A Randomized, Double-blind, Placebo-controlled Safety Study of DS-5565 for Treatment of Pain Due to Fibromyalgia in Subjects With Chronic Kidney Disease
Phase: PHASE3
Conditions: Fibromyalgia
Sponsor: Daiichi Sankyo

Pr o prietar y  a n d C o nfi de ntial
Pa ge 1
C LI NI C A L S T U D Y P R O T O C O L
A 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 S A F E T Y S T U D Y O F D S - 5 5 6 5 F O R 
T R E A T M E N T O F P AI N D U E T O FI B R O M Y A L GI A 
I N S U B J E C T S WI T H C H RO NI C KI D N E Y DI S E A S E
D S 5 5 6 5 - A-U 3 0 7
I N D 1 1 8, 3 0 4
E U D R A C T 2 0 1 4 - 0 0 3 9 7 2- 2 1
V E R SI O N 3 . 0 1 4 M A R
2 0 1 7
V E R SI O N 2. 0 0 7 A P R 2 0 1 6
V E R SI O N 1. 0 3 0 M A R 2 0 1 5
S P O N S O R:  
Daiic hi Sa n k y o P har ma De vel o p me nt
3 9 9 T h or nall Street 
E dis o n, NJ 0 8 8 3 7 U nite d States
Daiic hi Sa n k y o De vel o p me nt L i mite d 
C hilter n Place, C half o nt Par k 
Gerrar ds Cr oss, B uc ki n g ha ms hire 
S L 9 0 B G U nite d Ki n g d o m
C O N FI D E N TI A LI T Y S T A T E M E N T
I nf or mati o n c o ntai ne d i n t his d oc u me nt is pr o prietar y t o Daiic hi Sa n ky o.  T he 
i nf or mati o n is pr o vi de d t o y o u i n c o nfi de nce w hic h is re q ueste d u n der a n a gree d u p o n 
a n d si g ne d C o nfi de ntialit y a n d Discl os ure A gree me nt.  D o n ot gi ve t his d oc u me nt or a n y 
c o p y of it or re veal a n y pr o prietar y i nf or mati o n c o ntai ne d i n it t o a n y t hir d part y ( ot her 
t ha n t h ose i n yo ur o r ga nizati o n w h o are assisti n g yo u i n t his w or k a n d are b o u n d b y  t he 
C o nfi de ntialit y  a n d Discl os ure A gree me nt) wit h o ut t he pri or writte n per missi o n of a n 
a ut h orize d re prese ntati ve of Daiic hi Sa n k y o.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

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

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3
P R O T O C O L S Y N O P SI S
E u dra C T/I N D N u m ber:  
E u dra C T 2 0 1 4 - 0 0 3 9 7 2-2 1/ I ND 1 1 8 ,3 0 4
Pr ot oc ol N u m ber:
D S 5 5 6 5 - A-U 3 0 7
I n vesti gati o nal Pr o d uct:  
D S - 5 5 6 5
Acti ve I n gre die nt(s)/ IN N :  
[( 1 R, 5 S, 6 S)- 6-( A mi n o met h yl)- 3-et h yl bic y cl o[ 3. 2. 0] he pt - 3-
e n- 6-yl ]acetic aci d m o n o be nze nes ulf o nate/ mir o ga bali n
St u d y  Title:
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d Safet y  
St u d y  of D S-5 5 6 5 f or Treat me nt o f Pai n D ue t o 
Fi br o m yal gia i n S u bjects wit h C hr o nic Ki d ne y  Disease
St u d y  P hase:
P hase 3
I n dicati o n U n der 
I n vesti gati o n:
F i br o myal gia ( F M)
St u d y  O bjecti ves:  
T he pri mar y  o bjecti ve is:

T o deter mi ne t he safet y a n d t olera bilit y of 
s u bjects wit h F M a n d m o derate t o se vere re nal 
d y sf u ncti o n d uri n g 1 3 wee ks of re nally a dj uste d 
d o si n g of D S - 5 5 6 5 c o m pare d t o place b o.
T he sec o n dar y  o bjecti ves are:

T o c o m pare c ha n ge i n wee kl y a vera ge pai n as 
assesse d b y a vera ge dail y pai n sc ore ( A DP S) 
fr o m baseli ne meas ure d at ra n d o mizati o n t o 
Wee k 1 3 i n s u bjects recei vi n g eit her d ose of 
D S - 5 5 6 5 vers us place b o . Wee kl y  A D P S is 
base d o n dail y pai n sc ores re p orte d b y t h e 
s u bject t hat best descri bes t he w orst pai n o ver 
t he pre vi o us 2 4 h o urs 

T o assess t he effects of D S -5 5 6 5 o n patie nt 
gl o bal i m pressi o n of c ha n ge ( P GI C) at Wee k 
1 3/ E T .
St u d y  Desi g n:
T his is a stratifie d, ra n d o mize d, d o u ble-bli n d, place b o -
c o ntr olle d, m ulti -ce nter safety st u d y of D S-5 5 6 5 i n s u bjects 
wit h F M a n d re nal d ysf u ncti o n. Eli gi ble s u bjects will be 
ra n d o mize d 2: 1 t o recei ve eit her D S -5 5 6 5 7. 5 m g o nce 
dail y  ( Q D) or place b o f or t he cate g or y of s u bjects wit h 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4
creati ni ne cleara nce ( Cr Cl) 1 5 - 2 9 m L / mi n, or 2: 1 t o recei ve 
treat me nt wit h D S-5 5 6 5 7. 5 m g t wice dail y  ( BI D) or 
place b o f or t he cate g or y of s u bjects wit h Cr Cl 3 0- 5 9 
m L / mi n. S u bject s will be stratifie d f or re nal i m pair me nt b y  
Cr Cl . T he treat me nt peri o d is 1 3 wee ks i n d urati o n.
St u d y  D uratio n:
T he t otal st u d y  d urati o n (i n di vi d ual s u bject) will be 
a p pr o xi matel y 2 1 wee ks. T he st u d y  i ncl u des a scree ni n g 
peri o d ( a p pr o xi matel y 3 wee ks b ut n o l o n ger t ha n 3 5 da y s,
i ncl u di n g a was h o ut peri o d [if necessar y ] a n d a 1- wee k 
baseli ne peri o d ), d o u ble -bli n d treat me nt peri o d ( 13 wee ks) , 
a n d a 4 wee k f oll o w-u p peri o d .
St u d y  Sites a n d L ocati o n:  
A p pr o xi matel y  1 0 0 sites i n t he U S ( U nite d States), E ur o pe, 
a n d ot her c o u ntries will partici pate i n t he st u d y.
Pla n ne d Sa m ple Size:  
A p pr o xi matel y  6 0 s u bjects will be ra n d o mize d.  Ass u mi n g 
a 2 5 % dr o p o ut rate, a p pr o xi matel y 4 5 s u bjects will 
c o m plete t he d o u ble-bli n d treat me nt peri o d.  T his sa m ple 
size is t h o u g ht t o be s ufficie nt t o a d dress t he o bjecti ves of 
t his cli nical trial.
S u bject Eli gi bilit y  Criteria:
Incl usi o n C riteria:
1.
A ge ≥1 8 y ears
2.
A ble t o gi ve writte n i nf or me d c o nse nt
3.
A ble t o c o m plete patie nt -re p orte d q uesti o n naires 
per t he I n vesti gat or's j u d g me nt
4.
Esti mate d Cr Cl bet wee n 1 5 - 5 9 m L / mi n fr o m ser u m 
creati ni ne b y t he ce ntral la b orat or y usi n g t he 
C oc kcr oft -Ga ult e q uati o n
5.
Fi br o m yal gia meeti n g A merica n C olle ge of 
R he u mat ol o g y  criteria f or F M: 
a.
Wi des prea d pai n i n de x ( W PI) ≥7 a n d s y m pt o m 
se verity ( S S) scale sc ore ≥5, or W PI  3 t o 6 a n d 
S S scale sc ore ≥ 9,
b.
Pai n i n at least 1 1 of 1 8 s pecific te n der p oi nt 
sites,
c.
S y m pt o ms ha ve bee n prese nt at a si milar le vel 
f or at least 3 m o nt hs, a n d
d.
T he s u bject d oes n ot ha ve a dis or der t hat w o ul d 
ot her wise e x plai n t he pai n
6.
A D P S of ≥4 o n t he 1 1 -p oi nt n u meric rati n g scale 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5
( N R S) o ver t he 7 da ys pri or t o ra n d o mizati o n 
( base d o n c o m pleti o n of at least 4 dail y pai n 
assess me nts d uri n g t he 7 -da y  baseli ne peri o d pri or 
t o ra n d o mizati o n)
7.
W o me n of c hil d beari n g p ote ntial ( W O C B P) m ust 
be usi n g a de q uate met h o d s of c o ntrace pti o n (as 
detaile d i n Secti o n 4. 1. 3) t o a v oi d pre g na nc y d uri n g 
t he st u d y a n d f or 4 wee ks after st u d y c o m pleti o n.
E xcl usi o n C riteria:
1.
Nee d f or o n g oi n g use of c o nc o mita nt c hr o nic pai n 
me dicati o ns or a n y ne w n o n -p har mac ol o gical pai n 
ma na ge me nt tec h ni q ues t hat ma y  c o nf o u n d 
assess me nts of efficac y a n d/ or safety , i ncl u di n g 
ne ur ol y tic treat me nts ( destr ucti o n of ner ves b y 
c he micals, heat, c ol d) or s ur ger y , i ntrat hecal p u m ps, 
s pi nal c or d sti m ulat ors or ps yc h ol o gical s u p p ort 
wit hi n t he pre vi o us year. Als o e xcl u de d: t o pical 
ca psaici n wit hi n 6 m o nt hs; or s yste mic 
c ortic oster oi ds wit hi n 3 m o nt hs of baseli ne peri o d.  
2.
U na ble t o u n der g o pre -st u d y was h o ut of pr o hi bite d 
c o nc o mita nt me dicati o ns 
3.
S u bject s wit h rece nt hist or y (i.e., wit hi n 1 year pri or 
t o scree ni n g) of alc o h ol a b use or illicit dr u g use 
(c ocai ne, her oi n, marij ua na [i ncl u di n g me dical, 
prescri be d], etc.)
4.
Use of a n y s electi ve ser ot o ni n re u pta ke i n hi bit or 
( S S RI), u nless t he s u bject has bee n o n a sta ble d ose 
f or ≥ 9 0 da y s pri or t o scree ni n g a n d is n ot 
a ntici pate d t o nee d a n y d ose a dj ust me nt d uri n g t he 
c o urse of t he st u d y
5.
S u bjects wit h se vere or u nc o ntr olle d de pressi o n 
t hat, i n t he j u d g me nt of t he I n vesti gat or, ma kes t he 
s u bject i na p pr o priate f or e ntr y i nt o t he st u d y
6.
Si g nifica nt ne ur ol o gical or ps y c hiatric dis or der 
u nrelate d t o ne ur o pat hic pai n
7.
Ot her se vere pai n (e g, sciatica , r he u mat oi d art hritis) 
t hat mi g ht i m pair t he assess me nt of ne ur o pat hic 
pai n
8.
Cr Cl ≥6 0 m L/ mi n esti mate d fr o m ser u m creati ni ne
b y  t he ce ntral la b orat or y usi n g t he C oc kcr oft-Ga ult 
e q uati o n.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6
9.
S u bjects w h o are o n he m o dial y sis or w h o re q uire 
he m o dial y sis bef ore t he f oll o w-u p assess me nt; 
ac ute re nal fail ure; hist or y of ki d ne y  tra ns pla nt
1 0. A n y  hist or y of a mali g na nc y ot her t ha n basal cell 
carci n o ma wit hi n t he past 5 years
1 1. Cli nicall y  si g nifica nt u nsta ble ne ur ol o gic, 
o p ht hal m ol o gic, he pat o biliar y , res pirat or y, or 
he mat ol o gic ill ness or u nsta ble car di o vasc ular 
disease (e g, se vere h y p ote nsi o n, u nc o ntr olle d 
car diac arr h yt h mia, or m y ocar dial i nfarcti o n) wit hi n 
1 2 m o nt hs pri or t o scree ni n g 
1 2. Pre g na nc y  or breast fee di n g or i nte nt t o bec o me 
pre g na nt d uri n g t he st u d y  peri o d 
1 3. K n o w n h y perse nsiti vit y  t o α 2δ li ga n ds or ot her 
c o m p o ne nts of t he st u d y me dicati o ns. N ote: Pri or 
e x p os ure t o D S-5 5 6 5 is all o we d, as l o n g as 
h y perse nsiti vit y  t o D S-5 5 6 5 was n ot o bser ve d.
1 4. Cli nicall y  si g nifica nt E C G a b n or malities at t he 
Scree ni n g Visit
1 5. S u bjects w h o are at ris k of s uici de, as defi ne d b y
t heir res p o nses t o t he C-S S R S or i n t he o pi ni o n of 
t he In vesti gat or.  N ote: S u bjects a ns weri n g " yes" t o 
a n y of t he C- S S R S q uesti o ns m ust be e xcl u de d .
S uc h s u bjects s h o ul d be referre d i m me diately t o a 
me ntal healt h pr ofessi o nal f or a p pr o priate 
e val uati o n. 
1 6. S u bjects wit h c urre nt se vere or u nc o ntr olle d maj or 
de pressi ve dis or der or a n xiet y  dis or ders as assesse d 
b y  t he Mi ni-i nter nati o nal Ne ur o psyc hiatric 
I nter vie w ( MI NI) i nter vie w ( Versi o n 6. 0) at 
scree ni n g, or w h o a ns wer “ y es” t o t he s uici dality 
q uesti o n (c urre nt or past) o n t he Maj or De pressi ve 
E pis o de M o d ule ( M o d ule A) or w h o a ns wer “ y es”
t o a n y q uesti o n i n t he S uici dalit y M o d ule ( M o d ule 
B) are e xcl u de d. S u bjects wit h m il d t o m o derate
maj or de pressi o n or a n xiet y  dis or ders are per mitte d 
t o e nr oll pr o vi de d t hat t he i n vesti gat or assesses t he 
s u bject as cli nicall y sta ble a n d a p pr o priate f or e ntr y 
i nt o t he st u d y.
1 7. S u bjects w h o are u nli kel y t o c o m pl y wit h t he 
pr ot oc ol (e g, u nc o o perati ve attit u de, i na bilit y  t o 
ret ur n f or s u bse q ue nt visits, a n d/ or ot her wise 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7
c o nsidere d b y t he I n vesti gat or t o be u nli kel y t o 
c o m plete t he st u d y)
1 8. S u bject is c urre ntl y e nr olle d i n , or it has bee n fe wer 
t ha n 3 0 da ys si nce e n di n g, a n ot her i n vesti gati o nal 
de vice or dr u g st u d y  or is recei vi n g a n ot her 
i n vesti gati o nal a ge nt. 
1 9. S u bjects w h o are e m pl o yees or i m me diate fa mil y of 
e m pl o yees of t he st u d y site, S p o ns or, or c o ntract 
researc h or ga nizati o n ( C R O) 
2 0. Scree ni n g la b orat or y  val ues o utsi de t he li mits liste d 
i n t he ta ble bel o w:
He mat ol o g y
He m o gl o bi n  
< 8 g/ d L 
Platelet c o u nt 
< 1 0 0, 0 0 0 /m m 3
A bs ol ute 
ne utr o p hil 
c o u nt
< 1, 5 0 0/ m m 3
Bl o o d 
c he mistr y
A S T   
> 2. 0 × U L N
A L T  
> 2. 0 × U L N
Al kali ne 
p h os p hatase
> 1. 5 × U L N
T otal bilir u bi n
> 1. 2 × U L N a
Creati ne 
ki nase
> 3. 0 × U L N
Calc ulate d 
Cr Cl
≥6 0 m L/ mi n
a If a s u bject has t otal bilir u bi n > U L N: u nc o nj u gate d a n d c o nj u gate d 
bilir u bi n fracti o ns s h o ul d be a nal yze d a n d o nl y s u bjects d oc u me nte d t o 
ha ve Gil bert’s s y n dr o me ma y be e nr olle d.
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase, A S T = as partate 
a mi n otra nsferase, Cr Cl = creati ni ne cleara nce ( deter mi ne d b y t he 
ce ntral la b orat or y usi n g t he C oc kcr oft -Ga ult e q uati o n), U L N = u p per 
li mit of n or mal
D osa ge F or m, D ose a n d 
R o ute of A d mi nistrati o n:
S t u d y me dicati o ns will be pr o vi de d i n blister car ds 
(“ wallets”).
D S - 5 5 6 5 will be s u p plie d i n t he f or m of 7. 5 m g ta blets f or 
or al a d mi nistrati o n.  D oses of D S -5 5 6 5 i ncl u de 7. 5 m g Q D 
a n d 7.5 m g BI D.  M atc hi n g place b o ta blets are als o use d .
St u d y  E n d p oi nts:
T he pri mar y  safety o bjecti ve is t he safety a n d t olera bilit y of 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8
re nally a dj uste d d oses of D S - 5 5 6 5 vers us place b o.
S pecific safet y e n d p oi nts assesse d i ncl u de:

All t reat me nt-e mer ge nt a d verse e ve nts ( T E A Es)

C ha n ge i n c li nical la b orat or y e val uati o ns fr o m 
baseli ne meas ure d at ra n d o mizati o n t o Wee k 
1 3 / E T f or D S-5 5 6 5 vers us place b o

C ha n ge i n n e ur ol o gical e xa mi nati o ns fr o m 
baseli ne t o Wee k 1 3/ E T
f or D S -5 5 6 5 vers us 
place b o

C ha n ge i n e lectr ocar di o gra ms fr om baseli ne t o 
Wee k 1 3/ E T
f or D S -5 5 6 5 vers us place b o

C ha n ge i n C ol u m bia -S uici de Se verit y Rati n g 
Scale ( C -S S R S) fr o m baseli ne t o Wee k 1 3/ E T
f or D S -5 5 6 5 vers us place b o

Assess me nt of P h y sicia n Wit h dra wal C hec klist 
( P W C).
T he sec o n dar y  efficac y e n d p oi nts i ncl u de: 

C ha n ges i n A D P S fr o m baseli ne meas ure d at 
ra n d o mizati o n t o Wee k 1 3/ E T
f or D S- 5 5 6 5 
vers us place b o . Wee kl y  A D P S is base d o n dail y 
pai n sc ores re p orte d b y t he s u bject t hat best 
descri bes t he w orst pai n o ver t he pre vi o us 2 4 
h o urs.

Pr o p orti o n of s u bjects wit h i m pr o ve me nt i n 
o verall stat us at Wee k 1 3/ E T
as assesse d b y 
P GI C f or D S -5 5 6 5 vers us place b o .
Statistical A nal y ses:  
Pri m ary E n d p oi nt
T he pri mar y  o bjecti ve is t he safety a n d t olera bilit y of D S -
5 5 6 5. Safet y data will be s u m marize d b y treat me nt gr o u p . 
Q ua ntitati ve data will be ta b ulate d wit h descri pti ve 
s u m mar y statistics: arit h metic mea n, sta n dar d de viati o n 
( S D), me dia n, mi ni m u m a n d ma xi m u m val ues, a n d n u m ber 
of o bser vati o ns.  F or cate g orical data, fre q ue nc y  ta bles will 
be pr o vi de d.
Sec o n d ary E n d p oi nt
T he sec o n dar y  efficac y e n d p oi nts will be s u m marize d b y 
treat me nt a n d n u mericall y c o m pare d bet wee n treat me nt 
gr o u ps .
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 9
T A B L E O F C O N T E N T S
I NV E S TI G A T O R A G R E E M E N T ...................................................................................................2
P R O T O C O L  S Y N O P SI S ................................................................................................................ 3
T A B L E O F C O N T E N T S ................................................................................................................. 9
LI S T O F T A B L E S ......................................................................................................................... 1 4
LI S T O F FI G U R E S ....................................................................................................................... 1 5
LI S T O F A B B R E VI A TI O N S ........................................................................................................ 1 6
1.  
I NT R O D U C TI O N A N D B A C K G R O U N D I N F O R M A TI O N .................................. 1 9
1. 1.  
I n vesti gati o nal Pr o d uct(s)........................................................................................... 1 9
1. 1. 1.  
Na me ........................................................................................................................... 1 9
1. 1. 2.  
Descri pti o n .................................................................................................................. 1 9
1. 1. 3.  
I nte n ded Use U n der I n vesti gati o n .............................................................................. 1 9
1. 1. 4.  
N o ncli nical St u dies..................................................................................................... 1 9
1. 1. 5.  
Cli nical E x perie nce..................................................................................................... 1 9
1. 2.  
S t u d y Rati o nale........................................................................................................... 2 1
1. 3.  
Ris ks a n d Be nefits f or St u d y  S u bjects........................................................................ 2 2
1. 4.  
P o p ulati o n, R o ute, D osa ge, D osa ge Re gi me n, Treat me nt Peri o d.............................. 2 2
1. 5.  
C o m plia nce State me nt, Et hics, a n d Re g ulat or y  C o m plia nce..................................... 2 3
1. 5. 1.  
S u bject C o nfi de ntialit y ...............................................................................................2 3
1. 5. 2.  
I nf or me d C o nse nt Pr oce d ure ...................................................................................... 2 4
1. 5. 3.  
Re g ulat or y  C o m plia nce..............................................................................................2 4
2.  
S T U D Y O BJ E C TI V E S A N D H Y P O T H E S E S .......................................................... 2 6
2. 1.  
St u d y  O bjecti ves......................................................................................................... 2 6
2. 1. 1.  
Pri mar y  O bjecti ve.......................................................................................................2 6
2. 1. 2.   
S ec o n dar y O bjecti ves .................................................................................................2 6
2. 2.  
St u d y  H yp ot hesis ........................................................................................................2 6
3.  
S T U D Y D E SI G N .......................................................................................................2 7
3. 1.  
O verall Pla n................................................................................................................ 2 7
3. 1. 1.  
St u d y  T ype ..................................................................................................................2 7
3. 1. 2.  
Treat me nt Gr o u ps .......................................................................................................2 8
3. 1. 3.   
S t u d y E n d p oi nts..........................................................................................................2 8
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 0
3. 1. 4.  
D urati o n of t he St u d y .................................................................................................. 2 8
3. 1. 4. 1.  
D urati o n of S u bject Partici pati o n............................................................................... 2 8
3. 1. 5.  
St o p pi n g R ules............................................................................................................ 2 9
3. 1. 5. 1.  
St o p pi n g R ules f or I n di vi d ual S u bjects ...................................................................... 2 9
3. 1. 5. 2.  
S uici dal Be ha vi or a n d I deati o n ................................................................................... 2 9
3. 1. 5. 3.  
Decrease d Cr Cl Bel o w Mi ni m u m .............................................................................. 3 0
3. 1. 5. 4.  
St o p pi n g R ules f or t he St u d y ...................................................................................... 3 1
3. 2.  
Selecti o n of D oses ...................................................................................................... 3 1
3. 2. 1.  
E x peri me ntal Treat me nts f or t he St u d y ...................................................................... 3 1
3. 2. 1. 1.  
E x peri me ntal Treat me nt f or I n di vi d ual S u bjects........................................................ 3 3
3. 2. 2.  
C o ntr ol Treat me nts ..................................................................................................... 3 3
4.  
S T U D Y P O P U L A T I O N............................................................................................. 3 4
4. 1.  
E nr oll me nt .................................................................................................................. 3 4
4. 1. 1.  
I ncl usi o n Criteria ........................................................................................................ 3 4
4. 1. 2.  
E xcl usi o n Criteria ....................................................................................................... 3 5
4. 1. 3.  
W o me n of C hil d Beari n g P ote ntial ............................................................................. 3 7
4. 2.  
Re m o val of S u bjects Fr o m T hera p y ........................................................................... 3 7
4. 2. 1.  
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n ......................................................... 3 7
4. 2. 2.  
Wit h dra wal Pr oce d ures ...............................................................................................3 8
4. 2. 3.  
S u bject Re place me nt .................................................................................................. 3 9
4. 2. 4.  
S u bject Re -scree ni n g Pr oce d ures ............................................................................... 3 9
5.  
T R E A T M E N T S A D MI NI S T E R E D ........................................................................... 4 0
5. 1.  
I n vesti gati o nal Pr o d ucts..............................................................................................4 0
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Treat me nts a n d Bli n di n g................................ .......4 0
5. 1. 1. 1.  
E mer ge nc y  U n bli n di n g f or Safety Reas o ns ................................................................4 0
5. 1. 2.    
Met h o d of Assessi n g Treat me nt C o m plia nce................................ .............................4 1
5. 1. 3.  
La beli n g a n d Pac ka gi n g ..............................................................................................4 2
5. 1. 4.  
Pre parati o n ..................................................................................................................4 2
5. 1. 5.  
St ora ge ........................................................................................................................4 2
5. 1. 6.  
Dr u g Acc o u nta bilit y ...................................................................................................4 2
5. 2.   
C o nc o mita nt Me dicati o ns................................ ...........................................................4 3
5. 2. 1.   
Pr o hi bite d Me dicati o ns................................ ...............................................................4 3
5. 2. 2.  
All o wa ble Me dicati o ns ...............................................................................................4 4
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 1
6.   
S T U D Y P R O C E D U R E S............................................................................................ 4 5
6. 1.  
Scree ni n g .................................................................................................................... 4 5
6. 1. 1.  
Scree ni n g Visit ( Visit 1; Wee k ≤ -4, Pri or t o Ra n d o mizati o n) ................................... 4 5
6. 1. 2.  
Was h o ut Tele p h o ne C o ntact ( Visit 2, Wee k -3 t o -1)................................................ 4 6
6. 2.  
Baseli ne Visit ( Visit 3, Wee k - 1)................................................................................ 4 7
6. 3.  
Ra n d o mizati o n Visit ( Visit 4, Wee k 0) ...................................................................... 4 7
6. 4.  
Treat me nt Peri o d ........................................................................................................ 4 8
6. 4. 1.  
O n -treat me nt Visits ( Visit 5, Wee k 1; Visits 6-1 0, Wee ks 3, 5, 7, 9, 
& 1 1) ........................................................................................................................... 4 8
6. 4. 2.  
E n d - of-Treat me nt Visit ( Visit 1 1, Wee k 1 3) or Earl y  Ter mi nati o n........................... 4 9
6. 5.  
P ost -treat me nt F oll o w-u p ........................................................................................... 4 9
6. 5. 1.  
Tele p h o ne C o ntact Da y  3 of F oll o w-u p ( Visit 1 2, Wee k 1 3. 5) .................................. 4 9
6. 5. 2.  
Visit at Wee k 2 of F oll o w -u p ( Visit 1 3, Wee k 1 5) ..................................................... 5 0
6. 5. 3.  
Tele p h o ne c o ntact at Wee k 4 of F oll o w -u p ( Visit 1 4, Wee k 1 7) ............................... 5 0
6. 6.  
Pr ot oc ol De viati o ns .................................................................................................... 5 0
7.  
E F FI C A C Y A S S E S S M E N T S .................................................................................... 5 2
7. 1.  
Pri mar y  Efficac y Assess me nts ................................................................................... 5 2
7. 2.  
Sec o n dar y  Efficac y Assess me nts ............................................................................... 5 2
7. 2. 1.  
A vera ge Dail y Pai n Sc ore ........................................................................................... 5 2
7. 2. 2.  
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) ............................................................ 5 2
7. 3.  
E x pl orat or y  Efficac y Varia ble(s)................................................................................ 5 2
8.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T S ...................... 5 3
8. 1.  
P har mac o ki netic Varia ble(s) ...................................................................................... 5 3
8. 2.  
P har mac o d y na mic ( P D) Varia ble(s) ........................................................................... 5 3
8. 3.  
Bi o mar ker a n d E x pl orat or y  Varia ble(s) ..................................................................... 5 3
9.  
S A F E T Y A S S E S S M E N T S ................................ ........................................................5 4
9. 1.  
A d verse E ve nts ...........................................................................................................5 4
9. 2.   
S afet y Assess me nts..................................................................................................... 5 4
9. 3.  
E ve nts of S pecial I nterest................................ ...........................................................5 5
9. 3. 1.  
S uici dal Be ha vi or a n d I deati o n ................................................................................... 5 5
9. 3. 2.  
Li ver E nz y me Ele vati o ns/ L i ver D ysf u ncti o n ............................................................. 5 6
9. 4.  
Defi niti o ns................................ ..................................................................................5 7
9. 4. 1.  
A d verse E ve nt ( A E) ....................................................................................................5 7
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 2
9. 4. 2.  
Seri o us A d verse E ve nt ( S A E) .................................................................................... 5 7
9. 4. 3.  
A E Se verit y ................................................................................................................. 5 8
9. 4. 4.  
Ca usalit y  Assess me nt ................................................................................................. 5 8
9. 4. 5.  
Acti o n Ta ke n Re gar di n g t he St u d y  Pr o d uct...............................................................5 9
9. 4. 6.  
A d verse E ve nt O utc o me ............................................................................................. 5 9
9. 4. 7.  
Ot her Acti o n Ta ke n f or E ve nt .................................................................................... 5 9
9. 5.  
Seri o us A d verse E ve nt Re p orti n g Pr oce d ure F or I n vesti gat ors ................................. 5 9
9. 5. 1.  
N otif y i n g Re g ulat or y A ut h orities, In vesti gat ors, a n d I R B/ E C ................................... 6 0
9. 6.  
E x p os ure I n Uter o D uri n g Cli nical St u dies ................................................................6 0
9. 7.  
Cli nical L a b orat or y E val uati o ns................................................................................. 6 1
9. 7. 1.  
He mat ol o g y ................................................................................................................. 6 1
9. 7. 2.  
Bl o o d C he mistr y ......................................................................................................... 6 1
9. 7. 2. 1.  
Esti mati o n of Creati ni ne Cleara nce ............................................................................ 6 2
9. 7. 3.  
Uri nal y sis .................................................................................................................... 6 2
9. 7. 4.  
Pre g na n c y Testi n g ...................................................................................................... 6 2
9. 8.  
Vital Si g ns .................................................................................................................. 6 3
9. 9.  
Electr ocar di o gra ms ..................................................................................................... 6 3
9. 1 0.  
P h y sical Fi n di n gs ........................................................................................................ 6 3
9. 1 0. 1.  
B o d y Hei g ht a n d Wei g ht ............................................................................................ 6 3
9. 1 0. 2.  
P h y sical E xa mi nati o ns ................................................................................................ 6 3
9. 1 0. 3.  
Ne ur ol o gical E xa mi nati o ns ........................................................................................ 6 4
9. 1 1.  
Ot her Safet y Assess me nts ........................................................................................... 6 4
9. 1 1. 1.  
C ol u m bia S uici de Se verit y  Rati n g Scale.................................................................... 6 4
9. 1 1. 2.  
P h y sicia n Wit h dra wal C hec klist ................................................................................. 6 4
1 0.  
O T H E R A S S E S S M E N T S .......................................................................................... 6 6
1 1.  
S T A TI S TI C A L M E T H O D S .......................................................................................6 7
1 1. 1.  
A nal y sis Sets...............................................................................................................6 7
1 1. 2.  
Ge neral Statistical C o nsi derati o ns .............................................................................. 6 7
1 1. 3.  
St u d y  P o p ulati o n Data................................................................................................6 7
1 1. 4 .  
Efficac y  A nalys es .......................................................................................................6 8
1 1. 4. 1.  
Pri mar y  Efficac y A nalys es .........................................................................................6 8
1 1. 4. 2.  
Sec o n dar y  Efficac y A nal yses .....................................................................................6 8
1 1. 4. 3.  
E x pl orat or y  Efficac y A nal yses ...................................................................................6 8
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 3
1 1. 5.  
P har mac o ki netic A nal y ses .......................................................................................... 6 8
1 1. 6.  
Safet y  A nalys es .......................................................................................................... 6 8
1 1. 6. 1.  
A d verse E ve nt A nal ys es ............................................................................................. 6 9
1 1. 6. 2.  
Cli nical L a b orat or y A nal yses .....................................................................................6 9
1 1. 6. 3.  
Vital Si g n A nal ys es .................................................................................................... 6 9
1 1. 6. 4.  
Electr ocar di o gra m A nal yses ....................................................................................... 6 9
1 1. 6. 5.  
P h y sical E xa mi nati o n A nal yses.................................................................................. 6 9
1 1. 6. 6.  
Ne ur ol o gical E xa mi nati o ns ........................................................................................ 6 9
1 1. 6. 7.  
C ol u m bia -S uici de Se verit y  Rati n g Scale.................................................................... 6 9
1 1. 6. 8.  
P h y sicia n Wit h dra wal C hec klist ................................................................................. 7 0
1 1. 7.  
Ot her A nal ys es ............................................................................................................ 7 0
1 1. 8.  
I nteri m A nalys es ......................................................................................................... 7 0
1 1. 9.  
Data Safet y M o nit ori n g B oar d .................................................................................... 7 0
1 1. 1 0.  
He patic A dj u dicati o n C o m mittee ............................................................................... 7 1
1 1. 1 1.  
Sa m ple Size Deter mi nati o n ........................................................................................ 7 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 .............................................. 7 2
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns ........................................................................................ 7 2
1 2. 2.  
Data C ollecti o n ........................................................................................................... 7 2
1 2. 3.  
Data Ma na ge me nt ....................................................................................................... 7 3
1 2. 4.  
St u d y  D oc u me ntati o n a n d St ora ge ............................................................................. 7 3
1 2. 5.  
Rec or d Kee pi n g .......................................................................................................... 7 4
1 3.  
FI N A N CI N G A N D I N S U R A N C E ............................................................................. 7 5
1 3. 1.  
Fi na nces ...................................................................................................................... 7 5
1 3. 2.  
Rei m b urse me nt, I n de m nit y , a n d I ns ura nce................................................................7 5
1 4.  
P U B LI C A TI O N P O LI C Y .......................................................................................... 7 6
1 5.  
S T U D Y A D MI NI S T R A TI V E I NF O R M A TI O N ....................................................... 7 7
1 5. 1.  
Pr ot oc ol A me n d me nts ................................................................................................7 7
1 5. 2.  
A d dress List ................................................................................................................ 7 7
1 6.  
R E F E R E N C E S ...........................................................................................................7 8
1 7.  
S C H E D U L E O F E V E N T S .........................................................................................7 9
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 4
LI S T O F T A B L E S
Ta ble 3. 1:
Re nal a n d T otal Cleara nce of D S -5 5 6 5 a n d its Lacta m Meta b olite 
wit h Decreasi n g Re nal F u ncti o n ................................................................................. 3 2
Ta ble 3. 2:
Pre dicte d D S -5 5 6 5 A U C wit h Dail y  a n d T wice Dail y D oses of 
7. 5- 1 5 m g i n Re nal D y sf u ncti o n.................................................................................3 3
Ta ble 5. 1:
Pr o hi bite d Me dicati o ns a n d Treat me nts - D uri n g Baseli ne a n d 
Treat me nt Peri o ds ....................................................................................................... 4 4
Ta ble 9. 1:
He mat ol o g y  A nalyt es ................................................................................................. 6 1
Ta ble 9. 2:
Bl o o d C he mistr y  A nal yt es ..........................................................................................6 2
Ta ble 9. 3:
Uri nal y sis Deter mi nati o ns .......................................................................................... 6 2
Ta ble 1 7. 1: Sc he d ule of E ve nts ..................................................................................................... 8 0
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 5
LI S T O F FI G U R E S
Fi g ure 3. 1: Desi g n of P hase 3 St u d y  of D S- 5 5 6 5 i n S u bjects wit h F M........................................ 2 7
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 6
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
α 2δ
Al p ha- 2 Delta 
A D P S
A vera ge Dail y Pai n Sc ore 
A E
A d verse E ve nt
A E SI
A d verse E ve nt of S pecial I nterest 
A L P
Al kali ne P h os p hatase
A L T
Ala ni ne A mi n otra nsferase 
A S T
As partate A mi n otra nsferase
A U C
Area U n der t he C o nce ntrati o n -Ti m e C ur ve 
BI D
T wice Dail y 
C F R
C o de of Fe deral Re g ulati o ns
C K D
C hr o nic Ki d ne y Disease
C L/ F
T otal Cleara nce
C Lr/ F
Re nal Cleara nce
C ma x
Ma xi m u m Plas ma C o nce ntrati o n
C N S
Ce ntral Ner v o us S yste m
Cr Cl
Creati ni ne Cleara nce
C R F
Case Re p ort F or m
C R O
C o ntract Researc h Or ga nizati o n
C S P V
Cli nical Safet y a n d P har mac o vi gila nce
C- S S R S
C ol u m bia -S uici de Se verit y Rati n g Scale
D P N P
Dia betic Peri p heral Ne ur o pat hic Pai n
D S M B
Data a n d Safet y M o nit ori n g B oar d
E C
Et hics C o m mittee
E C G
Electr ocar di o gra m
e C R F
Electr o nic Case Re p ort F or m
E D C
Electr o nic Data Ca pt ure
E S R D
E n d Sta ge Re nal Disease
EI U
E x p os ure I n Uter o
E T
Earl y Ter mi nati o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 7
A B B R E VI A TI O N  
D E FI NI TI O N
F M
Fi br o m yal gia
G C P
G o o d Cli nical Practice (refers t o I C H a n d C F R)
H A C
He patic A dj u dicati o n C o m mittee
HI P A A
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act
I C F
I nf or me d C o nse nt F or m
I C H
I nter nati o nal C o nfere nce o n Har m o nisati o n
I E C
I n de pe n de nt Et hics C o m mittee
I N N
I nter nati o nal N o n-pr o prietar y Na me
I R B
I nstit uti o nal Re vie w B oar d
I XR S
I nteracti ve V oice /We b Res p o nse S yste m
L S
Least S q uares
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M.I. N.I
Mi ni -i nter nati o nal Ne ur o ps yc hiatric I nter vie w
N R S
N u meric Rati n g Scale
P D
P har mac o d y na mic
P GI C
Patie nt Gl o bal I m pressi o n of C ha n ge
P H N
P ost -Her petic Ne ural gia
P K
P har mac o ki netic
Q D
O nce Dail y
R B C
Re d Bl o o d Cell
P W C
P h ysicia n Wit h dra wal C hec klist
S A E
Seri o us A d verse E ve nt
S A P
Statistical A nal ysis Pla n
S A V E R
Seri o us A d verse E ve nt Re p ort
S D
Sta n dar d De viati o n
S F -M P Q
S h ort F or m -Mc Gill Pai n Q uesti o n naire
SI D
S u bject I de ntificati o n N u m ber
S N RI
Ser ot o ni n -N ore pi ne p hri ne Re u pta ke I n hi bit or
S O P
Sta n dar d O perati n g Pr oce d ure
S S
S y m pt o m Se verit y
S S RI
Selecti ve Ser ot o ni n Re u pta ke I n hi bit or
S U S A R
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 8
A B B R E VI A TI O N  
D E FI NI TI O N
t1/ 2
Ter mi nal Eli mi nati o n Half -Life
T E A E
Treat me nt -E m er ge nt A d verse E ve nt
U L N
U p per Li mit of N or mal
U S
U nite d States
U S A
U nite d States of A merica
V A S
Vis ual A nal o g Scale
W B C
W hite Bl o o d Cell
W H O
W orl d Healt h Or ga nizati o n
W O C B P
W o me n of C hil d -Beari n g P ote ntial
W PI
Wi des prea d Pai n I n de x
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 9
1.  
I N T R O D U C TI O N A N D B A CK G R O U N D I N F O R M A TI O N
1. 1.  
I n vesti g ati o n al Pr o d uct(s)
1. 1. 1.  
N a me
D S - 5 5 6 5 is t he c o m p o u n d c o de f or [( 1 R, 5 S, 6 S)- 6-( A mi n o met h yl)- 3-et h yl bic y cl o[ 3. 2. 0] 
he pt -3- e n-6- yl ]acetic aci d m o n o be nze nes ulf o nate/ mir oga bali n .
1. 1. 2.  
Descri pti o n
D S -5 5 6 5 is a p ote nt a n d s pecific li ga n d of t he al p ha 2-delta ( α 2δ) s u b u nit of v olta ge -
de pe n de nt calci u m c ha n nels i n t he ce ntral ner v o us s y ste m ( C N S).  T he α 2δ s u b u nit has 
bee n i de ntifie d as t he m olec ular tar get f or t he a nal g esic effects of pre ga bali n a n d 
ga ba pe nti n, t w o c urre ntl y  mar kete d dr u gs f or t he treat me nt of c hr o nic ne ur o pat hic pai n, 
t h us esta blis hi n g a n i m p orta nt t hera pe utic tar get f or pai n c o ntr ol.1
1. 1. 3.   
I nte n de d Use U n der I n vesti g ati o n
D S - 5 5 6 5 is bei n g de vel o pe d as treat me nt f or dia betic peri p heral ne ur o pat hic pai n 
( D P N P), fi br o m yal gia ( F M), a n d p ost-her petic ne ural gia ( P H N) .
1. 1. 4.  
N o ncli nic al St u dies
D S -5 5 6 5 has bee n e val uate d i n a ni mal m o dels of ne ur o pat hic pai n a n d has bee n f o u n d t o 
be as effecti ve as or m ore effecti ve t ha n pre ga bali n.  Precli nical e val uati o ns ha ve 
de m o nstrate d a fa v ora ble safet y pr ofile s u p p orti n g c hr o nic d osi n g i n h u ma ns.
D S - 5 5 6 5 was assesse d i n i nter mitte nt c ol d stress mice, a n e x peri me ntal a ni mal m o del f or 
F M, a n d de m o nstrate d a si g nifica nt a n d s usta i ne d a nal gesic effect. N o ncli nical 
e val uati o ns ha ve de m o nstrate d a fa v ora ble safet y pr ofile s u p p orti n g c hr o nic d osi n g i n 
h u ma ns.
Data fr o m n o ncli nical st u dies of D S - 5 5 6 5 are s u m marize d i n t he D S-5 5 6 5 I n vesti gat or 
Br oc h ure.
1. 1. 5.  
Cli nic al E x perie nce
Si xtee n P hase 1 cli nical p har mac ol o g y  st u dies of D S- 5 5 6 5 a n d t w o P hase 2 st u dies of 
D S - 5 5 6 5 i n s u bjects wit h D P N P ha ve bee n c o m plete d. A d diti o nall y , a gl o bal p hase 3 
eff ort is u n der wa y i n patie nts wit h pai n d ue t o fi br o m yal gia.  A p pr o xi matel y, 3 6 0 0 
s u bjects will be ra n d o mize d i nt o t hree i de ntical st u dies, eac h lasti n g a p pr o xi matel y  2 0 
wee ks.  A p pr o xi matel y  half of t h ose s u bjects ( 1 8 0 0) will be e x p ose d t o u p t o 3 0 m g 
D S 5 5 6 5 dail y  ( place b o a n d pre ga bali n treat me nt ar ms will als o be e m pl o ye d).
F oll o wi n g oral a d mi nistrati o n t o healt h y v ol u nteers i n t hese P hase 1 st u dies, D S- 5 5 6 5 
was ra pi dl y a bs or be d a n d ma xi m u m plas ma c o nce ntrati o n ( C ma x ) was ac hie ve d at 
a p pr o xi matel y 1 h. F oll o wi n g a si n gle a d mi nistrati o n of D S - 5 5 6 5, C ma x a n d area u n der 
t he c o nce ntrati o n-ti me c ur ve ( A U C) increase d al m ost pr o p orti o nall y  wit h d ose le vel, 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 0
fr o m 3 m g t hr o u g h 7 5 m g. Ne gli gi ble acc u m ulati o n was n ote d f oll o wi n g t wice daily 
( BI D) a d mi nistrati o n of D S- 5 5 6 5. Ter mi nal eli mi nati o n half-life (t1/ 2) was a p pr o xi matel y 
4 h t o 7 h f oll o wi n g BI D a d mi nistrati o n of D S - 5 5 6 5. T he maj orit y  of A 2 0 0-0 7 0 0, t he 
free f or m of D S- 5 5 6 5, is e xcrete d i n uri ne u nc ha n ge d. Rece ntl y, a f o o d effect st u d y was 
c o n d ucte d at t he tar get cli nical d ose of 1 5 m g usi n g t he fi nal f or m ulati o n a n d i n dicate d 
t hat f o o d di d n ot si g nifica ntl y affect t he t otal e x p os ure ( A U C) of A 2 0 0- 0 7 0 0. H o we ver, 
C ma x of A 2 0 0 -0 7 0 0 was decrease d b y a p pr o xi matel y 1 8 % u n der fe d c o n diti o ns w he n 
c o m pare d wit h t hat u n der faste d c o n diti o ns.
T he o verall e x p os ure t o D S- 5 5 6 5, base d o n A U C, i ncrease d wit h se verit y of re nal 
i m pair me nt. As assesse d usi n g t he ge o metric least s q uare ( L S) mea ns rati os, e x p os ure 
was a p pr o xi matel y  1. 4-, 2. 0-, 4. 0-, a n d 5. 0-f ol d greater f or s u bjects wit h mil d, m o derate, 
a n d se vere re nal i m pair me nt a n d e n d -sta ge re nal disease ( E S R D), res pecti vely, c o m pare d 
t o s u bjects wit h n or mal re nal f u ncti o n. A p pare nt cleara nce a n d re nal cleara nce of D S-
5 5 6 5 decrease d wit h i ncreasi n g se verit y of re nal i m pair me nt.
D S -5 5 6 5 di d n ot affect t he p har mac o ki netics ( P K) of et ha n ol, l oraze pa m, z ol pi de m, 
tra ma d ol, or metf or mi n i n healt h y s u bjects. T he P K of D S -5 5 6 5 was n ot si g nifica ntl y 
affecte d b y t h ose c o m p o u n ds.
I n a 1 4C- la bele d D S-5 5 6 5 mass bala nce st u d y i n healt h y s u bjects gi ve n a si n gle oral d ose 
of 3 0 m g, t he mea n t otal ra di oacti vit y  rec o vere d i n uri ne a n d feces was 9 6. 8 5 % a n d 
1. 2 1 % of t he a d mi nistere d d ose, res pecti vel y. I n a t h or o u g h Q T st u dy, t here were n o 
cli nicall y si g nifica nt c ha n ges i n 1 2-lea d electr ocar di o gra m ( E C G) para meters; neit her t he 
t hera pe utic d ose ( 1 5 m g of D S-5 5 6 5) n or t he s u prat hera pe utic d ose ( 5 0 m g of D S -5 5 6 5) 
affecte d car diac re p olarizati o n.
I n t he U nite d States ( U S ), o ne P hase 2 st u d y ( D S 5 5 6 5- A-U 2 0 1) i n s u bjects wit h D P N P 
w as c o m plete d. I n t he D S 5 5 6 5- A-U 2 0 1 st u d y , L S mea n differe nces vers us place b o i n 
c ha n ge i n a vera ge dail y pai n sc ore ( A D P S) fr o m baseli ne t o Wee k 5 were - 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 o nce dail y  ( 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 treat me nt gr o u ps, res pecti vel y . T hese L S mea n differe nces 
were statisticall y si g nifica nt at t he 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 ose le vels. I n t his st u d y pre ga balin 1 5 0 m g BI D 
di d n ot si g nifica ntl y differe ntiate fr o m place b o i n A D P S or pr o p orti o n of res p o n ders at 
e n d p oi nt. A sec o n d P hase 2 st u d y  wit h a si milar desi g n ( D S 5 5 6 5- A-J 2 0 2) was
c o m plete d i n Asia (Ja pa n, K orea, a n d Tai wa n). I n t he D S 5 5 6 5- A-J 2 0 2 st u d y, LS m ea n 
differe nces vers us place b o i n c ha n ge i n A D P S fr o m baseli ne t o Wee k 7 were - 0. 4 2, - 0. 3 7, 
a n d -0. 3 0 f or t he 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 treat me nt gr o u ps, 
res pecti vely. T hese L S mea n differe nces were n ot statisticall y si g nifica nt.
D S - 5 5 6 5 has bee n s h o w n t o be well t olerate d at si n gle d oses u p t o 3 0 m g. T he m ost 
fre q ue ntly re p orte d treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) ha ve bee n C N S -relate d 
e ve nts (e g, dizzi ness a n d s o m n ole nce) t hat are e x pecte d base d o n t he mec ha nis m of 
acti o n of D S - 5 5 6 5. M ost re p orte d T E A Es were j u d ge d t o be mil d or m o derate, a n d m ost 
were c o nsi dere d t o be relate d t o t he st u d y  dr u g. I n t he c o m plete d P hase 2 st u dies, all D S-
5 5 6 5 d ose le vels (fr o m 5 m g Q D t o 1 5 m g BI D) were ge nerall y  well t olerate d.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 1
A d diti o nal data fr o m cli nical st u dies of D S - 5 5 6 5 are s u m marize d i n t he D S- 5 5 6 5 
I n vesti gat or’s Br oc h ure.
1. 2.  
S t u d y R ati o n ale
Se veral classes of me dicati o ns, i ncl u di n g a ntic o n v ulsa nts, tric y clic a nti de pressa nts, 
ser ot o ni n-n ore pi ne p hri ne re u pta ke i n hi bit ors ( S N RI s), a n d o pi oi ds are use d t o treat t he 
s ym pt o ms of F M , wit h varia ble efficac y, safety, a n d t olera bilit y.  C urre ntl y a vaila ble α 2δ 
li ga n ds, ga ba pe nti n a n d pre ga bali n, are esta blis he d as effecti ve treat me nts f or pai n 
ass ociate d wit h dia betic peri p heral ne ur o pat h y. 2 ,3  I n a d ditio n t he y  are a p pr o ve d f or t he 
treat me nt of pai n i n F M i n t he U S A a n d s o me ot her c o u ntries, h o we ver n ot i n t he E U
( E ur o pea n U ni o n). The d osa ge, a n d t h us efficac y , of t hese a ge nts are li mite d b y fre q ue nt 
a n d si g nifica nt C N S -relate d si de effects, i ncl u di n g dizzi ness a n d s o m n ole nce; ass ociate d 
wei g ht gai n a n d peri p heral e de ma ca n als o be pr o ble matic .4  As a res ult, a lar ge 
pr o p orti o n of patie nts wit h F M are left wit h i ns ufficie nt pai n re lief a n d ne w treat me nt 
o pti o ns are nee de d.
D S -5 5 6 5 is a n oral a nal gesic dr u g bei n g de vel o pe d b y  Daiic hi Sa n k yo f or D P N P, F M , 
a n d P H N , gl o ball y.  T his st u d y  is bei n g c o n d ucte d i n patie nts wit h c hr o nic re nal 
d y sf u ncti o n a n d pai n d ue t o fi br o m yal gia s olel y, a fter recei vi n g g ui da nce fr o m t he U S 
F D A.  D S -5 5 6 5 bi n ds t o t he α 2δ s u b u nit of v olta ge- de pe n de nt calci u m c ha n nels, t he mai n 
tar get f or t he a nal gesic effect of pre ga bali n a n d ga ba pe nti n.  N o ncli nical a n d P hase 1 a n d 
P hase 2 cli nical data s u p p ort t he pr o gress of D S -5 5 6 5 i nt o P hase 3 st u dies of F M t o 
e val uate t he effect of D S - 5 5 6 5 o n A D P S as c o m pare d t o place b o d uri n g t he c o urse of a 
1 3- wee k (sta ble d ose, n ot i ncl u di n g 1 wee k of titrati o n f or t he D S- 5 5 6 5 1 5 m g BI D 
gr o u p) d o u ble -bli n d treat me nt peri o d.
D S -5 5 6 5 h as bee n st u die d i n s u bjects wit h re nal d ysf u ncti o n. St u d y D S 5 5 6 5 - A-E 1 0 6 
e val uate d t he p har mac o ki netics a n d safet y of a si n gle 5 m g d ose i n 4 0 s u bjects ( 8 n or mal 
re nal f u ncti o n a n d 8 eac h wit h mil d, m o derate, se vere, an d E S R D re q uiri n g 
he m o dial y sis). P har m ac o ki netics of D S -5 5 6 5 a n d its lacta m meta b olite were e val uate d 
o ver a 7 2- h o ur peri o d. F or t he a nal ys is,t he gr o u ps were a nalyz e d b y n or mal creati ni ne 
cleara nce ( Cr Cl) (≥ 9 0 m L/ mi n), mil d re d ucti o n i n Cr Cl ( 6 0 t o 8 9 m L / mi n), m o derate 
re d ucti o n i n Cr Cl ( 3 0 t o 5 9 m L/ mi n), a n d se vere re d ucti o n i n Cr Cl ( 1 5 t o 2 9 m L / mi n as 
per t he F D A Draft G ui da nce, P h ar m ac oki netics i n P atie nts wit h I m p aire d Re n al 
F u ncti o n — St u dy Desi g n, D at a A n alysis, a n d I m p act o n D osi n g a n d L a beli n g .5
T he P K a nal ys is i n dicate d t hat t here was a si g nifica nt re d ucti o n i n b ot h re nal cleara nce 
( C Lr/ F) a n d t otal cleara nce ( C L/ F) of D S-5 5 6 5 a n d its lacta m meta b olite as re nal 
f u ncti o n decrease d. 
I n or der t o test t he safet y a n d t olera bilit y of D S-5 5 6 5 i n s u bjects wit h re nal d ysf u ncti o n , t he 
d oses ( 7. 5 m g BI D f or s u bjects wit h Cr Cl bet wee n 3 0 - 5 9 m L/ mi n a n d 7. 5 m g Q D f or 
s u bjects wit h Cr Cl bet wee n 1 5 - 2 9 m L/ mi n) are pre dicte d t o pr o d uce e x p os ures si milar t o 
t h ose i n s u bjects wit h n or mal re nal f u ncti o n at 1 5 m g BI D .
D S -5 5 6 5 is a ne xt -ge nerati o n α 2δ li ga n d bei n g de vel o pe d as a p ote nt a nal gesic wit h a n 
a ntici pate d wi der t hera pe utic mar gi n t ha n pre ga bali n, se parati n g o pti mal efficac y  a n d 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 2
si de effects. T he prese nt st u d y ai ms t o e val uate t he safety a n d efficac y of D S-5 5 6 5 f or 
treati n g pai n i n s u bjects wit h F M wit h c hr o nic ki d ne y  disease.
1. 3.  
Ris k s a n d Be nefits f or St u d y S u bjects
T he res ults fr o m n o ncli nical st u dies s u g gest t hat s u bjects treate d wit h D S -5 5 6 5 ma y  
e x perie nce i m pr o ve me nt i n pai n ass ociate d wit h F M. T he c li nical efficac y of D S- 5 5 6 5 
has bee n e val uate d i n t w o P hase 2, m ulti -ce nter, ra n d o mize d, d o u ble-bli n d, a n d place b o -
a n d acti ve-c o m parat or c o ntr olle d a da pti ve st u dies i n s u bjects wit h D P N P.  I n t he first 
st u dy (c o n d ucte d i n t he U S), t he 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 
treat me nt gr o u ps de m o nstrate d statisticall y si g nifica nt mea n re d ucti o ns i n A D P S fr o m 
baseli ne t o e n d - of-treat me nt c o m pare d t o place b o.  T hese data pr o vi de pr o of - of-c o nce pt 
f or D S-5 5 6 5 as a treat me nt f or D P N P.  T he sec o n d P hase 2 st u d y  was si milarl y desi g ned 
a n d c o n d ucte d i n Asia (Ja pa n, S o ut h K orea a n d Tai wa n).  T he 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 treat me nt gr o u ps di d n ot de m o nstrate statisticall y si g nifica nt 
mea n re d ucti o ns i n A D P S; h o we ver, tre n ds fa v ori n g D S -5 5 6 5 o ver place b o were e vi de nt 
i n so me sec o n dar y  efficac y e n d p oi nts, i ncl u di n g mea n re d ucti o ns i n vis ual a nal o g scale 
( V A S) f or S h ort F or m -Mc Gill Pai n Q uesti o n naire ( S F -M P Q ) gi ve n at t he hi g hest d ose.
D S -5 5 6 5 is cleare d fr o m t he b o d y  pri maril y  via t he ki d ne y s. I n or der t o test t he safet y a nd 
t olera bilit y of D S-5 5 6 5 i n s u bjects wit h re nal d ysf u ncti o n , t he d oses ( 7. 5 m g BI D f or s u bjects 
wit h Cr Cl bet wee n 3 0 - 5 9 m L / mi n a n d 7. 5 m g Q D f or s u bjects wit h Cr Cl bet wee n 1 5- 2 9 
m L / mi n) are pre dicte d t o pr o d uce e x p os ures si milar t o t h ose i n s u bjects wit h n or mal re nal 
f u ncti o n at 1 5 m g BI D . Pre vi o us st u dies of s u bjects wit h re nal d y sf u ncti o n s u g geste d t he 
nee d f or re d uci n g t he d ose i n t h ose s u bjects wit h eit her m o derate or se vere i m pair me nt of 
re nal f u ncti o n.
A ntici pate d ri s ks of D S-5 5 6 5 i ncl u de t he occ urre nce of a d verse reacti o ns relate d t o C N S 
de pressi o n, s uc h as dizzi ness a n d s o m n ole nce, as well as peri p heral e de ma.  Ot her 
n ota ble T E A Es t hat ha ve bee n o bser ve d i n P hase 1 a n d P hase 2 st u dies i ncl u de ele vati o ns 
of he patic t ra nsa mi nases a n d s uici de.  F or t he a p pr o ve d α 2δ li ga n ds, i n a d diti o n t o 
dizzi ness, s o m n ole nce, a n d peri p heral e de ma, certai n a d verse reacti o ns re q uiri n g ca uti o n 
ha ve als o bee n re p orte d , i ncl u di n g b ut n ot li mite d t o: wei g ht gai n, o p ht hal m ol o gic 
dis or ders, s uici dal be ha vi or a n d i deati o n, a n gi oe de ma, h y perse nsiti vit y , a br u pt or ra pi d 
disc o nti n uati o n, a b use p ote ntial, c o n gesti ve heart fail ure, re nal fail ure, a n d creati ne 
ki nase ele vati o ns.  T hese ris ks are u n k n o w n i n s u bjects wit h c hr o nic ki d ne y disease 
(C K D ). D S - 5 5 6 5 is c urre ntl y bei n g st u die d i n a gl o bal p hase 3 pr o gra m i n patie nts wit h 
pai n d ue t o F M.
A f ull descri pti o n of safet y  data relate d t o D S-5 5 6 5, i ncl u di n g t he res ults of P hase 1 a n d
P hase 2 cli nical st u dies of D S -5 5 6 5, is pr o vi de d i n t he D S -5 5 6 5 I n ve sti gat or Br oc h ure.  
Safet y  m o nit ori n g pr oce d ures descri be d i n t he pr ot oc ol are c o nsi dere d t o be a de q uate t o 
pr otect s u bject safet y.
1. 4.  
P o p ul ati o n, R o ute, D os a ge, D os a ge Re gi me n, Tre at me nt Peri o d
T he st u d y  p o p ulati o n will be a d ult (a ge ≥ 1 8 y ears) male a n d fe male s u bjects wit h a Cr Cl
bet wee n 1 5 -5 9 m L / mi n, a n d a dia g n osis of F M f or u p t o 5 years pri or t o scree ni n g.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 3
S u bjects m ust meet s pecific pai n criteria at t he Scree ni n g a n d Ra n d o mizati o n Visit s f or 
i ncl usi o n.  F ull details re gar di n g eli gi bilit y criteria are pr o vi de d i n Secti o n 4 .
T he d osa ge f or m of D S -5 5 6 5 dr u g pr o d uct is w hite o val 7. 5 m g t a blets.  T he ta blet 
f or m ulati o n i ncl u des D S-5 5 6 5 dr u g s u bsta nce, ma n nit ol, car b o x y m et h ylcell ul ose 
calci u m, ma g nesi u m stearate, a n d O pa dr y ® O Y -S- 9 6 0 7 (a pre - mi xe d p o w der f or c oati n g 
s us pe nsi o n c o ntai ni n g hy pr o mell ose, tita ni u m di o xi de, a n d talc).  T he ta blet s will be 
orall y  a d mi nistere d.  St u d y  treat me nt ma y be ta ke n wit h or wit h o ut f o o d o nce i n t he 
m or ni n g a n d o nce i n t he e ve ni n g . Matc hi n g place b o ta blets will als o be use d.
F ull details re gar di n g st u d y  treat me nt are pr o vi de d i n Secti o n 5 .
1. 5.  
C o m pli a nce St ate me nt, Et hics ,a n d Re g ul at or y C o m pli a nce
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter nati o nal C o nfere nce o n 
Har m o nis ati o n (I C H) c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( G C P) 
( C P M P/IC H/ 1 3 5/ 9 5), a n d a p plica ble re g ulat or y  re q uire me nt(s) i ncl u di n g: 

F o o d a n d Dr u g A d mi nistrati o n ( F D A) G C P Re g ulati o ns: C o de of Fe deral 
Re g ulati o ns ( C F R) Title 2 1, parts 1 1, 5 0, 5 4, 5 6, a n d 3 1 2 a n d/ or

E ur o pea n C o m missi o n Directi ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1) a n d/ or

E ur o pea n C o m missi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) as a p pr o priate.
1. 5. 1.  
S u bject C o nfi de nti alit y
T he I n vesti gat ors a n d t he S p o ns or will preser ve t he c o nfi de ntialit y of all s u bjects ta ki n g 
part i n t he st u d y , i n acc or da nce wit h G C P a n d l ocal re g ulati o ns.
T he S p o ns or will o bser ve t he r ules lai d d o w n i n t he E ur o pea n Data Pr otecti o n Directi ve 
9 5/ 4 6/ E C o n t he pr otecti o n of i n di vi d uals wit h re gar d t o t he pr ocessi n g of pers o nal data 
a n d t he free m o ve me nt of s uc h data .
T he I n vesti gat or m ust e ns ure t hat t he s u bject’s a n o n y mit y  is mai ntai ne d.  O n t he 
Electr o nic Case Re p ort F or ms (e C R F) or ot her d oc u me nts s u b mitte d t o t he S p o ns or or 
desi g nee, s u bjects s h o ul d be i de ntifie d b y a u ni q ue s u bject i de ntifier as desi g nate d by t he 
S p o ns or.  D oc u me nts t hat are n ot f or s u b missi o n t o t he S p o ns or or desi g nee (e g, si g ne d 
I nf or me d C o nse nt F or ms [IC F]) s h o ul d be ke pt i n strict c o nfi de nce b y  t he I n vesti gat or.
I n c o m plia nce wit h a p plica ble re g ulati o ns a n d I CH G C P G ui deli nes, it is re q uire d t hat t he 
I n vesti gat or a n d i nstit uti o n per mit a ut h orize d re prese ntati ves of t he S p o ns or , of t he 
re g ulat or y a ge nc y(s), a n d t he In de pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal 
Re vie w B oar d (I R B) direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or 
verificati o n of st u d y -relate d pr oce d ures a nd data.  T he I n vesti gat or is o bli gate d t o i nf or m 
t he s u bject t hat his/ her st u d y-relate d rec or ds will be re vie we d by t he a b o ve na me d 
re prese ntati ves wit h o ut vi olati n g t he c o nfi de ntialit y of t he s u bject.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 4
1. 5. 2.  
I nf or me d C o nse nt Pr oce d ure
Bef ore a s u bject’s partici p ati o n i n t he st u d y, it is t he I n vesti gat or’s res p o nsi bilit y t o 
o btai n freel y gi ve n c o nse nt, i n writi n g, fr o m t he s u bject after a de q uate e x pla nati o n of t he 
ai ms, met h o ds, a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y a n d bef ore a n y 
pr ot oc ol -s pecific scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  T he writte n 
I CF s h o ul d be pre pare d i n t he l ocal la n g ua ge(s) of t he p ote ntial s u bject p o p ulati o n.
I n o btai ni n g a n d d oc u me nti n g i nf or me d c o nse nt, t he I n vesti gat or s h o ul d c o m pl y wit h t he 
a p plica ble re g ulat or y re q uire me nts, a n d s h o ul d a d here t o G C P a n d t o t he et hical 
pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y 
re visi o n(s) s h o ul d be a p pr o ve d by t he I RB/I E C pri or t o bei n g pr o vi de d t o p ote ntial 
s u bjects.
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or t o his/ her partici pati o n i n 
t he st u d y a n d s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or ds, as re q uire d b y  la w.  
T he I C F s h o ul d be si g ne d a n d pers o nall y date d b y t he s u bject, a n d b y t he p ers o n w h o 
c o n d ucte d t he i nf or me d c o nse nt disc ussi o n ( n ot necessaril y t he I n vesti gat or).  T he 
ori gi nal si g ne d I C F s h o ul d be retai ne d i n acc or da nce wit h i nstit uti o nal p olic y, a n d a c o p y 
of t he si g ne d c o nse nt f or m s h o ul d be pr o vi de d t o t he s u bject or le gal re prese ntati ve.  T he 
date a n d ti me (if a p plica ble) t hat i nf or me d c o nse nt was gi ve n s h o ul d be rec or de d o n t he 
C R F .
S u g geste d m o del te xt f or t he I C F f or t he st u d y  a n d a n y a p plica ble s u b parts are pr o vi de d 
i n t he S p o ns or I CF te m plate f or t he I n vesti gat or t o pre pare t he d oc u me nts t o be use d at 
his or her site.  U p dates t o a p plica ble f or ms will be c o m m u nicate d via letter fr o m t he 
S p o ns or .
A d diti o nal c o nse nt is re q uire d f or t he Healt h I ns ura nce P orta bilit y  an d Acc o u nta bilit y  
Act (HI P A A ) o nl y  i n t he U S A.
1. 5. 3.  
Re g ul at or y C o m pli a nce
T he st u d y  pr ot oc ol, s u bject i nf or mati o n a n d c o nse nt f or m, t he I n vesti gat or B r oc h ure, a ny 
s u bject diar y car d or writte n i nstr ucti o ns t o be gi ve n t o t he s u bject, a vaila ble safety 
i nf or mati o n, s u bject recr uit me nt pr oce d ures (e g, a d vertise me nts), i nfor mati o n a b o ut 
pa y me nts a n d c o m pe nsati o n a vaila ble t o t he s u bjects ,a n d d oc u me ntati o n e vi de nci n g t he 
I n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o t he I RB/I E C f or et hical re vie w a n d 
a p pr o val acc or di n g t o l ocal re g ulati o ns pri or t o t he st u d y  start.  T he writte n a p pr o val 
s h o ul d i de ntif y all d oc u me nts re vie we d by na me a n d versi o n.
C ha n ges i n t he c o n d uct of t he st u d y  or pla n ne d a nal ysis will be d oc u me nte d i n a pr ot oc ol 
a me n d me nt a n d/ or t he Statistical A nal y sis Pla n ( S A P).
T he I n vesti gat or m ust s u b mit a n d , w here necessar y, o btai n a p pr o val fr o m t he I RB/I E C 
f or all s u bse q ue nt pr ot oc ol a me n d me nts a n d c ha n ges t o t he i nf or me d c o nse nt d oc u me nt 
or c ha n ges of t he i n vesti gati o nal site, facilities, or pers o n nel.  T he I n vesti gat or s h o ul d 
n otif y  t he I RB/I E C of de viati o ns fr o m t he pr ot oc ol or seri o us a d verse e ve nts occ urri n g at 
t he site a n d ot her a d verse e ve nt re p orts recei ve d fr o m t he S p o ns or or desi g nee, i n 
acc or da nce wit h l ocal pr oce d ures.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 5
As re q uire d b y l ocal re g ulati o ns, t he S p o ns or’s l ocal Re g ulat or y  Affairs gr o u p will i ns ure 
all le gal as pects are c o vere d a n d a p pr o val of t he a p pr o priate re g ulat or y  b o dies o btai ne d, 
pri or t o st u d y  i nitiati o n, a n d t hat i m ple me ntati o n of c ha n ges t o t he i nitial pr ot oc ol a n d 
ot her rele va nt st u d y  d oc u me nts ha p pe n o nl y after t he a p pr o priate n otificati o n of or 
a p pr o val b y t he rele va nt re g ulat or y b o dies.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 6
2.  
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S
2. 1.  
St u d y O bjecti ves
2. 1. 1.  
Pri m ar y O bjecti ve
T he pri mar y  o bjecti ve is t o deter mi ne t he safety a n d t olera bilit y of s u bjects wit h F M a n d 
m o derate t o se vere re na l d ysf u ncti o n d uri n g 1 3 wee ks of re nally a dj uste d d o si n g of D S -
5 5 6 5 c o m pare d t o place b o.
2. 1. 2.  
Sec o n d ar y O bjecti ves
T he sec o n dar y  o bjecti ves of t his st u d y are:

T o c o m pare c ha n ge i n wee kl y a vera ge dail y  pai n as assesse d b y  A DP S fr o m 
baseli ne meas ure d at ra n d o mizati o n t o Wee k 1 3/ E T
i n s u bjects recei vi n g 
eit her d ose of D S -5 5 6 5 vers us place b o . Wee kl y  A D P S is base d o n dail y pai n 
sc ores re p orte d by t he s u bject t hat best descri bes t he w orst pai n o ver t he 
pre vi o us 2 4 h o urs 

T o assess t he effects of D S- 5 5 6 5 o n patie nt gl o bal i m pressi o n of c ha n ge 
( P GIC) at Wee k 1 3/ E T.
2. 2.  
St u d y H y p ot hesis
T he h y p ot hesis of t his P hase 3 st u d y  is t hat d oses of 7. 5 m g BI D of D S-5 5 6 5 i n s u bjects 
wit h Cr Cl bet wee n 3 0 -5 9 m L / mi n a n d 7. 5 m g Q D of D S-5 5 6 5 i n s u bjects wit h Cr Cl
bet wee n 1 5 -2 9 m L / mi n D S-5 5 6 5 will be safe a n d well t olerate d.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

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

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 8
3. 1. 2.  
Tre at me nt Gr o u ps
S u bjects w h o meet all eli gi bilit y  criteria will be ra n d o mize d 2: 1 t o recei ve eit her D S -
5 5 6 5 7. 5 m g Q D or place b o f or t he cate g or y  of s u bjects wit h Cr Cl 1 5 - 2 9 m L/ mi n , or 2: 1 
t o recei ve treat me nt wit h D S-5 5 6 5 7. 5 m g BI D or place b o f or t he cate g or y  of s u bjects 
wit h Cr Cl 3 0 - 5 9 m L/ mi n .
Matc hi n g place b o will be utilize d t o c o n d uct t he d o u ble -bli n d treat me nt peri o d.
T he Sc he d ule of E ve nts is liste d i n Secti o n 1 7 a n d t he St u d y  Pr oce d ures i n Secti o n 6 .
3. 1. 3.  
St u d y E n d p oi nts
T he pri mar y  safety e n d p oi nt is t he safet y a n d t olera bilit y  of re nally a dj uste d d oses of D S -
5 5 6 5 vers us place b o.
S pecific safet y  e n d p oi nts assesse d i ncl u de:

All t reat me nt-e mer ge nt a d verse e ve nts ( T E A Es)

C ha n ge i n cli nical la b orat or y  e val uati o ns fr o m baseli ne meas ure d at 
ra n d o mizati o n t o Wee k 1 3/ E T
f or D S-5 5 6 5 vers us place b o

C ha n ge i n ne ur ol o gical e xa mi nati o ns fr o m baseli ne t o Wee k 1 3/ E T
f or D S-
5 5 6 5 vers us place b o

C ha n ge i n electr ocar di o gra ms fr o m baseli ne t o Wee k 1 3/ E T f or D S- 5 5 6 5 
vers us place b o 

C ha n ge i n C ol u m bia -S uici de Se verit y Rati n g Scale ( C - S S R S) fr o m baseli ne 
t o Wee k 1 3/ E T
f or D S-5 5 6 5 vers us place b o

Assess me nt of P h y sicia n Wit h dra wal C hec klist ( P W C) at f oll o w-u p visi ts.
T he sec o n dar y  efficac y e n d p oi nts i ncl u de: 

C ha n ges i n A D P S fr o m baseli ne meas ure d at ra n d o mizati o n t o Wee k 1 3/ E T
f or D S-5 5 6 5 vers us place b o . Wee kl y  A D P S is base d o n dail y pai n sc ores 
re p orte d by t he s u bject t hat best descri bes t he w orst pai n o ver t he pre vi o us 2 4 
h o urs.

Pr o p orti o n of s u bjects wit h i m pr o ve me nt i n o verall stat us at Wee k 1 3/ E T as 
assesse d b y P GI C f or D S -5 5 6 5 vers us place b o.
3. 1. 4.  
D ur ati o n of t he St u d y
3. 1. 4. 1.    
D ur ati o n of S u bject P artici p ati o n
T he t otal st u d y  d urati o n (f or i n di vi d ual s u bject’s partici pati o n) will be a p pr o xi matel y 2 1 
wee ks. T he st u d y i ncl u des a scree ni n g peri o d (a p pr o xi matel y 3 wee ks b ut n o l o n ger t ha n 
3 5 da y s, i ncl u di n g a was h o ut peri o d [if necessar y] a n d a 1 -wee k baseli ne peri o d) , d o u ble-
bli n d treat me nt peri o d ( 1 3 wee ks), a n d a 4 wee k f oll o w-u p peri o d.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 9
3. 1. 5.  
St o p pi n g R ules
3. 1. 5. 1.  
St o p pi n g R ules f or I n di vi d u al S u bjects 
F or a n y s u bject disc o nti n ue d fr o m t he st u d y base d o n o ne of t he st o p pi n g r ules o utli ne d 
i n Secti o n 3. 1. 5. 1. 1 , t he ass ociate d e ve nt m ust be re p orte d as a n a d verse e ve nt (A E ) or 
seri o us A E ( S A E) i n t he e C R F wit hi n 2 4 h o urs of a ware ness. Please refer t o Secti o n 9. 4
f or f urt her i nstr ucti o ns. 
3. 1. 5. 1. 1.
Ele v ati o ns of A mi n otr a nsfer ases 
Alt h o u g h a mec ha nis m - or meta b olis m -base d p ote ntial f or dr u g -i n d uce d li ver i nj ur y has
n ot bee n esta blis he d f or D S -5 5 6 5, i nsta nces of i ncrease d he patic tra nsa mi nases ha ve bee n 
o bser ve d d uri n g t he de vel o p me nt pr o gra m. I n a d diti o n, aceta mi n o p he n, a n a ge nt k n o w n 
t o ca use li ver i nj ur y ( d ue t o sat urati o n of its meta b olis m w he n o ver d ose d), is c o mm o nl y  
use d i n t his p o p ulati o n a n d is i ncl u de d i n t his st u d y  as a n all o we d treat me nt f or pai n. As 
s uc h, a sta n dar dize d a p pr oac h f or st o p pi n g r ules a n d caref ul m o nit ori n g of ser u m 
tra nsa mi nases is c o nsi dere d pr u de nt. St o p pi n g r ules f or ele vati o n i n ser u m transa mi nases 
are i ncl u de d as a ge neral preca uti o n, wit h atte nti o n t o F D A g ui da nce f or detecti o n a n d 
assess me nt of dr u g- i n d uce d li ver i nj ur y pre mar keti n g cli nical e val uati o ns, a n d are 
descri be d bel o w. S pecific rec o m me n dati o ns re gar di n g m o nit ori n g of s u bjects wit h 
ele vati o ns are descri be d i n Secti o n 9. 3. 2 .
S u bjects wit h a n y  of t he f oll o wi n g ele vati o ns i n a mi n otra nsferases s h o ul d be 
disc o nti n ue d fr o m treatme nt a n d f oll o we d cl osel y , as n ote d a b o ve. 

I ncrease i n ala ni ne a mi n otra nsferase ( A L T) or as partate a mi n otra nsferase 
( A S T) ≥ 5 x u p per li mit of n or mal ( U L N) 

A L T or A S T i ncreases t o ≥ 3 x U L N a n d persists f or m ore t ha n 2 wee ks 

C o nc urre nt i ncreases i n A L T or A S T ≥ 3 x U L N a n d t otal bilir u bi n ≥ 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 (i. e., i ncl u di n g t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or t e n der ness, fe ver, ras h, a n d/ or e osi n o p hilia) 
3. 1. 5. 2.  
S uici d al Be h a vi or a n d I de ati o n 
T he α 2δ li ga n d class of me dicati o ns has bee n ass ociate d wit h i ncrease d ris k of s uici dal 
t h o u g hts or be ha vi or (Secti o n 9. 3. 1 ). T w o se parate cases of c o m plete d s uici de were 
o bser ve d i n t he P hase 2 D S 5 5 6 5 - A-J 2 0 2 st u d y. 
T he C -S S R S a n d Mi ni -i nter nati o nal Ne ur o ps yc hiatric I nter vie w ( MI NI) ( Versi o n 6. 0) are 
t o be a d mi nistere d at a n y ti me d uri n g t he st u d y (i ncl u di n g u nsc he d ule d visits) w here t he 
i n vesti gat or/st u dy c o or di nat or/site staff rec o g nizes or bec o me a ware of (a n d t his i ncl u des 
if t his a ware ness arises d uri n g u nsc he d ule d visits or n o n-face-t o-face c o m m u nicati o ns 
wit h t he pat ie nt or his/ her fa mil y):

A n y  s u g gesti o n of m o o d dist ur ba nce a n d/ or a n y a ware ness of a p ote ntial 
s uici dal ris k,
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 0

S u bsta ntial c ha n ges i n t heir ps y c h os ocial e n vir o n me nt (ie, t he deat h of or 
se parati o n of cl ose fa mil y/frie n d, s u d de n fi na ncial b ur de n, w orse ni n g of 
me dical c o n diti o n, etc); i n t his case a d mi nistrati o n of t he C- S S R S/ MI NI  a n d 
c o ns ultati o n wit h a ps yc hiatrist ( o nsite prefera bl y) s h o ul d be perf or me d.
I n t his st u dy, t he C -S S R S will be a d mi nistere d at all cli nic visits. Base d o n t he C -S S R S 
a n d I n vesti gator j u d g me nt, if a s u bject is i de ntifie d as bei n g at ris k f or s uici de, 
a p pr o priate safet y meas ures s h o ul d be i m ple me nte d, i ncl u di n g: 

A s u bject s h o ul d be disc o nti n ue d fr o m t he st u d y , a n d i m me diatel y referre d t o 
a me ntal healt h pr ofessi o nal f or f urt her e val u ati o n, if a ‘ Y E S’ res p o nse has 
bee n rec or de d f or a n y q uesti o n o n t he C -S S R S at a n y  visit (c urre nt or past), 
u nless t he s u bject falls i nt o t he ‘ P ossi ble E xce pti o n’ cate g or y  bel o w. 

P ossi ble E xce pti o n ( wit h re gar d t o a ‘ Y E S’ res p o nse(s) t o C- S S R S Q 1 
a n d/ or Q2 o nl y):
1.
T he be nefit fr o m c o nti n uati o n o n t he st u d y  me dicati o n si g nifica ntly o ut wei g hs t he 
ris k of c o nti n ui n g t he s u bject o n st u d y dr u g. S uc h cases nee d t o be disc usse d wit h 
t he s p o ns or me dical direct or a n d s h o ul d ta ke i nt o acc o u nt t he me ntal healt h 
pr ofes si o nal e val uati o n A N D
2.
T he j ustificati o n f or c o nti n ui n g t he s u bject i n t he st u d y  u n der t hese circ u msta nces 
is t o be a p pr o priately d oc u me nte d per st u d y pr oce d ure 
S u bjects s h o ul d be disc o nti n ue d fr o m t he cli nical st u d y  a n d i m me diately referre d t o a 
me ntal he alt h pr ofessi o nal ( prefera bl y  a n o nsite ps yc hiatrist e val uati o n if p ossi ble) if 
s u bjects are assesse d as ha vi n g c urre nt se vere or u nc o ntr olle d maj or de pressi ve dis or der 
or a n xiet y  dis or ders by t he MI NI at a n y visit (c urre nt or past) a n d if a n y of t he f oll o wi n g 
c o n diti o ns a p pl y:

T he i n vesti gat or deter mi nes t hat t here is a s uici dalit y  ris k, irres pecti ve of a n y 
scales or

A n y  “ Yes" res p o nse t o:

MI NI  q uesti o ns
o
M o d ule A ( Maj or De pressi ve Dis or der) q uesti o n A 3, G or
o
A n y  q uesti o n o n M o d ule B ( S uici dalit y) or

Rele va nt C - S S R S q uesti o ns, wit h disc o nti n uati o n criteria as o utli ne d 
a b o ve.
3. 1. 5. 3.  
Decre ase d Cr Cl B el o w Mi ni m u m
If at a n y ti me d uri n g t he st u d y  t he Cr Cl dr o ps bel o w 1 5 m L / mi n, t he s u bject m ust be 
disc o nti n ue d fr o m t he st u d y  utilizi n g t he state d wit h dra wal pr oce d ures a n d referre d t o a 
ne p hr ol o gist .
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 1
3. 1. 5. 4.  
St o p pi n g R ules f or t he St u d y 
Circ u msta nces u n der w hic h t he st u d y  ma y be st o p pe d base d u p o n i n de pe n de nt Data a n d 
Safet y  M o nit ori n g B oar d ( D S M B) rec o m me n dati o n are s pecifie d i n Secti o n 1 1. 9 . In 
a d diti o n, t he st u d y ma y be ter mi nate d at a n y ti me at t he S p o ns or ’s discreti o n.
3. 2.  
Selecti o n of D oses
3. 2. 1.  
E x peri me nt al Tre at me nts f or t he St u d y
D ose re gi me ns were selecte d base d o n res ults of si n gle- d ose st u dies i n healt h y  
v ol u nteers, as well as d ose o pti mizati o n m o deli n g a n d si m ulati o n. At d oses fr o m 3 t o 7 5 
m g, D S -5 5 6 5 was ra pi dl y  a bs or be d, wit h a me dia n ti me t o ma xi m u m plas ma 
c o nce ntrati o n (tma x) of a p pr o xi matel y  1 h o ur.  Mea n t
1/ 2 ra n ge d fr o m a p pr o xi matel y 3 
h o urs t o 5 h o urs, a n d C ma x a n d A U C a p peare d t o i ncrease pr o p orti o nall y wit h d oses fr o m 
3 m g t hr o u g h 7 5 m g.  T he maj orit y  of a d mi nistere d D S-5 5 6 5 is e xcrete d i n t he uri ne 
(a p pr o xi matel y 6 1 % t o 7 7 % of t he d ose).  T he o verall e x p os ure t o D S-5 5 6 5, base d o n 
A U C, i ncrease d wit h se verit y  of re nal i m pair me nt.
I n t he c o m plete d P hase 2, ra n d o mize d, d o u ble-bli n d, place b o - a n d pre ga bali n -c o ntr olle d 
st u d y of D S- 5 5 6 5 i n s u bjects wit h D P N P i n t he U S ( D S 5 5 65- A- U 2 0 1), t he pri mar y  
efficac y e n d p oi nt was met.  Greater mea n decreases fr o m baseli ne t o e n d-of -treat me nt 
( Wee k 5) i n A D P S were o bser ve d i n t he D S- 5 5 6 5 treat me nt gr o u ps c o m pare d t o place b o.  
T he mea n c ha n ges fr o m baseli ne t o Wee k 5 ( wit h last o bser vati o n carrie d f or war d 
i m p ute d f or missi n g val ues) i n A D P S were - 2. 0, - 2. 3,
-2. 7, - 2. 6, a n d -2. 8 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 treat me nt gr o u ps, res pecti vel y.  B y  c o m paris o n, place b o a n d pre ga bali n 
s h o we d mea n c ha n ges of -1. 9 a n d -1. 8, res pecti vel y .
D S -5 5 6 5 has bee n s h o w n t o be ge nerall y  well -t olerate d at si n gle d oses u p t o 3 0 m g.  T he 
m ost fre q ue ntl y  re p orte d T E A Es are C N S-relate d e ve nts t hat are e x pecte d base d o n t he 
mec ha nis m of acti o n of D S -5 5 6 5 a n d i ncl u de d hi g h rates of dizzi ness a n d s o m n ole nce.  
M ost re p orte d T E A Es were j u d ge d t o be mil d or m o derate, a n d m ost were c o nsi dere d t o 
be relate d t o t he st u d y dr u g.  I n t he c o m plete d P hase 2 st u d y  ( D S 5 5 6 5- A-U 2 0 1), all D S -
5 5 6 5 d ose le vels were ge nerall y well t olerate d.
D S - 5 5 6 5 has bee n st u die d i n s u bjects wit h re nal d y sf u ncti o n. St u d y E 1 0 6 e val uate d t he 
P K a n d safet y of a si n gle 5 m g d ose i n 4 0 s u bjects ( 8 s u bjects wit h n or mal re nal f u ncti o n 
a n d 8 s u bjects eac h wit h mil d, m o derate, se vere , an d E S R D , res pecti vely ). 
P har mac o ki netics of D S -5 5 6 5 a n d its lacta m meta b olite were e val uate d o ver a 7 2 -h o ur 
peri o d. F or t he a nal ys is, t he gr o u ps were a nalyz e d b y n or mal Cr Cl (≥9 0 m L / mi n), mil d 
re d ucti o n i n Cr Cl ( 6 0 t o 8 9 m L/ mi n), m o derate re d ucti o n i n Cr Cl ( 3 0 t o 5 9 m L/ mi n), a n d
se vere re d ucti o n i n Cr Cl ( 1 5 t o 2 9 m L/ mi n).
T he P K a nal ys is i n dicate d t hat t here was a si g nifica nt re d ucti o n i n b ot h C Lr/ F a n d C L/ F 
of D S -5 5 6 5 a n d its lacta m meta b olite as re nal f u ncti o n decrease d (Ta ble 3. 1 ).
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 2
T a ble 3. 1:  
Re n al a n d T ot al Cle ar a nce of D S -5 5 6 5 a n d its L act a m Met a b olite 
wit h Decre asi n g Re n al F u ncti o n
Cr C L 
(m L/ mi n )
N
C L/ F ( L/ hr)
O bser ve d
Me di a n
( Mi n, M a x)
Pre dicte d
Me di a n
( Mi n, M a x)
≥ 9 0   
6
2 0. 0
( 1 2. 7, 2 3. 2)
1 8. 9
( 1 0. 7, 2 2. 9)
6 0 -8 9   
8
1 7. 4
( 8. 9 4, 2 0. 5)
1 7. 2
( 9. 2 8, 1 9. 5)
3 0 -5 9    
1 0
8. 0 4
( 6. 9 0, 1 1. 3)
8. 0 1
( 7. 2 1, 1 1. 2)
1 5 -2 9   
4
4. 7 3
( 3. 8 0, 5. 7 5)
4. 8 1
( 3. 8 3, 5. 9 5)
< 1 5
4
3. 7 6
( 2. 7 5, 5. 9 8 )
3. 8 7
( 2. 8 2, 5. 7 6)
Cr Cl = creati ni ne cleara nce; C L/ F = t otal cleara nce
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 3
I n s u bjects wit h m o derate a n d se vere re nal dys f u ncti o n BI D d oses of 7. 5 m g a n d Q D 
d osi n g of 7. 5 m g are e x pecte d t o pr o d uce e x p os ures e q ui vale nt t o a BI D d oses of 1 5 m g 
i n s u bjects wit h n or mal re nal f u ncti o n (Ta ble 3 .2 ).
T a ble 3. 2:  
Pre dicte d D S -5 5 6 5 A U C wit h D ail y a n d T wice D ail y D oses of 
7. 5- 1 5 m g i n Re n al D ysf u ncti o n
Cr Cl 
Gr o u p 
( m L/ mi n)
D ose  
A U C ss, 0-2 4 h ( n g * h/ m L)
C m a x,ss ( n g/ m L)
Me a n  
Me di a n  
Me a n
Me di a n
≥ 9 0
1 5 m g BI D  
1 8 3 4
1 5 9 0
2 4 1
2 5 2
6 0 -8 9  
1 5 m g BI D  
1 9 5 8
1 7 4 7
2 3 8
2 2 6
3 0 -5 9  
7. 5 m g BI D   
1 7 5 4
1 8 7 3
1 6 1
1 5 2
1 5 -2 9  
7. 5 m g Q D  
1 5 8 6
1 5 6 3
1 5 7
1 6 5
A U C = area u n der t he plas ma c o nce ntrati o n -ti me c ur ve; A U C ss, 0- 2 4 h = area u n der t he plas ma c o nce ntrati o n -
ti me c ur ve at stea d y state fr o m 0 t o 2 4 h o urs; Cma x,ss = m a xi m u m plas ma c o nce ntrati o n at stea d y state; 
Cr Cl = creati ni ne cleara nce; BI D = t wice dail y; Q D = o nce dail y
3. 2. 1. 1.  
E x peri me nt al Tre at me nt f or I n di vi d u al S u bjects
T he re will be n o d ose a dj ust me nts.
3. 2. 2.  
C o ntr ol Tre at me nts
Place b o will ser ve as t he c o ntr ol treat me nt.  I ncl usi o n of place b o is re q uire d i n li g ht of 
t he k n o w n place b o effect i n pai n st u dies.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 4
4.  
S T U D Y P O P U L A TI O N
4. 1.  
E nr oll me nt
I n vesti gat ors will mai ntai n a c o nfi de ntial scree ni n g l o g of all p ote ntial st u d y ca n di dates 
t hat i ncl u des li mite d i nf or mati o n of t he s u bjects (i nitials, a ge, se x) date a n d o utc o me of 
scree ni n g pr ocess (e g, e nr oll i n t he st u d y, reas o n f or i neli gi bilit y, ref use d t o partici pate).
Pri or t o i nitiati o n of f or mal scree ni n g pr oce d ures, eac h s u bject will be as ke d t o re vie w 
a n d si g n t he I CF pr o vi de d b y  t he site.  All s u bjects m ust pers o nall y si g n a n d date t he I C F 
bef ore a n y st u d y -s pecific acti vities occ ur. F or a d diti o nal i nf or mati o n o n i nf or me d 
c o nse nt, see Se cti o n 1. 5. 2 .
Eac h s u bject will be assi g ne d a u ni q ue s u bject i de ntificati o n n u m ber ( SI D) u p o n 
si g nat ure of t he I C F at t he Scree ni n g Visit .  T he SI D will be a n 8-di git n u m ber wit h t he 
first 4 di gits c orres p o n di n g t o t he site n u m ber a n d t he last 4 di gits as se q ue ntiall y 
assi g ne d b y t he i nteracti ve v oice/ we b res p o nse s ys te m (I X R S).  T he SI D will be use d t o 
i de ntif y t he s u bject t hr o u g h o ut t he st u d y a n d will be e ntere d o n all st u d y  d oc u me ntati o n.  
If a s u bject disc o nti n ues fr o m t he st u d y at a n y ti me, his/ her SI D ca n n ot be reassi g ne d t o 
a n ot her s u bject.
I n vesti gat ors will mai ntai n a c o nfi de ntial s u bject i de ntificati o n c o de list.  T his 
c o nfi de ntial list of na mes of all s u bjects all ocate d t o st u d y n um bers o n e nr olli n g i n t he 
st u d y all o ws t he I n vesti gat or t o re veal t he i de ntit y of a ny s u bject w he n necessar y.
A s u bject will be c o nsi dere d e nr olle d u p o n bei n g ra n d o mize d i nt o t he st u d y .  
I n vesti gat ors will mai ntai n a n e nr oll me nt l o g of all s u bjects e nr olle d i n t he st u d y , 
i n dicati n g t heir assi g ne d st u d y n u m ber.
4. 1. 1.  
I ncl usi o n Criteri a
S u bjects m ust satisf y  all of t he f oll o wi n g criteria t o be i ncl u de d i n t he st u d y:
1.
A ge ≥1 8 y ears
2.
A ble t o gi ve writte n i nf or me d c o nse nt
3.
A ble t o c o m plete patie nt -re p orte d q uesti o n naires per t he I n vesti gat or's j u d g me nt
4.
Esti mate d Cr Cl bet wee n 1 5 - 5 9 m L / mi n fr o m ser u m creati ni ne b y t he ce ntral 
la b orat or y usi n g t he C oc kcr oft-Ga ult e q uati o n
5.
Fi br o m yal gia meeti n g A merica n C olle ge of R he u mat ol o g y  criteria f or F M:
a.
Wi des prea d pai n i n de x ( W PI) ≥7 a n d s y m pt o m se verit y ( S S) scale sc ore 
≥5, or W PI  3 t o 6 a n d S S scale sc ore ≥ 9,
b.
Pai n i n at least 1 1 of 1 8 s pecific te n der p oi nt sites,
c.
S y m pt o ms ha ve bee n prese nt at a si milar le vel f or at least 3 m o nt hs, a n d
d.
T he s u b ject d oes n ot ha ve a dis or der t hat w o ul d ot her wise e x plai n t he pai n
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 5
6.
A D P S of ≥4 o n t he 1 1 -p oi nt n u meric rati n g scale ( N R S ) o ver t he 7 da y s pri or t o 
ra n d o mizati o n ( base d o n c o m pleti o n of at least 4 dail y pai n assess me nts d uri n g 
t he 7-da y  baseli ne peri o d prior t o ra n d o mizati o n)
7. 
W o me n of c hil d beari n g p ote ntial ( W O C B P) m ust be usi n g a de q uate met h o ds of 
c o ntrace pti o n (as detaile d i n Secti o n 4. 1. 3 ) t o a v oi d pre g na nc y  d uri n g t he st u d y 
a n d f or 4 wee ks after st u d y  c o m pleti o n. 
4. 1. 2.  
E xcl usi o n Criteri a
S u bjects w h o meet a n y of t he f oll o wi n g criteria will be dis q ualifie d fr o m e nteri n g t he 
st u d y:
1.
Nee d f or o n g oi n g use of c o nc o mita nt c hr o nic pai n me dicati o ns or a n y ne w n o n-
p har mac ol o gical pai n ma na ge me nt tec h ni q ues t hat ma y  c o nf o u n d assess me nts of 
efficac y a n d/ or safety , i ncl u di n g ne ur ol ytic treat me nts ( destr ucti o n of ner ves b y 
c he micals, heat, c ol d) or s ur ger y , i ntrat hecal p u m ps, s pi nal c or d sti m ulat ors or 
ps y c h ol o gical s u p p ort wit hi n t he pre vi o us year. Als o e xcl u de d: t o pical ca psaici n 
wit hi n 6 m o nt hs; or s y ste mic c ortic oster oi ds wit hi n 3 m o nt hs of baseli ne peri o d. 
2.
U na ble t o u n der g o pre -st u d y was h o ut of pr o hi bite d c o nc o mita nt me dicati o ns 
3.
S u bjects wit h rece nt hist or y  (ie, wit hi n 1 y ear pri or t o scree ni n g) of alc o h ol a b use 
or illicit dr u g use (c ocai ne, her oi n, marij ua na [i ncl u di n g me dical, prescri be d], 
etc.)
4.
Use of a n y s electi ve ser ot o ni n re u pta ke i n hi bit or ( S S RI), u nless t he s u bject has 
bee n o n a sta ble d ose f or ≥9 0 da y s pri or t o scree ni n g a n d is n ot a ntici pate d t o 
nee d a n y d ose a dj ust me nt d uri n g t he c o urse of t he st u d y
5.
S u bjects wit h se vere or u nc o ntr olle d de pressi o n t hat, i n t he j u d g me nt of t he 
I n vesti gat or, ma kes t he s u bject i na p pr o priate f or e ntr y i nt o t he st u d y
6.
Si g ni fica nt ne ur ol o gical or ps yc hiatric dis or der u nrelate d t o ne ur o pat hic pai n
7.
Ot her se vere pai n ( e g, sciatica, r he u mat oi d art hritis) t hat mi g ht i m pair t he 
assess me nt of ne ur o pat hic pai n
8.
Cr Cl ≥6 0 m L/ mi n esti mate d fr o m ser u m creati ni ne b y  t he ce ntral la b orat or y
usi n g t he C oc kcr oft -Ga ult e q uati o n.  
9.
S u bjects w h o are o n he m o dial y sis or w h o re q uire he m o dial ysis bef ore t he f oll o w-
u p assess me nt; ac ute re nal fail ure; hist or y  of ki d ne y tra ns pla nt
1 0. A n y  hist or y of a mali g na nc y ot her t ha n basal cell carci n o ma wit hi n t he past 5 
ye ars
1 1. Cli nicall y  si g nifica nt u nsta ble ne ur ol o gic, o p ht hal m ol o gic, he pat o biliar y, 
res pirat or y, or he mat ol o gic ill ness or u nsta ble car di o vasc ular disease (e g, se vere 
h y p ote nsi o n, u nc o ntr olle d car diac arr h y t h mia, or m yocar dial i nfarcti o n) wit hi n 1 2 
m o nt h s pri or t o scree ni n g 
1 2. Pre g na nc y  or breast fee di n g or i nte nt t o bec o me pre g na nt d uri n g t he st u d y  peri o d 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 6
1 3. K n o w n h y perse nsiti vit y  t o α 2δ li ga n ds or ot her c o m p o ne nts of t he st u d y 
me dicati o ns. N ote: Pri or e x p os ure t o D S- 5 5 6 5 is all o we d, as l o n g as 
h y perse nsiti vit y  t o D S-5 5 6 5 was n ot o bser ve d.
1 4. Cli nicall y  si g nifica nt E C G a b n or malities at t he Scree ni n g Visit
1 5. S u bjects w h o are at ris k of s uici de , as defi ne d b y t heir res p o nses t o t he C-S S R S or 
i n t he o pi ni o n of t he I nvesti gat or . N ote: S u bject s a ns weri n g " yes" t o a n y of t he C -
S S R S q uesti o ns m ust be e xcl u de d. S uc h s u bjects s h o ul d be referre d i m me diatel y 
t o a me ntal healt h pr ofessi o nal f or a p pr o priate e val uati o n. 
1 6. S u bjects wit h c urre nt se vere or u nc o ntr olle d maj or de pressi ve dis or der or a n xiet y  
dis or ders as assesse d b y t he Mi ni -i nter nati o nal Ne ur o ps yc hiatric I nter vie w 
( MI NI) i nter vie w ( Versi o n 6. 0) at scree ni n g, or w h o a ns wer “ yes” t o t he 
s uici dalit y q uesti o n (c urre nt or past) o n t he Maj or De pressi ve E pis o de M o d ule 
( M o d ule A) or w h o a ns wer “ yes” t o a n y q uesti o n i n t he S uici dalit y  M o d ule 
( M o d ule B) are e xcl u de d . S u bject wit h mil d t o m o derate maj or de pressi o n or 
a n xiet y dis or ders are per mitte d t o e nr oll pr o vi de d t hat t he i n vesti gat or assesses 
t he s u bject as cli nicall y s ta ble a n d a p pr o priate f or e ntr y i nto t he st u d y .
1 7. S u bjects w h o are u nli kel y t o c o m pl y wit h t he pr ot oc ol ( e g, u nc o o perati ve attit u de, 
i na bilit y t o ret ur n f or s u bse q ue nt visits, a n d/ or ot her wise c o nsi dere d b y t he 
I n vesti gat or t o be u nli kel y t o c o m plete t he st u d y)
1 8. S u bject is c urre ntl y e nr olle d i n, or it has bee n fe wer t ha n 3 0 da y s si nce e n di n g,
a n ot her i n vesti gati o nal de vice or dr u g st u d y  or is recei vi n g a n ot her i n vesti gati o nal 
a ge nt. 
1 9. S u bjects w h o are e m pl o yees or i m me diate fa mil y  of e m pl oye es of t he st u d y site, 
S p o ns or , or c o ntract researc h or g a nizati o n (C R O )
2 0. Scree ni n g la b orat or y  val ues o utsi de t he limits liste d i n t he ta ble bel o w :
He mat ol o g y  
He m o gl o bi n
< 8 g/ d L 
Platelet c o u nt  
< 1 0 0, 0 0 0 /m m 3
A bs ol ute ne utr o p hil 
c o u nt
< 1, 5 0 0/ m m 3
Bl o o d c he mistr y  
A S T 
> 2. 0 × U L N
A L T
> 2. 0 × U L N
Al kali ne p h os p hatase  
> 1. 5 × U L N
T otal bilir u bi n  
> 1. 2 × U L N a
Creati ne ki nase  
> 3. 0 × U L N
Calc ulate d Cr Cl  
≥6 0 m L/ mi n
a If a s u bject has t otal bilir u bi n > U L N, u nc o nj u gate d a n d c o nj u gate d bilir u bi n fracti o ns s h o ul d be a nal yze d 
a n d o nl y s u bjects d oc u me nte d t o ha ve Gil bert’s s y n dr o me ma y be e nr olle d.
A b bre viati o ns: A L T = ala ni ne a mi n otra nsferase, A S T = as partate a mi n otra nsferase, Cr Cl = creati ni ne 
cleara nce ( deter mi ne d b y t he ce ntral la b orat or y usi n g t he C oc kcr oft -Ga ult e q uati o n), U L N = u p per li mit 
of n or mal W o m e n of C hil d Beari n g P ote ntial
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 7
4. 1. 3.    
W o me n of C hil d Be ari n g P ote nti al
F or t he p ur p oses of t his st u d y, all fe male partici pa nts will be c o nsi dere d as W O C B P 
u nless t he y  ha ve u n der g o ne s ur gical sterilizati o n ( wit h d oc u me nte d h y sterect o m y, 
bilateral sal pi n gect o m y a n d bilateral o ö p h orect o m y) or are p ost me n o pa usal a n d ha ve a 
d oc u me nte d ser u m f ollicle sti m ulati n g h or m o ne le vel > 3 5 mI U/ m L ( wit h or wit h o ut 
h or m o ne re place me nt t hera p y) a n d n o me nses wit hi n t he pre vi o us 1 2 m o nt hs.
W O C B P are per mitte d i n t he st u d y  b ut m ust c o nse nt t o a v oi d bec o mi n g pre g na nt b y 
usi n g a p pr o ve d c o ntrace pti o n met h o ds t hr o u g h o ut t he st u d y a n d f or u p t o 4 wee ks after 
c o m pleti o n, as descri be d bel o w.
St u d y -acce pta ble met h o ds of birt h c o ntr ol are d o u ble -barrier met h o ds, w hic h i ncl u de a 
c o m bi nati o n of a n y 2 of t he f oll o wi n g: s yste mic c o ntrace pti ves, dia p hra g m, c o n d o m, a n y 
i ntra uteri ne de vice, part ner’s vasect o m y, or s p o n ge wit h s per mici de. S per mici de ca n be 
use d i n c o m bi nati o n wit h a n y  of t he ot her met h o ds liste d. 
W O C B P
m ust ha ve a ne gati ve pre g na nc y  test at all cli nic visits . 
Daiic hi Sa n k y o m ust be n otifie d of a n y st u d y s u bject w h o bec o mes pre g na nt w hile 
partici pati n g i n t his cli nical st u d y , as descri be d i n Secti o n 9. 6.
4. 2.  
Re m o v al of S u bjects Fr o m T her a p y
Data fr o m all ra n d o mize d s u bjects are i m p orta nt t o ac hie ve st u d y o bjecti ves a n d s u bjects 
s h o ul d be e nc o ura ge d t o a d here t o pr ot oc ol i nstr ucti o ns a n d visit sc he d ules.  H o we ver, i n 
acc or da nce wit h t he Declarati o n of Helsi n ki a n d ot her a p plica ble re g ulati o ns, a s u bject 
has t he ri g ht t o wit h dra w fr o m t he st u d y  at a n y ti me, a n d f or a ny reas o n, wit h o ut 
prej u dice t o his or her f ut ure me dical care b y t he st u d y  p h ysicia n or at t he st u d y site.  T he 
I n vesti gat or is als o free t o ter mi nate a s u bject’s i n v ol ve me nt i n t he st u d y at a n y ti me if 
t he s u bject’s cli nical c o n diti o n warra nts s uc h acti o n.  T he S p o ns or or re g ulat or y  
a ut h orities als o ma y re q uest ter mi nati o n of t he st u d y at a n y ti me d ue t o safet y iss ues or 
c o ncer ns relate d t o st u d y c o n d uct.
N O T E: I n t his st u d y , t he C-S S R S will be a d mi nistere d at all cli nic visits.  Base d o n t he 
C- S S R S a n d i n vesti gat or j u d g me nt, if a s u bject is i de ntifie d as bei n g at ris k f or s uici de, 
a p pr o priate safet y meas ures s h o ul d be i m ple me nte d (see Secti o n 3. 1. 5. 2 ).
T he MI NI a n d C -S S R S are t o be a d mi nistere d at a n y ti me d uri n g t he st u d y (i ncl u di n g 
u nsc he d ule d visits) base d o n i n vesti gat or’s discreti o n (see Secti o n 3. 1. 5. 2 ).
4. 2. 1.  
Re as o ns f or Wit h dr a w al/ E arl y Disc o nti n u ati o n
A n y  s u bject w h o disc o nti n ues fr o m t he st u d y treat me nt f or a ny reas o n will ha ve t heir 
reas o n f or st u d y treat me nt disc o nti n uati o n rec or de d o n t he e C R F usi n g t he f oll o wi n g 
criteria.
F or s u bjects wit h dra w n pri or t o ra n d o mizati o n b ut after si g ni n g i nf or me d c o nse nt :

Di d n ot satisf y  all i ncl usi o n/e xcl usi o n criteria

A d verse e ve nt
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 8

L ost t o f oll o w - u p

Wit h dra wal b y s u bject ( i n dicate reas o n) 

P h y sicia n decisi o n

St u d y  ter mi nate d b y S p o ns or
F or s u bjects disc o nti n ue d or wit h dra w n after ra n d o mizati o n b ut bef ore c o m pleti n g t he 
treat me nt peri o d:

A d verse e ve nt

Deat h

Lac k of percei ve d efficac y b y  s u bject or i n vesti gat or

Cr Cl < 1 5 m L / mi n

L ost t o f oll o w - u p

Pr ot oc ol vi olati o n

St u d y  ter mi nate d b y S p o ns or

Wit h dra wal b y  su bject (i n dicate reas o n)

Ot her (i n dicate reas o n)
A s u bject ma y  be wit h dra w n d ue t o n o n-c o m plia nce wit h a n y as pect of t he pr ot oc ol, as 
deter mi ne d b y t he I n vesti gat or a n d/ or t he S p o ns or ’s me dical m o nit or or desi g nee.
S u bjects w h o miss > 7 da ys of c o nsec uti ve d oses of st u d y  me dicati o n will be wit h dra w n 
fr o m t he st u d y a n d early ter mi nati o n st u d y pr oce d ures perf or me d.
If t he s u bject is wit h dra w n d ue t o a n a d verse e ve nt, t he In vesti gat or will f oll o w t he 
s u bject u ntil t he a d verse e ve nt has res ol ve d or sta bilize d.
All s u bjects w h o are wit h dra w n fr o m t he st u d y  s h o ul d c o m plete pr ot oc ol s pecifie d 
wit h dra wal pr oce d ures ( Secti o n 4. 2. 2 ).
4. 2. 2.  
Wit h dr a w al Pr oce d ures
If a s u bject wit h dra ws ( or is wit h dra w n) fr o m t he st u d y, t he I n vesti gat or s h o ul d c o m plete 
a n d re p ort all o bser vati o ns as t h or o u g hl y as p ossi ble u p t o t he date of wit h dra wal, 
i ncl u di n g t he date of last treat me nt a n d t he reas o n f or wit h dra wal. Reas o ns rec or de d 
u n der “ pr ot oc ol vi olati o n” ma y  i ncl u de fail ure t o c o m pl y wit h pr ot oc ol re q uire me nts or 
st u d y pr oce d ures, pre g na nc y, etc. 
If t he s u bject is wit h dra w n d ue t o a n A E, t he I n vesti gat or s h o ul d f oll o w t he s u bject u ntil 
t he A E has res ol ve d or sta bilize d. 
All s u bjects w h o are wit h dra w n fr o m t he st u d y  s h o ul d co m plete all e n d- of-
treat me nt/early ter mi nati o n pr oce d ures as s o o n as p ossi ble after earl y wit h dra wal.  All 
s u bjects w h o are wit h dra w n fr o m t he st u dy s h o ul d ret ur n f or p ost -treat me nt f oll o w-u p 
visits.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 9
4. 2. 3.  
S u bject Re pl ace me nt
S u bjects re m o ve d fr o m t he st u d y  f or a n y reas o n will n ot be re place d.
4. 2. 4.  
S u bject Re -scree ni n g Pr oce d ures
Re -scree ni n g of s u bjects is n ot per mitte d e xce pt wit h per missi o n fr o m t he s p o ns or.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 0
5.  
T R E A T M E N T S A D MI NI S T E R E D
5. 1.  
I n vesti g ati o n al Pr o d ucts
T he I n vesti gat or m ust e ns ure t hat t he i n vesti gati o nal pr o d u ct will be use d o nl y i n 
acc or da nce wit h t he pr ot oc ol.
T he i n vesti gati o nal pr o d ucts f or t his st u d y  are:

D S - 5 5 6 5 7. 5 m g ta blets

Place b o ta blets matc hi n g D S - 5 5 6 5 7. 5 m g ta blets
5. 1. 1.  
Met h o d of Assi g ni n g S u bjects t o Tre at me nts a n d Bli n di n g
Ra n d o mizati o n will be perf or me d ce ntrall y  usi n g a n I X R S.  At t he Scree ni n g Visit , t he 
I n vesti gat or, or ot her site pers o n nel u n der t he directi o n of t he I n vesti gat or, s h o ul d c o ntact 
or access t he I X R S t o re gister t he s u bject, o btai n t he SI D, a n d rec or d t he s u bject’s 
i nitials, date of birt h, se x, a n d i nitial scree ni n g date.  U p o n c o nfir mati o n of a s u bject’s 
eli gi bilit y at t he Ra n d o mizati o n Visit , t he I nvesti gat or , or desi g nee, will c o ntact t he I X R S 
t o re gister t he s u bject as ra n d o mize d a n d o btai n t he i de ntificati o n n u m ber of t he i nitial 
st u d y me dicati o n blister pac k (“ wallet”) t o be dis pe nse d t o t his s u bject.  At eac h 
o n- treat me nt v isit, t he I nvesti gat or , or desi g nee, s h o ul d c o ntact t he I X R S t o rec or d t he 
s u bject’s visit a n d stat us a n d o btai n t he c orrect wallet n u m ber t o be dis pe nse d at t hat 
visit.  St u d y  me dicati o n s h o ul d o nl y be dis pe nse d i n acc or da nce wit h I X R S i nstr ucti o ns 
a n d wallet n u m ber assi g n me nt.  At t he E n d - of-treat me nt/ Earl y Ter mi nati o n Visit s, t he 
s u bject’s visit a n d stat us s h o ul d als o be rec or de d usi n g t he I X R S.
T he ra n d o mi zati o n sc he d ule will be ge nerate d b y a n i n de pe n de nt statisticia n at t he C R O 
a n d re vie we d a n d a p pr o ve d b y  a statisticia n at Daiic hi Sa n k yo w h o is i n de pe n de nt of all 
ot her as pects of st u d y c o n d uct.  T he ra n d o mizati o n sc he d ule will be mai ntai ne d b y  t he 
i n de pen de nt statisticia n at t he C R O a n d will be ke pt strictl y  c o nfi de ntial.  I X R S a n d 
Cli nical S u p pl y  O perati o ns pers o n nel will ha ve access t o me dicati o n i de ntificati o n c o des 
b ut will re mai n bli n de d t o treat me nt.  All ot her pers o n nel i n v ol ve d wit h t he c o n d uct a n d 
t he i nter pretati o n of t he st u d y, i ncl u di n g t he I n vesti gat ors, i n vesti gati o nal site pers o n nel, 
a n d Daiic hi Sa n k y o e m pl o yees, will be bli n de d t o t he treat me nt u ntil after t he data base 
l oc k.
Ra n d o mizati o n will be stratifie d b y C K D strata t hr o u g h t he I X R S.  E li gi ble s u bjects will 
be ra n d o mize d i n t he rati o of 2: 1 t o recei ve 1 3 wee ks of treat me nt wit h D S -5 5 6 5 7. 5 m g 
Q D or place b o f or Cr Cl 1 5- 2 9 m L / mi n or wit h D S -5 5 6 5 7. 5 m g BI D or place b o f or Cr Cl 
3 0 - 5 9 m L / mi n. I n or der t o mai ntai n t he bli n d, t he pac ka ge will ha ve o ne of t he f oll o wi n g 
m or ni n g a n d ni g ht d ose sc he mes ( BI D: 2 acti ve; Q D: 1 acti ve + place b o; Place b o: 2
place b o ).
5. 1. 1. 1.  
E mer ge nc y U n bli n di n g f or S afet y Re as o ns
I n t he case of a rare e mer ge nc y w here, i n t he i n vesti gat or’s o pi ni o n, u n bli n di n g of t he 
treat me nt is necessar y i n or der t o e val uate f urt her c o urse of acti o n, t he i n vesti gat or 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 1
s h o ul d access t he I X R S a n d f oll o w t he i nstr ucti o ns t o i nitiate s u bject u n bli n di n g. T he 
i n vesti gat or ma y als o c o ntact t he s p o ns or or desi g nee’s Me dical M o nit or f or i nf or mati o n 
relate d t o D S 5 5 6 5’s a d verse effects i n ma ki n g t he decisi o n t o u n bli n d. ( C o ntact 
i nf or mati o n – please refer t o t he St u d y  O perati o ns Ma n ual, w hic h c o ntai ns t he ke y  
Me dical M o nit ori n g st u d y pers o n nel a n d t heir c o ntact i nf or mati o n.) 
T he i n vesti gat or s h o ul d pr o m ptl y  d oc u me nt a n d re p ort t o t he s p o ns or a n y u n bli n di n g (e g, 
acci de ntal u n bli n di n g, u n bli n di n g d ue t o a seri o us a d verse e ve nt) of t he i n vesti gati o nal 
pr o d uct(s).
I n t he e ve nt of u n bli n di n g, t he s u bject will be i nf or me d a b o ut t heir treat me nt assi g n me nt 
( D S-5 5 6 5 or place b o). If t he s u bject is recei vi n g D S-5 5 6 5, t he s pecific treat me nt gr o u p 
( 7.5 m g Q D or 7. 5 m g BI D) will n ot be re veale d. I nf or mati o n a b o ut t he treat me nt 
assi g n me nt m ust be restricte d t o desi g nate d st u d y  site staff/ pers o n nel t hat are pr o vi di n g 
i m me diate care t o t he s u bject.  A ny d oc u me ntati o n of t he treat me nt assi g n me nt m ust be 
mai ntai ne d se paratel y ( i. e., a sec ure d file).  T he i nf or mati o n m ust n ot be i ncl u de d i n t he 
s u bject’s s o urce files t o e ns ure t he treat me nt assi g n me nt will re mai n bli n de d t o t he C R O 
m o nit or a n d ot her st u d y  pers o n nel n ot i n v ol ve d wit h t he s u bject’s i m me diate care.
W he n a n e mer ge nc y  u n bli n di n g has occ urre d, a n a ut o matic n otificati o n ( via e-mail) will 
be se nt t o t he In vesti gat or a n d selecte d Daiic hi Sa n k y o st u d y  pers o n nel fr o m t he IX R S 
ve n d or.  T he n otificati o n will n ot c o ntai n a n y  u n bli n di n g i nf or mati o n.  T his will tri g ger 
t he f oll o w-u p pr ocess t o d oc u me nt t he u n bli n di n g b y  c o m pleti n g t he E mer ge nc y 
U n bli n di n g b y I n vesti gat or F or m (t o be pr o vi de d b y st u d y pers o n nel u p o n recei pt of 
I X R S n otificati o n) a n d s u b mit t o Daiic hi Sa n k yo Cli nical Safet y  a n d P har mac o vi gila nce 
( C S P V); please refer t o t he f or m f or c o m pleti o n i nstr ucti o ns.
O nce t he st u d y treat me nt has bee n u n bli n de d, t he st u d y  treat me nt s h o ul d be disc o nti n ue d, 
a n d t he s u bject s h o ul d lea ve t he st u d y treat me nt P hase .  T he s u bject will be see n f or e n d-
of- treat me nt assess me nts a n d f oll o w - u p, as define d i n Secti o n 6. 5 a n d Secti o n 6. 6 .
5. 1. 2.  
Met h o d of Assessi n g Tre at me nt C o m pli a nce
Rec or ds of treat me nt c o m p lia nce f or eac h s u bject will be ke pt d uri n g t he st u d y.  T he 
i de ntificati o n n u m ber of all dis pe nse d a n d ret ur ne d st u d y dr u g wallets s h o ul d be 
rec or de d, al o n g wit h t he SID.  T he n u m ber of ta blets use d a n d re mai ni n g i n eac h wallet 
s h o ul d be d oc u me nte d at eac h o n- treat me nt v isit a n d t he E n d - of-treat me nt/ Early 
Ter mi nati o n Visit .  If a n y ta blets ha ve bee n re m o ve d fr o m t he wallets ( b ut n ot ta ke n), 
t hese s h o ul d be c o u nte d, d oc u me nte d, a n d retai ne d.
Treat me nt c o m plia nce will be calc ulate d b y di vi di n g t he n u m ber of d oses ta ke n b y  t he 
n u m ber of d oses assi g ne d f or t he a p pr o priate visit i nter val (a dj uste d f or a n y c ha n ges i n 
t he visit i nter val).  C o m plia nce f or eac h visit i nter val is defi ne d as ta ki n g at least 8 0 % of 
t he st u d y dr u g d osa ge prescri be d f or t hat i nter val.  If a s u bject is n o nc o m plia nt, t he 
s u bject will be c o u nsele d b y st u d y staff o n t he i m p orta nce of ta ki n g t he c orrect a m o u nt of 
st u d y me dicati o n.  As t he pri mar y a nalys is will f oll o w t he i nte nt-t o-treat pri nci ple, 
s u bjects s h o ul d n ot be disc o nti n ue d fr o m t he stu d y  f or treat me nt n o nc o m plia nce u nless 
t he s u bject meets t he disc o nti n uati o n criteria o utli ne d i n Secti o n 4. 2. 1 .
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 2
5. 1. 3.  
L a beli n g a n d P ac k a gi n g
D o u ble- bli n d st u d y me dicati o n will be pr o vi de d i n la bele d blister car ds ( wallets).  T he 
blister la bel will i ncl u de all i nf or mati o n re q uire d b y  fe deral a n d l ocal re g ulati o ns. 
A d diti o nal details o n t he i n vesti gati o nal dr u g pr o d ucts, s uc h as t he e x pirati o n date, ca n be 
f ou n d i n d oc u me ntati o n acc o m pa n yi n g dr u g s hi p me nt.
C o de -brea k e n vel o pes or scratc h -off la bels will n ot be use d f or u n bli n di n g i n t his st u d y .  
U n bli n di n g of i n di vi d ual s u bjects will be c o ntr olle d usi n g t he I X R S (see Secti o n 5. 1. 1 ).
5. 1. 4.  
Pre p ar ati o n
D o u ble -bli n d st u d y  dr u g will be pr o vi de d t o sites as f ull y pre pare d blister car ds 
( wallets). All wallets will ha ve 1 ta blet f or t he m or ni n g d ose a n d 1 ta blet f or t he be dti me 
d ose f or eac h da y  of d osi n g f or b ot h Q D a n d BI D, as well as p lace b o.
St u d y  treat me nt ca n be ta ke n irres pecti ve of f o o d i nta ke. Wallets will be i n di vi d uall y 
n u m bere d; o nl y  t he c orrectl y n u m bere d wallet(s) s h o ul d be distri b ute d t o st u d y s u bjects 
i n acc or da nce wit h I X R S i nstr ucti o ns.
5. 1. 5.  
St or a ge
Dr u g s u p plies m ust be st ore d a p pr o priatel y i n a l oc ke d ca bi net i n a r o o m wit h li mite d a n d 
c o ntr olle d access u n der t he rec o m me n de d st ora ge c o n diti o ns.  T he rec o m me n de d st ora ge 
c o n diti o ns are pr o vi de d wit h t he s h i p me nt of dr u g s u p plies ( o n t he cart o n a n d wallets of 
I n vesti gati o nal material) .
N O T E:  If st ora ge c o n diti o ns g o o utsi de of t he rec o m me n de d st ora ge c o n diti o ns, t he site 
m ust n ot dis pe nse t he affecte d s u p plies (affecte d s u p plies s h o ul d be place d i n q uara nti ne
per I X RS re q uire me nts). Pr o per n otificati o n pr ocesses m ust be f oll o we d i m me diatel y 
after recei pt of I M P i de ntifie d as ha vi n g a te m perat ure e xc ursi o n.
5. 1. 6.    
Dr u g Acc o u nt a bilit y
W he n a dr u g s hi p me nt is recei ve d, t he I n vesti gat or or desi g nee will c hec k t he a m o u n t 
a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal la n g ua ge i n t he la bel, dr u g 
e x pirati o n date (if a vaila ble), a n d re gister recei pt i n IX R S . The I n vesti gat or or desi g nee 
s hall re p ort a pr o ble m wit h t he s hi p me nt via IX R S as s o o n as p ossi ble , as well as f oll o w 
t he i nstr ucti o ns o n t he Te m plate® i nstr ucti o n f or m as t he y pertai n t o a n y te m perat ure 
e xc ursi o ns.     
A Dr u g Acc o u nta bilit y  Rec or d will be pr o vi de d t o eac h site f or d oc u me nti n g t he use of 
t he i n vesti gati o nal pr o d uct.  T he rec or d m ust be ke pt c urre nt a n d s h o ul d i ncl u de t he date 
a n d q ua ntit y of dr u g ( n u m ber of wallets) recei ve d at eac h s hi p me nt, t he SI D (a n d i nitials) 
of eac h ra n d o mize d s u bject f or w h o m t he i n vesti gati o nal pr o d uct was dis pe nse d, t he 
wallet n u m bers, date a n d q ua ntities of i n vesti gat i o nal pr o d uct dis pe nse d at eac h visit, 
a m o u nt of re mai ni n g or ret ur ne d pr o d uct recei ve d at eac h s u bject visit (i ncl u di n g t he 
n u m ber of ta blets i nsi de or o utsi de of ret ur ne d wallets), a n d t he i nitials of t he dis pe nser.
At t he e n d of t he st u d y, or as directe d, all st u d y  treat me nt, i ncl u di n g u n use d, partiall y 
use d, or e m pt y wallets, a n d a n y dr u g t hat ma y ha ve bee n re m o ve d fr o m t he wallets ( b ut 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 3
n ot ta ke n), will be destr o y e d l ocall y. If a site or c o u ntr y d oes n ot ha ve a mea ns f or 
destr ucti o n, t he material will b e ret ur ne d t o t he s hi p pi n g de p ot, as i nstr ucte d b y t he 
S p o ns or. I nvesti gati o nal pr o d uct will be destr o ye d  or ret ur ne d o nl y after t he st u d y 
m o nit or has c o m plete d a fi nal i n ve nt or y  t o verif y t he q ua ntit y t o be ret ur ne d.  T he ret ur n 
a n d/ or destr ucti o n of I P are t o als o be pr ocesse d t hr o u g h t he I X R S. 
At t he e n d of t he st u d y, a fi nal i n vesti gati o nal pr o d uct rec o nciliati o n state me nt m ust be 
c o m plete d b y t he I n vesti gat or, or desi g nee, a n d pr o vi de d t o t he S p o ns or .  U n use d dr u g 
s u p plies ma y be destr o ye d b y t he I nvesti gat or w he n a p pr o ve d i n writi n g b y t he S p o ns or
a n d t he S p o ns or has recei ve d c o pies of t he site’s dr u g ha n dli n g a n d dis p ositi o n sta n dar d 
o perati n g pr oce d ures ( S O Ps). T he ret ur n of I n vesti gati o nal Pr o d uct m ust be d oc u me nte d
a n d t he d oc u me ntati o n i ncl u d e d i n t he s hi p me nt as well as c o ntai ne d wit hi n t he pac ki n g 
sli p.
All i n vesti gati o nal pr o d uct i n ve nt or y  f or ms m ust be ma de a vaila ble f or i ns pecti o n b y t he 
S p o ns or ’s a ut h orize d re prese ntati ve (e g, C R O site m o nit or) a n d a ny a ut h orize d i ns pect or 
fr o m a re g ulat or y a ge nc y.  T he I n vesti gat or is res p o nsi ble f or t he acc o u nta bilit y of all 
use d a n d u n use d st u d y s u p plies at t he site.
5. 2.  
C o nc o mit a nt Me dic ati o ns
5. 2. 1.  
Pr o hi bite d Me dic ati o ns
Use of c o nc o mita nt me dicati o ns t hat ma y  c o nf o u n d assess me nts of safet y or efficac y  is
n ot per mitte d d uri n g t he st u d y .  T his is partic ularl y i m p orta nt f or a nal gesics a n d/ or ot her 
me dicati o ns or t hera pies t hat ma y  be i nte n de d s pecifically as treat me nts f or F M .  
S u bjects w h o are recei vi n g me dicati o n f or F M ( or a n y pr o hi bite d me dicati o n liste d i n
Ta ble 5. 1 ) will be re q uire d t o u n der g o dr u g was h o ut pri or t o t he Baseli ne Peri o d.  T he 
I nvesti gat or s h o ul d c o m pl y wit h pr o d uct la beli n g i nstr ucti o ns f or dr u g disc o nti n uati o n 
(e g, ta peri n g of o pi oi ds t o a v oi d si de effects relate d t o de pe n de nce).  Mi ni m u m was h o ut 
re q uire me nts f or s pecific classes of pr o hi bite d me dicati o ns are pr o vi de d i n Ta ble 5. 1 .  
S u bjects recei vi n g treat me nt f or F M s h o ul d n ot be gi n was h o ut of pai n me dicati o n u ntil 
t he y are deter mi ne d t o be p ote ntiall y eli gi ble f or t he st u d y b y  t he I n vesti gat or a n d 
c o ntacte d via tele p h o ne b y t he In vesti gat or or desi g nee . 
S u bjects s h o ul d be i nstr ucte d n ot t o ta ke a n y pr o hi bite d a nal gesic me dici ne, as liste d o n
Ta ble 5. 1 , d uri n g t he Baseli ne Peri o d, pri or t o Ra n d o mizati o n, or d uri n g t he s u bse q ue nt 
treat me nt peri o d.  Use of pr o hi bite d me dicati o ns ma y necessitate s u bject disc o nti n uati o n 
fr o m t he st u d y.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 4
T a ble 5. 1:   
Pr o hi bite d Me dic ati o ns a n d Tre at me nts - D uri n g B aseli ne a n d 
Tre at me nt Peri o ds
Me dic ati o n Cl ass/ E x a m ple Dr u gs
Mi ni m u m  W as h o ut Peri o d Pri or t o C ollecti o n of 
Pre -R a n d o m iz ati o n B aseli ne P ai n Assess me ntsa
A ntic o n v ulsa nts, i ncl u di n g pre ga bali n a n d ga ba pe nti n
3 da ys
O pi oi ds, i ncl u di n g tra ma d ol; ta pe nta d ol
7 da ys
C O X -1 a n d -2 i n hi bit ors
3 da ys
Be nz o diaze pi nes
7 da ys
Tric yclic a nti de pressa nts a n d S N RI (e g, d ul o xeti ne)
7 da ys
Ot her: N o n -be nz o diaze pi ne h y p n otics, s uc h as z ol pi de m, 
s keletal m uscle rela xa nts, t o pical ca psaici n, c hr o mi u m 
pic oli nate, l ocal a nest hetics , -li p oic aci d, e ve ni n g 
pri mr ose oil, fatt y aci d s u p ple m e nts, a n d me ma nti ne
3 da ys
a I n vesti gat ors s h o ul d als o c o m pl y wit h pr o d uct la beli n g rec o m me n dati o ns f or dr u g disc o nti n uati o n.
C O X -1 a n d -2 = c ycl o o x y ge nase t y pe 1 a n d 2
N o n -p har mac ol o gical t hera pies f or ne ur o pat hic pai n, s uc h as ac u p u nct ure, laser t hera p y, 
s pi nal c or d sti m ulati o n, electrical ner ve sti m ulati o n, s ur ger y, i nitiati o n of ps yc h ol o gical 
s u p p ort, or a ny ot her treat me nt desi g ne d t o m o d ulate t he perce pti o n of pai n, are als o 
pr o hi bite d d uri n g t he st u d y .
S u bjects s h o ul d be i nstr ucte d t o a v oi d e xcessi ve c o ns u m pti o n of alc o h ol d uri n g t he 
treat me nt peri o d, as st u d y dr u g ma y i ncrease si de effects of slee pi ness a n d dizzi ness a n d 
p ote ntiate t he i m pair me nt of m ot or s kills.
5. 2. 2.    
All o w a ble Me dic ati o ns
Use of S S RI s ( b ut n ot S N RIs) is all o we d if t he s u bject has bee n o n a sta ble d ose f or
≥9 0 da y s pri or t o scree ni n g a n d is n ot a ntici pate d t o nee d a dj ust me nt d uri n g t he st u d y 
peri o d.
As piri n ( u p t o 1 6 0 m g/ da y) f or m y ocar dial i nfarcti o n a n d str o ke pr o p h yl a xis is per mitte d.  
A ceta mi n o p he n/ paraceta m ol ( u p t o 2 gra ms/ da y i n di vi de d d oses at i nter vals of 4- 6 
h o urs ) is t he s ole resc ue me dicati o n.  T he use of all pai n-relate d me dicati o ns i ncl u di n g 
aceta mi n o p he n/ paraceta m ol m ust be d oc u me nte d as a c o nc o mita nt me dicati o n.  T he 
reas o n or i n dicati o n f or its use s h o ul d als o be rec or de d as a n a d verse e ve nt i n t he e C R F.  
T he s u bject s h o ul d be i nstr ucte d o n ris ks ass ociate d wit h aceta mi n o p he n / paraceta m ol
o ver d ose. 
A n y  ot her n o n- st u d y me dicati o n ta ke n b y t he s u bject d uri n g t he c o urse of t he st u d y 
s h o ul d be rec or de d as a c o nc o mita nt me dicati o n o n t he e C R F.  T he c o n diti o n or 
i n dicati o n s h o ul d be rec or de d as a n a d verse e ve nt, as a p pr o priate, a n d t he d ose, r o ute of 
a d mi nistrati o n, start a n d e n d-of- treat me nt, a n d ot her rele va nt i nf or mati o n (e g, reas o n f or 
use) s h o ul d be d oc u me nte d.
Birt h c o ntr ol me dicati o ns are per mitte d.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 5
6.  
S T U D Y P R O C E D U R E S
A st u d y  visit sc he d ule i n ta b ular f or mat is pr o vi de d i n Secti o n 1 7 .
N O T E : T he MI NI a n d C-S S R S are t o be a d mi nistere d at a ny ti me d uri n g t he st u d y  
(i ncl u di n g u nsc he d ule d visits) base d o n i n vesti gat or’s discreti o n (Secti o n 3. 1. 5. 2 ).
6. 1.  
Scree ni n g 
If a s u bject d oes n ot ha ve a creati ni ne cleara nce ( Cr Cl) deter mi nati o n wit hi n 6 m o nt hs 
pri or t o scree ni n g , a pre -scree ni n g deter mi nati o n s h o ul d be d o ne. If t he Cr Cl le vel 
q ualifies f or t he st u d y, t he s u bject ma y  pr ocee d t o t he f ull scree ni n g pa nel.
T he scree ni n g peri o d will last fr o m t he Scree ni n g Visit ( Visit 1) u p t o t he da y of 
ra n d o mizati o n ( Visit 4 ).  T he scree ni n g peri o d will i ncl u de a Scree ni n g Visit ( Visit 1), 
a n d a Baseli ne Visit ( Visit 3), i m me diatel y f oll o we d b y a 7-da y  baseli ne peri o d (f or 
assess me nt of baseli ne pai n i nte nsit y  usi n g s u bject diaries). T he d urati o n of t he Scree ni n g 
Peri o d will be a p pr o x i matel y 3 wee ks, b ut n o l o n ger t ha n 3 5 da y s.
S u bjects recei vi n g treat me nt f or F M ( or a ny pr o hi bite d me dicati o n liste d i n Secti o n 5. 2 ) 
will be re q uire d t o u n der g o dr u g was h o ut i n acc or da nce wit h i nstr ucti o ns f or treat me nt 
disc o nti n uati o n o n t he res pecti ve pr o d uct la bel (see  Ta ble 5. 1 f or mi ni m u m was h o ut 
re q uire me nts).  H o we ver, s u bjects recei vi n g treat me nt f or F M will be re q ueste d n ot t o 
be gi n was h o ut of pai n me dicati o n u ntil t he y  are deter mi ne d t o be p ote ntiall y eli gi ble f or 
t he st u d y b y t he I n vesti gat or.  O nce p ote ntial eli gi bilit y is c o nfir me d, t he I nvesti gat or , or 
a pers o n desi g nate d b y t he I n vesti gat or, will c o ntact t he s u bject b y tele p h o ne t o be gi n t he 
s pecifie d Was h o ut Peri o d.  T he na me of t he pri or F M me dicati o n a n d date of last 
a d mi nistrati o n will be rec or de d o n t he e C R F.
All s u bjects will be re q uire d t o u n der g o a 1 -wee k Base li ne Peri o d ( pre-ra n d o mizati o n), 
d uri n g w hic h dail y pai n sc ores will be rec or de d i n electr o nic diaries.  Electr o nic diaries 
will be distri b ute d t o s u bjects at start of t he Baseli ne Peri o d.  S u bjects w h o are n ot 
recei vi n g treat me nt f or F M ( or a ny pr o hi bite d me dicati o n liste d i n Secti o n 5. 2 ) at or pri or 
t o t he Scree ni n g Visit ca n be gi n t he 1 -wee k Baseli ne Peri o d as s o o n as t he y  are n otifie d 
b y  t he I nvesti gat or ( or site pers o n nel) t hat t he y are p ote ntiall y eli gi ble f or partici pati o n i n 
t he trial.  S u bjects w h o re q uire dr u g was h o ut will be gi n t he 1 -wee k Baseli ne Peri o d after 
t he y ha ve c o m plete d t he s pecifie d Was h o ut Peri o d.  Fasti n g is n ot re q uire d pri or t o t he 
Scree ni n g or Ra n d o mizati o n Visit s.
6. 1. 1.   
Scree ni n g Visit ( Visit 1; Wee k
≤ - 4, Pri or t o R a n d o miz ati o n)
T he i nitial Scree ni n g Visit s h o ul d occ ur n o m ore t ha n 3 5 da y s pri or t o t he Ra n d o mizati o n 
Visit .  N o fasti n g is re q uire d f or t he Scree ni n g Visit .  At t he Scree ni n g Visit ( Visit 1), 
s u bjects will be scree ne d f or partici pati o n base d o n assess me nt of all n o ni n vasi ve 
eli gi bilit y criteria liste d i n S ecti o n 4. 1 .  If a s u bject is c o nsi dere d li kel y t o satisf y 
eli gi bilit y criteria, t he I nvesti gat or is res p o nsi ble f or o btai ni n g writte n i nf or me d c o nsent 
fr o m t he s u bject, after pr o vi di n g a n a de q uate e x pla nati o n of t he ai ms, met h o ds, 
a ntici pate d be nefits, a n d p ote ntial hazar ds of t he st u d y  a n d bef ore a ny pr ot oc ol -s pecific 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 6
scree ni n g pr oce d ures or a n y st u d y dr u gs are a d mi nistere d.  F or a d diti o nal i nf or mati o n o n 
i nf or me d c o nse nt, refer t o Secti o n 1. 5. 2 .
T he f oll o wi n g acti vities a n d/ or assess me nts will be p erf or me d at/ d uri n g t he Scree ni n g
Visit :

O btai n writte n i nf or me d c o nse nt pri or t o perf or mi n g a n y of t he f or mal 
scree ni n g pr oce d ures.  

A d m i nister t he C-S S R S (see Secti o n 9. 3. 1 )

A d mi nister t he M .I. N.I. Versi o n 6. 0 i nter vie w .  

Rec or d de m o gra p hic i nf or mati o n

O btai n me dical a n d s ur gical hist or y , i ncl u di n g date of o nset of F M

Rec or d pri or a n d c o nc o mita nt me dicati o ns

Rec or d vital si g ns (te m perat ure, heart rate, s u pi ne a n d ort h ostatic bl o o d 
press ure), b o d y hei g ht, a n d b o d y wei g ht

Perf or m p h ys ical e xa mi nati o n

Perf o r m ne ur ol o gical assess me nt

Perf or m a 1 2 -lea d E C G (Secti o n 9. 9 )

C ollect bl o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d cli nical la b orat or y 
safety tests (c he mistr y, he mat ol o g y, a n d uri nal ys is) 

C ollect a bl o o d sa m ple f or a ser u m pre g na nc y  test o n all W O C B P s u bjects

Assess all a p plica ble i ncl usi o n a n d e xcl usi o n criteria

F or s u bjects w h o re q uire was h o ut of pai n me dicati o n, deter mi ne a p pr o priate 
d urati o n of t he Was h o ut Peri o d, ta ki n g i nt o acc o u nt a n y  la beli n g re q uire me nts 
f or ta peri n g of me dicati o n d ose, as well as t he mi ni mal was h o ut re q uire me nts 
liste d i n Ta ble 5. 1 ; i nstr uct s u bjects n ot t o be gi n was h o ut u ntil n otifie d b y 
p h o ne t he y  ha ve satisfie d all eli gi bilit y re q uire me nts (e g, d oc u me nti n g 
satisfact or y la b orat or y res ults)

Pr o vi de i nstr ucti o ns o n pr o hi bite d me dicati o ns.

Assess f or a n d rec or d A Es

C o ntact I X R S t o re gister t he s u bject a n d o btai n SI D
6. 1. 2.  
W as h o ut Tele p h o ne C o nt act ( Visit 2 , Wee k -3 t o - 1)
W he n t he s u bject’s p ote ntial eli gi bilit y  is deter mi ne d base d o n t he res ults of t he Visit 1 
assess me nts, t he site will c o ntact t he s u bject b y tele p h o n e t o sc he d ule t he Baseli ne V isit.  
If t he s u bject is eli gi ble a n d c urre ntly o n a pr o hi bite d me dicati o n (see Ta ble 5. 1 ), t he 
f oll o wi n g acti vities a n d/ or assess me nts will als o be perf or me d d uri n g t his tele p h o ne 
c o ntact ( Visit 2): 

Assess f or a n d rec or d A Es
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 7

Assess f or a n d rec or d pri or a n d c o nc o mita nt me dicati o n use

Pr o vi de i nstr ucti o ns o n was h o ut of c urre nt pai n me dicati o n, i ncl u di n g t he 
d urati o n of t he Was h o ut Peri o d ( per Ta ble 5. 1 )   
6. 2.  
B aseli ne Visit ( Visit 3 , Wee k  - 1)
T he Baseli ne Visit will occ ur after t he s u bject has bee n deter mi ne d t o be p ote ntiall y  
eli gi ble ( base d o n t he res ults of t he Visit 1 assess me nts) , if t he s u bject d oes n ot re q uire a 
Was h o ut Peri o d or after t he Was h o ut Peri o d,
if a p plica ble.
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at/ d uri n g t he Baseli ne 
Visit :

Assess f or a n d rec or d A Es

Assess f or a n d rec or d c o nc o mita nt me dicati o n use d ur i n g t he was h o ut peri o d 
(if a p plica ble)

Pr o vi de s u bjects wit h electr o nic dail y diaries a n d i nstr ucti o ns f or rec or di n g 
baseli ne pai n rati n gs e ver y m or ni n g
6. 3.  
R a n d o miz ati o n Visit ( Visit 4 , Wee k 0 )
T he f oll o wi n g acti vities a n d/ or assess me nts will be p erf or me d at/d uri n g Ra n d o mizati o n:

Assess f or a n d rec or d A Es

Rec or d pri or a n d c o nc o mita nt me dicati o ns

Re vie w s u bject’s electr o nic dail y  diar y data a n d e ns ure t hat diar y data has 
bee n c o m plete d a n d tra ns mitte d pr o perl y . 

A d mi nister t he C -S S R S a n d e val uate f or eli gi bilit y (see Secti o n 9. 3. 1 )

E val uate f or c o nti n ue d eli gi bilit y . If t he s u bject is f o u n d t o be eli gi ble base d o n 
t he baseli ne A D P S a n d res ults of C -S S R S , pr ocee d t o perf or m t he f oll o wi n g 
pr oce d ures:

Perf or m p h ys ical e xa mi nati o n

Perf or m ne ur ol o gical assess me nt

Rec or d vital si g ns (te m perat ure, heart rate, s u pi ne a n d ort h ostatic bl o o d 
press ure) a n d b o d y wei g ht

C ollect bl o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d cli nical la b orat or y 
safety tests (c he mistr y, he mat ol o g y, a n d uri nal ys is) 

Perf or m a uri ne pre g na nc y test f or W O C B P. If p ositi ve, d o n ot ra n d o mize. 
C ollect a bl o o d sa m ple f or ser u m pre g na nc y  c o nfir mati o n

C o ntact I X R S t o ra n d o mize s u bject a n d o btai n st u d y me dicati o n wallet 
n u m ber
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 8

Dis pe nse st u d y  me dicati o n wallet a n d re vie w d osi n g i nstr ucti o ns wit h t he 
s u bject. T he first d ose of st u d y me dicati o n is t o be ta ke n o n t he sa me da y as 
t he Ra n d o mizati o n visit after c o m pleti o n of t he st u d y visit, at be dti me. 
S u bjects are t o be i nstr ucte d t o N O T ta ke t he “ A M” d ose i n t he me dicati o n 
wallet f or Da y  1 
6. 4.  
Tre at me nt Peri o d
T he Treat me nt peri o d be gi ns wit h t he first d ose o n t he e ve ni n g of t he Ra n d o mizati o n 
visit ( Wee k 0) a n d c o ncl u des wit h t he E n d of Treat me nt visit ( Wee k 1 3, Visit 1 1), a n d 
t heref ore will be 1 3 wee ks i n d urati o n. D uri n g t he T reat me nt peri o d, s u bjects will visit 
t he cli nic after 1 wee k of treat me nt ( Wee k 1) a n d e ver y 2 wee ks t hereafter ( Wee ks 3, 5, 
7, 9, a n d 1 1).

Fasti n g is n ot re q uire d pri or t o t he visits. 

S u bjects s h o ul d be i nstr ucte d t o bri n g t heir electr o nic diaries a n d st u d y 
me dicati o n wallets wit h t he m t o eac h cli nic visit.
S u bjects s h o ul d mai ntai n t heir re g ular diar y  c o m pleti o n a n d d osi n g sc he d ule (i.e., s h o ul d 
c o m plete t heir pai n diaries u p o n a wa ke ni n g a n d ta ke t heir m or ni n g d ose bef ore visiti n g 
t he cli nic) pri or t o t he o n-treat me nt visits, e xce pt as f oll o ws:

S u bjects s h o ul d n ot ta ke t heir m or ni n g d ose bef ore visiti n g t he cli nic o n t he 
m or ni n g of a P K sa m pli n g visit ( Visit s 5, 6, 8, a n d 1 0 [Wee ks 1, 3, 7, a n d 1 1])
6. 4. 1.  
O n -tre at me nt Visits ( Visit 5, Wee k 1; Visits 6 -1 0, Wee ks 3, 5, 7, 9 , & 1 1)
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at/ d uri n g t he o n-t reat me nt 
visits :
•
Assess f or a n d rec or d A Es
•
Rec or d pri or a n d c o nc o mita nt me dicati o ns
•
Re vie w dail y  diaries a n d e ns ure diar y data has bee n tra ns mitte d pr o perly
•
C ollect st u d y  me dicati o n wallets a n d re vie w me dicati o n c o m plia nce
•
Rec or d vital si g ns (te m perat ure, heart rate, s u pi ne a n d ort h ostatic bl o o d press ure), a n d 
b o d y  wei g ht
• 
Perf or m ne ur ol o gical assess me nt 
•
C ollect bl o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d la b orat or y  safet y tests 
(c he mistr y, he mat ol o g y, a n d uri nalys is) 
• 
P K bl o o d sa m pli n g. T hese bl o o d sa m ples will be c ollecte d at t he f oll o wi n g visits:
Visit s 5, 6, 8, a n d 1 0 ( Wee ks 1, 3, 7, a n d 1 1)
•
C o m plete t he C-S S R S a n d e val uate f or c o nti n ue d eli gi bilit y (see Secti o n 9. 3. 1 ).
•
Perf or m a uri ne pre g na nc y test o n all W O C B P s u bjects
•
C o ntact I X R S a n d o btai n ne w st u d y  me dicati o n wallet n u m ber 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 9
•    Dis pe nse st u d y  dr u g a n d re vie w d osi n g i nstr ucti o ns. W he n s u bjects are assi g ne d a 
ne w me dicati o n wallet, t he first d ose ta ke n fr o m t he ne w me dicati o n wallet s h o ul d be 
t he “ P M” d ose o n Da y 1.
6. 4. 2.  
E n d -of- Tre at me nt Visit ( Visit 1 1 ,
Wee k 1 3) or E arl y Ter mi n ati o n
T h e f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at t he E n d -Of -Treat me nt 
visit ( W ee k 1 3 ± 2 da y s) or at t he Early Ter mi nati o n visit:

Assess f or a n d rec or d A Es

Rec or d pri or a n d c o nc o mita nt me dicati o ns

Re vie w dail y diaries a n d e ns ure diar y data has bee n tra ns mitte d pr o perly

C ollect st u d y  me dicati o n wallets a n d re vie w me dicati o n c o m plia nce

As k t he s u bject t o c o m plete t he P GI C

Rec or d vital si g ns (te m perat ure, heart rate, s u pi ne a n d ort h ostatic bl o o d 
press ure), a n d b o d y wei g ht

Perf or m p h ys ical e xa mi nati o n

Perf or m ne ur ol o gical assess me nt 

Perf or m 1 2 -lea d E C G

C ollect bl o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d cli nical la b orat or y 
safety tests (c he mistr y, he mat ol o g y, a n d uri nal ys is) 

C o m plete t he C-S S R S (see Secti o n 9. 3. 1 )

Perf or m a uri ne pre g na nc y  test o n all W O C B P s u bjects; dra w bl o o d f or ser u m 
pre g na nc y  test

C o ntact I X R S a n d u p date s u bject stat us
6. 5.  
P ost -tre at me nt F oll o w-u p
P ost -treat me nt f oll o w-u p will be pe rf or me d after t he E n d of Treat me nt visit f or t h ose 
w h o c o m plete t he 1 3 wee k Treat me nt or after Earl y Ter mi nati o n visit f or t h ose 
ter mi nated fr o m t he st u d y earl y.
6. 5. 1.  
Tele p h o ne C o nt act D a y 3 of F oll o w -u p ( Visit 1 2 , Wee k 1 3. 5 )
T he Da y  3 Tele p h o ne C o ntact will occ ur 3 da ys (± 1 da y ) after t he e n d of treat me nt or 
earl y ter mi nati o n visit as n ote d a b o ve. T he f oll o wi n g acti vities a n d/ or assess me nts will be 
perf or me d d uri n g t he tele p h o ne c o ntact:

Assess f or a n d rec or d A Es

Rec or d pri or a n d c o nc o mita nt me dicati o ns

A d mi nister P W C
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 0
6. 5. 2.    
Visit at Wee k 2 of F oll o w -u p ( Visit 1 3 , Wee k 15)
T he 2 Wee k F oll o w -u p cli nic visit will occ ur 2 wee ks ( ± 3 da y s) after t he e n d of 
treat me nt or earl y ter mi nati o n visit as n ote d a b o ve. T he f oll o wi n g acti vities a n d/ or 
assess me nts will be perf or me d d uri n g t he cli nic visit:

Rec or d vital si g ns (te m perat ure, heart rate, s u pi ne a n d ort h ostatic bl o o d 
press ure), a n d b o d y wei g ht

C ollect bl o o d a n d uri ne sa m ples f or e val uati o n of sta n dar d cli nical la b orat or y 
safety tests (c he mistr y, he mat ol o g y, a n d uri nal ys is)

A d mi nister P W C

A d mi nister t he C -S S R S (see Secti o n 9. 3. 1 )

Perf or m uri ne pre g na nc y test o n all W O C B P s u bjects

Assess f or a n d rec or d A Es

Rec or d pri or a n d c o nc o mita nt me dicati o n s
A n y  a b n or mal fi n di n gs (i ncl u di n g a b n or mal la b orat or y val ues) o bser ve d at t he 
last e n d of treat me nt visit s h o ul d be rec hec ke d at t he F oll o w-u p cli nic visit.
6. 5. 3.   
Tele p h o ne c o nt act at Wee k 4 of F oll o w -u p ( Visit 1 4 , Wee k 1 7)
T he 4 Wee k F oll o w -u p tele p h o ne c o ntact will occ ur 4 wee ks ( ± 7 da y s) after t he e n d of 
treat me nt or earl y ter mi nati o n visit as n ote d a b o ve. T he f oll o wi n g acti vities a n d/ or 
assess me nts will be perf or me d d uri n g t he tele p h o ne c o ntact:

Assess f or a n d rec or d A Es

Rec o r d pri or a n d c o nc o mita nt me dicati o ns

A d mi nister P W C
6. 6.  
Pr ot oc ol De vi ati o ns
T he I n vesti gat or s h o ul d c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a gree d t o b y 
t he S p o ns or a n d, if re q uire d, b y t he re g ulat or y a ut h orit y(ies), a n d w hic h was gi ve n 
a p pr o val/fa v ora ble o pi ni o n b y  t he I RB/I E C.
A de viati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y state d criteria will n ot be all o we d 
i n t his st u d y, e xce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  
T he S p o ns or m ust be n otifie d o n a n e x pe dite d basis of all i nte n de d or u ni nte n de d 
de viati o ns t o t he pr ot oc ol ( e g, i ncl usi o n/e xcl usi o n criteria, d osi n g, misse d st u d y visits).
T he I n vesti gat or, or pers o n desi g nate d b y t he I n vesti gat or, s h o ul d d oc u me nt a n d e x plai n 
a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol.
If a s u bject was i neli gi ble or recei ve d t he i nc orrect d ose of i n vesti gati o nal treat me nt, a n d 
ha d at least o ne a d mi nistrati o n of i n vesti gati o na l pr o d uct, data s h o ul d be c ollecte d f or 
safety p ur p oses.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 1
T he I n vesti gat or s h o ul d n otif y  t he I E C or I RB of de viati o ns fr o m t he pr ot oc ol i n 
acc or da nce wit h l ocal pr oce d ures.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 2
7.  
E F FI C A C Y A S S E S S M E N T S
Efficac y  assess me nts were sec o n dar y t o t he pri mar y o bjecti ve of safety a n d t olera bilit y.
7. 1.  
Pri m ar y Effic ac y Assess me nts
N ot a p plica ble.
7. 2.  
Sec o n d ar y Effic ac y Assess me nts
Sec o n dar y  efficac y assess me nts f or t his st u dy will i ncl u de t he A D P S a n d t he P GI C.
7. 2. 1.  
A ver a ge D ail y P ai n Sc ore
A D P S will be calc ulate d b y  a vera gi n g u p t o 7 a vaila ble pai n sc ores.  Pai n sc ores will be 
rec or de d i n a daily diar y usi n g a n 1 1 -p oi nt N R S ra n gi n g fr o m 0 ( n o pai n) t o 1 0 ( w orst 
p ossi ble pai n).  E ver y m or ni n g u p o n a wa ke ni n g, pri or t o ta ki n g st u d y  me dicati o n, t he 
s u bject will circle t he n u m ber ( 0 t o 1 0) t hat best descri bes t he w orst pai n o ver t he 
pre vi o us 2 4 h o urs .6  T he diar y will be c o m plete d e ver y m or ni n g u p o n a wa ke ni n g fr o m 
t he start of t he baseli ne peri o d ( Da y -6) t hr o u g h t he m or ni n g f oll o wi n g t he last da y  of 
st u d y dr u g a d mi nistrati o n.  Baseli ne A D P S will be calc ulate d as t he a vera ge of t he last 7 
a vaila ble pai n rati n gs o btaine d d uri n g t he Baseli ne Peri o d, i ncl u di n g t he fi nal rati n g o n 
t he m or ni n g pri or t o ra n d o mizati o n (a mi ni m u m of 4 dail y pai n rati n gs will be re q uire d as 
a n i ncl usi o n criteri o n).  D uri n g t he treat me nt peri o d, wee kl y A D P S will be deter mi ne d at 
t he e n d of eac h wee k base d o n all a vaila ble dail y pai n sc ores f or t he pri or wee k.  
7. 2. 2.  
P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C)
S u bjects will c o m plete t he P GI C usi n g t he st u d y -s pecific ta blet at t he E n d - of-treat me nt
visits ( E n d of Treat me nt, Earl y Ter mi nati o n). 
T his sta n dar d i nstr u me nt (refer t o t he St u d y  Ma n ual f or a c o p y) is a well-vali date d 
o utc o me meas ure f or pai n treat me nt a n d s h o ws cl ose c orrelati o n wit h t he 1 1 -p oi nt pai n 
i nte nsit y N R S i n t he setti n g of c hr o nic pai n.7  T he 7 -p oi nt P GI C meas ures c ha n ge i n t he 
s u bject's o verall stat us usi n g t he f oll o wi n g cate g orical scale: 1) ver y m uc h i m pr o ve d, 2) 
m uc h i m pr o ve d, 3) mi ni mall y  i m pr o ve d, 4) n o c ha n ge, 5) mi ni mall y w orse, 6) m uc h 
w orse, a n d 7) ver y  m uc h w orse.
7. 3.  
E x pl or at or y Effic ac y V ari a ble(s)
N ot a p plica ble.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 3
8.  
P H A R M A C O KI N E TI C / P H A R M A C O D Y N A MI C
A S S E S S M E N T S
8. 1.  
P h ar m ac o k i netic V ari a ble(s)
As part of t his st u d y , bl o o d sa m ples fr o m s u bjects will be c ollecte d f or P K a nalys is.  
T hese bl o o d sa m ples will be c ollecte d at t he f oll o wi n g visits:

Visit s 5, 6, 8, a n d 1 0 (Wee k s 1, 3, 7, a n d 1 1 )
Bl o o d ( 4 m L) will be c ollecte d i nt o pre- c hille d 2 m L  Vac utai ner T M K 2 et h y le ne dia mi ne 
tetraacetic aci d t u bes f or t he pre parati o n of plas ma a n d pr ocesse d as descri be d i n t he 
La b orat or y  Ma n ual.  
T he ti me of t he P K bl o o d sa m ple will be rec or de d i n s o urce d oc u me nts a n d e C R Fs.  At 
t he visits s pecifie d a b o ve, P K sa m ples will be c ollecte d bef ore t he m or ni n g d ose of st u d y 
me dicati o n a n d 1 ( ± 0. 5) h o ur after t he m or ni n g d ose.  T he date/ti me of t he m or ni n g d ose 
a n d t he pri or e ve ni n g d ose will be rec or de d i n s o urce d oc u me nts a n d e C R F.  T he s u bject 
will be i nstr ucte d 1 visit bef ore t he sc he d ule d visit f or P K sa m pli n g n ot t o ta ke st u d y  
me dicati o n bef ore c o mi n g t o t he site.  A n acc urate re p orti n g of ti mes of d o si n g ( o n t he 
pre vi o us da y  a n d o n t he m or ni n g of P K sa m pli n g) a n d P K sa m pli n g is i m p orta nt f or
p o p ulati o n P K a n d e x p os ure -res p o nse a nalys es. 
P K a nal y sis will o nl y be c o n d ucte d o n s u bjects recei vi n g D S-5 5 6 5.
8. 2.  
P h ar m ac o d y n a mic ( P D) V ari a ble(s)
N ot a p plica ble.
8. 3.  
Bi o m ar k er a n d E x pl or at or y V ari a ble(s)
N ot a p plica ble.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 4
9.  
S A F E T Y A S S E S S M E N T S
9. 1.  
A d verse E ve nts
All cli nical A Es occ urri n g after t he s u bject si g ns t he I CF a n d u p t o 4 wee ks after t he last 
d ose of st u d y  me dicati o n (i.e., f oll o w-u p peri o d) , w het her o bser ve d b y t he I n vesti gat or or 
re p orte d by t he s u bject, will be rec or de d o n t he A E eC R F pa ge.  Me dical c o n diti o ns 
(i ncl u di n g la b orat or y val ues/ vital si g ns t hat are o ut of ra n ge) t hat were dia g n ose d or 
k n o w n t o e xist pri or t o inf or me d co nse nt will be rec or de d as part of me dical hist or y .  
All cli nical la b orat or y, vital si g n, or E C G val ues s h o ul d be a p praise d by t he I n vesti gat or
as t o cli nical si g nifica nce. Isolate d a b n or mal la b orat or y  res ults, vital si g n fi n di n gs, or 
E C G fi n di n gs s h o ul d be re p orte d as A Es if t he y  are s ym pt o matic, lea d t o st u d y  dr u g 
disc o nti n uati o n, re q uire c orrecti ve treat me nt, or are ot her wise defi ne d as a n a d verse e ve nt 
of s pecial i nterest ( A E SI) [ please refer t o Secti o n 9. 7 ].
All S A Es are t o be re p orte d acc or di n g t o t he pr oce d ures i n Secti o n 9. 5 .  Al wa y s re p ort 
t he dia g n osis as t he A E or S A E ter m .
Whe n a dia g n osis is u na vaila ble, re p ort t he 
pri mar y  si g n or s ym pt o m as t he A E or S A E ter m wit h a d diti o nal details i ncl u de d i n t he 
narrati ve u ntil t he dia g n osis bec o mes a vaila ble .  If t he si g ns a n d sy m pt o ms are disti nct
a n d d o n ot s u g gest a c o m m o n dia g n osis, re p ort t he m as i n di vi d ual e ntries of A E or S A E.   
F or e ve nts t hat are seri o us d ue t o h os pitalizati o n, t he reas o n f or h os pitalizati o n m ust be 
re p orte d as t he S A E ( dia g n osis or sy m pt o m re q uiri n g h os pitalizati o n).   A pr o ce d ure is n ot 
a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y  be a n A E or S A E .  Pre -pla n ne d 
( pri or t o si g ni n g t he I CF ) pr oce d ure or treat me nt re q uiri n g h os pitalizat i o n f or pre-e xisti n g 
c o n diti o ns, w hic h d o n ot w orse n i n se verit y , s h o ul d n ot be re p orte d as S A Es (see 
Secti o n 9. 4. 2 f or Defi niti o ns).  F or deat hs, t he u n derl y i n g or i m me diate ca use of deat h 
s h o ul d al wa ys be re p orte d as a n S A E. I n a d diti o n, a n y seri o us, u nt o war d e ve nt t hat ma y  
occ ur s u bse q ue nt t o t he re p orti n g peri o d t hat t he I n vesti gat or assesses as relate d t o st u d y  
dr u g s h o ul d als o be re p orte d a n d ma na ge d as a n S A E.
At eac h visit, t he I n vesti gat or will deter mi ne w het her a n y  a dverse e ve nts ha ve occ urre d 
b y  e val uati n g t he s u bject.  A d verse e ve nts ma y be directl y o bser ve d, re p orte d 
s p o nta ne o usl y b y t he s u bject, or b y q uesti o ni n g t he s u bject at eac h st u d y visit.  S u bjects 
s h o ul d be q uesti o ne d i n a ge neral wa y, wit h o ut as ki n g a b o ut t he occ urre nce of a ny 
s pecific sy m pt o ms.  T he I n vesti gat or m ust assess all A Es t o deter mi ne seri o us ness, 
se verity, a n d ca usalit y, i n acc or da nce wit h t he defi niti o ns i n Secti o n 9. 4 .  T he 
I n vesti gat or’s assess me nt m ust be clearly d oc u me nte d i n t he site’s s o urce d oc u me ntati o n 
wit h t he I n vesti gat or’s si g nat ure.  I n vesti gat or s h o ul d f oll o w s u bjects wit h A Es u ntil t he 
e ve nt has res ol ve d or t he c o n diti o n has sta bilize d.  I n case of u nres ol ve d a d verse e ve nts, 
i ncl u di n g si g nifica nt a b n or mal cli nical la b orat or y val ues at t he e n d of st u d y assess me nt, 
t hese e ve nts will be f oll o we d u p u ntil res ol uti o n or u ntil t he y bec o me cli nicall y n ot 
rele va nt.
9. 2.  
S afet y Assess me nts
T he pri mar y  o bjecti ve is t he safety a n d t olera bilit y of D S -5 5 6 5. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 5
9. 3.  
E ve nts of S peci al I nterest
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 he patic tra nsa mi nas es ha ve bee n o bser ve d i n t he D S- 5 5 6 5 
de vel o p me nt pr o gra m a n d will be treate d as A Es of s pecial i nterest.
9. 3. 1.  
S uici d al Be h a vi or a n d I de ati o n
A n F D A -c o n d ucte d p o ole d a nal ys is of place b o -c o ntr olle d cli nical st u dies of a ntie pile ptic 
dr u gs wit h var y i n g mec ha nis ms of acti o ns a n d i n dicati o ns, i ncl udi n g pre ga bali n a n d 
ga ba pe nti n, s h o we d a n i ncrease d ris k of s uici dal t h o u g hts or be ha vi or i n patie nts 
recei vi n g t hese dr u gs.  
T he C -S S R S a n d MI NI  are t o be a d mi nistere d at a n y ti me d uri n g t he st u d y (i ncl u di n g 
u nsc he d ule d visits) w here t he i n vesti gat or/st u d y c o or di nat or/site staff rec o g nizes or 
bec o me a ware of (a n d t his i ncl u des if t his a ware ness arises d uri n g u nsc he d ule d visits or 
n o n- face-t o-face c o m m u nicati o ns wit h t he patie nt or his/ her fa mily):

A n y  s u g gesti o n of m o o d dist ur ba nce a n d/ or a n y a ware ness of a p ote ntial 
s uici dal ris k,

S u bsta ntial c ha n ges i n t heir ps y c h os ocial e n vir o n me nt (ie, t he deat h of or 
se parati o n of cl ose fa mil y/frie n d, s u d de n fi na ncial b ur de n, w orse ni n g of 
me dical c o n diti o n, etc); i n t his case a d mi nistrati o n of t he C- S S R S/ MI NI  a n d 
c o ns ultati o n wit h a ps yc hiatrist ( o nsite prefera bl y) s h o ul d be perf or me d.
T he C - S S R S will be a d mi nistere d at scree ni n g a n d at e ver y cli nical assess me nt t hereafter.
Base d o n t he C -S S R S a n d i n vesti gat or j u d g me nt, if a s u bject is i de ntifie d as bei n g at ris k 
f or s uici de, a p pr o priate safety meas ures s h o ul d be i m ple me nte d, i ncl u di n g:

A s u bject s h o ul d be disc o nti n ue d fr o m t he st u d y , a n d i m me diatel y referre d t o 
a me ntal healt h pr ofessi o nal f or f urt her e val uati o n, if a ‘ Y E S’ res p o nse has 
bee n rec or de d f o r a n y q uesti o n o n t he C-S S R S at a n y  visit (c urre nt or past), 
u nless t he s u bject falls i nt o t he ‘ P ossi ble E xce pti o n’ cate g or y  bel o w. 

P ossi ble E xce pti o n ( wit h re gar d t o a ‘ Y E S’ res p o nse(s) t o C -S S R S Q 1 
a n d/ or Q 2 o nl y):
1.
T he be nefit fr o m c o nti n uati o n o n t he s t u d y me dicati o n si g nifica ntly 
o ut wei g hs t he ris k of c o nti n ui n g t he s u bject o n st u d y  dr u g. S uc h cases 
nee d t o be disc usse d wit h t he s p o ns or me dical direct or a n d s h o ul d ta ke 
i nt o acc o u nt t he me ntal healt h pr ofessi o nal e val uati o n A N D
2.
T he j ustificati o n f or c o n ti n ui n g t he s u bject i n t he st u d y u n der t hese 
circ u msta nces is t o be a p pr o priatel y d oc u me nte d per st u d y pr oce d ure 
S u bjects s h o ul d be disc o nti n ue d fr o m t he cli nical st u d y  a n d i m me diately referre d t o a 
me ntal healt h pr ofessi o nal ( prefera bl y  a n o nsite ps yc hiatrist e val uati o n if p ossi ble) if 
s u bjects are assesse d as ha vi n g c urre nt se vere or u nc o ntr olle d maj or de pressi ve dis or der 
or a n xiet y  dis or ders by t he MI NI at a n y visit (c urre nt or past) a n d if a n y of t he f oll o wi n g 
c o n diti o ns a p pl y:
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 6

T he i n vesti gat or deter mi nes t hat t here is a s uici dalit y  ris k, irres pecti ve of a n y 
scales or

A n y  “ Yes" res p o nse t o:

MI NI  q uesti o ns
o
M o d ule A ( Maj or De pressi ve Dis or der) q uesti o n A 3, G or
o
A n y  q uesti o n o n M o d ule B ( S uici dalit y) or

Rele va nt C - S S R S q uesti o ns, wit h disc o nti n uati o n criteria as o utli ne d 
a b o ve.
9. 3. 2.  
Li ver E nz y me Ele v ati o ns/ Li ver D ysf u ncti o n
Increases i n a mi n otra nsferases ha ve bee n o bser ve d i n t he D S -5 5 6 5 de vel o p me nt pr o gra m 
t o date.  S pecial m o nit ori n g of s uc h ele vati o ns d uri n g P hase 3 is descri be d bel o w.  T he 
He patic A dj u dicati o n C o m mittee ( H A C) c harter i ncl u des a pr ocess b y w hic h selecte d 
cases will be a dj u dicate d b y a li ver disease s pecialist.  In cases of li ver la b orat or y 
a b n or malities, it is i m p orta nt t o e ns ure t hat t he nat ure a n d t he e xte nt of li ver i nj ur y  is 
i de ntifie d a n d st u d y s u bjects are m o nit ore d u ntil t he li ver la b orat or y assess me nts ret ur n t o 
n or mal.  S u bjects w h o ha ve a n y tra nsa mi nase el e 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  (i.e. i ncl u di n g t he a p peara nce of fati g ue, na usea, 
v o miti n g, 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) or 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) at a n y visit s h o ul d be m o nit ore d cl osely, acc or di n g t o t he f oll o wi n g:

Re peat li ver tests of at least all f o ur of t he us ual ser u m meas ures ( A L T, A S T, 
al kali ne p h os p hatase [A L P ], a n d t otal bilir u bi n at least 2 ti mes wee kl y [t he 
first re peat s h o ul d be wit hi n 4 8 t o 7 2 h o urs of i nitial a b n or malit y] u ntil val ues 
ha ve decrease d t o < 2 x U L N, t he n at least e ver y  1 or 2 wee ks u ntil res ol uti o n 
or ret ur n t o baseli ne ).  A n a d diti o nal 8. 5 m L ser u m se parati n g t u be of bl o o d 
will be c ollecte d at ti me of e ve nt a n d u ntil val ues ret ur n t o baseli ne.  Sa m ples 
will be st ore d f or f urt her a nal ys is, as re q uire d.

Re vie w or o btai n a detaile d hist or y  of s ym pt o ms a n d pri or or c o nc urre nt 
diseases

Re vie w or o btai n a hist or y of t he use of c o nc o mita nt dr u gs, i ncl u di n g 
n o n prescri pti o n me dicati o ns, her bal a n d dietar y s u p ple me nts, alc o h ol, 
recreati o nal dr u gs, a n d s pecial diets

R ule o ut alc o h olic he patitis, n o n- alc o h olic steat o he patitis , h yp o xic/isc he mic 
he pat o pat h y, a n d biliar y tract disease

O btai n a hist or y  of e x p os ure t o e n vir o n me ntal c he mical a ge nts

Perf or m a d diti o nal la b orat or y  li ver tests (e g, lactate de h ydr o ge nase, A L P , 
ga m ma -gl uta m y l tra ns pe pti dase, pr ot hr o m bi n ti me), e val uati o ns f or p ote ntial 
viral eti ol o gies (i ncl u di n g he patitis A, B, C, E; c yt o me gal o vir us; a n d E pstei n -
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 7
Barr vir us) a n d a ut oi m m u ne eti ol o gies (a nti -n uclear a nti b o d y, a nti -s m o ot h 
m uscle a nti b o d y , a nti-mit oc h o n drial a nti b o d y )
C o m bi ne d ele vati o ns of a mi n otra nsferases a n d bilir u bi n meeti n g t he criteri a of a p ote ntial 
H y ’s La w case ( A L T or A S T ≥ 3 x U L N wit h si m ulta ne o us t otal bilir u bi n ≥ 2 x U L N) , 
eit her seri o us or n o n -seri o us a n d w het her or n ot ca usall y relate d, s h o ul d al wa ys be 
re p orte d t o t he S p o ns or wit hi n 2 4 h o urs ( refer t o Secti o n 9. 5 ), wit h t he I n vesti gat or’s 
assess me nt of seri o us ness, ca usalit y , a n d a detaile d narrati ve.  ( F D A’s G ui da nce f or 
I n d ustr y: Dr u g-I n d uce d Li ver I nj ur y: Pre mar keti n g Cli nical E val uati o n; J ul y 2 0 0 9; 
htt p:// w w w.f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui d
a nces/ UC M 0 7 2 2 7 8. p df ).8  T hese e ve nts s h o ul d be re p orte d as s o o n as p ossi ble f oll o wi n g 
t he pr oce d ures o utli ne d i n Secti o n 9. 4 f or S A E re p orti n g.  T he S p o ns or will be 
res p o nsi ble f or re p orti n g t he case(s) t o t he F D A.
Criter ia f or disc o nti n ui n g s u bjects base d o n tra nsa mi nase i ncreases are pr o vi de d i n 
Secti o n 3. 1. 5. 1. 1 .
F or s u bjects disc o nti n ue d fr o m t he st u d y  d ue t o a n y tra nsa mi nase i ncrease or he patic 
e ve nt, t he f oll o wi n g s h o ul d be perf or me d:

Gastr oe nter ol o g y  or he pat ol o g y c o ns ultati o n 

He pat o biliar y  ultras o u n d
9. 4.  
Defi niti o ns
9. 4. 1.  
A d verse E ve nt ( A E)
A n A E is defi ne d as a n y  u nt o war d me dical occ urre nce i n a s u bject or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot 
necessaril y  ha ve t o ha ve a ca usal relati o ns hi p wit h t his treat me nt.  A n A E ca n, t heref ore, 
be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g, f or 
e xam ple), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, 
w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct (I C H E 2 A G ui deli ne.  Cli nical 
Safet y  Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, Oct 1 99 4).
It is t he res p o nsi bilit y of I n vesti gat ors, base d o n t heir k n o wle d ge a n d e x perie nce, t o 
deter mi ne t h ose circ u msta nces or a b n or mal la b orat or y fi n di n gs w hic h s h o ul d be 
c o nsi dere d a d verse e ve nts.
9. 4. 2.  
Seri o us A d verse E ve nt ( S A E)
A n y  u nt o war d me dical occ urre nce t hat at a ny d ose:

Res ults i n deat h,

Is life-t hreate ni n g,

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n,

Res ults i n persiste nt or si g nifica nt disa bilit y /i nca pacit y,

Is a c o n ge nital a n o maly/ birt h defect, or
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 8

Is a n i m p orta nt me dical e ve nt.
N ote: T he ter m “life -t hreate ni n g” i n t he defi niti o n of “seri o us” refers t o a n e ve nt i n w hic h 
t he s u bject was at ris k of deat h at t he ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h 
h y p ot heticall y  mi g ht ha ve ca use d deat h if it were m ore se vere (I C H E 2 A G ui deli ne.  
Cli nical Safet y  Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or E x pe dite d Re p orti n g, 
Oct 1 9 9 4).
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her e x pe dite d 
re p orti n g is a p pr o priate i n ot her sit uati o ns, s uc h as i m p orta nt me dical e ve nts t hat ma y  n ot 
be i m me diatel y  life-t hreate ni n g or res ult i n deat h or h os pitalizati o n b ut ma y je o par dize 
t he s u bject or ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d i n t he 
defi niti o n a b o ve.  E xa m ples i ncl u de aller gic br o nc h os pas m, c o n v ulsi o ns, a n d bl o o d 
d y scrasias or de vel o p me nt of dr u g de pe n de nc y or dr u g a b use.
N ote:

A pr oce d ure is n ot a n A E or S A E, b ut t he reas o n f or t he pr oce d ure ma y  be a n 
A E or S A E .

Pre -pla n ne d ( pri or t o si g ni n g t he I CF ) pr oce d ures or tr eat me nt re q uiri n g 
h os pitalizati o ns f or pre -e xisti n g c o n diti o ns w hic h d o n ot w orse n i n se verit y 
are n ot S A Es.
9. 4. 3.  
A E Se verit y
T he f oll o wi n g defi niti o ns s h o ul d be use d t o assess i nte nsit y  of A Es :

Mil d: A ware ness of si g n o r s ym pt o m, b ut easil y t olerate d ( i. e., d oes n ot 
i nterfere wit h s u bject’s us ual f u ncti o n).

M o derate: Disc o mf ort e n o u g h t o ca use i nterfere nce wit h us ual acti vit y .

Se vere: I nca pacitati n g wit h i na bilit y t o w or k or d o us ual acti vit y (i. e., 
i nterferes si g nifica ntly wit h s u bject’s us ual f u ncti o n ).
9. 4. 4.  
C a u s alit y Assess me nt
T he I n vesti gat or s h o ul d assess ca usal relati o ns hi p bet wee n a n A E a n d t he st u d y pr o d uct 
o n t he basis or his/ her cli nical j u d g me nt a n d t he f oll o wi n g defi niti o ns .  T he ca usalit y 
assess me nt s h o ul d be ma de base d o n t he a vaila ble i nf or mati o n a n d ca n be u p date d as ne w 
i nf or mati o n bec o mes a vaila ble.

1 = Relate d:

T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y  dr u g 
a d mi nistrati o n, a n d ca n n ot be reas o na bl y  e x plai ne d b y t he s u bject’s 
cli nical state or ot her fact ors ( e g, disease u n der st u d y, c o nc urre nt diseases, 
a n d c o nc o mita nt me dicati o ns).

T he A E f oll o ws a reas o na ble te m p oral se q ue nce fr o m st u d y  dr u g 
a d mi nistrati o n, a n d is a k n o w n reacti o n t o t he dr u g u n der st u d y  or its 
c he mical gr o u p, or is pre dicte d b y k n o w n p har mac ol o g y.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 9

2 = N ot Relate d:

T he A E d oes n ot f oll o w a reas o na ble se q ue nce fr o m st u d y  pr o d uct 
a d mi nistrati o n, or ca n be reas o na bl y e x plai ne d b y t he s u bject’s cli nical 
state or ot her fact ors (e g, disease u n der st u dy, c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns).
9. 4. 5.  
Acti o n T a ke n Re g ar d i n g t he St u d y Pr o d uct

1 = D ose N ot C ha n ge d : N o c ha n ge i n st u d y dr u g d osa ge was ma de.

2 = Dr u g Wit h dra w n : T he st u d y pr o d uct was per ma ne ntl y st o p pe d.

3 = Dr u g I nterr u pte d: T he st u d y pr o d uct was te m p orarily st o p pe d.
9. 4. 6.  
A d verse E ve nt O utc o me

1 = Rec o vere d/ Res ol ve d

T he s u bject f ull y rec o vere d fr o m t he a d verse e ve nt wit h n o resi d ual effect 
o bser ve d.

2 = Rec o vere d/ Res ol ve d wit h Se q uelae

T he resi d ual effects of t he a d verse e ve nt are still prese nt a n d o bser va ble.

I ncl u de se q uelae/resi d ual effects.

3 = N ot Rec o vere d/ N ot Res ol ve d

T he A E itself is still prese nt a n d o bser va ble.

4 = Fatal
9. 4. 7.  
Ot her Acti o n T a ke n f or E ve nt

1 = N o ne.

N o treat me nt was re q uire d.

2 = Me dicati o n re q uire d.

Prescri pti o n a n d/ or O T C me dicati o n was re q uire d t o treat t he A E .

3 = Ot her.
9. 5.  
Seri o us A d verse E ve nt Re p orti n g Pr oce d ure F or I n vesti g at ors
All A Es, S A Es, a n d A E SIs will be re p orte d i n t he e C R F.
T he f oll o wi n g t y p es of e ve nts s h o ul d be re p orte d i n t he e C R F wit hi n 2 4 h o urs of 
a ware ness:

S A Es (see Secti o n 9. 4. 2 f or defi niti o n)
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 0

He patic e ve nts meeti n g c o m bi na ti o n a b n or malities (e g, A L T or A S T ≥3 x 
U L N wit h si m ulta ne o us t otal bilir u bi n ≥2 x U L N) ( p ote ntial H y's La w case), 
b ot h seri o us a n d n o n-seri o us

A n y  e ve nt meeti n g t he st o p pi n g r ules f or i n di vi d ual s u bjects (see 
Secti o n 3. 1. 5. 1 ).
All e ve nts (seri o us a n d n o n -seri o us) m ust be re p orte d wit h I n vesti gat or's assess me nt of 
t he e ve nt's seri o us ness, se verity, a n d ca usalit y t o t he bli n de d st u d y dr u g.  A detaile d 
narrati ve s u m marizi n g t he c o urse of t he e ve nt, i ncl u di n g its e val uati o n, treat me nt, a n d 
o utc o me s h o ul d be pr o vi de d.  S pecific or esti mate d dates of e ve nt o nset, treat me nt, a n d 
res ol uti o n s h o ul d be i ncl u de d w he n a vaila ble.  Me dical hist or y, c o nc o mita nt me dicati o ns, 
a n d la b orat or y data t hat are rele va nt t o t he e ve nt s h o ul d als o be s u m marize d i n t he 
narrati ve.  F or fatal e ve nts, t he narrati ve s h o ul d state w het her a n a ut o ps y was or will be 
perf or me d, a n d i ncl u de t he res ults if a vaila ble.  S o urce d oc u me nts will be retai ne d i n 
site's files a n d s h o ul d n ot be s u b mitte d t o t he S p o ns or f or S A E re p orti n g p ur p oses.
Ur ge nt safet y  q ueries m ust be f oll o we d u p a n d a d dresse d pr o m ptly.  F oll o w - u p 
i nf or mati o n a n d res p o nse t o n o n-ur ge nt safet y  q ueries s h o ul d be c o m bi ne d f or re p orti n g 
via t he e C R F t o pr o vi de t he m ost c o m plete data p ossi ble wit hi n eac h f oll o w - u p. 
I n t he e ve nt t hat t he e C R F is u na vaila ble, re p ort S A Es b y fa xi n g t he pa per Seri o us 
A d verse E ve nt Re p ort ( S A V E R) F or m t o t he C R O usi n g t he pr o vi de d fa x c o ver s heet a n d 
t he a p pr o priate fa x n u m ber pr o vi de d f or y o ur c o u ntr y . O nce t he e C R F bec o mes a vaila ble, 
please e nter S A Es re p orte d o n t he S A V E R F or m i nt o t he e C R F as s o o n as p ossi ble. 
Please refer t o t he e C R F C o m pleti o n G ui de f or a d diti o nal i nstr ucti o ns.
Please call t he l ocal S A E H otli n e or yo ur st u d y  m o nit or f or a n y q uesti o ns o n S A E 
re p orti n g.
9. 5. 1.  
N otif yi n g Re g ul at or y A ut h orities, I n vesti g at ors, a n d I R B/ E C
Daiic hi Sa n k y o a n d/ or C R O will i nf or m I n vesti gat ors , I RBs (I nstit uti o nal Re vie w 
B oar d)/ E Cs ( Et hics C o m mittees) , a n d re g ulat or y a ut h orities of a n y  S us pecte d 
U ne x pecte d Seri o us A d verse Reacti o ns ( S U S A Rs) occ urri n g i n ot her st u d y ce nters or 
ot her Daiic hi Sa n k y o st u dies of t he i n vesti gati o nal pr o d uct, as a p pr o priate per l ocal 
re p orti n g re q uire me nts.
I n t he U S, u p o n recei pt of t he S p o ns or’s n otificati o n of S U S A Rs t hat occ urre d wit h t he 
in vesti gati o nal p r o d uct, u nless dele gate d t o t he S p o ns or, it is t he In vesti gat or’s 
res p o nsi bilit y t o i nf or m t he IR B per S p o ns or’s i nstr ucti o n.
I n t he E ur o pea n Ec o n o mic Area states, it is t he S p o ns or’s res p o nsi bilit y t o re p ort 
S U S A Rs t o all E Cs.
9. 6.  
E x p os ure I n Uter o D uri n g Cli nic al St u dies
Daiic hi Sa n k y o m ust be n otifie d of a n y  s u bject w h o bec o mes pre g na nt w hile recei vi n g or 
wit hi n 4 wee ks of disc o nti n ui n g t he i n vesti gati o nal pr o d uct.
Alt h o u g h pre g na nc y  is n ot tec h nicall y a n A E , all pre g na ncies m ust be f oll o we d t o 
c o ncl usi o n t o deter mi ne t heir o utc o me.  T his i nf or mati o n is i m p orta nt f or b ot h dr u g 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 1
safety a n d p u blic healt h c o ncer ns.  It is t he res p o nsi bilit y  of t he I n vesti gat or, or desi g nee, 
t o re p ort a ny pre g na nc y i n a fe male s u bject usi n g t he E x p os ure In Uter o ( EI U) Re p orti n g 
f or m.  Please c o ntact y o ur st u d y m o nit or t o recei ve t he EI U Re p orti n g F or m u p o n 
lear ni n g of a pre g na nc y.  T he I n vesti gat or s h o ul d ma ke e ver y eff ort t o f oll o w t he s ubject 
u ntil c o m pleti o n of t he pre g na nc y.  If t he o utc o me of t he pre g na nc y meets t he criteria f or 
i m me diate classificati o n as a n S A E ( i.e., p ost-part u m c o m plicati o ns, s p o nta ne o us 
a b orti o n, still birt h, ne o natal deat h, or c o n ge nital a n o mal y , i ncl u di n g t hat i n a n a b orte d 
fet us), t he I n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g S A Es o utli ne d i n 
Secti o n 9. 5 .
9. 7.  
Cli nic al L a b or at or y E v al u ati o ns
Bl o o d a n d uri ne sa m ples f or cli nical la b orat or y  e val uati o ns will be s hi p pe d t o a ce ntral 
la b orat or y f or a nalys is.  Res ults of all cli nical la b orat or y tests will be re p orte d i n t he 
s u bject’s e C R F or mer ge d electr o nicall y wit h t he cli nical data base.
9. 7. 1.  
He m at ol o g y
A si n gle 4 m L E D T A t u be of bl o o d will be dra w n f or t he he mat ol o g y  assess me nts liste d 
i n Ta ble 9. 1.  T hese will be meas ure d fr o m sa m ples o btai ne d at t he visits i n dicate d at t he 
S c he d ule of E ve nts ( Secti o n 1 7 ).
T a ble 9. 1:  
He m at ol o g y A n al ytes
He m o gl o bi n
He mat ocrit
Re d bl o o d cell ( R B C) c o u nt ( wit h i n dices)
Retic ul oc yte c o u nt
W hite bl o o d cell ( W B C) c o u nt ( wit h differe ntial)
Platelet c o u nt
9. 7. 2.  
Bl o o d C he mistr y
A n 8. 5 m L  ser u m se parati n g t u be of bl o o d will be dra w n f or t he bl o o d c he mistr y 
assess me nts liste d i n  Ta ble 9. 2 .  T hese will be meas ure d fr o m sa m ples o btai ne d at t he 
visits i n dicate d at t he Sc he d ule of E ve nts ( Secti o n 1 7 ).
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 2
T a ble 9. 2:  
Bl o o d C he mistr y A n al ytes
S o di u m
Lactate De h y dr o ge nase 
P otassi u m
Creati ni ne
Ma g nesi u m
Bl o o d urea nitr o ge n
Bicar b o nate
T otal pr otei n
Calci u m
Al b u mi n
I n or ga nic p h os p h or us
Uric aci d
A S T
Creati ne ki nase
A L T
T otal c h olester ol
A L P
Tri gl yceri des
T otal bilir u bi n
A L P: al kali ne p h os p hatase; A L T: ala ni ne a mi n otra nsferase; A S T: as partate a mi n otra nsferase; 
9. 7. 2. 1.  
Esti m ati o n of Cre ati ni ne Cle ar a nce
Creati ni ne cleara nce will be esti mate d fr o m ser u m creati ni ne b y t he ce ntral la b orat or y 
usi n g t he C oc kcr of t-Ga ult e q uati o n .
9. 7. 3.  
Uri n al ysis
Sta n dar d uri nal ys is (Ta ble 9. 3 ), i nclu di n g a micr osc o pic e xa mi nati o n, will be c o n d ucte d 
f or all s u bjects at t he visits i n dicate d at t he S c he d ule of E ve nts ( Secti o n 1 7 ).
T a ble 9. 3:  
Uri n al ysis Deter mi n ati o ns
S pecific gra vit y
Bl o o d
p H
R B C
Pr otei n
W B C
Gl uc ose
Bilir u bi n
Ket o nes
Ur o bili n o ge n
R B C: re d bl o o d cell; W B C: w hite bl o o d cell.
F or sa m ples wit h fi n di n gs o n macr osc o pic a nal ys is, micr osc o pic e xa mi nati o n f or R B Cs, 
W B Cs, bacteria, a n d casts s h o ul d be perf or me d.
9. 7. 4.  
Pre g n a nc y Testi n g
Ser u m pre g na nc y  testi n g will be perf or me d f or all W O C B P w o me n, at t he S cree ni n g a n d 
E n d- of- T reat me nt V isits.  Uri ne pre g na nc y tests m ust be c o nfir me d as ne gati ve bef ore 
ra n d o mizati o n a n d dis pe nsi n g of st u dy me dicati o n. If a uri ne test is p ositi ve, a bl o o d 
sa m ple will be dra w n f or ser u m c o nfir mati o n.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 3
9. 8.  
Vit al Si g ns
Vital si g ns will be rec or de d at all cli nic visits (e xce pt t he Baseli ne Visit ) a n d will i ncl u de 
te m perat ure, heart rate, a n d s u pi ne a n d ort h ostatic bl o o d press ure. 
F or meas ure me nt of s u pi ne bl o o d press ure, s u bject s s h o ul d be i n a s u pi ne or se mi-
rec u m be nt p ositi o n f or a mi ni m u m of 5 mi n utes bef ore t he bl o o d press ure meas ure me nt.  
Meas ure me nt of ort h ostatic bl o o d press ure s h o ul d f oll o w meas ure me nt of s u pi ne bl o o d 
press ure.  S u bjects s h o ul d be as ke d t o sta n d f or 3 mi n utes bef ore meas ure me nt of 
ort h ostatic bl o o d press ure.  Meas ure me nt of bl o o d press ure s h o ul d be c o n d ucte d usi n g a 
cali brate d s p h yg m o ma n o meter or a ut o matic i nflata ble c uff m o nit or; t he bl o o d press ure 
c uff s h o ul d be ke pt i n place bet wee n s u p i ne a n d ort h ostatic bl o o d press ure 
meas ure me nts.
Bl o o d press ure s h o ul d be meas ure d usi n g t he sa me ar m a n d meas uri n g de vice t hr o u g h o ut 
t he st u d y.  At t he Scree ni n g Visit ( Visit 1) o nl y, a bl o o d press ure rea di n g s h o ul d be ta ke n 
i n b ot h ar ms ( u nless t here is a me dical reas o n n ot t o use a partic ular ar m).  T he ar m wit h 
t he hi g her sys t olic rea di n g s h o ul d t he n be use d t hr o u g h o ut t he rest of t he st u d y.  
Bl o o d press ure s h o ul d be rec or de d t o t he nearest 2 m m H g mar k o n t he ma n o meter or t o 
t he nearest w h ole n u m ber o n a n a ut o matic de vice.
9. 9.  
Electr oc ar di o gr a ms
A 1 2 -lea d E C G will be c o n d ucte d at t he Scree ni n g Visit a n d at t he E n d -of- treat me nt
Visit .  E C G rec or di n gs s h o ul d be assesse d as n or mal or a b n or mal, a n d a n y a b n or mal 
fi n di n gs s h o ul d be assesse d as n ot cli nically si g n ifica nt or si g nifica nt.  Cli nicall y  
si g nifica nt a b n or mal fi n di n gs s h o ul d be re p orte d as me dical hist or y (if pre-e xiste nt or as 
A Es ).  Refer t o Secti o n 9. 1 f or ge neral g ui da nce o n w he n t o re p ort a b n or mal fi n di n gs as 
A Es.
9. 1 0.  
P h ysic al Fi n di n gs
9. 1 0. 1.  
B o d y Hei g ht a n d Wei g ht
Meas ure me nt
of hei g ht will be perf or me d at S cree ni n g V isit, wit h t he s u bject i n a 
sta n di n g p ositi o n a n d wit h s h oes re m o ve d.  T he s u bject’s k nees s h o ul d be strai g hte ne d, 
hea d hel d erect, wit h e y es f or war d.
S u bjects s h o ul d be wei g he d o n t he sa me scale w he n p ossi ble .
9. 1 0. 2.  
P h ysic al E x a mi n ati o ns
A f ull p h y sical e xa mi nati o n, wit h t he e xce pti o n of pel vis, breast, a n d rect u m i n w o me n 
a n d t he ge nit o uri nar y sys te m a n d pr ostate i n me n, will be perf or me d at t he Screeni n g 
Visit a n d E n d - of-treat me nt Visit .  
T he f ull p h y sical e xa mi nati o n s h o ul d mi ni mall y i ncl u de cli nical e val uati o ns of t he hea d, 
nec k, t h yr oi d, e yes, ears, n ose, t hr oat, heart, l u n gs, l y m p h n o des, a b d o me n, s ki n, 
e xtre mities, a n d m usc ul os keletal s yste m.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 4
F or a gi ve n s u bject, p h ys ical e xa mi nati o ns s h o ul d be perf or me d by t he sa me e xa mi ner
w he n p ossi ble.
9. 1 0. 3.  
Ne ur ol o gic al E x a mi n ati o ns
A ne ur ol o gical e xa mi nati o n will be perf or me d at t he i n dicate d visits i n t he S c he d ule of 
E ve nts ( Secti o n 1 7 ).
T he ne ur ol o gical e xa mi nati o n will i ncl u de t he f oll o wi n g:  Cra nial ner ve e xa mi nati o n 
(se nse of s mell (I), vis ual fiel ds a n d ac uity ( II), e ye m o ve me nts (III, I V, VI) a n d p u pils 
(III, sy m pat hetic a n d paras y m pat hetic), se ns or y  f u ncti o n of face ( V), stre n gt h of facial 
( VII) a n d s h o ul der gir dle m uscles ( XI), heari n g ( VII, VIII), taste ( VII, I X, X), p har yn geal 
m o ve me nt a n d re fle x (I X, X), t o n g ue m o ve me nts ( XII). M ot or sys te m e xa mi nati o n 
i ncl u des m uscle stre n gt h ( 0 t o 5 rati n g; gri p stre n gt h, el b o w fle xi o n, k nee fle xi o n, a n kle 
d orsifle xi o n), m uscle t o ne a n d si g ns of ri gi dit y . Dee p te n d o n refle xes ( 0 t o 4 rati n g scale; 
bice ps, b rac hi ora dialis, k nee jer k, a n kle jer k, pla ntar fle xi o n [i.e., Ba bi ns ki si g n]), 
Se ns or y  sys te m testi n g b y pr o v o ki n g se nsati o ns of fi ne t o uc h, pai n a n d te m perat ure. 
Cere bellar testi n g ( great t oe a n d i n de x fi n ger, t he n pr o xi mal assess me nts; le vel of 
a b n or mali t y rec or de d), a n d gait/stati o n ( o bser vati o n of re g ular wal ki n g, heel-t o-t oe 
[ta n de m] wal ki n g, eac h assesse d as n or mal or a b n or mal).  
F or a gi ve n s u bject, ne ur ol o gical e xa mi nati o ns s h o ul d be perf or me d b y t he sa me 
e xa mi ner w he n p ossi ble.
9. 1 1.  
Ot her S afet y Assess me nts
9. 1 1. 1.  
C ol u m bi a S uici de Se verit y R ati n g Sc ale 
T he C -S S R S will be a d mi nistere d b y  t he I n vesti gat or or a q ualifie d desi g nee trai ne d i n its 
a d mi nistrati o n usi n g t he st u d y-s pecific ta blet at all t he i n dicate d visits i n t he Sc he d ule of 
E ve nts ( Secti o n 1 7 ).
T he C -S S R S is a sta n dar dize d i nstr u me nt t hat was de vel o pe d t o assess t he se verit y of a n d 
m o nit or c ha n ges i n s u ici dal i deati o n a n d be ha vi or.9  F o ur c o nstr ucts are meas ure d. T he 
first is se verit y of i deati o n, rate d o n a 5-p oi nt or di nal scale.  T he sec o n d is i nte nsit y  of 
i deati o n, w hic h c o m prises 5 ite ms (fre q ue nc y, d urati o n, c o ntr olla bilit y, deterre nts, a n d 
reas o n f or i deati o n); eac h rate d o n a 5 -p oi nt or di nal scale.  T he t hir d is be ha vi or , rate d o n 
a n o mi nal scale t hat i ncl u des act ual, a b orte d, a n d i nterr u pte d atte m pts; pre parat or y  
be ha vi or; a n d n o n -s uici dal self-i nj uri o us be ha vi or. T he f o urt h is let halit y, w hic h assesses 
act ual atte m pts; act ual let halit y is rate d o n a 6-p oi nt or di nal scale, a n d if act ual let halit y  is 
zer o, p ote ntial let halit y of atte m pts is rate d o n a 3-p oi nt or di nal scale.
9. 1 1. 2.   
P h ysici a n Wit h dr a w al C hec klist 
T he P W C will be a d mi nistere d b y t he I n vesti gat or or desi g nee usi n g t he st u d y -s pecific 
ta blet at t he F oll o w-u p Visits 1 2, 1 3 a n d 1 4 . At F oll o w-u p Visits 1 2 a n d 1 4 , t he P W C will 
be a d mi nistere d b y tele p h o ne. 
Alt h o u g h de vel o pe d s pecificall y  t o meas ure sy m pt o ms of be nz o diaze pi ne wit h dra wal, 1 0
t he P W C als o has bee n use d i n st u dies of pre ga bali n.1 1 ,1 2 ,1 3 T he P W C rates 2 0 c o m m o n 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 5
s ym pt o ms of wit h dra wal. T he s y m pt o ms meas ure d are base d o n t h ose t hat are p ote ntiall y 
relate d t o be nz o diaze pi ne wit h dra wal: s o matic, m o o d, c o g niti ve, fati g ue, a n d 
gastr oi nt esti nal. 
Eac h of t he 2 0 i n di vi d ual ite ms o n t he P W C is rate d as n ot prese nt, mil d, m o derate, or 
se vere. I n di vi d ual ite ms rate d as mil d, m o derate or se vere s h o ul d n ot be ha n dle d as 
i n di vi d ual T E A Es. Rat her, f or a ny s u bject wit h at least 1 i n di vi d ual ite m r ate d as mil d, 
m o derate, or se vere, t he I n vesti gat or s h o ul d re p ort “ wit h dra wal” as a T E A E. 
I n a d diti o n, t he I n vesti gat or s h o ul d be partic ularly atte nti ve t o a n y p ote ntial T E A Es t hat 
s u g gest o piate wit h dra wal at t he F oll o w-u p visits.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 6
1 0.  
O T H E R A S S E S S M E N T S
N ot a p plica ble.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 7
1 1.  
S T A TI S TI C A L M E T H O D S
1 1. 1.  
A n al ysis Sets
T he f oll o wi n g a nal ys is sets will be use d t o s u m marize t he data fr o m t his st u d y:

T he R a n d o mize d A nal y sis Set will i ncl u de all s u bjects w h o si g ne d t he I C F 
a n d were ra n d o mize d i nt o t he st u d y . 

T he S afet y A nal y sis Set will i ncl u de all s u bjects w h o recei ve d at least 1 d ose 
of st u d y  me dicati o n.

T he m o difie d Inte nt -t o-treat ( mI T T) a nalys is set will i ncl u de all ra n d o mize d 
s u bjects w h o recei ve d at least 1 d ose of st u dy me dicati o n.

T he P er-P r ot oc ol A nal y sis S et will i ncl u de all s u bjects w h o were ra n d o mize d 
a n d recei ve d at least o ne d ose of st u d y  me dicati o n, a n d w h o were s ufficie ntl y 
c o m plia nt wit h t he pr ot oc ol acc or di n g t o pre -s pecifie d criteria, w hic h will be 
fi nalize d pri or t o data base u n bli n di n g.

T he P K A nal ys is Set will i ncl u de all s u bjects w h o recei ve d at least o ne d ose 
of D S - 5 5 6 5 a n d ha d at least o ne P K c o nce ntrati o n meas ure d.
1 1. 2.  
Ge ner al St atistic al C o nsi der ati o ns
T he statistical pac ka ge S A S ® ( Versi o n 9. 2 or hi g her) will be use d t o pr o d uce all 
s u m mar y ta bles, fi g ures, a n d data listi n gs.  
Q ua ntitati ve data will be ta b ulate d wit h descri pti ve s u m mar y  statistics: arit h metic mea n, 
sta n dar d de viati o n ( S D), me dia n, mi ni m u m a n d ma xi m u m val ues, a n d n u m ber of 
o bser vati o ns.  F or cate g orical data, fre q ue nc y  ta bles will be pr o vi de d.
F or varia bles e x presse d as a perce nt a ge, t he de n o mi nat ors f or t he calc ulati o n of 
perce nta ge will be t he n u m ber of s u bjects w h o ha d t hat varia ble assesse d. 
A detaile d S A P descri bi n g t he met h o d ol o g y  t o be use d i n t he fi nal a nalys is will be 
pre pare d bef ore data u n bli n di n g.  A c ha n ge i n t he pla n ne d statistical a nal ys is will re q uire 
a pr ot oc ol a me n d me nt o nl y if it s u bsta nti vel y alters t he pri nci pal feat ures of t he pr ot oc ol.  
A n y  de viati o ns fr o m t he pla n ne d statistical a nalys es i n t he pr ot oc ol will be f ull y  
descr i be d i n t he S A P.
1 1. 3.  
St u d y P o p ul ati o n D at a
De m o gra p hic c haracteristics will be s u m marize d f or t he R a n d o mize d A nal ysis Set 
acc or di n g t o treat me nt assi g n me nt.  C o nti n u o us de m o gra p hic varia bles (a ge [calc ulate d 
fr o m date of birt h t o t he date of first d ose], wei g ht, hei g ht, a n d b o dy mass i n de x) f or all 
ra n d o mize d s u bjects will be s u m marize d wit h descri pti ve statistics.  Cate g orical 
de m o gra p hic varia bles ( se x, race, et h nicity, a n d a ge gr o u p [ e g, n o n-el derl y, el derl y, ver y 
el derl y] ) will be s u m marize d wit h fre q ue nc y c o u nts a n d c orres p o n di n g perce nta ges.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 8
S u bject dis p ositi o n will be s u m marize d as t he n u m ber of s u bjects scree ne d, t he n u m ber 
ra n d o mize d, a n d t he n u m ber a n d perce nta ge of t h ose w h o c o m plete d treat me nt or 
wit h dre w ( wit h t he latter s u m marize d b y  reas o n f or with dra wal).
Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d b y  n u m ber a n d perce nta ge of 
s u bjects f or eac h W orl d Healt h Or ga nizati o n ( W H O)-Dr u g preferre d base na me a n d 
A nat o mical T hera pe utic C he mical cate g or y .
1 1. 4.  
Effic ac y A n al yses
1 1. 4. 1.  
Pri m ar y Effic ac y A n al yses
N ot a p plica ble.
1 1. 4. 2.   
Sec o n d ar y Effic ac y A n al yses
F or A D P S , c ha n ge fr o m baseli ne meas ure d at ra n d o mizati o n t o Wee k 1 3/ E T
will be 
s u m marize d b y treat me nt a n d c o m pare d n u mericall y  bet wee n treat me nt gr o u ps . 
F or P GI C at Wee k 1 3/ E T , t he pr o p orti o ns of s u bjects w h o are “ mi ni mall y i m pr o ve d or 
better” (i .e., sc ore ≤ 3) a n d of s u bjects w h o are “ m uc h i m pr o ve d or better” (ie, sc ore ≤ 2) 
will be s u m marize d a n d c o m pare d n u mericall y bet wee n treat me nt gr o u p s.
F or eac h efficac y  e n d p oi nt , bet wee n treat me nts gr o u p differe nces wi ll be s u m marize d 
wit hi n eac h C K D strat u m b y  calc ulati n g 9 5 % c o nfi de nce i nter vals.
1 1. 4. 3.   
E x pl or at or y Effic ac y A n al yses
N ot a p plica ble.
1 1. 5.  
P h ar m ac o ki netic A n al yses
P K a nal y ses, s u m maries, a n d listi n gs will be ge nerate d b y d ose gr o u p usi n g t he P K 
a nal ys is set.  Descripti ve statistics f or plas ma c o nce ntrati o ns of D S -5 5 6 5 (sa m ple size, 
mea n, S D, c oefficie nt of variati o n, sta n dar d err or of t he mea n, mi ni m u m, ma xi m u m, a n d 
me dia n) will be calc ulate d at eac h e val uati o n ti me- p oi nt. 
A p o p ulati o n P K m o del will be de vel o pe d t o q ua ntif y  t he p ote ntial i m pact of 
de m o gra p hic c o variates o n t he e x p os ure t o D S -5 5 6 5.  F or t his p ur p ose, data fr o m t his 
st u d y ma y be p o ole d wit h data fr o m ot her D S-5 5 6 5 st u dies a n d re p orte d se paratel y  fr o m 
t he cli nical st u d y re p ort.
1 1. 6.  
S afet y A n al yses
F or safet y e n d p oi nts, t he data fr o m A E assess me nts, cli nical la b orat or y assess me nts, 
p h y sical a n d ne ur ol o gic e xa mi nati o ns, 1 2-lea d E C Gs, vital si g ns (i ncl u di n g wei g ht) 
assess me nts, C -S S R S , a n d P W C e val uati o n will ma ke u p t he safet y a nal ys es.  T he S afet y 
A nal y sis Se t will be use d f or all safet y a nalys es.
T he pri mar y  o bjecti ve is t he safety a n d t olera bilit y of D S -5 5 6 5.  Safet y data will be 
s u m marize d b y treat me nt gr o u p . Q ua ntitati ve data will be ta b ulate d wit h descri pti ve 
s u m mar y statistics: arit h metic mea n, sta n dar d de viati o n ( S D), me dia n, mi ni m u m a n d 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 9
ma xi m u m val ues, a n d n u m ber of o bser vati o ns.  F or cate g orical data, fre q ue nc y  ta bles 
will be pr o vi de d.
1 1. 6. 1.    
A d verse E ve nt A n al yses
A Es will be c o de d usi n g t he Me dical Dicti o nar y  f or Re g ulat or y Acti vities ( Me d D R A) 
classificati o n s ys te m.  A T E A E is defi ne d as a n A E t hat e mer ges d uri n g treat me nt 
( ha vi n g bee n a bse nt pri or t o treat me nt) or w orse ns relati ve t o t he pre-treat me nt state.  T he 
fre q ue nc y of patie nts e x perie nci n g a s pecific T E A E will be ta b ulate d b y treat me nt, 
s yste m or ga n class, preferre d ter m, seri o us ness (see Secti o n 9. 4. 2 ), w orst se verit y (see 
Secti o n 9. 4. 3 ), a n d relati o ns hi p t o st u d y dr u g (see Secti o n 9. 4. 4 ). Treat me nt -e mer ge nt
A E s of s pecial i nterest ( defi ne d i n t he S A P) will be s u m marize d se parately.   In t he b y -
s u bject a nalys is, a s u bject ha vi n g t he sa me e ve nt m ore t ha n o nce will be c o u nte d o nl y 
o nce.  Listi n gs of deat hs, S A Es, a n d A Es lea di n g t o treat me nt disc o nti n uati o n of a s u bject 
will be prese nte d.
1 1. 6. 2.  
Cli nic al L a b or at or y A n al yses
He mat ol o g y , ser u m c he mistr y, a n d uri nalys is para meters e val uate d at eac h pla n ne d 
assess me nt, a n d c ha n ges fr o m baseli ne at eac h pla n ne d p ost- baseli ne assess me nt, will be 
s u m marize d b y treat me nt gr o u p .  Shift ta bles (i n cate g ories of l o w, n or mal, a n d hi g h, 
w he n a p pr o priate) will be pr o vi de d b y treat me nt gr o u p.  S u bjects wit h a b n or mal val ues 
will be i de ntifie d i n t he data listi n gs.
1 1. 6. 3.  
Vit al Si g n A n al yses
Vital si g n fi n di n gs at eac h pla n ne d assess me nt, a n d c ha n ges fr o m baseli ne at eac h 
pla n ne d p ost -baseli ne assess me nt, will be s u m marize d b y  treat me nt gr o u p .
1 1. 6. 4.  
Electr oc ar di o gr a m A n al yses
E C G data will be liste d a n d s u m marize d b y  treat me nt gr o u p a n d visit.  S hift ta bles f or 
E C G res ults ( n or mal or a b n or mal) will be prese nte d b y treat me nt gr o u p t o s h o w c ha n ges 
fr o m baseli ne ( n or mal or a b n or mal) t o e n d-of -treat me nt ( n or mal or a b n or mal).
1 1. 6. 5.  
P h ysic al E x a mi n ati o n A n al yses
Cli nicall y  si g nifica nt a b n or mal ph y sical e xa mi nati o n fi n di n gs will be re p orte d as A Es.  
Data fr o m p h ys ical e xa mi nati o ns will be liste d a n d s u m marize d b y treat me nt gr o u p a n d 
visit.
1 1. 6. 6.  
Ne ur ol o gic al E x a mi n ati o ns
Data fr o m ne ur ol o gical e xa mi nati o ns will be liste d a n d s u m marize d b y treat me nt gr o u p
a n d visit.
1 1. 6. 7.  
C ol u m bi a - S uici de Se verit y R ati n g Sc ale
C- S S R S data will be liste d a n d s u m marize d b y  treat me nt gr o u p a n d visit.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 0
1 1. 6. 8.  
P h ysici a n Wit h dr a w al C hec klist
P W C data will be liste d a n d s u m marize d b y treat me nt gr o u p a n d visit.
1 1. 7.  
Ot her A n al yses
N ot a p plica ble.
1 1. 8.  
Interi m A n al yses
N ot a p plica ble.
1 1. 9.  
D at a S afet y M o nit ori n g B o ar d
A n i n de pe n de nt D S M B will be res p o nsi ble f or re vie wi n g u n bli n de d safet y data i n a n 
o n g oi n g ma n ner a n d f or m o nit ori n g a n d ass uri n g o verall safet y  of t he st u d y s u bjects i n 
t he D S- 5 5 6 5 Phase 3 pr o gra m .  I n acc or da nce wit h a n a gree d-u p o n c harter, t he D S M B 
will meet peri o dicall y, o n a re g ular a n d/ or a d h oc basis, t o disc uss a n d a d dress a n y 
e mer gi n g safet y or t olera bilit y iss ues, i ncl u di n g S A Es, disc o nti n uati o ns d ue t o A Es, etc., 
as well as ot her rele va n t st u d y i nf or mati o n, s uc h as recr uit me nt stat us, i neli gi bilit y rates, 
a n d data q ualit y.  Base d o n a n y f or mal D S M B re vie w meeti n g w here bli n de d or 
u n bli n de d safet y data are re vie we d a n d disc usse d, t he D S M B will rec o m me n d t o t he 
S p o ns or o ne of t he f oll o wi n g:

C o nti n ue t he st u d y  wit h o ut m o dificati o n

C o nti n ue t he st u d y  b ut m o dif y t he pr ot oc ol a n d/ or I C F

S us pe n d t he st u d y  u ntil f urt her n otice, wit h rec o m me n dati o ns f or f urt her 
acti o n t o a d dress s pecific iss ues a n d a p pr o priatel y  ma na gi n g acti ve st u d y 
s u bjects

Ter mi nate t he st u d y wit h pr o visi o ns f or or derl y disc o nti n uati o n i n acc or da nce 
wit h G C P.
M o dificati o n, s us pe nsi o n, or ter mi nati o n ma y  be ma de f or a n y of t he f oll o wi n g reas o ns:

C o ncer n a b o ut dr u g -i n d uce d li ver i nj ur y

C o ncer n a b o ut s uici de

A n y  ot her safety c o ncer n
T he a p pr oac h t o st u d y  ( or c o h ort) m o dificati o n, s us pe nsi o n, or ter mi nati o n will be 
descri be d i n t he D S M B c harter.
T he S p o ns or ( Hea d of C S P V ) will be n otifie d of t he D S M B decisi o n b y  t he D S M B 
c hair ma n wit hi n 3 da ys after t he meeti n g.  Mi n utes of all f or mal D S M B meeti n gs a n d 
disc ussi o ns will be mai ntai ne d b y t he i n de pe n de nt statisticia n, i n a sec ure l ocati o n, u ntil 
c o m pleti o n or ter mi nati o n of t he st u d y, at w hic h p oi nt t he y will be f or war de d t o Daiic hi 
Sa n k y o f or arc hi vi n g.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 1
1 1. 1 0. 
He p atic A dj u dic ati o n C o m mittee
T he H A C will c o m prise at least t w o q ualifie d he pat ol o gists, w h o are n ot I nvesti gat or s i n 
t he st u d y a n d n ot ot her wise directly ass ociate d wit h t he S p o ns or .  T he H A C will f oll o w 
its o w n c harter f or pr ocessi n g a n d a dj u dicati n g he patic e ve nts fr o m t he D S- 5 5 6 5 Phase 3 
pr o gra m .  T he H A C will a dj u dicate he patic e ve nts i n a bli n de d ma n ner.  T his 
a dj u dicati o n will be i n de pe n de nt of t he I n vesti gat ors.  T he H A C will c o m plete 
assess me nts o n a n o n g oi n g basis. A dj u dicati o n of he patic e ve nts will be base d o n 
e val uati o n of e C R Fs a n d s o urce d oc u me nts, as a vaila ble, i ncl u di n g b ut n ot li mite d t o 
h os pital disc har ge s u m maries, dia g n ostic i ma gi n g, hist o pat h ol o g y , c o ns ultati o n, a n d 
cli nical la b orat or y re p orts.
1 1. 1 1. 
S a m ple Si ze Deter mi n ati o n
A p pr o xi matel y  6 0 s u bjects will be ra n d o mize d.  Ass u mi n g a 2 5 % dr o p o ut rate, 
a ppr o xi matel y  4 5 s u bjects will c o m plete t he d o u ble -bli n d treat me nt peri o d.  T his sa m ple 
size is t h o u g ht t o be s ufficie nt t o a d dress t he o bjecti ves of t his cli nical trial. All atte m pts 
will be ma de t o e nr oll a reas o na ble distri b uti o n of patie nts wit h m o derate t o se vere re nal 
i ns ufficie nc y i n t his st u d y.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 2
1 2.  
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E
T he I n vesti gat or/i n vesti gati o nal site will per mit st u d y -relate d m o nit ori n g, a udits, 
I RB/I E C re vie w a n d re g ulat or y  i ns pecti o ns b y pr o vi di n g direct access t o s o urce 
data/ d oc u me nts.  Direct access i ncl u des per missi o n t o e xa mi ne, a nal y ze, verif y, a n d 
re pr o d uce a ny rec or ds a n d re p orts t hat are i m p orta nt t o t he e val uati o n of a cli nical st u d y .
1 2. 1.  
M o nit ori n g a n d I ns pecti o ns
T he S p o ns or or desi g nee’s m o nit or a n d re g ulat or y a ut h orit y  i ns pect ors are res p o nsi ble f or 
c o ntacti n g a n d visiti n g t he I n vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, 
u p o n re q uest, i ns pecti n g t he vari o us rec or d s of t he st u d y (e g, C R F s, s o urce data, a n d 
ot her perti ne nt d oc u me nts).
T he m o nit or is res p o nsi ble f or visiti n g site(s) at re g ular i nter vals t hr o u g h o ut t he st u d y  t o 
verif y  a d here nce t o t he pr ot oc ol; c o m plete ness, acc urac y, a n d c o nsiste nc y of t he data; 
a n d a d here nce t o IC H G C P a n d l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  T he 
m o nit or is res p o nsi ble f or i ns pecti n g t he C R F s a n d e ns uri n g c o m plete ness of t he st u d y 
esse ntial d oc u me nts.  T he m o nit or s h o ul d ha ve access t o s u bject me dica l rec or ds a n d 
ot her st u d y -relate d rec or ds nee de d t o verif y t he e ntries o n t he C R F s.
T he m o nit or will c o m m u nicate de viati o ns fr o m t he pr ot oc ol, S O Ps, G C P, a n d a p plica ble 
re g ulati o ns t o t he I n vesti gat or a n d will e ns ure t hat a p pr o priate acti o n desi g ne d t o preve nt 
rec urre nce of t he detecte d de viati o ns is ta ke n a n d d oc u me nte d.
T he I n vesti gat or a grees t o c o o perate wit h t he m o nit or t o e ns ure t hat a n y pr o ble ms 
detecte d i n t he c o urse of t hese m o nit ori n g visits are a d dresse d a n d d oc u me nte d.
I n acc or da nce wit h I C H G C P a n d t he S p o ns or’s a u dit pla ns, t his st u d y  ma y be selecte d 
f or a u dit by re prese ntati ves fr o m S p o ns or .  I ns pecti o n of site facilities (e g, p har mac y, 
dr u g st ora ge areas, la b orat ories, etc. ) a n d re vie w of st u d y-relate d rec or ds will occ ur i n 
or der t o e val uate t he st u d y c o n d uct a n d c o m plia nce wit h t he pr ot oc ol, I C H G C P, a n d 
a p plica ble re g ulat or y re q uire me nts.
1 2. 2.  
D at a C ollecti o n
All rele va nt o bser vati o ns a n d data relate d t o t he st u d y , as per t he st u d y pr ot oc ol, will be 
rec or de d o n e C R F pa ges.  A re prese ntati ve of Daiic hi Sa n k yo or t heir desi g nee will 
pr o vi de i nstr ucti o n f or c o m pleti n g t he e C R F.  A de q uate a n d acc urate case rec or ds s h o ul d 
be mai ntai ne d, i ncl u di n g t he e val uati o n of i ncl usi o n a n d e xcl usi o n criteria, me dical 
hist or y , p h ysical e xa mi nati o ns, cli nical assessme nts, a rec or d of cli nical safet y la b orat or y 
sa m ple c ollecti o n, dr u g a d mi nistrati o n, A Es, a n d fi nal e val uati o n.  
T he e C R Fs m ust be c o m plete d f or eac h s u bject w h o si g ns t he I C F a n d u n der g oes 
scree ni n g pr oce d ures.  F or s u bjects w h o are scree ne d b ut n ot ra nd o mize d, mi ni mal data 
will be rec or de d o n t he e C R F, i ncl u di n g de m o gra p h y , s u bject stat us, a n d A Es.  All st u d y -
relate d data f or t hese s u bjects will be mai ntai ne d i n t he me dical rec or ds at t he site.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 3
T he e C R F data e ntr y  s hall be c o m plete d o n t he da y of t he visit or as s o o n as p ossi ble 
t hereafter.  T he I n vesti gat or m ust electr o nicall y si g n a n d date t he e C R F.  T he si g nat ure 
s hall i n dicate t hat t he I n vesti gat or has re vie we d t he data a n d data q ueries rec or de d o n 
e C R Fs a n d t he site n otificati o ns, a n d a grees wit h t he c o nte nt.  After t he c o m pleti o n of t he 
st u d y, e C R Fs i ncl u di n g a u dit trail will be ret ur ne d t o Daiic hi Sa n k yo a n d st ore d i n t he 
arc hi ves.
1 2. 3.  
D at a M a n a ge me nt
Eac h s u bject will be i de ntifie d i n t he data base b y a u ni q ue s u bject i de ntifier as defi ne d b y 
t he S p o ns or.
T o e ns ure t he q ualit y  of cli nical data acr oss all s u bjects a n d sites, a Cli nical Data 
Ma na ge me nt re vie w will be perf or me d o n s u bject data acc or di n g t o s pecificati o ns gi ve n 
t o t he S p o ns or or desi g nee.  Data will be vette d electr o nicall y a n d/ or ma n uall y  as 
a p pr o priate.  D uri n g t his re vie w, s u bject data will be c hec ke d f or c o nsiste nc y , o missi o ns, 
a n d a n y a p pare nt discre pa ncies.  I n a d diti o n, t he data will be re vie we d f or a d here nce t o 
t he pr ot oc ol a n d G C P.  F or e C R Fs, t he data will be electr o nically vette d b y pr o gra m me d 
data r ules wit hi n t he a p plicati o n.  Q ueries ge nerate d b y  r ules a n d raise d b y re vie wers will 
be ge nerate d wit hi n t he electr o nic data ca pt ure ( E D C) a p plicati o n a n d als o res ol ve d 
wit hi n t he E D C a p plicati o n. 
Data recei ve d fr o m e xter nal s o urces s uc h as ce ntral la b orat ories will be rec o ncile d t o t he 
cli nical data base.
Seri o us a d verse e ve nts i n t he cli nical data base will be rec o ncile d wit h t he safet y  data base.
All me dical hist or y  (e xce pt pre-pri nte d ter ms) a n d A Es will be c o de d usi n g Me d D R A.  
All pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g W H O Dr u g Dicti o nar y .
1 2. 4.  
St u d y D oc u me nt ati o n a n d St or a ge
T he I n vesti gat or will mai ntai n a Si g nat ure List of a p pr o priatel y q ualifie d pers o ns t o
w h o m he/s he has dele gate d st u d y  d uties.  All pers o ns a ut h orize d t o ma ke e ntries a n d/ or 
c orrecti o ns o n C R F s will be i ncl u de d o n t he Si g nat ure List.
S o urce d oc u me nts are ori gi nal d oc u me nts, data, a n d rec or ds fr o m w hic h t he s u bject’s 
C R F da ta are o btai ne d.  T hese i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical 
a n d office c harts, la b orat or y a n d p har mac y rec or ds, diaries, micr ofic hes, X-ra ys, a n d 
c orres p o n de nce.
T he I n vesti gat or a n d st u d y staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g sys te m ( Trial Master File) of all st u d y-relate d (esse ntial) 
d oc u me ntati o n, s uita ble f or i ns pecti o n at a n y ti me b y  re prese ntati ves fr o m t he S p o ns or
a n d/ or a p plica ble re g ulat or y a ut h orities.  Esse ntial d oc u me nts i ncl u de:

S u bject files c o ntai n i n g c o m plete d C R F s, i nf or me d c o nse nts, a n d s u p p orti n g 
c o pies of s o urce d oc u me ntati o n (if ke pt).

St u d y  files c o ntai ni n g t he pr ot oc ol wit h all a me n d me nts, In vesti gat or’s 
Br oc h ure, c o pies of rele va nt esse ntial d oc u me nts re q uire d pri or t o 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 4
c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d fr o m t he I E C/I R B 
a n d t he S p o ns or.

Rec or ds relate d t o t he I n vesti gati o nal Pr o d uct(s) i ncl u di n g ac k n o wle d g me nt 
of recei pt at site, acc o u nta bilit y  rec or ds a n d fi nal rec o nciliati o n a n d a p plica ble 
c orres p o n de nce.
I n a d diti on, all ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he C R F s m ust be 
mai ntai ne d a n d be rea dil y  a vaila ble.
All esse ntial d oc u me ntati o n will be retai ne d b y t he i nstit uti o n u ntil t ol d ot her wise b y t he 
S p o ns or .
N o st u d y  d oc u me nt s h o ul d be destr o ye d wit h o ut pri or writte n a gree me nt bet wee n t he 
S p o ns or a n d t he I n vesti gat or.  S h o ul d t he I nvesti gat or wis h t o assi g n t he st u d y  rec or ds t o 
a n ot her part y or m o ve t he m t o a n ot her l ocati o n, he/s he m ust n otif y t he S p o ns or i n writi n g 
of t he ne w res p o nsi ble pers o n a n d/ or t he ne w l ocati o n.
All I nvesti gat or s a n d site pers o n nel m ust e ns ure s u bject c o nfi de ntialit y as o utli ne d i n 
Secti o n 1. 5. 1 .
1 2. 5.  
Rec or d Kee pi n g
Rec or ds of s u bjects, s o urce d oc u me nts, m o nit ori n g visit l o gs, data c orrecti o n f or ms, 
C R Fs, i n ve nt or y  of st u d y pr o d uct, re g ulat or y d oc u me nts (e g, pr ot oc ol a n d a me n d me nts, 
I RB/ E C c orres p o n de nce a n d a p pr o vals, a p pr o ve d a n d si g ne d I C Fs, I n vesti gat or’s 
A gree me nt, cli nical s u p plies recei pts, distri b uti o n a n d ret ur n rec or ds), a n d ot her S p o ns or
c orres p o n de nce pertai ni n g t o t he st u d y m ust be ke pt i n a p pr o priate st u d y files at t he site.  
S o urce d oc u me nts i ncl u de all rec or di n gs a n d o bser vati o ns or n otati o ns of cli nical 
acti vities a n d all re p orts a n d rec or ds necessar y  f or t he e val uati o n a n d rec o nstr ucti o n of 
t he cli nical st u d y.  T hese rec or ds will be retai ne d i n a sec ure file f or t he peri o d re q uire d 
b y  t he i nstit uti o n or site p olic y.  Pri or t o tra nsfer or destr ucti o n of t hese rec or ds, t he 
S p o ns or m ust be n otifie d i n writi n g a n d be gi ve n t he o p p ort u nit y  t o f urt her st ore s uc h 
rec or ds.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 5
1 3.  
FI N A N CI N G A N D I N S U R A N C E
1 3. 1.  
Fi n a nces
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit u ti o n will si g n a cli nical 
st u d y a gree me nt wit h t he S p o ns or or desi g nee.   T his a gree me nt will i ncl u de t he fi na ncial 
i nf or mati o n a gree d u p o n b y t he parties.
1 3. 2.  
Rei m b urse me nt, I n de m nit y, a n d I ns ur a nce
Rei m b urse me nt, i n de m nit y , a n d i ns ura nce s hall be a d dresse d i n a se parate a gree me nt o n 
ter ms a gree d u p o n by t he parties.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

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

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 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
1 5. 1.  
Pr ot oc ol A me n d me nts
A n y  a me n d me nts t o t he st u d y pr ot oc ol t hat see m t o be a p pr o priate as t he st u d y 
pr o gresses will be c o m m u nicate d t o t he I n vesti gat or b y  t he S p o ns or.  All pr ot oc ol 
a me n d me nts will u n der g o t he sa me re vie w a n d a p pr o val pr ocess as t he ori gi nal pr ot oc ol.  
A pr ot oc ol a me n d me nt ma y  be i m ple me nte d after it has bee n a p pr o ve d b y t he IR B/ E C
a n d re g ulat or y a ut h orities, w here rele va nt, u nless i m me diate i m ple me ntati o n of t he 
c ha n ge is necessar y f or s u bject safety.  I n t his case, t he sit uati o n m ust be d oc u me nte d a n d 
re p orte d t o t he I R B/ E C wit hi n fi ve w or ki n g da ys.  T he S p o ns or will ass ure t he ti mel y  
s u b missi o n of a me n d me nts t o re g ulat or y a ut h orities.
1 5. 2.  
A d dress List
A list of ke y  st u d y pers o n nel (i ncl u di n g pers o n nel at t he S p o ns or , C R O, la b orat ories, a n d 
ot her ve n d ors) a n d t heir c o ntact i nf or mati o n (a d dress, tele p h o ne, fa x, e mail) will be ke pt 
o n file a n d u p date d i n t he St u d y  O perati o ns Ma n ual.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 8
1 6.  
R E F E R E N C E S
1 Fiel d MJ, C o x PJ, St ott E, Melr ose H, Off or d J, S u T Z, et al. I de ntificati o n of t he al p ha 2 -delta -1 s u b u nit 
of v olta ge -de pe n de nt calci u m c ha n nels as a m olec ular tar get f or pai n me diati n g t he a nal gesic acti o ns of 
pre ga bali n. Pr ocee di n gs of t he Nati o nal Aca de m y of Scie nces of t he U nite d States of A merica. 
2 0 0 6; 1 0 3( 4 6): 1 7 5 3 7 -4 2.
2 Bril V, E n gla n d J, Fra n kli n G M, Bac k o nja M, C o he n J, Del T or o D, et al. E vi de nce -base d g ui deli ne: 
Treat me nt of pai nf ul dia betic ne ur o pat h y: re p ort of t he A merica n Aca de m y of Ne ur ol o g y, t he A merica n 
Ass ociati o n of Ne ur o m usc ular a n d Electr o dia g n ostic Me dici ne, a n d t he A merica n Aca de m y of P h ysical 
Me dici ne a n d Re ha bilitati o n. Ne ur ol o g y. 2 0 1 1; 7 6( 2 0): 1 7 5 8 -6 5.
3O' C o n n or A B, D w or ki n R H. Treat me nt of ne ur o pat hic pai n: a n o ver vie w of  rece nt g ui deli nes. T he 
A merica n J o ur nal of Me dici ne. 2 0 0 9; 1 2 2( 1 0 S u p pl): S 2 2 -3 2.
4 Free ma n R, D urs o -Decr uz E, E mir B. Efficac y, safet y, a n d t olera bilit y of pre ga bali n treat me nt f or pai nf ul 
dia betic peri p heral ne ur o pat h y: fi n di n gs fr o m se ve n ra n d o mize d, c o ntr olle d trials acr oss a ra n ge of d oses. 
Dia betes Care. 2 0 0 8; 3 1( 7): 1 4 4 8 -5 4.
5 G ui da nce f or I n d ustr y: P har mac o ki netics i n Patie nts wit h I m paire d Re nal F u ncti o n —
St u d y Desi g n, Dat a 
A nal ysis, a n d I m pact o n D osi n g a n d La beli n g, D R A F T G UI D A N C E, Marc h 2 0 1 0. 
htt p:// w w w f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nces/ U C M 2 0 4 9 5 9. p df: accesse d o n Fe br uar y 1 9, 2 0 1 5. 
6 G ui da nce f or I n d ustr y A nal gesic I n dicati o ns: De vel o pi n g Dr u g a n d Bi ol o gical Pr o d ucts, D R A F T 
G UI D A N C E, Fe br uar y 2 0 1 4; 
htt p:// w w w f da. g o v/ d o w nl oa ds/ Dr u gs/ G ui da nce C o m plia nce Re g ulat or yI nf or mati o n/ G ui da nces/ U C M 3 8 4 6 9
1. p df: accesse d o n Ma y 5, 2 0 1 4
7 Farrar J T, Y o u n g J P, Jr., La M orea u x L, Wert h J L, P o ole R M. Cli nical i m p orta nce of c ha n ges i n c hr o nic
pai n i nte nsit y meas ure d o n a n 1 1 -p oi nt n u merical pai n rati n g scale. Pai n. 2 0 0 1; 9 4( 2): 1 4 9 -5 8.
8 F D A. G ui da nce f or I n d ustr y: Dr u g -I n d uce d Li ver I nj ur y: Pre mar keti n g Cli nical E val uati o n. 2 0 0 9.
9 P os ner K, Br o w n G K, Sta nle y B, Bre nt D A, Yers h o va K V, O q ue n d o M A, et al. T he C ol u m bia -S uici de 
Se verit y Rati n g Scale: i nitial vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h 
a d olesce nts a n d a d ults. T he A merica n j o ur nal of ps yc hiatr y. 2 0 1 1; 1 6 8( 1 2): 1 2 6 6 -7 7 .
1 0 Ric kels K, Garcia -Es pa na F, Ma n d o s L A, Case G W. P h ysicia n Wit h dra wal C hec klist ( P W C-2 0). J o ur nal 
of cli nical ps yc h o p har mac ol o g y. 2 0 0 8; 2 8( 4): 4 4 7 -5 1 .
1 1 Ric kels K, P ollac k M H, Felt ner D E, L y diar d R B, Zi m br off D L, Biels ki RJ, et al. Pre ga bali n f or treat me nt 
of ge neralize d a n xiet y dis or der: a 4 -we e k, m ultice nter, d o u ble -bli n d, place b o -c o ntr olle d trial of pre ga bali n 
a n d al praz ola m. Arc hi ves of ge neral ps yc hiatr y. 2 0 0 5; 6 2( 9): 1 0 2 2 -3 0 .
1 2 Pa n de A C, Cr oc katt J G, Felt ner D E, Ja n ne y C A, S mit h W T, Weisler R, et al. Pre ga bali n i n ge neralize d 
a n xiet y dis o r der: a place b o-c o ntr olle d trial. T he A merica n j o ur nal of ps yc hiatr y. 2 0 0 3; 1 6 0( 3): 5 3 3 -4 0 .
1 3 P o hl R B, Felt ner D E, Fie ve R R, Pa n de A C. Efficac y of pre ga bali n i n t he treat me nt of ge neralize d 
a n xiet y dis or der: d o u ble -bli n d, place b o -c o ntr olle d c o m paris o n of BI D vers us TI D d osi n g. J o ur nal of 
cli nical ps yc h o p har mac ol o g y. 2 0 0 5; 2 5( 2): 1 5 1 -8.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 9
1 7.  
S C H E D U L E O F E V E N T S
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 0
T a ble 1 7 .1 : 
Sc he d ule o f E ve nts 
St u d y Peri o d
Scree ni n g/ B aseli ne a
R a n d o miz ati o n  Tre at me nt
E n d of T x or E T  
3- D a y F U  
2 Wee k  F oll o w-u p  4 Wee k  F oll o w-u p
Visit
1   
2   
3   
4
5   
6- 1 0  
1 1
1 2
1 3
1 4
Wee k
≤ - 4   
-3 t o - 1   
- 1   
0
1  
bi wee k l y  
1 3
1 3. 5
1 5
1 7
Visit Wi n d o w ( d a ys)  
--
--
± 2   
± 2   
± 2
± 1
± 3
± 7
Tele p h o ne C o ntact
X
X
X
St u d y i nf or me d c o nse nt  
X
I ncl usi o n/e xcl usi o n criteria  
X
X
De m o gra p hic i nf or mati o n  
X
Me dical/s ur gical hist or y  
X
Dis pe nse Dail y e Diar y
X
Re vie w dail y diaries
X
X    
X
X
P h ysical e xa mi nati o n  
X
X
X
Ne ur ol o gical assess me nt  
X
X
X    
X
X
Vital si g ns
X
X
X    
X
X
X
1 2 -lea d electr ocar di o gra m  
X
X
Cli nical la b orat or y
e val uati o ns
X
X
X    
X
X
X
P W C b
X
X
X
C- S S R S
X
X
X    
X
X
X
M.I . N.I ( Versi o n 6. 0)    
X
P K bl o o d sa m pli n g
X c
X c
Pre g na nc y test
X
X d
X d
X d
X
X d
A d verse e ve nt re p orti n g  
X    
X    
X    
X
X    
X
X
X
X
X
Pri or/c o nc o mita nt 
me dicati o ns
X
X    
X    
X
X    
X
X
X
X
X
St u d y dr u g dis pe nsi n g
X
X    
X
St u d y dr u g c o m plia nce
X    
X
X
C o ntact I X R S
X
X
X    
X
X
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-U 3 0 7
Versi o n 3 . 0, 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 1
a Scree ni n g peri o d c o m prises a n i nitial cli nic visit ( Visit 1), a tele p h o ne c o ntact ( Visit 2), a n d a cli nic visit at t he start of t he Baseli ne Peri o d ( Visit 3) at 
w hic h ti me s u bjects w ill be gi ve n a n electr o nic dail y diar y f or rec or di n g of pai n sc ores at h o me.
b All s u bjects ha ve P W C d uri n g f oll o w -u p. S u bjects disc o nti n ue d fr o m st u d y at or bef ore Visit 1 1 ( Wee k 1 3) w ill be gi n f oll o w-u p 3 da ys later wit h 
Visit 1 2 tele p h o ne c o ntact.
c P K sa m pli n g at Wee ks 1, 3, 7, a n d 1 1 .
d Uri ne pre g na nc y tests f or W O C B P at t hese visits; if p ositi ve, als o ser u m test; uri ne a n d ser u m tests at scree ni n g, e n d of tre at me nt or earl y ter mi nati o n.
A b bre viati o ns: C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale, E T = Earl y Ter mi nati o n, F U = f oll o w - u p, M.I. N.I = Mi ni I nter nati o nal 
Ne ur o ps yc hiatric I nter vie w ( Versi o n 6. 0), P GI C = Patie nt Gl o bal I m pressi o n of C ha n ge, P K = p har mac o ki netic, P W C = P h ysicia n Wit h dra w al 
C hec klist, T x = treat me nt, W O C B P = w o m e n of c hil d beari n g p ote ntial; I X R S = I nteracti ve We b/ V oice/ We b Res p o nse S yste m .
P GI C
X
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a