ns e nt F or m ( I C F) 
f or t his st u d y at Visit 1 0. 
S u bjects ar e t o b e e nr oll e d i n t his st u d y usi n g t h e I nt eracti v e We b R es p o nse S yst e m 
(I W R S) i n acc or d a n ce wit h t he pr o ce d ures s p ecifi e d b el o w.   T h e  i de ntifi cati o n c o d e will 
be r ec or de d i n a s u bj ect i de ntifi cati o n l o g.  
 
4. 1. 1  
Pr o ce d u res f o r S u bj ect E nr oll me nt  
T h e  i n v esti gat or or s u b-i n v esti gat or will p erf or m a m a n d at or y i nter vi e w t o ass ess t h e 
eli gi bilit y of s u bj ects f or t h e st u d y, aft er o bt ai ni n g eac h s u bj ect’s writt e n i nf or m e d 
c o ns e nt, a n d will m a k e n ecess ar y e ntri es i n t h e I W R S at V isit 1 0 of t h e d o u bl e- bli n d 
st u d y. 
 
If t h e s u bj ect is c o nsi d er e d i n eli gi bl e f or t h e st u d y, t h e i n v esti gat or or s u b-i n v esti gat or 
will i nf or m t h e s u bj ect, a n d f oll o w-u p o bs er v ati o ns  will b e c o n d u ct e d  at Visit 11 of t h e 
d o u bl e- bli n d st u d y. 
 
4. 1. 2  
I n cl usi o n C rit eri a 
S u bjects m ust s atisf y all of t h e f oll o wi n g crit eri a t o be i n cl u d e d i n t h e st u d y . 
1)  C o m pl et e d 1 4 w ee ks of a d mi nistrati o n i n th e d o u bl e- bli n d st u d y 
2)  A ble t o gi v e writt e n i nf or m e d c o nse nt f or st u d y p arti ci p ati o n , u n d erst a n d pr o ce d ure s 
of t his st u d y, a n d c o m pl ete p ati e nt -re p ort e d q u esti o n naires a d e q u at el y  
 
Rati o n al e  
1)  T his crit eri a w as s elect e d t o ass ess  a p pr o priat el y t h e l o n g-t er m s afet y of t he 
i n v esti gati o n al pr o d u ct . 
2)  T h e st u d y will b e c o n d u ct e d i n acc or d a n ce wit h G o o d Cli nical P racti ce ( G C P ). 
 
4. 1. 3  
E x cl usi o n C rit eri a  
S u bjects w h o m eet a n y of t h e f oll o wi n g crit eri a will b e e x cl u d e d fr o m p artici p ati o n i n t h e 
st u d y. 
1)  Dr u g c o m pli a nce < 8 0 % i n t h e d o u bl e- bli n d st u d y 
2)  Cr eati ni n e cl ear a n ce  ( usi n g t h e C o c k cr oft-G a ult e q u ati o n) < 6 0 m L/ mi n at Visit 9 of 
th e d o u bl e- bli n d st u d y 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 7 of 5 0 
3)  E x p eri e n ce d  criti cal s afet y iss u e i n th e d o u bl e- bli n d st u d y 
4)  K n o w n hist or y of p ositi v e H e p atitis B a nti ge n or H e p atitis C a nti b o d y  
5)  Pr e vi o us tr eat m e nt wit h dr u gs t h at c o ul d ca us e irre v ersi bl e reti n al d e ge n erati o n 
6)  Pr e g n a n c y, p ot e nti al pr e g n a n c y, breast fee di n g, or s u bj ect u n willi n g t o t a k e reli a ble 
c o ntr ace pti ve m eas ur es d uri n g t h e st u d y or f or 4 w ee ks aft er st u d y c o m pl eti o n  
7)  T h e s u bj ect is c o nsi d er e d i n a p pr o pri at e f or t h e st u d y at t h e dis creti o n of t he 
i n v esti gat or or s u b-i n vesti gat or 
 
Rati o n al e  
1) , 2), 3), 4), 5), 6), 7) T hes e crit eri a w ere sel ect e d s o t h at effi cac y a n d s afet y c o ul d b e 
a p pr o pri at el y ass ess e d i n s u bj ects.  
 
4. 2  
S u bj ect Wit h d r a w al  
Ref er t o S ecti o n 4. 2 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
4. 2. 1  
Wit h d r a w al C rit eri a  
Ref er t o S ecti o n 4. 2. 1 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
4. 2. 2  
R e as o ns f o r Wit h d r a w al  
If a s u bj ect dis c o nti n u es fr o m t h e st u d y treat m e nt f or a n y reas o n, t h e d at e an d t h e reas o n 
f or dis c o nti n u ati o n m ust be r ec or de d o n t h e electr o ni c cas e re p ort f or m ( e C R F) usi n g t h e 
f oll o wi n g criteria. 
• 
A E  
• 
D eat h  
• 
Lac k of e ffi cac y ( L O E) 
• 
L ost t o f oll o w-u p  
• 
Pr ot o c ol vi ol ati o n 
• 
Pr e g n a n c y  
• 
St u d y ter mi n at e d b y s p o ns or 
• 
Wit h dr a w al b y su bj ect ( e g, A E , L O E , Ot h er) 
• 
Ot her  
 
If a s u bj ect is wit h dr a w n d ue t o n ee d f or a pr o hi bit e d m e di cati o n, t h e reas o n m a y b e 
r ec or de d as L O E , as a p pr o pri at e.    R eas o ns rec or de d u n d er “Pr ot o c ol vi ol ati o n ” m a y 
i n cl u d e f ail ur e t o c o m pl y wit h pr ot o c ol re q uire m e nts or st u d y pr o ce d ures.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 8 of 5 0 
 
F or all s u bj ects w h o wit h dr a w fr o m t h e st u d y, t h e i n v esti gat or m ust c o m plete a n d re p ort  
perti n e nt o bs er v ati o ns as t h or o u g hl y as p ossi bl e u p t o t h e d at e of wit h dra w al , i n cl u di n g 
t h e d at e of l ast tr eat m e nt a n d t h e r eas o n f or wit h dra w al. 
 
If a s ubj ect is wit h dr a w n d u e t o a n A E, t h e in v esti gat or s h o ul d f oll o w t h e s u bj ect u ntil  t h e 
A E h as r es ol v e d or st a bilize d.  
 
All s u bj ects w h o ar e wit h dr a w n fr o m t h e st u d y s h o ul d c o m plet e pr ot o c ol -s p ecifi e d 
wit h dr a w al pr oce d ur es (s ee S ecti o n 4. 2. 3  a n d S ecti o n 6. 5 ). 
 
4. 2. 3  
Wit h d r a w al Pr o ce d u res  
If t h e s u bj ect wit h dr a ws or is wit h dra w n fr o m t h e st u d y b ef ore t h e c o m pl eti o n of 
i n v esti gati o n al pr o d u ct a d mi nistrati o n, a p pr o pri at e m eas ures will b e i m pl e me nt e d.    I n 
a d diti o n, t o t h e e xte nt t h at t h e s u bj ect ’s c o o p erati o n ca n b e o bt ai ne d, all o bs er v ati o ns a n d 
tests s c h e d ul e d f or t h e E n d of Tr eat m e nt / E arl y Ter mi n ati o n Visit (Visit 2 4) will b e 
c o n d u ct e d , assess m e nts will b e m a d e at t h at ti m e p oi nt , all o bs er v ati o ns a n d t ests 
sc h e d ul e d f or t h e P ost-tr eat m e nt F oll o w- u p Visit ( Visit 2 5 ) will b e c o n d u cte d, a n d 
as s ess m e nts will b e m a d e aft er 5 t o 1 4 d a ys aft er t h e l ast d os e .    T his will be d o ne f or all 
s u bj ects w h o w er e tr eat e d wit h e v e n o n e d os e of t he i n v esti gati o n al pr o d u ct .    If t h e 
wit h dr a w al w as d u e t o A Es, t h e o ut c o me f or t hat s u bj ect will b e rec or d e d t o t h e e xte nt 
p ossi bl e i n t h e cas e r e p ort f or m ( C R F ) (s ee S ecti o n 9. 1. 4 ).   If th e wit h dra w al w as d u e t o 
s ui ci d al b e h a vi or a n d/or s ui ci d al i d eati o n, a p pr o pri at e m eas ures will b e i m pl e m e nt e d 
s u c h as r ef erri n g t h e s u bj ect t o a s p ecialist. 
 
4. 2. 4  
St o p pi n g R ul es f o r t h e St u d y  
Ref er t o S ecti o n 4. 2. 4 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol  ( D S 5 5 6 5- A-J 3 0 3). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 9 of 5 0 
5.  
T R E A T M E N T A D MI NI S T E R E D  
5. 1  
I n v esti g ati o n al Pr o d u cts 
T h e in v esti gat or m ust e ns ur e t h at t h e i n v esti gati o nal pr o d u ct will b e us e d o nl y i n 
acc or d a n ce wit h t h e pr ot oc ol.  
 
5. 1. 1  
St u d y Tre at m e nts  
F or det ails a n d h a n dli n g of t h e i n vesti gati o n al pr o d u ct, refer t o t h e I n v esti gat or ’s 
Br oc h ur e a n d t h e m a n u al f or ma n a ge m e nt of t h e i n v esti gati o n al pr o d u ct . 
 
5. 1. 1. 1  
I n v esti g ati o n al Pr o d u ct  
I n v esti gati o n al pr o d u ct c o d e: D S -5 5 6 5  
C h e mi cal  n a m e: [( 1 R, 5 S, 6 S)- 6-( ami n o m et h yl )- 3-et h yl bi c ycl o[ 3. 2. 0] h e pt- 3-e n - 6-yl] 
aceti c aci d m o n o b e nz e n es ulf o n at e  
C o nt e nt a n d d os a ge f or m:  
Na me of  
i n vesti g ati o nal pr o d u ct  
C o nte nt a n d d osa g e f or m  
D S - 5 5 6 5 Ta blets 5 m g  
W hite fil m -c oate d ta blet c o ntai ni n g 5 m g of t he free f or m of D S - 5 5 6 5 
D S - 5 5 6 5 Ta blets 1 0  m g    
W hite fil m -c oate d ta blet c o ntai ni n g 1 0 m g of t he fre e f or m of D S - 5 5 6 5 
D S - 5 5 6 5 Ta blets 1 5  m g    
W hite fil m -c oate d ta blet c o ntai ni n g 1 5 m g of t he fre e f or m of D S- 5 5 6 5 
 
5. 1. 2  
D osi n g Re gi me ns f o r t h e St u d y  
T h e d ur ati o n of i n v esti gati o n al pr o d u ct a d mi nistrati o n will b e 5 2 w ee ks, c o nsisti n g of a 2 
w ee k s of titr ati o n a n d a 5 0 w ee ks of d os a ge a dj ust m e nt  p eri o d .   T h e i n v esti gati o n al 
pr o d u ct will be a d mi nist er e d or all y t wi ce d ai ly (i n t h e m or ni n g i n t h e sa m e m a n n er as 
d o u bl e- bli n d st u d y a n d at b e dti m e).    T h e first 2 w ee k s will b e a titrati o n peri o d wit h 
a d mi nistr ati o n of 5 m g BI D .    F or t h e s ec o n d 2 w ee k s, t h e d os a ge will b e 1 0 m g BI D .   
Fr o m t h e fift h w ee k, if t her e ar e n o c o n cer ns i n s afet y w hi c h t h e i n v esti gat or j u d ge , 
a d mi nistr ati o n will b e i n cr eas e d t o 1 5 m g BI D .    F or t h e f oll o wi n g visits, t h e d os a ge m a y 
be c h a n ge d t o eit h er 1 0 m g BI D  or 1 5 m g BI D , d e p e n di n g o n s afet y fi n di n gs at t h e ti m e 
of eac h visit . 
 
5. 1. 3  
Met h o d of Assessi n g Tre at me nt C o m pli a n ce  
All d os es i n t his st u dy will b e s elf -a d mi nist ere d orall y.   E ac h s u bj ect is t o ret ur n t h e 
i n v esti gati o n al pr o d u ct at e v er y visit.    C o m pli a n ce will b e ass ess e d b y ret ur n e d t a bl et 
c o u nt.    A d mi nistr ati o n of t h e i n vesti gati o n al pr o d u ct will be rec or de d i n t he e C R F/ Dr u g 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 0 of 5 0 
A cc o u nt a bilit y R ec or d  ( nu m b er of ta bl ets ta k e n, d ose ) at all treat m e nt visits.   If  n o  
ta bl ets ar e ret ur n e d, t h e s u bj ect will b e as k e d w h et h er a n y w ere dis car d e d or t hr o w n a w a y, 
or if all of t h e t a bl ets w er e ta k e n or all y.  
 
5. 1. 4  
L a b eli n g a n d P a c k a gi n g  
D S - 5 5 6 5 t a bl ets of 5 m g, 1 0 m g a n d 1 5 m g will b e p ac k a ge d s e p aratel y i n al u mi n u m 
blist er p ac ks.   T h e blist er p ac k a ge of eac h d os e will b e p ac k a ge d s e p arat el y i n a b o x.   
T h e b o x will b e cl earl y mar ke d " F or Cli ni cal St u d y Us e O nl y," a n d will s h o w t h e 
I n v esti gati o n al Pr o d u ct C o d e, t h e i n v esti gati o n al pr o d u ct l ot n u m b er, t h e na m e a n d 
a d dr ess of t h e s p o ns or, a n d t h e  e x pir e d d at e of t h e i n v esti gati o n al pr o d u ct i n acc or da n ce 
wit h l o cal r e g ul ati o ns.  
 
5. 1. 5  
St o r a g e  
U p t o 2 5° C; d o n ot fr eez e ( ex c ursi o n p er mitt e d u p t o 3 0° C ). 
 
5. 1. 6  
D r u g A cc o u nt a bilit y 
T h e s p o ns or will d eli v er t h e i n v esti gati o n al pr o d u ct as n ee de d t o t h e i n vesti gati o n al 
pr o d u ct a d mi nistr at or d esi g n at e d at t h e st u d y sit e.    T h e a d mi nistrat or will st ore a n d 
ma n a ge t h e i n v esti gati o n al pr o d u ct b as e d o n t h e ma n u al f or m a na ge m e nt  of 
i n v esti gati o n al pr o d u ct, a n d will m ai nt ai n rec or ds a n d pre p are re p orts as re q uire d. 
 
5. 2  
C o n c o mit a nt Me di c ati o ns a n d Tre at me nts  
A n y c o n c o mit a nt m e di cati o ns a n d a n y c o n c o mit a nt treat m e nts us e d b y a s u bj ect d uri n g 
t h e p eri o d fr o m his/ h er Visit 1 0 u ntil his/ h er p ost- treat m e nt f oll o w- u p (Visit 2 5) , w h et h er 
per mitte d or n ot, will be d o c u m e nte d i n t h e C R F.    T h e r o ut e of a d mi nistrati o n, t h e t ot al 
dail y d os e, t h e d ur ati o n of us e, t h e i n di cati o n f or us e , a n d t h e cl assifi cati o n of t h era pi es 
will als o b e d o c u m e nt e d i n t h e C R F.  
 
5. 2. 1  
Pr o hi bite d C o nc o mit a nt Me di c ati o ns  
T h e f oll o wi n g dr u gs ar e pr o hi bit e d f or c o nc o mit a nt us e fr o m t h e titrati o n peri o d ( Visit 
1 0) t hr o u g h t he p ost- tr eat m e nt f oll o w- u p ( Visit 2 5 ). 
1)  Pr e ga b ali n , g a b a p e nt i n 
2)  Dr u gs t h at c o ul d ca us e irr e v ersi bl e reti n al d e ge n erati o n ( p h e n ot hi azi n e 
a nti ps yc h oti cs, d ef er o x a mi n e, q ui ni n e, q ui ni di n e, et h a m b ut ol, v ori c o n az ol e, et c.)  
3)  Ot her i n v esti gati o n al pr o d u cts  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 1 of 5 0 
 
5. 2. 2  
Ot h er  
S u bjects s h o ul d be i nstr u ct e d t o a v oi d e x cessi v e c o ns u m pti o n of al c o h ol d uri n g t h e 
tr eat m e nt p eri o d, as t h e i n v esti gati o n al pr o d u ct m a y i n creas e si de effects of sl ee pi n ess 
a n d dizzi n ess a n d p ot e nti at e t he i m p air m e nt of m ot or s kills.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 2 of 5 0 
6.  
S T U D Y P R O C E D U R E S  
A st u d y visit s c h e d ul e i n ta b ul ar f or m at is pr o vi d e d i n  s ecti o n 1 7. 1 . 
 
I n pri n ci pl e, all of t h e acti viti es a n d/ or e x a mi n ati o n s will b e rec or d e d wit h t h e d at e i n t h e 
C R F.  
 
6. 1  
Visit  1 0 
At  t h e b e gi nn i n g of t h e titr ati o n p eri o d, t h e f oll o wi n g acti viti es a n d/ or e x a mi n ati o ns will 
be p erf or m e d  a n d 5 m g BI D of n e w i n v esti gati o nal pr o d u ct  will b e iss u e d t o t h e p ati e nt .   
H o w e v er, if t h e s a m e e x a mi n ati o n s are  alrea d y p erf or m e d at  Visit 1 0 of t he d o u bl e- bli n d 
st u d y, t hos e  d at a wi ll b e us e d . 
• 
O btai n writt e n i nf or m e d c o ns e nt  
• 
E v al u at e i n cl usi o n crit eri a a n d e x cl usi o n crit eri a 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m o p ht h al m ol o gi c e x a mi nati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m 1 2 -l ea d E C G 
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  
• 
E v al u at e A Es  
• 
C o m pl et e C -S S R S  
• 
Perf or m p r e g n a n c y t est ( o nl y i n w o m e n of  c hil d b eari n g p ot e nti al)  
• 
E v al u at e pri or dr u g tr eat me nt, c o n c o mit a nt dr u gs, a n d c o nc o mit a nt t h era p y  
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
 
6. 2  
Visit  11  
Aft er t h e first 2 w ee k s of t h e titrati o n p eri o d  (st arti n g at Visit 1 0 ), t h e s u bject will c o m e 
t o t h e st u d y site ( Visit 1 1 ).  At Visit 1 1,  th e f oll o wi n g acti vities a n d/ or e x a mi n ati o n s will 
be p erf or m e d  a n d 1 0 m g BI D of n e w i n v esti gati o nal pr o d u ct will b e iss ue d t o t h e p ati e nt 
aft er t h e i n v esti gat or or s u b -i n v esti gat or c o nfir ms t ol era bilit y a n d re vi e ws c o nti n u ati o n of 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 3 of 5 0 
t h e tr eat m e nt. 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m n e ur ol o gi cal e x a mi n ati o n  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d t h e d at e of t h e first d os e t a k e n a n d 
r e vie w dr u g-t a ki n g c o m pli a n ce 
 
6. 3  
Visit 1 2 
T w o  w ee k s after Visit 1 1 , t h e s u bj ect will c o m e t o t h e st u d y sit e ( Visit 1 2 ).   Th e 
f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e perf or m e d at V isit 1 2.   At t his p oi nt, 1 0 
m g BI D or 1 5 m g BI D of n e w i n v esti gati o nal pr o d u ct will be iss u e d t o t h e p ati e nt aft er 
t h e i n v esti gat or or s u b-i n vesti gat or c o nfir ms t olera bilit y a n d re vi e ws c o nti n u ati o n of t h e 
tr eat m e nt. 
• 
C o m pl et e S F -M P Q  
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m n e ur ol o gi cal e x a mi n ati o n  
• 
C oll ect bl o o d  a n d uri n e s a m pl e s f or l a b orat or y t ests 
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  
• 
E v al u at e A Es  
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d a n d re vi e w dr u g -t a ki n g 
c o m pli a n ce  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 4 of 5 0 
• 
Iss u e t he i n v esti gati o n al pr o d u ct 
 
6. 4  
Visit  1 3 t o Visit 2 3 
Aft er Visit 1 2 , t h e s u bj ect will c o m e t o t h e st u d y sit e e v er y 4 w ee ks ( Visit 1 3 t o Visit  2 3).  
T h e f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e p erf or m e d at eac h visit, a n d 1 5 m g 
BI D  of n e w i n v esti gati o nal pr o d u ct will b e iss u e d t o t h e p ati e nt aft er t h e i n v esti gat or or 
s u b-i n v esti gat or c o nfir ms t ol er a bilit y a n d re vi e ws c o nti n u ati o n of t h e treat me nt.  If 
t h ere ar e a n y s af et y iss u es, 1 0 m g BI D of n e w i n v esti gati o n al pr o d u ct will be iss u e d  
i nst ea d. 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Perf or m p h ysi cal e x a mi n ati o n  ( Visit 1 4, 1 6, 1 8, 2 0, 2 2 ) 
• 
Meas ur e b o d y w ei g ht  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m n e ur ol o gi cal e x a mi n ati o n  ( Visit 1 4, 1 6, 1 8, 2 0, 2 2) 
• 
Perf or m o p ht h al m ol o gi c e x a mi nati o n ( Visit 1 4, 1 6, 1 8, 2 0, 2 2)  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or l a b orat or y t ests 
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  ( Visit 1 4, 1 6, 1 8, 2 0, 2 2)  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  ( Visit 1 4, 1 6, 1 8, 
2 0, 2 2)  
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , a n d rec or d a n d re vi e w dr u g -t a ki n g 
c o m pli a n ce  
• 
Iss ue t he i n v esti gati o n al pr o d u ct 
 
6. 5  
E n d of Tre at me nt / E a rl y Ter mi n ati o n ( Visit 2 4 ) 
T h e tr eat m e nt p eri o d will b e c o m pl et e d aft er 5 2 w ee ks of a d mi nistrati o n ( Visit 2 4 ).   T h e  
f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e perf or m e d at t h e e n d of treat m e nt / earl y 
ter mi n ati o n. 
• 
C o m pl et e  S F -M P Q  
• 
C o m pl et e H A D S  
• 
Perf or m p h ysi cal e x a mi n ati o n  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 5 of 5 0 
• 
Meas ur e b o d y w ei g ht  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
Perf or m 1 2 -l ea d E C G 
• 
Perf or m e v al u ati o n of e d e m a  
• 
Perf or m n e ur ol o gi cal e x a mi n ati o n  
• 
Perf or m o p ht h al m ol o gi c e x a mi nati o n  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of H b A 1 c  
• 
C oll ect bl o o d s a m ple f or e v al u ati o n of fasti n g bl o o d gl u c os e l e v els  
• 
Perf or m pr e g n a n c y t est ( o nl y i n w o m e n of c hil d b eari n g p ot e nti al ) 
• 
E v al u at e A Es  
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
• 
C oll ect u n us e d i n v esti gati o n al pr o d u ct , rec or d t h e d at e of t h e l ast d os e ta ke n a n d 
r e vie w dr u g-t a ki n g c o m pli a n ce 
 
6. 6  
P ost -t re at me nt F oll o w-u p ( Visit  2 5, 7 d a ys after t h e c o m pl eti o n of 
a d mi nistr ati o n ) 
F oll o w- u p o bs er v ati o ns will b e c o n d u ct e d 7 d a ys after t h e c o m pl eti o n of a d mi nistrati o n 
( Visit 2 5 ).    T h e f oll o wi n g acti viti es a n d/ or e x a mi n ati o n s will b e p erf or m e d at f oll o w-u p . 
• 
C o m pl et e H A D S  
• 
Meas ur e b o d y w ei g ht 
• 
Perf or m p h ysi cal e x a mi n ati o n  
• 
Perf or m n e ur ol o gi cal e x a mi n ati o n  
• 
Meas ur e bl o o d pr ess ur e a n d p uls e rat e  
• 
C oll ect bl o o d  a n d uri n e  s a m pl es f or la b orat or y t ests  
• 
E v al u at e A E s 
• 
C o m pl et e C -S S R S  
• 
Rec or d a n d e v al u at e c o n c o mit a nt dr u gs a n d c o nc o mit a nt t hera p y  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 6 of 5 0 
7.  
E F FI C A C Y A S S E S S M E N T S  
S F -M P Q
1 8 
S u bjects will pr o vi d e a s e lf-ass ess m e nt usi n g t h e S F -M P Q fr o m Visit 1 0 t o Visit 2 4 .  
T h e S F -M P Q c o nsists of 3 p arts.  
• 
Fift ee n p ai n d es cri pt ors t hat ar e gi v e n a s c ore of 0 ( n o n e) t o 3 (s e v ere) b as e d o n 
i nt e nsit y.    T h e s c ores ar e s u m m ariz e d as a s e ns or y s c ore of 1 1 d es cri pt ors, a n 
aff ecti v e s c or e of 4 d es cri pt ors, a n d a t ot al s c ore of 1 5 d es cri pt ors.  
• 
A Vis u al A n al o g S cale ( V A S ), i n w hic h t h e s u bj ect rat es p ai n i nt e nsit y o n a 
1 0 0 m m -l o n g h oriz o nt al li n e, w h ere 0 m m = n o p ai n a n d 1 0 0 m m = w orst p ossi bl e 
pai n. 
• 
A Pr es e nt Pai n I nt e nsit y i n d e x t h at pr o vi d es a s c ore of 0 t o 5 b ase d o n i nt e nsit y . 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 7 of 5 0 
8.  
P H A R M A C O KI N E TI C  A N D BI O M A R K E R A S S E S S M E N T S  
8. 1  
P h a r m a c o ki n eti c Va ri a ble(s)  
N o p h ar m ac o ki n eti c ass ess m e nt  will b e p erf or m e d.  
 
8. 2  
Bi o m a r k er Va ri a bl e(s)  
N o bi o m ar k er ass ess m e nt  will be perf or m e d.  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 8 of 5 0 
9.  
S A F E T Y A S S E S S M E N T S  
Saf et y e n d p oi nts will b e b o d y w ei g ht, A Es, l a b orat or y v al u es, vit al si g ns, 1 2 -l ea d E C G, 
fi n di n gs fr o m p h ysi cal e x a mi n ati o n, fi n di n gs fr o m n e ur ol o gi cal e x a mi n ati o n, C-S S R S, 
H A D S, e d e m a, a n d fi n di n gs  fr o m o p ht h al m ol o gi c e x a mi n ati o n. 
 
9. 1  
A d v ers e E v e nts  
9. 1. 1  
D efi niti o n of A d v ers e E ve nt  
A n A E  is a n y u nf a v or a bl e a n d u ni nt e n d e d si g n (i ncl u di n g a n a b n or m al l a b orat or y v al u e 
or a b n or mal vit al si g n), s y m pt o m, or dis eas e t h at de v el o ps fr o m Visit 1 0 t o 7 d a ys aft er 
t h e l ast d os e of st u d y m e di cati o n ( Visit 2 5), re gar dl ess of rel ati o ns hi p t o t he 
i n v esti gati o n al pr o d u ct . 
 
A n y s y m pt o m t h at t h e i n vesti gat or or s u b-i n v esti gat or c o nsi d ers ass o ci at e d wit h D P N 
will b e e v al u at e d as a n effi cac y v aria bl e a n d will n ot b e re gar d e d as a n A E .   H o w e v er, if 
t h e s y m pt o m is c o nsi d er e d p ot e nti all y rel at e d t o t he i n v esti gati o n al pr o d u ct, s u c h a 
s y m pt o m will b e r e gar d e d as a n A E.  If a n y pre-e xisti n g s y m pt o m or dis eas e is 
a g gr a v at e d d uri n g t h e st u d y p eri o d, t h e a g gra v ati o n will b e re p ort e d as a n A E , a n d t h e 
dat e of c o nfir mi n g t h e a g gr a v ati o n will b e c o nsi dere d t h e d at e of e v e nt o ns et.  
 
Dizzi n ess , s o m n ol e n ce, e de m a, a n d w ei g ht i n crease  are c urre ntl y d efi n e d as si g nifi ca nt 
A Es .   A n y ot h e si g nifi ca nt A Es t o b e a d d e d will be s p ecifi e d i n t h e statistical a n al ysis 
pl a n  ( S A P). 
 
All a nti e pil e pti c dr u gs carr y a ris k of i ncrease d s uici d al b e h a vi or a n d i d eati o n.   
F urt h er m or e, i ncr ease d h e p ati c tra ns a mi nas es h a v e b ee n o bs er v e d i n t h e D S - 5 5 6 5 
de v el o p me nt  pr o gr a m.   T h er ef or e,  t h e f oll o wi n g “s ui ci d al b e h a vi or a n d i d eati o n” a n d 
“li v er e nz y m e el e v ati o ns/li v er d ysf u n cti o n ” will b e treat e d as a d vers e e v e nts of s p eci al 
i nt er est.    
•  
I n cr eas e i n A L T or A S T ≥ 5 x U L N 
•  
A L T or A S T ris es t o ≥ 3 x U L N a n d p ersists f or m ore t h a n 2 w ee ks  
•  
C o n c urr e nt i ncr eases i n A L T or A S T ≥ 3 x U L N a n d T -Bil ≥ 2 x U L N  
•  
A L T  or  A S T  ≥ 3 x  U L N  ass o ci at e d wit h  a  cli nical prese nt ati o n  s u g gesti v e  of li v er 
i nj ur y  (i e,  i n cl u di n g  t h e  a p p eara n ce  of  fati g u e,  na us ea,  v o miti n g,  j a u n di ce,  rig ht 
u p per q u a dr a nt p ai n or t e n d er n ess, fe v er, ras h, a n d/ or e osi n o p hili a)  
•  
Seri o us h e p at o bili ar y a d vers e e v e nt  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 2 9 of 5 0 
•  
Se ver e h e p at o bili ar y a d v ers e e v e nt  
•  
H e p at o bili ar y A d v ers e e ve nt l ea di n g t o Dis c o nti n uati o n 
•  
A n y  tr a ns a mi n ase  el e v ati o n  ass o ci at e d  wit h  a  cli ni cal  pre s e nt ati o n  s u g gesti ve  of  
Li v er i nj ur y  
•  
A n el e v ati o n of A L T or A S T > = 3 x U L N ( wit h o ut cli ni cal pres e nt ati o n s u g gesti v e of 
li v er i nj ur y) 
•  
A E r el at e d t o s ui ci d e (if t h ere ar e a n y “ yes ” res p o nses t o a n y of t h e q u esti o ns i n t h e 
C- S S R S)  
 
9. 1. 2  
It e ms t o B e I n v esti g at e d C o n cer ni n g A d v ers e E v e nts  
If a n A E  d e v el o ps d uri n g t h e cli ni cal st u d y, t he it e ms i n Ta bl e 9- 1  will b e i n v esti gat e d 
a n d t h e r es ults will b e r ec or d e d.   T h e s u bj ect s h o ul d b e q u esti o n e d i n a g e n eral w a y, 
wit h o ut as ki n g a b o ut t h e o cc urr e nce of a n y s p ecific s y m pt o ms.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 0 of 5 0 
Ta bl e 9- 1   It e ms t o b e I n v esti gat e d f or A d v ers e E v e nt 
Ite ms re vie we d 
C o nte nt of r e vie w  
C o nte nt of A E  
Na me of A E , date of o ns et 
Acti o n ta k e n re gar di n g 
t he i n vesti g ati o nal 
pr o d uct 
N o ne  
N o c ha n ge i n  i n vesti gati o nal pr o d u ct d osa ge was 
ma d e.  
Dis c o nti n u e d 
P er ma n e n tl y 
T he i n vesti g ati o nal pr o d u ct was p er ma ne ntl y 
st o p p e d. 
I nterr u pte d 
T he i n vesti g ati o nal pr o d u ct was te m p oraril y 
st o p p e d 
D ose R e d u ce d  
T he d os a ge of t he i n vesti gati o n al pr o d ucts was 
re d uce d. 
O utc o me  
Classificati o n of o utc o me, d ate of o utc o me ass ess me nt, date of r es ol uti o n  
 
Classificati o n 
of o utc o me  
Rec o ver e d/ Res ol ve d  
• 
T he s u bje ct f ull y re c o ver e d fr o m t he A E , 
wit h n o resi d ual effect s o bs er ve d.  
Rec o ver e d/ Res ol ve d 
wit h S e q u elae  
• 
T he resi d ual effects of t he A E  ar e still 
prese nt a n d o bs er va ble.  
• 
I de ntif y s e q uelae/resi d ual effects. 
N ot Re c o ver e d/ N ot 
Res ol ve d  
• 
T he A E  itself is still prese nt a n d o bs er va ble. 
Rec o veri n g/ R es ol vi n g  • 
T he A E  was al m ost f ull y res ol ve d, a n d t he 
s u bj ect r ec o vere d t o near-bas eli ne stat us.  
U n k n o w n  
•  
N o i nf or mati o n a n d t h e o utc o me was 
u n k n o w n.  
Fatal  
 
Se verit y  
Mil d  
A war e ness of si g n or s y m pt o m, b ut easil y 
t olerate d, ie, d o es n ot i nterfere wit h s u bject’s 
us u al f u ncti o n 
M o derate  
Dis c o mf ort e n o u g h t o c a us e i nterfere n ce wit h 
us u al acti vit y  
Se vere  
I nc a pa citati n g wit h i na bilit y t o w or k or d o us ual 
acti vit y, ie, i nterf er es si g nifica ntl y wit h s u bject’s 
us u al f u ncti o n  
Seri o us n ess  
Seri o us ( acc or di n g t o t he f oll o wi n g defi niti o n of S A E s) / N ot s eri o us 
 
 
Defi niti o n of S A E  
1. Res ults i n deat h  
2. Lif e -t hr eate ni n g 
3. Re q uir es i n p atie nt h os pitalizati o n or pr ol o n g ati o n of e xisti n g 
h os pitaliz ati o n  
4. Res ults i n persiste nt or si g nific a nt disa bilit y/i nc a pa cit y  
5. A c o n ge nital a n o mal y/ birt h defe ct  
6. A n i m p orta nt me dic al e ve nt  


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 1 of 5 0 
Ta bl e 9- 1   It e ms t o b e I n v esti gat e d f or A d v ers e E v e nt (c o nt.) 
Ite ms re vie we d 
C o nte nt of r e vie w  
Relati o ns hi p t o t he 
i n vesti g ati o nal pr o d u ct 
Classificati o n of relati o ns hi p (i n a cc or d a nc e wit h t h e f oll o wi n g 
classific ati o ns of relati o ns hi p), r eas o n f or t hat assess me nt  
 
Classificati o n of 
relati o ns hi p 
Relate d  
• 
T he A E f oll o ws a r eas o n a ble te m p oral 
se q ue n ce fr o m i n vesti g ati o n al pr o d u ct 
a d mi nistr ati o n, a n d c a n n ot b e r eas o n a bl y 
e x plai n e d b y t h e s u bje ct’s cli nic al state or 
ot h er f act ors (e g, dise ase u n der st u d y, 
c o nc urre nt dis eases, c o n c o mita nt 
me dic ati o ns).  
• 
T he A E f oll o ws a r eas o n a b le te m p oral 
se q ue n ce fr o m i n vesti g ati o n al pr o d u ct 
a d mi nistr ati o n, a n d is a k n o w n re acti o n t o 
t he dr u g u n der st u d y or its c he mic al gr o u p, 
or is pre dicte d b y k n o w n p h ar mac ol o g y.  
 
 
N ot relate d  
• 
T he A E d oes n ot f oll o w a r e as o na ble 
te m p oral s e q ue nce fr o m i n vesti gati o n al 
pr o d uct a d mi nistrati o n, or c a n b e reas o na bl y 
e x plai n e d b y t h e s u bje ct’s cli nic al state or 
ot h er f act ors (e g, dise ase u n der st u d y, 
c o nc urre nt dis eases, c o n c o mita nt 
me dic ati o ns).  
Ot her acti o n ta ke n f or 
e ve nt  
N o ne  
N o tre at me nt was re q uire d.  
Me dic ati o n re q uir e d  
Prescri pti o n a n d/ or o ver -t h e-c o u nter me dicati o n 
was re q uir e d t o tr eat t h e A E.  
H os pitalizati o n or 
pr ol o n gati o n of 
h os pitaliz ati o n 
re q uire d 
H os pitalizati o n was re q uire d or pr ol o n ge d d u e t o 
t he A E, w het her or n ot me dicati o n was re q uire d. 
Ot her  
 
 
9. 1. 3  
D efi niti o n of A d v ers e D r u g R e a cti o n  
T h os e A E s f or w hi c h t h e r elati o ns hi p t o t h e i n vesti gati o n al pr o d u ct is c o nsi d ere d 
“ R el at e d ” will b e h a n dl e d as a d v ers e dr u g reacti o ns  ( A D Rs). 
 
9. 1. 4  
A cti o ns t o B e Ta k e n W he n A d v ers e E v e nts O cc u r  
W he n a n A E  o cc urs, t h e i n v esti gat or or s u b-i n vesti gat or will pr o vi d e a p pr o pri at e 
tr eat m e nt, will r e p ort t h e A E  t o t h e s p o ns or if n ecess ar y, a n d t o t h e e xte nt p ossi bl e will 
m o nit or pr o gr ess u ntil t h e s u bj ect r ec o v ers or t h e A E  is res ol v e d or reli e v e d.    If it 
a p p ears u nli k el y fr o m a me di cal p ers p ecti v e t h at t h e s u bj ect will rec o v er, t his will b e 
e x pl ai n e d t o t h e s u bj ect, a n d m o nit ori n g of t h e s u bj ect as a p art of t h e cli nical tri al will 
be c o n cl u d e d ( alt h o u g h t he tr eat me nt f or t h e A E  will b e c o nti n u e d).   I n a d diti o n, cli ni cal 
tri al f oll o w- u p will b e t er mi n at e d a n d t he cli ni cal tri al will b e c o n cl u d e d if t h e 
i n v esti gat or or s u b-i n vesti gat or d eci d es f urt h er f oll o w-u p  is u n n ecess ar y f or t h e A E 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 2 of 5 0 
beca us e t her e is n o r el ati o n s hi p b et w ee n t h e A E a n d t h e i n v esti gati o n al pr o d uct, or if t h e 
s u bj ect r ef us es f urt h er f oll o w-u p . 
 
9. 2  
A cti o ns t o B e Ta k e n W he n S eri o us A d vers e E v e nts O cc u r  
If a s eri o us a d v ers e e v e nt (S A E ) o cc urs aft er o bt ai ni n g t he s u bj ect’s writt e n I C F  a n d u p 
t o Visit  2 5, t h e i n v esti gat or or s u b-i n v esti gat or will pr o vi d e a p p r o pri at e treat me nt f or t h e 
s u bj ect a n d will r e p ort t h e e v e nt vi a t h e e C R F  t o t he s p o ns or wit hi n 2 4 h o urs aft er 
bec o mi n g a w ar e of t h e e ve nt.    T h e i n v esti gat or will pr o m ptl y e ntr y a d et aile d 
i nf or m ati o n of t h e e v e nt t o t h e s p o ns or  i n t h e e C R F.   S A E  re p orts will b e pre p are d a n d 
s u b mitt e d t o t h e h ea d of t h e st u d y sit e or t o t h e I nstit uti o nal Re vi e w B o ar d (I R B), usi n g 
t h e f or m a n d pr o ce d ur es s p ecifi e d b y t h e st u d y sit e.    D et ail e d i nf or m ati o n re gar di n g t h e 
pr o ce d ur es f or r e p orti n g S A E s is pr o vi d e d s e p arat el y, i n t he st a n d ar d o perati n g 
pr o ce d ur es f or S A Es.  
I n a d diti o n, t h e f oll o wi n g t y p es of e v e nts s h o ul d be re p ort e d t o t h e s p o ns or wit hi n 2 4 
h o urs aft er b ec o mi n g a w ar e of t h e e v e nt i n t h e d esi g n at e d f or m of t h e e C R F: 
• 
I n cr eas e i n A L T or A S T ≥ 5 x U L N 
• 
A L T o r  A S T ri s es  t o ≥ 3 x U L N a n d p ersists f or m ore t h a n 2 w ee ks 
• 
C o n c urr e nt i ncr eases i n A L T or A S T ≥ 3 x U L N a n d T -Bil ≥ 2 x U L N  
• 
A L T or A S T ≥ 3 x U L N ass o ciat e d wit h a cli ni cal pres e nt ati o n s u g gesti v e of li v er 
i nj ur y (i e, i ncl u di n g t he a p p ear a n ce of fati g u e, n a us ea, v o miti n g, ja u n di ce, ri g ht 
u p per q u a dr a nt p ai n or t e n d er n ess, fe v er, ras h, a n d/ or e osi n o p hili a)  
• 
A E r el at e d t o s ui ci de (if t h ere ar e a n y “ yes ” res p o ns es t o a n y of t h e q u esti o ns i n t h e 
C- S S R S)  
T h e f oll o wi n g t y p es of e ve nts s h o ul d b e re p orte d t o t h e s p o ns or as pr o m ptl y as p ossi bl e 
aft er b ec o mi n g a w ar e of t h e e v e nt vi a t h e e C R F.  
•  
Se ver e h e p at o bili ar y a d v ers e e v e nt  
•  
H e p at o bili ar y A d v ers e e ve nt l ea di n g t o Dis c o nti n uati o n 
•  
A n y  tr a ns a mi n ase  el e v ati o n  ass o ci at e d  wit h  a  cli ni cal  pres e nt ati o n  s u g gesti ve  of  
Li v er i nj ur y  
•  
A n el e v ati o n of A L T or A S T > = 3 x U L N ( wit h o ut cli ni cal pres e nt ati o n s u g gesti v e of 
li v er i nj ur y) 
 
9. 3  
E x p os u re I n Ut er o D u ri n g Cli ni c al St u di es  
D aii c hi S a n k y o m ust b e n otifi e d of a n y s u bj ect w h o b ec o m es pre g n a nt w hil e recei vi n g or  
at t h e ti m e of disc o nti n ui n g t h e i n v esti gati o n al pr o d uct.    All pre g n a n ci es m ust b e 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 3 of 5 0 
f oll o w e d t o c o ncl usi o n t o det er mi n e t h eir o ut c o m e.    T his i nf or m ati o n is i m p orta nt f or 
b ot h dr u g s afet y a n d p u bli c h ealt h c o n cer ns.    It is t h e res p o nsi bilit y of t h e in v esti gat or 
t o r e p ort a n y pr e g n a n c y i n a s u bj ect usi n g t h e E x p os ure I n Ut er o ( EI U) R e p orti n g f or m.   
T h e i n v esti gat or will c o ntact t h e st u d y m o nit or t o o bt ai n t h e EI U R e p orti n g F or m u p o n 
lear ni n g of a pr e g n a n c y.  If t h e o ut c o m e of t h e pre g n a n c y m eets t h e crit eri a f or 
i m m e di at e classifi cati o n as a S A E (i e, p ost-p art u m c o m pli cati o ns, s p o nt a ne o us a b orti o n, 
still birt h, n e o n at al d eat h, or c o n ge nit al a n o m al y, i ncl u di n g c o n ge nit al a n o mal y i n a n 
a b ort e d f et us), t h e in v esti gat or s h o ul d f oll o w t h e pr o ce d ures f or re p orti n g S A Es.  
 
9. 4  
Cli ni c al L a b o r at o r y E v al u ati o ns  
T h e st u d y site st aff will c oll ect bl o o d a n d uri n e s peci m e ns f or r o uti n e l a b orat or y t ests at 
s p ecifi e d ti m es.    S p eci me ns will b e st ore d u n der c o n diti o ns sti p ul at e d i n t h e S a m pl e 
H a n dli n g M a n u al u ntil t he y ar e tr a ns p ort e d f or meas ure m e n t.    S p eci m e ns will b e 
tr a ns p ort e d a n d m eas ur e d b y a ce ntral l a b orat or y.  Ta bl e 9- 2  s u m m ariz es t h e l a b orat or y 
par a m et ers t o b e assess e d a n d t h e ti m es of ass ess me nt.  
 
Res ults of all l a b or at or y tests will b e re p ort e d fr o m t h e ce ntral l a b orat ory t o t h e sit e. 
 
A v al u e or fi n di n g  t h at r e pr es e nts a cli ni call y si g nifi ca nt a b n or m al c h a n ge s h o ul d b e 
r e gar de d as a n A E , a n d s h o ul d b e d es cri b e d ( di a g n ose d) a p pr o pri atel y i n t he C R F. 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 4 of 5 0 
Ta bl e 9- 2   La b or at or y P ar a m et ers t o b e Ass ess e d, a n d Ti m e of Ass ess m e nt  
 
Para m et ers  
Ti m e of ass ess m e nt  
He mat ol o g y  
W B C, R B C, h e m o gl o bi n, he mat ocrit, 
platelet c o u nt, differe ntial le u k oc yte 
( ne utr o p hil, e osi n o p hil, b as o p hil, 
m o n o c yte, l y m p h oc yte) c o u nts , r etic ul oc yte 
c o u nt 
Visit  1 0  t o Visit 2 5 
Bl o o d 
c he mistr y 
Total pr otei n, al b u mi n, A/ G rati o, T -Bil , 
A S T ( G O T), A L T ( G P T), A L P, γ-G T 
(γ-G T P), L D H, B U N, creati ni n e, uric a ci d, 
cre ati ne ki nase, t otal c h olester ol, 
tri gl yceri d es, Na, K, Cl, Ca, M g, i n or g a nic 
p h os p h or us, bicar b o nate, C R P  
Uri nal ysis  
Sta n d ar d uri n al ysis , i ncl u di n g micr osc o pic 
e xa mi nati o n 
S pecific gr a vit y, p H, pr otei n, gl u c os e, 
ket o nes, ur o bili n o ge n, o cc ult bl o o d , R B C, 
W B C, bilir u bi n  
H b A 1c 
H b A 1c 
Visit 1 0 , Visit 1 2, Visit 
1 4 , Visit 1 6, Visit 1 8, 
Visit  2 0 , Visit 2 2, Visit 2 4 
Fasti n g bl o o d 
gl u c ose  
Fasti n g bl o o d gl uc ose le vel  
Visit 1 0, Visit 1 2, Visit 
1 4, Visit 1 6, Visit 1 8, 
Visit 2 0, Visit 2 2, Visit 2 4  
Pre g na n c y  
Q ualitati ve test ( uri ne)  
Visit 1 0, Visit 2 4  
 
As d es cri b e d i n S ecti o n 4. 2. 1 , i ncr eases i n a mi n otrasferas es h a v e b ee n o bser v e d i n t h e 
D S -5 5 6 5 d e v el o p m e nt pr o gr a m t o dat e.  S p eci al m o nit ori n g of s u c h el e v ati o ns d uri n g 
P h as e 3 is d es cri b e d b el o w.  T h e H e p ati c A d j u di cati o n C o m mitt ee ( H A C) c h art er 
i n cl u d es a pr o cess b y w hic h s el ect e d cas es will b e a dj u di cat e d b y a li v er diseas e 
s p eci alist ( S ecti o n 1 1. 1 0). I n cas es of li v er la b orat or y a b n or m alities, it is i m p orta nt t o 
e ns ur e t hat t h e n at ur e a n d t h e e xt e nt of li v er i nj ur y is i d e ntifi e d a n d st u d y s u bj ects are 
m o nit or e d u ntil t h e li v er la b or at or y assess m e nts ret ur n t o n or m al.   S u bjects w h o h a v e 
a n y tr a nsa mi n as e el e v ati o n ass o ci at e d wit h a cli nical pres e nt ati o n s u g gesti v e of li v er 
i nj ur y (i e, incl u di n g t he a p p ear a n ce of fati g u e, n a us ea, v o miti n g, ja u n di ce, ri g ht u p p er 
q u a dr a nt p ai n or t e n der n ess, f e v er, r as h, a n d/ or e osi n o p hili a) or a n el e v ati o n of A L T or 
A S T ≥ 3 x U L N ( wit h o ut cli ni cal pr es e nt ati o n s u g gesti v e of li ver i nj ur y) at a n y visit 
s h o ul d b e m o nitor e d cl os el y, acc or di n g t o t h e f oll o wi n g:  
•  
Re p eat li v er t ests  of at l east all f o ur of t h e us u al s er u m m eas ures ( A L T, A S T, al k ali n e 
p h os p h at as e ( A L P), a n d t ot al bilir u bi n  at l east 2 ti mes w ee kl y (t h e first re p eat s h o ul d 
be wit hi n 4 8 t o 7 2 h o urs of i niti al a b n or m alit y) u ntil v al u es h a v e decreas e d t o < 2 x 
U L N, t h e n at l east e ver y 1 or 2 w ee ks u ntil res ol uti o n or ret ur n t o b as eli n e.    A n 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 5 of 5 0 
a d diti o n al s er u m s e p ar ati n g t u b e of bl o o d will b e c oll ect e d at ti m e of e v e nt a n d u ntil 
val u es r et ur n t o bas eli n e.  S a m pl es will b e st ore d f or f urt h er a n al ysis, as re q uire d.  
•  
Re vi e w or o bt ai n a d et ail e d  hist or y of s y m pt o ms a n d pri or or c o n c urre nt dis eas es . 
•  
Re vi e w or o bt ai n a hist or y of t h e us e of  c o n c o mit a nt dr u gs, i n cl u di n g 
n o n pr es cri pti o n m e di cati o ns, h er b al a n d di et ar y s u p pl e m e nts, al c o h ol, recreati o n al 
dr u gs, a n d s p ecial di ets . 
•  
R ul e o ut al c o h oli c h e p atitis; n o n -alc o h oli c st eat o h e p atitis ( N A S H);  h y p o xi c/is c h e mi c 
he p at o p at h y; a n d bili ar y tr act d is eas e. 
•  
O btai n a hist or y of e x p os ur e t o e n vir o n m e nt al c h e mical a ge nts.  
•  
Perf or m a d diti o n al li v er f u n cti o n t ests ( L F Ts ) (e g, s er u m l actat e d e h y dr o ge n as e  
( L D H), al k ali ne p h os p h atas e ( A L P), ga m m a-gl ut a m yl tra ns p e pti d as e  (γ-G T[ γ -G T P]) , 
pr ot hr o m bi n ti m e  [ P T]), e v al u ati o ns f or p ot e nti al viral eti ol o gi es (i n cl u di n g he p atitis 
A, B, C, E; c yt o m e gal o vir us  [ C M V]; E pst ei n-Barr vir us  [ E B V]) a n d a ut oi m m u n e 
eti ol o gi es ( a nti -n u cl ear a nti b o d y  [ A N A], a nti-s m o ot h m us cl e a nti b o d y [ A S M A], 
a nti -mit o c h o n drial a nti b o d y  [ A M A]). 
 
C o m bi n e d el e v ati o ns of a mi n otr a nsf erases a n d bilir u bi n m eeti n g t h e crit eria of a 
p ot e nti al H y’s La w cas e [ A L T or A S T ≥ 3 x U L N wit h si m ult a n e o us t ot al bilir u bi n ≥ 2 x 
U L N],  eit h er s eri o us or n o n -s eri o us a n d w h et h er or n ot ca us all y rel at e d, s h o ul d al w a ys b e 
r e p ort e d t o t h e s p o ns or wit hi n 2 4 h o urs (refer t o Secti o n 9.2 ), wit h t h e i n vesti gat or’s 
ass ess m e nt of seri o us n ess, ca us alit y, a n d a d et ail e d narrati v e. ( F D A’s G ui d a n ce f or  
I n d ustr y: Dr u g-I n d u ce d Li v er I nj ur y: Pre m ar keti n g Cli ni cal E v al u ati o n; J ul y 2 0 0 9; 
htt p:// w w w.f d a. g o v/ d o w nl o a ds/ Dr u gs/ G ui d a nce/ U C M 1 7 4 0 9 0. p df ). T h ese e v e nts s h o ul d 
be r e p ort e d as s o o n as p ossi bl e f oll o wi n g  t h e pr o ce d ures o utli n e d i n S ecti o n 9.2 f or S A E 
r e p orti n g. T h e s p o ns or will b e r es p o nsi bl e f or re p orti n g t h e cas e(s) t o t h e F D A. 
 
Crit eri a f or dis c o nti n ui n g s u bj ects bas e d o n tra ns a mi n as e i n creas es are pr o vi d e d i n 
Secti o n 4. 2. 1 . 
 
F or s u bj ects dis c o nti n u e d fr o m t h e st u d y d u e t o a n y tra ns a mi n as e i n creas e or h e p ati c 
e v e nt, t h e f oll o wi n g s h o ul d b e p erf or m e d:  
•  
G astr o e nter o l o g y or h e p at ol o g y c o ns ult ati o n 
•  
H e p at o bili ar y ultr as o u n d  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 6 of 5 0 
 
 
 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 7 of 5 0 
9. 5  
Vit al Si g ns  
Vit al si g ns will b e r ec or d e d at all visits a n d will i n cl u d e s u pi n e p uls e rat e a n d s u pi n e a n d 
ort h ost ati c bl o o d pr ess ur e.   F or m eas ure m e nt of s u pi n e bl o o d press ure, s u bj ects s h o ul d 
be i n a s u pi n e or s e mir ec u m b e nt p ositi o n f or at l east 5 mi n ut es b ef ore t h e b l o o d press ure 
meas ur e m e nt.    M eas ure me nt of ort h ost ati c bl o o d press ure s h o ul d f oll o w meas ure m e nt 
of s u pi n e bl o o d pr ess ur e.    S u bjects s h o ul d b e as k e d t o st a n d f or 3 mi n ut es b ef ore 
meas ur e m e nt of ort h ost ati c bl o o d pr ess ure.    M eas ure m e nt of bl o o d press ure s h o u l d b e 
c o n d u ct e d usi n g a cali br at e d ma n o m et er or a ut o mati c i nfl at a bl e c uff m o nit or; t h e bl o o d 
pr ess ure c uff s h o ul d b e k e pt i n pl ace b et w ee n s u pi n e a n d ort h ost ati c bl o o d press ure 
meas ur e m e nts.  R es ults will b e rec or d e d i n t h e C R F.  
 
9. 6  
El ect r o c a r di o g r a ms  
At t h e sti p ul ate d ti m es ( Visit 1 0 a n d Visit  2 4), 1 2 -l ea d E C G will b e p erf or me d .   Res ults  
(N or m al / A b n or m al, n ot cli ni call y si g nifi ca nt / A b n or m al, cli ni call y si g nifica nt ) will b e 
r ec or de d i n t h e C R F . 
 
9. 7  
P h ysi c al Fi n di n gs  
9. 7. 1  
B o d y Wei g ht  
B o d y w ei g ht will b e m eas ur e d at  eac h visit.    R es ults will b e rec or d e d i n t he C R F . 
 
9. 7. 2  
P h ysi c al E x a mi n ati o ns  
At Visit 1 0 , Visit  1 4, Visit 1 6 , Visit 1 8 , Visit 2 0 , Visit 2 2, Visit  2 4 , a n d Visit 2 5 p h ysi cal 
e x a mi nati o n will b e p erf or m e d .   T h e e x a mi n ati o n s h o ul d mi ni m all y i n cl u de cli ni cal 
e v al u ati o ns of t h e h ea d, nec k, t h yr oi d,  e yes, ears, n os e, t hr o at, h eart, l u n gs, l y m p h n o d es, 
a b d o m e n, s ki n, e xtr e miti es, a n d  m us c ul os k el et al s yst e m.   R es ults will b e rec or d e d i n t h e 
C R F.  
 
9. 7. 3  
E v al u ati o n of E d e m a  
E v al u ati o n of e d e ma will b e p erf or m e d , i n cl u di n g p h ysi cal e x a mi n ati o n a n d/ or pitti n g , at 
e ac h  visit  e x c pti n g Visit 2 5 .   R es ults  ( pres e n ce or a bs e n ce of e d e m a a n d e x pressi o n sit e) 
will b e r ec or d e d i n t h e C R F.  
 
9. 8  
Ot h er S af et y Ass ess me nts  
9. 8. 1  
N e u r ol o gi c al E x a mi n ati o n 
At  Visit 1 1, Visit 1 2 , Visit 1 4 , Visit 1 6 , Visit 1 8 , Visit 2 0 , Visit 2 2 , Visit 2 4 , a n d Visit 2 5, 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 8 of 5 0 
t h e a b br e vi at e d ne ur ol o gical e x a mi n ati o n will b e perf or m e d .   T h e ass ess me nt s i n cl u d e 
m us cle stre n gt h a n d gait/st ati o n.  Eac h ass ess e d res ults will b e rec or d e d as [ N or m al / 
A b n or m al] i n t h e C R F , b as e d o n p h ysi cal e x a mi n ati o n a n d a m e di cal i nt er vi e w.  
 
9. 8. 2  
O p ht h al m ol o gic E x a mi n ati o n  
T h e o p ht h al m ol o gi c e x a mi n ati o n  will b e p erf or m e d at Visit 1 0, Visit  1 4 , Visit 1 6 , Visit 1 8 , 
Visit 2 0 , Visit 2 2 , a n d Visit 2 4 .   T h e  e x a mi n ati o n  i n cl u d es e x a mi nati o n of vis u al ac uit y 
a n d f u n d us c o pi c  e x a mi n ati o n.   F or a gi v e n s u bj ect, vis u al ac uit y s h o ul d be e x a mi n e d 
u n der t h e sa m e c o n diti o ns ( u n c orr ect e d or c orrect e d) at b ot h visits , a n d f u n d us c o p y 
s h o ul d b e p erf or m e d wit h  t h e s a m e d e vi ce .   R es ults of vis u al ac uit y will be rec or de d as 
val u es, a n d r es ults of f u n d usc o pi c e x a mi n ati o n will b e rec or d e d as [ N or m al / A b n or m al, 
n ot cli ni call y si g nifi ca nt / A b n or m al, cli ni call y si g nifica nt] i n t h e C R F.  
 
9. 8. 3  
C ol u m bi a -S ui ci d e S e v erit y R ati n g S c al e 2 4 
T h e C - SS R S is a t o ol d esi g n e d t o s yst e m ati call y ass ess a n d trac k s ui ci d al A E s ( b e h a vi or 
a n d i d eati o n).    T h e C -S S R S ass ess es lifeti m e s ui ci d alit y d uri n g a n i niti al bas eli n e 
e v al u ati o n usi n g st a n d ar diz e d q u esti o ns, a n d t h e n pr os p ecti v el y m o nit ors i d eati o ns a n d 
be h a vi ors at s u bs e q u e nt f oll o w -u p ass ess me nts t hr o u g h o ut t h e trial.    T he re vie w er is a n 
i n v esti gat or or s u b-i n vesti gat or w h o h as c o m pl et e d trai ni n g pri or t o t h e st u d y usi n g t h e 
tr ai ni n g D V D.   T h e C -S S R S will b e a d mi nist ere d b y t h e i n v esti gat or or s u b-i n v esti gat or 
at eac h  visit.   A ns wers t o all r el e v a nt q u esti o ns will b e rec or d e d i n t h e C R F.    If t h e 
s u bj ect is j u d ge d t o ha v e s ui ci dal b e h a vi or a n d/ or s ui ci dal i d eati o n, a p pr o pri at e m eas ures 
will b e i m pl e m e nt e d s uc h as r eferri n g t h e s u bj ect t o a s p eci alist  as d es cri b e d i n t h e 
wit h dr a w al pr oce d ur es  (s ee S ecti o n 4. 2. 3 ). 
 
9. 8. 4  
H os pit al A n xi et y a n d D e p ressi o n S c al e 2 2 
At eac h visit , s u bj ects will pr o vi d e a s elf-ass ess m e nt usi n g t h e H A D S.    T he H A D S 
c o nsists of 7 it e ms t o s c or e d e pr essi o n ( 4 -p oi nt s cal e) a n d 7 it e ms t o s c ore a n xi et y 
( 4-p oi nt s cale).    T h e s u bj ect will res p o n d t o eac h it e m o n t h e q u esti o n n aire.   Bas e d o n 
t h e r es ults, t h e i n v esti gat or will c hec k f or th e pres e n ce or a bse n ce of d e pressi o n a n d / or 
a n xi et y.  If t h e s u bj ect is j u d ge d t o h a v e a n A E , a p pr o pri at e m eas ures will b e 
i m pl e m e nt e d s u c h as r ef erri n g t h e s u bject t o a s p eci alist.   R es ults will b e rec or d e d i n t h e 
C R F.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 3 9 of 5 0 
9. 8. 5  
Pre g n a n c y t est  
Pr e g n a n c y t ests ( uri n e t ests) will b e c o n d u ct e d at t h e sti p ul at e d ti m es (Visit 1 0  a n d Visit 
2 4 ), f or w o m e n of c hil d-beari n g p ot e ntial o nl y.   All fe m al e s u bj ects will be c o nsi d ere d 
as w o m e n of c hil d-b eari n g  p ot e nti al u nl ess t h e y ha v e u n d er g o ne s ur gi cal st er iliz ati o n 
( wit h d o c u m e nt e d bil at er al o o p h or ect o m y) or are p ost m e n o p a usal a n d h a v e e x p eri e n ce d 
n o m e ns es wit hi n t h e pre vi o us 6 m o nt hs.    T h e s u bj ect is c o nsi d ere d t o b e 
p ost m e n o p a usal w he n 1 2 c o ns ec uti v e m o nt hs of a bs e n ce of m e nstr uati o n is c o nfir m e d 
wit h n o  pat h ol o gi cal or p h ysi ol o gi cal fact ors.   R es ults will b e rec or d e d i n t h e C R F . 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 0 of 5 0 
1 0.  O T H E R A S S E S S M E N T S  
N o ot h er  ass ess m e nts will b e p erf or m e d.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 1 of 5 0 
1 1.  S T A TI S TI C A L M E T H O D S  
1 1. 1  O bj ecti v e  
To ass ess t h e l o n g -t er m saf et y a n d effi cac y of D S-5 5 6 5 f or a fl e xi ble d osi n g of 1 0 m g 
BI D a n d 1 5 m g BI D i n s u bj ects wit h D P N P.  
 
1 1. 2  Ge n er al St atistic al C o nsi d er ati o ns  
T h e st atisti cal p ac k a ge S A S ®  ( Ve rs i o n 9. 2 or hi g h er) will b e us e d t o pr o d u ce t a bl es, 
fi g ur es, a n d listi n gs.    All s af et y a n d effi cac y e n d p oi nts will b e s u m m ariz e d f or t h e 
saf et y a nal ysis s et.  
N o i m p ut ati o n will b e d o ne f or t he missi n g d at a of s afet y v al u a bl es.    F or t h e effi cac y 
e n d p oi nt of S F- M P Q, a missi n g d at a will b e h a n dl e d usi n g t he st a n d ar d s c ori n g 
i nstr u cti o ns.    D etails will b e s p ecifi e d i n t he S A P.  
Ra w d at a will b e pr es e nt e d  t o t h e e x act precisi o n at w hi c h t h e y w ere c oll ect e d. 
F or s u m m ar y st atisti cs, mea ns a n d m e di a ns will be dis pl a ye d t o o n e m ore d eci mal pl ace 
t h a n was d et er mi n e d f or r a w dat a d is p ersi o n st atisti cs will h a v e  t w o m ore deci m al places, 
a n d t h e mi ni m u m a n d m a xi m u m will b e dis pl a ye d t o t h e s a m e n u m b er of deci m al places 
as t h e r a w d at a. 
Q u a ntit ati v e d at a will b e t a b ul at e d wit h d es cri pti ve s u m mar y st atisti cs: arit h m eti c m ea n, 
st a n d ar d d e vi ati o n ( S D), me di a n, mi ni m u m a n d m a xi m u m v al u es, a n d n u m ber of 
o bser v ati o ns.   F o r cate g ori cal d at a , fre q u e n c y t a bl e will b e pr o vi d e d . 
A n al ysis f or t h e c h a n ge fr o m b as eli n e, i n cl u di n g t he s hift t a bl e, will b e c o n d uct e d f or t h e 
s u bj ects w h o h a v e a n a v aila bl e b as eli n e v al u e a n d at l east o n e p ost-e nr oll me nt ( Visit 1 0) 
val u e.  
S u b gr o u p a n al ys es b y c o u ntr y ( e g, J a p a n, K orea, a n d Tai w a n) will b e c o n d u ct e d f or s o m e 
of t h e effi cac y a n d s af et y a n al ys es.  
A d etail e d S A P d es cri bi n g t h e m et h o d ol o g y t o b e us e d i n t h e fi n al a n al ysis will b e 
pr e p are d b ef or e t h e d at a bas e l o c k.    A c h a n ge i n t h e pl a n n e d statisti cal a n al ysis  will 
r e q uir e a pr ot oc ol a m e n d me nt o nl y if it s u bst a nti v el y alt ers t h e pri n ci p al feat ures of t h e 
pr ot o c ol.    A n y d e vi ati o ns fr o m t h e pl a n n e d st atisti cal a n al ys es i n t h e pr ot o c ol will b e 
f ull y d es cri be d i n t h e S A P. 
 
1 1. 3  A n al ysis S ets 
T h e s af et y  a n al ysis s et will i n cl u de all s u bj ects w h o si g n e d t h e I C F a n d recei v e d at l east 
o n e d os e of st u d y m e di cati o n.  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 2 of 5 0 
1 1. 4  St u d y P o p ul ati o n D at a 
D e m o gr a p hi c a n d b as eli ne c h ar act eristi cs will b e s u m m ariz e d f or t h e safet y a n al ysis s et. 
 
1 1. 5  Effi c a c y A n al ys es  
S u m m ar y st atis ti cs will be cal c ul at e d f or t h e m eas ure d v al u e a n d t h e c h a n ge fr o m 
bas eli n e i n t h e s e ns or y s c or e, aff ecti v e s c ore, t ot al s c ore, V A S, a n d t h e prese nt p ai n 
i nt e nsit y i n d e x at eac h s c he d ul e d visit f or t h e s afet y a n al ysis s et. 
 
1 1. 6  P h a r m a c o ki n eti c/ Bi o m ar ker A n al ys es  
N ot a p pli ca bl e.  
 
1 1. 7  S af et y A n al ys es  
All s af et y a n al ys es will be p erf or m e d usi n g t h e s afet y a n al ysis s et.  
 
1 1. 7. 1  A d vers e E v e nt A n al ys es  
A n y A E s t h at a p p ear aft er t h e first a d mi nistrati o n of t h e o p e n-l a b el e xt e nsi o n st u d y, or 
t h at w ors e n r el ati v e t o t h e pr e -tr eat m e nt st at e b ef ore t h e o p e n-l a b el e xt e nsi o n st u d y, are 
c o nsi d er e d as tr eat m e nt -e m er ge nt a d v ers e e v e nts ( T E A Es).    T E A Es will be c o d e d usi n g 
t h e M e di cal Di cti o n ar y f or R e g ul at or y A cti viti es ( M e d D R A). 
 
T h e n u m b er a n d p erce nt a ge of s u bjects re p orti n g T E A Es will b e cal c ul at e d f or t h e 
cat e g ori es liste d b el o w.    T h e n u m b er a n d p erce nta ge of s u bj ects re p orti n g T E A Es a n d 
A D R s will b e s u m m arize d b y s yst e m or ga n cl ass a n d preferre d t er m. 
• 
T E A E  
• 
A D R  
• 
Seri o us T E A E  
• 
Seri o us A D R  
• 
Se ver e T E A E  
• 
Se ver e A D R  
• 
Si g nifi ca nt T E A E  
• 
Si g nifi ca nt A D R  
• 
T E A E l ea di n g t o tr eat m e nt dis c o nti n u ati o n  
• 
A D R lea di n g t o tr eat m e nt dis c o nti n u ati o n 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 3 of 5 0 
1 1. 7. 2  Cli ni c al L a b o r at o r y E v al u ati o n A n al ys es  
F or t h e h e m at ol o g y a n d bl o o d c h e mistr y t est p ara meters, s u m m ar y st atisti cs will b e 
cal c ul at e d f or t h e m eas ur e d v al u e s a n d c h a n ge fr o m b as eli n e at eac h s c h e d ul e d visit.    A 
s hift t a bl e will b e cr eate d bas e d o n t h e cat e g ori es of “a b n or m al l o w ”, “ n or mal”, a n d 
“a b n or mal hi g h ” b et w ee n bas eli n e a n d eac h s c h e d ul e d visit . 
 
A d diti o n all y, f or  A L T, A S T, T- Bil , a n d A L P, t h e n u m b er an d p erce nt a ge of s u bj ects w h o 
meet t h e crit eri a s p ecifi e d i n F o o d Dr u g A d mi nistrati o n  (F D A ) Dr u g -I n d u ce d Li v er 
I nj ur y ( DI LI) g ui d eli n e 2 6 a n d ev al u ati o n of dr u g -i n d uce d s eri o us he p at ot o xicit y (e-DI S H ) 
pl ot will b e pr o vi d e d.    F or t h e uri nal ysis para m et ers e x ce pti n g s p ecifi c gra vit y, t h e 
n u m b er a n d p er ce nt a ge of s u bj ects will b e pr o vi d e d at eac h visit.    S u m m ar y statisti cs 
will b e t a b ul at e d f or t he s p ecifi c gr a vit y.    A s hift t a bl e will b e creat e d bas e d o n  t h e 
cat e g ori es of “ n or m al ” a n d “a b n or m al ” b et w ee n bas eli n e a n d eac h s c he d ule d visit.  
 
1 1. 7. 3  Vit al Si g n A n al ys es  
S u m m ar y st atisti cs will be cal c ul at e d f or m eas ure d v al u es a n d c h a n ges fr o m b as eli n e i n 
t h e s u pi n e a n d ort h ost ati c bl o o d pr ess ure, a n d s u pi n e p uls e rat e at eac h sc he d ul e d visit. 
 
1 1. 7. 4  El ect r o c a r di o g r a m A n al ys es  
A s hift t a bl e will b e pr o vi d e d f or E C G e v al u ati o n bet w ee n b as eli n e a n d Visit 2 4 . 
 
1 1. 7. 5  P h ysi c al Fi n di n g A n al yses  
S u m m ar y st atisti cs will be cal c ul at e d f or m eas ure d v al u es a n d c h a n ges fr o m b as eli n e i n 
b o d y w ei g ht at eac h s c h e d ul e d visit.    F or t h e e val u ati o n of e d e ma, t h e res ults ( pres e n ce 
or a bs e n ce) will b e t a b ul at e d f or eac h e x pressi o n  sit e. 
 
1 1. 7. 6  C ol u m bi a -s ui ci d e S e v erit y R ati n g S c al e 
T h e d at a c oll ect e d fr o m C -S S R S will b e t a b ul at e d.  
 
1 1. 7. 7  H os pit al A n xi et y a n d D e p ressi o n S c al e  
T h e s u bscal es of a n xi et y a n d de pr ess i on f or H A D S will b e s u m m ariz e d at eac h s c h e d ul e d 
visit.  
 
1 1. 7. 8  Ot h er S af et y A n al ys es  
T h e d at a c oll ect e d fr o m t he o p ht h al m ol o gi c e x a mi n ati o n will b e t a b ul at e d at eac h 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 4 of 5 0 
sc h e d ul e d visit. 
 
1 1. 8  Ot h er A n al ys es  
N ot a p pli ca bl e.  
 
1 1. 9  D at a S af et y M o nit o ri n g B o a r d  
Ref er t o S ecti o n 1 1. 9  of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 03 ). 
 
1 1. 1 0  H e p ati c A dj u di c ati o n C o m mittee  
Ref er t o S ecti o n 1 1. 1 0  of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 1. 1 1  S a m ple Si ze Det er mi n ati o n  
T h e l o n g-t er m st u d y is e x pect e d t o e nr oll u p t o a p pr o xi mat el y 4 0 0 s u bj ects.    Of t h os e 
s u bj ects e nr oll e d, o v er 1 5 0 ar e e x p ect e d t o c o m pl et e 1-year treat m e nt wit h D S -5 5 6 5.   
T his m eets t h e r ec o m m e n d ati o ns ge n erall y a gree d u p o n i n t h e I C H E 1 g ui d eli n e ( 1 0 0 
s u bj ects e x p os e d f or a mi ni m u m of 1 year). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 5 of 5 0 
1 2.  D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E  
Ref er t o S ecti o n 1 2 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 2. 1  M o nit o ri n g a n d I ns p ecti o ns 
Ref er t o S ecti o n 1 2. 1 of d o u bl e- bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 2. 2  D at a C oll ecti o n 
Ref er t o S ecti o n 1 2. 2 of d o u bl e- bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
T h e d es cri pti o n of e P R O is n ot a p pli ca bl e i n t his pr ot o c ol  
 
1 2. 3  D at a M a n a g e me nt  
Ref er t o S ecti o n 1 2. 3 of d o u bl e- bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
T h e d es cri p ti o n of e P R O is n ot a p pli ca bl e i n t his pr ot o c ol 
 
1 2. 4  St u d y D o c u me nt ati o n a n d St or a ge  
Ref er t o S ecti o n 1 2. 4 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
T h e d es cri pti o n of e P R O is n ot a p pli ca bl e i n t his pr ot o c ol  
. 
1 2. 5  R ec o r d Kee pi n g  
Ref er t o S ecti o n 1 2. 5 of d o u bl e - bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
T h e d es cri pti o n of e P R O is n ot a p pli ca bl e i n t his pr ot o c ol  
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 6 of 5 0 
1 3.  FI N A N CI N G A N D I N S U R A N C E  
1 3. 1  Fi n a n ces  
Ref er t o S ecti o n 1 3. 1 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 3. 2  R ei m b u rs e me nt, I n d e m nit y, a n d I ns u r a n ce 
Ref er t o S ecti o n 1 3. 2 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 7 of 5 0 
1 4.  P U B LI C A TI O N P O LI C Y  
Ref er t o S ecti o n 1 4 of d o u bl e - bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 8 of 5 0 
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  C o m pli a n ce St at e me nt, Et hi cs , a n d Re g ul a t o r y C o m pli a n ce 
Ref er t o S ecti o n 1 5. 1 of d o u bl e - bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 5. 2  S u bj ect C o nfi d e nti alit y  
Ref er t o S ecti o n 1 5. 2 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 5. 3  I nf or me d C o ns e nt Pr o ce d u res 
Ref er t o S ecti o n 1 5. 3 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 5. 4  R e g ul at o r y C o m pli a n ce  
Ref er t o S ecti o n 1 5. 4 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 5. 5  Pr ot o c ol D e vi ati o ns  
Ref er t o S ecti o n 1 5. 5 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 5. 6  S u p pl y of N e w I nf o r m ati o n Affecti n g t h e C o n d uct of t h e St u d y  
Ref er t o S ecti o n 1 5. 6 of d o u bl e - bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5- A-J 3 0 3). 
 
1 5. 7  D u r ati o n of t h e St u d y  
Ref er t o S ecti o n 1 5. 7 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 5. 8  Pr ot o c ol A me n d me nts  
Ref er t o S ecti o n 1 5. 8 of d o u bl e- bli n d st u d y in t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 5. 9  St u d y Dis c o nti n u ati o n o r S us p e nsi o n  
Ref er t o S ecti o n 1 5. 9 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 
1 5. 1 0  O r g a ni z ati o n  
Ref er t o S ecti o n 1 5. 1 0 of d o u bl e -bli n d st u d y i n t h e pr ot o col ( D S 5 5 6 5 - A-J 3 0 3). 
 


 
 
Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
 
 
Versi o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 4 9 of 5 0 
1 6.  R E F E R E N C E S  
Ref er t o S ecti o n 1 6 of d o u bl e -bli n d st u d y i n t h e pr ot o c ol ( D S 5 5 6 5 - A-J 3 0 3). 
 


Pr ot oc ol D S 5 5 6 5- A-J 3 0 3 
Ve r s i o n 6. 0, 1 8 A pr 2 0 1 6 
Pa ge 5 0 of 5 0 
1 7.  A P P E N DI C E S  
1 7. 1  S c h e d ul e of E v e nts  
Ta bl e 1 7 - 1  St u d y Visits  
 
Titr ati o n peri o d  
D os a ge  a dj ust me nt pe ri o d  
E n d of 
Tre at me nt/ E arl y 
Ter  mi n ati o n  
P ost -tre at me nt 
f oll o w-u p  
Visit  
1 0  
11  
1 2  
1 3 t o 2 3  
2 4  
2 5  
Wee k  
1 4  
1 6  
1 8  
E ver y 4 
w ee ks  
6 6  
6 7  
D a y  
9 9  
11 3  
1 2 7  
1 5 5 t o 4 3 5  
4 6 3  
4 7 0  
Visit wi n d o w 
( d a ys) 
 
+/ - 3 
+/ - 3 
+/ - 7 
+/ - 7 
D a y 5 t o 1 4 
p ost -l ast d ose  
I n cl usi o n/ e xcl u
si o n crit eria 
X 
 
 
 
 
 
B o d y wei g ht  
X a) 
X  
X  
X  
X  
X  
I nf or m e d 
c o ns e nt  
X 
 
 
 
 
 
P h ysical 
e xa mi n ati o n  
X a) 
 
 
X b) 
X 
X 
E val u ati o n of 
e d e m a  
X a) 
X 
X 
X 
X 
 
N e ur ol o gical 
e xa mi n ati o n  
 
X 
X 
X b) 
X 
X 
O p ht h al m ol o gi
c e xa mi n ati o n  
X a) 
 
 
X b) 
X 
 
Vital si g ns  
X a) 
X  
X  
X  
X  
X  
1 2 -lea d E C G 
X a) 
 
 
 
X  
 
Cli nical saf et y 
la b orat or y t ests 
X a) 
X 
X 
X 
X 
X 
H b A 1 c  
X a) 
 
X  
X b) 
X  
 
Fasti n g bl o o d 
gl u c os e  
X a) 
 
X 
X b) 
X 
 
C -S S R S  
X a) 
X  
X  
X  
X  
X  
H A D S  
X a) 
X   
X   
X   
X  
X  
S F -M P Q  
X a) 
X 
X 
X 
X 
 
Pr e g n a n c y t est  
X a) 
 
 
 
X  
 
A E r e p orti n g  
 
 
 
 
 
 
Pri or a n d 
c o n c o mita nt 
m e dicati o n  
X a) 
X 
X 
X 
X 
X 
I n v esti gati o n al 
pr o d u ct 
dis p e nsi n g  
X 
X 
X 
X 
 
 
I n v esti gati o n al 
pr o d u ct 
c o m plia n c e  
 
X 
X 
X 
X 
 
a) T h e r es ult at Visit 1 0 i n t h e d o u ble -bli n d st u d y will b e a p pli e d.  
b) T h es e will b e p erf or m e d o n Visit  1 4 , Visit 1 6 , Visit 1 8 , Visit 2 0 , a n d Visit 2 2 . 


Pr o t oc ol D S 5 5 6 5- A-J 3 0 3 
Ve r s i o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 9 9 of 1 0 1 
 
Scree ni n g  
R a n d o miz ati o n  
T re at me nt peri o d  
E n d of Tre at me nt  
P ost -tre at me nt 
f oll o w-u p d)  
E arl y 
Ter  mi n ati o n  
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
11  
 
Wee k  
−1  
0  
1  
2  
4  
6  
8  
1 0  
1 2  
1 4  
1 5  
 
D a y  
≤ −7  
1 
8 
1 5  
2 9  
4 3  
5 7  
7 1  
8 5  
9 9  
D a y 7 
p ost -l ast-d ose  
 
Visit wi n d o w 
( d a ys) 
−7 t o −1 4  
－ 
6 t o 
1 0  
1 3 t o 
1 7  
2 6 t o 
3 2  
4 0 t o 
4 6  
5 4 t o 
6 0  
6 8 t o 
7 4  
8 2 t o 
8 8  
9 6 t o 1 0 2  
D a y 5 t o 1 4 
p ost -l ast-d ose  
 
Cli nical saf et y 
la b orat or y t ests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
H b A 1 c  
X  
 
 
 
 
X  
 
 
 
X  
 
X  
Fasti n g bl o o d 
gl u c os e  
X  c) 
 
 
 
 
X 
 
 
 
X 
 
X 
C -S S R S  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
H A D S  
 X  
X   
X   
X   
X   
X   
X  
X  
X  
X  
X  
X  
Pr e g n a nc y t est  
X  
 
 
 
 
 
 
 
 
X  
 
X  
A E r e p orti n g  
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d 
c o n c o mita nt 
m e dicati o n  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
I n v esti gati o nal 
pr o d u ct 
dis p e nsi n g  
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
S electi o n of   
I n v esti gati o nal 
pr o d u ct d os e 
ti mi n g 
 
X 
 
 
 
 
 
 
 
 
 
 
I n v esti gati o nal 
pr o d u ct 
c o m plia nc e  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
P K sa m pli n g 
 
 
 
X  
X  
 
X  
 
X  
 
X  
 
X  
MI NI  ( o nl y 
M o d ule A a n d B)  
X 
 
 
 
 
 
 
 
 
 
 
 
a: Aft er i nf or m e d c o ns e nt is o btai n e d, s u bj ects w h o ar e u n d er tr eat m e nt wit h t he pr o hi bit e d c o nc o mita nt m e dicati o ns (s ee 5. 2. 1) will u n d er g o a was h o ut p eri o d of 7 da ys or m or e.  
b: B o d y wei g ht o nl y.  
c: T h es e will b e p erf or m e d b et wee n Visit  1 a n d Visit  2.  
d: F oll o w -u p o bs er vati o n is n ot r e q uir e d f or s u bj ects w h o ar e e nr olle d i n o pe n -la b el e xt e nsi o n st u d y. 


Pr o t oc ol D S 5 5 6 5- A-J 3 0 3 
Ve r s i o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 0 0 of 1 0 1 
Ta bl e 1 7 - 2  Effi cac y Assess me nt b y Visit  
 
Scree ni n g  
R a n d o miz ati o n  
T re at me nt peri o d  
E n d of 
Tre at me nt  
P ost -tre at me nt 
f oll o w-u p  
E arl y 
Ter  mi n ati o n  
Visit  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
11  
 
Wee k  
−1  
0  
1  
2  
4  
6  
8  
1 0  
1 2  
1 4  
1 5  
 
D a y  
≤ −7  
1 
8 
1 5  
2 9  
4 3  
5 7  
7 1  
8 5  
9 9  
D a y 7 
p ost -l ast-d ose  
 
Visit wi n d o w 
( d a ys) 
−7 t o −1 4  
－ 
6 t o 
1 0  
1 3 t o 
1 7  
2 6 t o 
3 2  
4 0 t o 
4 6  
5 4 t o 
6 0  
6 8 t o 
7 4  
8 2 t o 
8 8  
9 6 t o 1 0 2  
D a y 5 t o 1 4 
p ost -l ast-d ose  
 
Pai n diari es  
 
 
 
 
 
 
 
 
 
 
 
 
Slee p i nt erf er e nc e 
diari es  
 
 
 
 
 
 
 
 
 
 
 
 
S F -M P Q  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
M o difi e d B PI -S F  
 
X  
 
 
 
 
 
 
 
X  
 
X  
P GI C  
 
 
 
 
 
 
 
 
 
X  
 
X  
M O S slee p scale  
 
X  
 
 
 
 
 
 
 
X  
 
X  
H A D S  
 
X  
 
 
 
 
 
 
 
X  
 
X  
S F -3 6  
 
X  
 
 
 
 
 
 
 
X  
 
X  
E val u ati o n of 
S y m pt o ms  
 
 
 
 
 
 
 
 
 
X 
 
X 
 


Pr o t oc ol D S 5 5 6 5- A-J 3 0 3 
Ve r s i o n 6. 0, 1 8 A pr  2 0 1 6 
Pa ge 1 0 1 of 1 0 1 
1 7. 2  Pr o cessi n g of Bl o o d S a m pl es f o r P h a r m a c o ki n eti c A n al ys es  
Bl o o d s a m pl es f or P K a n al ysis s h o ul d b e t a k e n b y v e ni p u n ct ure at ti m e p oi nts d etail e d i n 
Secti o n 6  a n d Ta bl e 1 7 - 1.   Bl o o d s h o ul d b e c oll ect e d i nt o V ac ut ai n er t u b es c o nt ai ni n g 
K 2 E D T A as a nti c o a g ul a nt f or t h e pr e p arati o n of pl as ma.  It is i m p ort a nt t o fill t h e 
Vac ut ai n er t u b es t o t h e s pecifi e d c oll ecti o n v ol u me.   T h e t u b e c o nt ai ni n g bl o o d f or 
pl as ma pr e p ar ati o n s h o ul d be ge ntl y i n v ert e d m ulti pl e ti mes (at l east 9) t o e ns ure 
t h or o u g h mi xi n g of a nti c oa g ul a nt a n d bl o o d, a n d t h e n i m m e di at el y pl ace d i n a c o ol b o x 
c o nt ai ni n g i ce- w at er.  T he s a m pl es s h o ul d b e ce n trif u ge d wit hi n 3 0 mi n utes aft er 
c oll ecti o n, at a p pr o xi m at el y 1 5 0 0 g a n d a p pr o xi m at el y + 4° C f or a p pr o xi m at el y 1 0 
mi n ut es.   I m m e di at el y f oll o wi n g ce ntrif u gati o n, t h e s e p arat e d pl as m a f or eac h s a m pl e 
s h o ul d b e di vi de d i nt o t w o ali q u ots of at l east 0. 5 m L.   T h e ali q u ots of pl as ma s h o ul d 
eac h b e pi p ett e d i nt o a p ol y pr o p yl e n e cr y o ge nic s a m pl e st ora ge vi al (at l east 2 – 3 m L i n 
siz e, wit h scr e w-ca p) wit h a p pr o pri at e i nf or m ati o n ( b arc o d e a n d/ or s u bject i d e ntifi cati o n 
c o d e, d at e, ti m e a n d ali q u ot n u m b er).    T h e ali q u o ts m ust b e k e pt c hill e d f or t h e e ntire 
ti m e u ntil t h e y ar e tr a nsf erre d t o t h e freezer. E ac h s et of ali q u ots s h o ul d b e st ore d i n 
se p ar at e b o x es. Wit hi n 6 0 mi n ut es aft er bl o o d dra w, t h e s a m pl e st ora ge vi als s h o ul d b e 
st or e d i n t h e d ar k i n a -2 0° C ( - 1 5° C t o -3 0° C) freez er. A n y s a m pl e a n o m alies s h o ul d b e 
r ec or de d o n t h e s a m pli n g f or ms. 
 
T h e s a m pl es at t he st u d y sit es will b e c oll ect e d b y t h e ce ntral l a b orat or y i n eac h c o u ntr y. 
 
D et aile d s hi p pi n g i nstr u cti o ns a n d a d dress es will be pr o vi d e d wit h t h e sit e l a b orat o r y 
ma n u al.