An Open-label Extension Study of DS-5565 for 52 Weeks in Pain Associated With Fibromyalgia
Phase: PHASE3
Conditions: Pain Associated With 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 N O P E N -L A B E L E X T E N SI O N S T U D Y O F D S - 5 5 6 5 
F O R 5 2 W E E K S I N P AI N A S S O CI A T E D WI T H
FI B R O M Y A L GI A
D S 5 5 6 5 - A-E 3 1 2
I N D 1 1 8, 3 0 4
E U D R A C T N U M B E R 2 0 1 3- 0 0 5 1 6 4- 2 6
V E R SI O N 4 U K 1 , 14 M A R 2 0 1 7
V E R SI O N 4. 0, 0 7 A P R 2 0 1 6
V E R SI O N 3. 0, 2 9 J A N 2 0 1 5
V E R SI O N 2. 0 , 3 1 J U L 2 0 1 4
V E R SI O N 1. 0, 2 2 M A Y 2 0 1 4
S P O N S O R 
D aiic hi S a n k y o P h ar m a De vel o p me nt
3 9 9 T h or n all Street 
E dis o n, N J 0 8 8 3 7 U nite d St ates
D aiic hi S a n k y o De vel o p me nt Li mite d 
C hilter n Pl ace, C h alf o nt P ar k 
Gerr ar ds Cr oss, B uc ki n g h a 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-E 3 1 2
Versi o n 4 U K 1 , 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
I ND / E u dra C T N u m ber: 
1 1 8, 3 0 4/ 2 0 1 3- 0 0 5 1 6 4- 2 6
Pr ot oc ol N u m ber:
D S 5 5 6 5 - A-E 3 1 2
I n vesti gati o nal Pr o d uct: 
D S - 5 5 6 5
Acti ve I n gre die nt(s)/I N 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
St u d y  Title:
A n O pe n -la bel E xte nsi o n St u d y of D S- 5 5 6 5 f or 5 2 Wee ks i n 
Pai n Ass ociate d wit h Fi br o m y al gia
St u d y  P hase:
P hase 3
I n dicati o n U n der 
I n vesti gati o n:
Pai n ass ociate d wit h fi br o m y al gia ( F M)
St u d y  O bjecti ves:
T he pri mar y o bjecti ve is t o assess t he l o n g-ter m safet y of 
D S - 5 5 6 5 i n s u bjects wit h F M .
T he sec o n dar y  o bjecti ves are:

T o o bser ve t he effects of D S -5 5 6 5 o n a vera ge 
dail y  pai n sc ore ( A D P S) a n d pai n -ass ociate d 
slee p i nterfere nce as assesse d b y a vera ge dail y 
slee p i nterfere nce sc ore ( AD SI S) (b ot h rec or de d 
i n a diar y). Wee kly 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 
his or her w orst pai n o ver t he pre vi o us 2 4 h o urs

T o o bser ve 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)

T o o bser ve t he effe cts of D S -5 5 6 5 o n de pressi o n 
a n d a n xiet y as assesse d b y t he H os pital A n xiet y 
a n d De pressi o n Scale ( H A D S) 

T o o bser ve t he effects of D S -5 5 6 5 o n s u bject 
q ualit y  of life as assesse d b y t he E ur o Q o L 
I nstr u me nt 5 D o mai ns ( E Q-5 D) a n d t he S h ort 
F or m 3 6 ( S F - 3 6)
S t u d y Desi g n:
T his is a n o pe n-la bel st u d y of D S - 5 5 6 5 i n s u bjects w h o 
eit her c o m plete d partici pati o n i n a prece di n g P hase 3 st u d y  
of D S - 5 5 6 5 i n F M (i.e. D S 5 5 6 5 - A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, 
or D S 5 5 6 5 - A-E 3 1 1 ) or are de n o v o s u bjects. Eli gi 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4
s u bjects will be assi g ne d t o recei ve o pe n -la bel D S-5 5 6 5 f or 
5 2 wee ks.  All s u bjects will recei ve D S -5 5 6 5 1 5 m g o nce 
da il y ( Q D) f or t he first t hree wee ks of t he treat me nt peri o d .  
After t hree wee ks, s u bjects ma y be titrate d t o 1 5 m g t wice 
dail y  (BI D ) base d o n pr ot oc ol -s pecifie d criteria.
St u d y  D urati o n:
F or r oll o ver s u bjects, the t otal st u d y  d urati o n (f or a n 
i n di vi d ual s u bject’s partici pati o n) will be a p pr o xi matel y 5 6
wee ks, i ncl u di n g 5 2 wee ks of o pe n -la bel treat me nt a n d 4 
wee ks of p ost -treat me nt f oll o w-u p.  De n o v o s u bjects will 
als o ha ve a scree ni n g/ baseli ne peri o d of u p t o 3 wee ks a n d 
t heref ore a t otal d urati o n of a p pr o xi matel y 5 9 wee ks.  
St u d y  Sites a n d L ocati o n: 
T his is a w orl d wi de st u d y w hic h i ncl u des sites t hat 
c o n d ucte d o ne of t he prece di n g st u dies of D S - 5 5 65 i n F M
( D S 5 5 6 5- A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1) 
a n d sites t hat di d n ot c o n d uct o ne of t he prece di n g D S 5 5 6 5 
st u dies as liste d a b o ve.
Pla n ne d Sa m ple Size: 
S u bjects w h o c o m plete t he d o u ble -bli n d st u dies are eli gi ble 
t o r oll o ver t o t his o pe n-la bel exte nsi o n st u d y . Alt h o u g h it’s 
u n k n o w n h o w ma n y s u bjects will c o m plete t he d o u ble -bli n d 
st u dies, t he n u m ber is a ntici pate d t o be bet wee n 2 1 0 0 a n d 
2 5 0 0.  I n a d diti o n s u bjects w h o di d n ot partici pate i n a 
prece di n g d o u ble -bli n d st u d y  (referre d t o as de n o v o 
s u bjects) m a y be e nr oll e d. O verall, t he g oal of t he o pe n -la bel 
e xte nsi o n st u d y is t o c ollect l o n g-ter m safety data o n 
a p pr o xi matel y 5 0 0 s u bjects e x p ose d t o D S-5 5 6 5 f or at least 
5 2 wee ks.  D uri n g t he c o n d uct of t he o pe n -la bel st u d y,
s u bject wit h dra wal rates will be cl osel y m o nit ore d. E ntr y 
i nt o t he o pe n-la bel st u dy will be st o p pe d w he n t he s p o ns or 
a ntici pates t hat t he desire d n u m ber of s u bjects c o m pleti n g 5 2 
wee ks ca n be ac hie ve d.   
S u bject Eli gi bilit y  Criteria: 
I ncl usi o n Criteria:
S u bjects w h o c o m plete d a P h ase 3 D S -5 5 6 5 st u dy ( D S 5 5 6 5 -
A -E 3 0 9, D S 5 5 6 5 - A-E 3 1 0 , or D S 5 5 6 5- A-E 3 1 1 )
1.
A ble t o gi ve writte n i nf or me d c o nse nt
2.
C o m plete d partici pati o n (i.e. c o m plete d t he E n d -of -
Ta peri n g visit) i n a prece di n g st u d y of D S-5 5 6 5 i n 
F M (D S 5 5 6 5 - A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 -
A- E 3 1 1 )
3.
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 n a de q uate met h o d of c o ntrace pti o n (as 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5
detaile d i n t he b o d y of t he pr ot oc ol) 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.
T he s u bject m ust n ot ha ve e x perie nce d a n y 
si g nifica nt safety iss ues d uri n g t he prece di n g st u d y 
t hat, i n t he i n vesti gat or’s j u d g me nt, w o ul d a d versel y 
i m pact t he s u bject’s well-bei n g i n t he l o n g-t er m 
e xte nsi o n
De N ov o S u bjects
5.
A ge ≥ 1 8 y ears
6.
A ble t o gi ve writte n i nf or me d c o nse nt
7.
A ble t o c o m plete s u bject -re p orte d q uesti o n naires per 
t he i n vesti gat or’s j u d g me nt
8.
At scree ni n g, s u bjects m ust meet t he 1 9 9 0 A merica n 
C olle ge of R he u mat ol o g y ( A C R) criteria f or F M, i.e.
wi des prea d pai n prese nt f or at least 3 m o nt hs a n d 
pai n i n at least 1 1 of 1 8 s pecific te n der p oi nt sites.  I n 
a d diti o n, t he 2 0 1 0 A C R criteria m ust be met:

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

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

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
9.
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 past 7 da ys pri or t o first d ose ( base d 
o n c o m pleti o n of at least 4 dail y  pai n diaries d uri n g 
t he 7-da y  baseli ne peri o d)
1 0. S u bject m ust ha ve d oc u me nte d e vi de nce of a 
f u n d osc o pic e xa mi nati o n ( wit h p u pil dilati o n) or a 
sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n wit hi n 
1 2 m o nt hs pri or t o scree ni n g or at scree ni n g
1 1.
W O C B P m ust be usi n g a n a de q uate met h o d of 
c o ntrace pti o n (as detaile d i n t he b o d y of t he pr ot oc ol) 
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 Criteria:
All S u bjects
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6
1.
Cli nicall y  si g nifica nt u nsta ble ne ur ol o gic, 
ps y c hiatric, 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 hy 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) or a n y  ot her c o nc urre nt disease d uri n g t he 
prece di n g st u d y (f or r oll o ver s u bjects) or wit hi n 1 2 
m o nt hs pri or t o scree ni n g (f or de n o v o s u bjects) t hat 
i n t he o pi ni o n of t he i n vesti gat or w o ul d i nterfere wit h 
st u d y partici pati o n or assess me nt of safet y a n d 
t olera bilit y
2.
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 ol u m bia-S uici de Se verit y Rati n g 
Scale ( C -S S R S ) or i n t he o pi ni o n of t he i n vesti gat or. 
N ote: S u bject s a ns weri n g “ yes” t o a n y of t he 
q uesti o ns a b o ut acti ve s uici dal 
i deati o n/i nte nt/ be ha vi ors occ urri n g wit hi n t he past 1 2 
m o nt hs m ust be e xcl u de d ( C -S S R S S uici de I deati o n 
secti o n – Q uesti o ns 3, 4, or 5; C- S S R S S uici dal 
Be ha vi or secti o n, a n y of t he s uici de be ha vi ors 
q uesti o ns).  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 
3.
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 att it 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 
4.
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
5.
S u bjects wit h pai n d ue t o ot her c o n diti o ns ( e. g.
dia betic peri p heral ne ur o pat hic pai n or p ost -her p etic 
ne ural gia ) t hat i n t he o pi ni o n of t he i n vesti gat or
w o ul d c o nf o u n d assess me nt or self -e val uati o n of t he 
pai n ass ociate d wit h F M
6.
S u bjects wit h pai n d ue t o a n y  wi des prea d 
i nfla m mat or y m usc ul os keletal dis or der (e. g., 
r he u mat oi d art hritis, l u p us) or wi des prea d r he u matic 
disease ot her t ha n F M
7.
A b use or de pe n de nc e of prescri pti o n me dicati o ns, 
street dr u gs, or alc o h ol wit hi n t he last 1 y ear
8.
A n y  hist or y of a mali g na nc y ot her t ha n basal cell 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7
carci n o ma wit hi n t he past 5 years
9.
A dia g n osis of u ntreate d slee p a p nea or i nitiati o n of 
treat me nt f or slee p a p nea wit hi n t he pa st 3 m o nt hs
1 0. K n o w n h y perse nsiti vit y  t o al p ha2-delta ( 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.  
1 1. 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 2. A b n or mal i n vesti gati ve tests ( i.e. E C Gs) a n d 
la b orat or y val ues j u d ge d b y t he i n vesti gat or t o be 
cli nicall y si g nifica nt at t he E n d - of-Treat me nt visit 
( Visit 1 1, Wee k 1 3) i n t he prece di n g st u d y (f or 
r oll o ver s u bjects) or at scree ni n g (f or de n o v o 
s u bjects), wit h partic ular f oc us o n: 

A b n or mal re nal f u ncti o n defi ne d a s calc ulate d 
creati ni ne cleara nce (Cr Cl ) < 6 0 m L / mi n 
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; bl o o d urea nitr o ge n > 
1. 5 × u p per li mit of n or mal ( U L N ); ser u m 
creati nine > 1. 6 m g/ d L ( > 1 4 1. 4 μ m ol/ L) ; or

A b n or mal li ver f u ncti o n defi ne d as as partate 
a mi n otra nsferase ( A S T) > 2. 0 × U L N, ala ni ne 
a mi n otra nsferase ( 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.
If a s u bject has t otal bilir u bi n > 1. 2 U L N, 
u nc o nj u gate d a n d c o nj u gate d bili r u bi n fracti o ns 
s h o ul d be a nalyz e d a n d o nl y s u bjects d oc u me nte d 
t o ha ve Gilbert’s s y n dr o me ma y be e nr olle d ; or

Creati ne ki nase > 3. 0 × U L N;
F or De N ov o S u bjects O nly
1 3. 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 (as liste d i n Se cti o n 5. 2. 1 of 
t he pr ot oc ol)  
1 4. 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 Neur o ps yc hiatric I nter vie w ( MI NI) 
i nter vie w ( Versi o n 6. 0) at scree ni n g are e xcl u de d, b ut 
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 pr o vi de d t hat t he i n vesti gat or 
assesses t he patie nt as cli nicall y sta ble a n d 
a p pr o priate f or e ntr y int o t he st u d y
1 5. A n y  dia g n osis of lifeti me bi p olar dis or der 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8
ps y c h otic dis or der
1 6. S u bject is c urre ntl y e nr olle d i n or has n ot yet 
c o m plete d at least 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 dy or is recei vi n g 
ot her i n vesti gati o nal a ge nts
1 7. S u bject is a n e m pl o y ee of t he st u d y ce nter, a n 
i m me diate fa mil y me m ber * of a n e m pl o yee of t he 
st u d y ce nter, or a n e m pl o y ee of Daiic hi Sa n k yo, I N C 
Researc h , or a n y of t he st u d y ve n d ors s u p p orti n g t his 
st u d y. *(s p o use, pare nt, c hil d, or si bli n g, w het her 
bi ol o gical or le gall y  a d o pte d)
D osa ge F or m, D ose a n d
R o ute of A d mi nistrati o n:
O pe n -la bel st u dy me dicati o n will be pr o vi de d i n blister car ds 
(“ wallets”).  
D S -5 5 6 5 is s u p plie d i n t he f or m of 1 5 m g  ta blets f or oral 
a d mi nistrati o n.  D oses of D S - 5 5 6 5 incl u de 1 5 m g Q D a n d 
1 5 m g BI D.   
Eac h s u bject will ta ke ( orall y) 1 ta blet eit her Q D at be dti me 
or BI D i n t he m or ni n g a n d at be dti me.
St u d y  E n d p oi nts:
T he pri mar y  e n d p oi nt is l o n g-ter m safet y base d o n 
assess me nt of treat me nt -e mer ge nt a d verse e ve nts ( T E A Es), 
cli nical la b orat or y e val uati o ns, p h ysical e xa mi nati o ns, 
electr ocar di o gra ms ( E C Gs), t he C-S S R S, a n d t he P h y sicia n 
Wit h dra wal C hec klist ( P W C) .
T he sec o n dar y  e n d p oi nts are:

C ha n ges fr o m baseli ne t o sc he d ule d ti me p oi nt i n 
A D P S a n d A D SI S

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 5 2 as assesse d b y  P GI C

C ha n ges fr o m baseli ne t o Wee k 5 2 i n H A D S 
de pressi o n a n d a n xiet y sc ores 

C ha n ges i n E Q -5 D a n d S F - 3 6 para meters fr o m 
baseli ne t o Wee k 5 2
Statistical A nal y ses: 
Efficac y  a n d safet y data will be s u m marize d usi n g 
descri pti ve statistics ; a n y a nal ys es will be e x pl orat or y a n d 
n ot f or mal .
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 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
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 8
1. 1. 
Data S u m mar y ............................................................................................................ 1 8
1. 1. 1. 
I n vesti gati o nal Pr o d uct(s)........................................................................................... 1 8
1. 1. 1. 1. 
Na me ........................................................................................................................... 1 8
1. 1. 1. 2. 
Descri pti o n .................................................................................................................. 1 8
1. 1. 1. 3. 
I nte n de d Use U n der I n vesti gati o n .............................................................................. 1 8
1. 1. 1. 4. 
N o ncli nical St u dies..................................................................................................... 1 8
1. 1. 1. 5.  
Cli nical E x perie nce..................................................................................................... 1 8
1. 2. 
St u d y  Rati o nale........................................................................................................... 1 8
1. 3. 
Ris ks a n d Be nefits f or St u d y  S u bjects........................................................................ 1 9
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.............................. 1 9
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...................................... 1 9
1. 5. 1. 
S u bject C o nfi de ntialit y ...............................................................................................2 0
1. 5. 2. 
I nf or me d C o nse nt Pr oce d ure ...................................................................................... 2 0
1. 5. 3. 
Re g ulat or y  C o m plia nce..............................................................................................2 1
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 2
2. 1. 
St u d y  O bjecti ves......................................................................................................... 2 2
2. 2. 
St u d y H y p ot hesis ........................................................................................................2 2
3. 
S T U D Y D E SI G N .......................................................................................................2 3
3. 1. 
O verall Pla n................................ ................................................................................2 3
3. 1. 1. 
St u d y  T ype................................ ..................................................................................2 3
3. 1. 2. 
Treat me nt Gr o u ps ....................................................................................................... 2 3
3. 1. 3. 
S t u d y E n d p oi nts..........................................................................................................2 3
3. 1. 4. 
D urati o n of t he St u d y ..................................................................................................2 3
3. 1. 5.   
D urati o n of S u bject Partici pati o n................................ ...............................................2 3
3. 1. 6.  
St o p pi n g R ules................................ ............................................................................2 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-E 3 1 2
Versi o n 4 U K 1 , 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. 6. 1. 
St o p pi n g R ules f or I n di vi d ual S u bjects ...................................................................... 2 4
3. 1. 6. 2. 
St o p pi n g R ules f or t he St u d y ...................................................................................... 2 6
3. 2. 
Selecti o n of D oses ...................................................................................................... 2 6
3. 2. 1. 
E x peri me ntal Treat me nts ............................................................................................ 2 6
3. 2. 1. 1. 
F or t he St u d y ............................................................................................................... 2 6
3. 2. 1. 2. 
F or I n di vi d ual S u bjects ...............................................................................................2 7
3. 2. 2. 
C o ntr ol Treat me nts ..................................................................................................... 2 7
4. 
S T U D Y P O P U L A T I O N............................................................................................. 2 8
4. 1. 
E nr oll me nt .................................................................................................................. 2 8
4. 1. 1. 
I ncl usi o n Criteria ........................................................................................................ 2 8
4. 1. 2. 
E xcl usi o n Criteria ....................................................................................................... 2 9
4. 1. 3. 
W o me n of C hil d -Beari n g P ote ntial ............................................................................ 3 1
4. 2. 
Re m o val of S u bjects Fr o m T hera p y ........................................................................... 3 1
4. 2. 1. 
Reas o ns f or Wit h dra wal/ Earl y Disc o nti n uati o n ......................................................... 3 2
4. 2. 2. 
Wit h dra wal Pr oce d ures ...............................................................................................3 3
4. 2. 3. 
S u bject Re place me nt .................................................................................................. 3 3
4. 2. 4. 
S u bject Rescree ni n g Pr oce d ures ................................................................................. 3 3
5. 
T R E A T M E N T S A D MI NI S T E R E D ........................................................................... 3 4
5. 1. 
I n vesti gati o nal Pr o d ucts..............................................................................................3 4
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....................................... 3 4
5. 1. 2. 
Met h o d of Assessi n g Treat me nt C o m plia nce............................................................. 3 5
5. 1. 3. 
La beli n g a n d Pac ka gi n g ..............................................................................................3 5
5. 1. 4. 
Pre parati o n .................................................................................................................. 3 5
5. 1. 5. 
St ora ge ........................................................................................................................ 3 5
5. 1. 6. 
Dr u g Acc o u n ta bilit y ...................................................................................................3 5
5. 2.  
C o nc o mita nt Me dicati o ns................................ ...........................................................3 6
5. 2. 1.  
Pr o hi bite d Me dicati o ns................................ ...............................................................3 6
5. 2. 2.   
Mai n All o wa ble Me dicati o ns ..................................................................................... 3 7
6. 
S T U D Y P R O C E D U R E S................................ ............................................................3 9
6. 1. 
Scree ni n g/ Baseli ne f or De N o v o S u bjects .................................................................. 3 9
6. 1. 1. 
Scree ni n g Visit f or De N o v o S u bjects ( Visit 1; Wee k - 3, Pri or t o 
E nr oll me nt) ................................................................................................................. 3 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 1
6. 1. 2. 
Was h o ut Tele p h o ne C o ntact
f or De N o v o S u bjects ( Visit 2; Wee k - 2, 
Pri or t o E nr oll me nt) .................................................................................................... 4 1
6. 1. 3. 
Baseli ne Visit f or De N o v o S u bjects ( Visit 3; Wee k -1, Pri or t o 
E nr oll me nt) ................................................................................................................. 4 2
6. 2. 
Start -of- Treat me nt Visit ( Visit 4; Wee k 0) ................................................................. 4 2
6. 2. 1. 
Start -of- Treat me nt Visi t f or R oll o ver S u bjects .......................................................... 4 2
6. 2. 2. 
Start -of- Treat me nt Visit f or De N o v o S u bjects.......................................................... 4 4
6. 3. 
O n -Treat me nt Peri o d ( Visits 5 t o 2 0; Wee ks 1 t o 4 8) ................................................ 4 5
6. 4. 
E n d - of-Treat me nt/ Earl y Ter mi nati o n ( Visit 2 1; Wee k 5 2) ........................................ 4 6
6. 5. 
F oll o w -U p ................................................................................................................... 4 6
6. 5. 1. 
P ost -Treat me nt F oll o w -U p ( Visits 2 2 t o 2 4; Wee ks 5 2 t o 5 6) ................................... 4 6
6. 5. 1. 1. 
Tele p h o ne C o ntact at Da y  3 of F oll o w-u p ( Visit 2 2; Wee k 5 2. 5) .............................. 4 6
6. 5. 1. 2. 
Visit at Wee k 2 of F oll o w -u p ( Visit 2 3; Wee k 5 4) .................................................... 4 7
6. 5. 1. 3. 
Tele p h o ne C o ntact at Wee k 4 of F oll o w -u p ( Visit 2 4; Wee k 5 6) .............................. 4 7
6. 6. 
Pr ot oc ol De viati o ns .................................................................................................... 4 7
7. 
E F FI C A C Y A S S E S S M E N T S .................................................................................... 4 9
7. 1. 
A vera ge Dail y Pai n Sc ore ( A D P S) ............................................................................. 4 9
7. 2. 
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C) ............................................................ 4 9
7. 3. 
H os pital A n xiet y  a n d De pressi o n Scale ( H A D S)....................................................... 4 9
7. 4. 
E ur o Q ol I nstr u me nt 5 Di me nsi o ns ( E Q -5 D) ..............................................................4 9
7. 5. 
S h ort F or m 3 6 ( S F -3 6) ................................................................................................ 5 0
7. 6. 
A vera ge Dail y Slee p I nterfere nce Sc ore ( A D SI S) ..................................................... 5 0
8. 
P H A R M A C O KI N E TI C A S S E S S M E N T S ................................................................. 5 1
8. 1. 
P har mac o ki netic ( P K) Varia ble(s).............................................................................. 5 1
8. 2. 
P har mac o d y na mic ( P D) Varia ble(s) ........................................................................... 5 1
8. 3. 
Bi o mar ker a n d E x pl orat or y  Varia ble(s) ..................................................................... 5 1
9. 
S A F E T Y A S S E S S M E N T S ................................ ........................................................5 2
9. 1. 
A d verse E ve nts ........................................................................................................... 5 2
9. 2. 
E ve nts of S pecial I nterest................................ ...........................................................5 3
9. 2. 1. 
S uici dal Be ha vi or a n d I deati o n ................................................................................... 5 3
9. 2. 2. 
Li ver E nz y me Ele vati o ns/ L i ver D ysf u ncti o n ............................................................. 5 4
9. 3. 
Defi niti o ns................................ ..................................................................................5 5
9. 3. 1. 
A d verse E ve nt ( A E) ....................................................................................................5 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 2
9. 3. 2. 
Seri o us A d verse E ve nt ( S A E) .................................................................................... 5 5
9. 3. 3. 
A d verse E ve nt Se verit y ..............................................................................................5 6
9. 3. 4. 
Ca usalit y  Assess me nt ................................................................................................. 5 6
9. 3. 5. 
Acti o n Ta ke n Re gar di n g t he I n vesti gati o nal Pr o d uct .................................................5 7
9. 3. 6. 
A d verse E ve nt O utc o me ............................................................................................. 5 7
9. 3. 7. 
Ot her Acti o n Ta ke n f or E ve nt .................................................................................... 5 7
9. 4. 
Seri o us A d verse E ve nt Re p orti n g Pr oce d ure f or I nvesti gat ors .................................. 5 7
9. 4. 1. 
Re p orti n g b y I n vesti gat ors.......................................................................................... 5 7
9. 4. 2. 
N otif y i n g Re g ulat or y A ut h orities, In vesti gat ors, a n d I nstit uti o nal 
Re vie w B oar ds/I nstit uti o nal Et hics C o m mittees ........................................................ 5 8
9. 5. 
E x p os ure I n Uter o D uri n g Cli nical St u dies ................................................................ 5 8
9. 6. 
Cli nical L a b orat or y E val uati o ns................................................................................. 5 9
9. 6. 1. 
He mat ol o g y ................................................................................................................. 5 9
9. 6. 2. 
Bl o o d C he mistr y ......................................................................................................... 5 9
9. 6. 2. 1. 
Esti mati o n of Creati ni ne Cleara nce ............................................................................ 6 0
9. 6. 3. 
Uri nal y sis .................................................................................................................... 6 0
9. 6. 4. 
Pre g na nc y  Testi n g ...................................................................................................... 6 0
9. 7. 
Vital Si g ns .................................................................................................................. 6 1
9. 8. 
Electr ocar d i o gra ms..................................................................................................... 6 1
9. 9. 
P h y sical Fi n di n gs ........................................................................................................ 6 1
9. 9. 1. 
B o d y Hei g ht a n d Wei g ht ............................................................................................ 6 1
9. 9. 2. 
P h y sical E xa mi nati o ns ................................................................................................ 6 1
9. 1 0. 
Ot her Safet y Assess me nts ........................................................................................... 6 2
9. 1 0. 1. 
C ol u m bia -S uici de Se verit y  Rati n g Scale ( C-S S R S) ................................................... 6 2
9. 1 0. 2. 
P h y sicia n Wit h dra wal C hec klist ( P W C) .................................................................... 6 2
1 0. 
O T H E R A S S E S S M E N T S .......................................................................................... 6 4
1 1. 
S T A TI S TI C A L M E T H O D S .......................................................................................6 5
1 1. 1. 
A nal y sis Sets............................................................................................................... 6 5
1 1. 2. 
Ge neral Statistical C o nsi derati o ns .............................................................................. 6 5
1 1. 3. 
St u d y  P o p ulati o n Data................................................................................................6 5
1 1. 4 . 
Efficac y  A nalys es .......................................................................................................6 6
1 1. 5. 
P har mac o ki netic/ P har mac o d y na mic A nal ys es ........................................................... 6 6
1 1. 6. 
Safet y  A nalys es .......................................................................................................... 6 6
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-E 3 1 2
Versi o n 4 U K 1 , 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. 6. 1. 
A d verse E ve nt A nal ys es ............................................................................................. 6 6
1 1. 6. 2. 
Cli nical L a b orat or y E val uati o n A nal yses ................................................................... 6 7
1 1. 6. 3. 
Vital Si g n A nal ys es .................................................................................................... 6 7
1 1. 6. 4. 
Electr ocar di o gra m A nal yses ....................................................................................... 6 7
1 1. 6. 5. 
P h y sical E xa mi nati o ns ................................................................................................ 6 7
1 1. 6. 6. 
C ol u m bia -S uici de Se verit y  Rati n g Scale ( C-S S R S) ................................................... 6 7
1 1. 6. 7. 
P h y sicia n Wit h dra wal C hec klist ( P W C) .................................................................... 6 7
1 1. 7. 
Ot her A nal ys es ............................................................................................................ 6 7
1 1. 8. 
I nteri m A nalys es ......................................................................................................... 6 7
1 1. 9. 
Data a n d Safet y M o nit ori n g B oar d ............................................................................. 6 8
1 1. 1 0. 
He patic A dj u dicati o n C o m mittee ............................................................................... 6 8
1 1. 1 1. 
Sa m ple Size Deter mi nati o n ........................................................................................ 6 9
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 0
1 2. 1. 
M o nit ori n g a n d I ns pecti o ns ........................................................................................ 7 0
1 2. 2. 
Data C ollecti o n ........................................................................................................... 7 0
1 2. 3. 
Data Ma na ge me nt ....................................................................................................... 7 1
1 2. 4. 
St u d y D oc u me ntati o n a n d St ora ge ............................................................................. 7 1
1 2. 5. 
Rec or d Kee pi n g .......................................................................................................... 7 2
1 3. 
FI N A N CI N G A N D I N S U R A N C E ............................................................................. 7 3
1 3. 1. 
Fi na nces ...................................................................................................................... 7 3
1 3. 2. 
Rei m b urse me nt, I n de m nit y , a n d I ns ura nce................................................................ 7 3
1 4. 
P U B LI C A TI O N P O LI C Y .......................................................................................... 7 4
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 5
1 5. 1. 
Pr ot oc ol A me n d me nts ................................................................................................ 7 5
1 5. 2. 
A d dress List ................................................................................................................7 5
1 6. 
R E F E R E N C E S ...........................................................................................................7 6
1 7. 
A P P E N DI C E S ............................................................................................................7 7
1 7. 1. 
A mi n otra nsferase Ele vati o ns: M o nit ori n g a n d Treat me nt 
Disc o nti n uati o n ........................................................................................................... 7 8
1 7. 2. 
C oc kcr oft -Ga ult E q uati o n ...........................................................................................7 9
1 7. 3. 
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-E 3 1 2
Versi o n 4 U K 1 , 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 5. 1:
D ose Escalati o n Criteria............................................................................................. 3 4
Ta ble 5. 2:
Pr o hi bite d Me dicati o ns a n d Tr eat me nts ..................................................................... 3 7
Ta ble 5. 3:
C o m m o n All o we d S S RI s............................................................................................ 3 8
Ta ble 6. 1:
Scree ni n g La b orat or y  Val ues ..................................................................................... 4 1
Ta ble 6. 2:
Re q uire d La b orat or y  Val ues (fr o m t he E n d -of- Treat me nt Visit of t he 
Prece di n g St u d y )......................................................................................................... 4 2
Ta ble 9. 1:
He mat ol o g y  A nalyt es ................................................................................................. 5 9
Ta ble 9. 2:
Bl o o d C he mistr y  A nalyt es .......................................................................................... 6 0
Ta ble 9. 3:
Uri nal y sis Deter mi nati o ns .......................................................................................... 6 0
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-E 3 1 2
Versi o n 4 U K 1 , 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 1 7. 1:
A mi n otra nsferase Ele vati o ns: M o nit ori n g a n d Treat me nt 
Disc o nti n uati o n ........................................................................................................... 7 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-E 3 1 2
Versi o n 4 U K 1 , 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 D SI S
a vera ge dail y slee p i nterfere nce 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 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 me c ur ve 
BI D
t wice dail y 
C F R
C o de of Fe deral Re g ulati o ns
Cr Cl
creati ni ne cleara nce 
C ma x
ma xi m u m plas ma c o nce ntrati o n 
C M V
c yt o me gal o vir us
C O X - 2
c ycl o o x y ge nase t y pe 2
C R O
c o ntract researc h or ga nizati o n
C- S S R S
C ol u m bia -S uici de Se verit y Rati n g Scale
D P N P
d ia 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 B V
E pstei n- Barr vir us 
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 
EI U
E x p os ure I n Uter o 
E Q - 5 D
E ur o Q o L I nstr u me nt 5 D o mai ns
F D A
F o o d a n d Dr u g A d mi nistrati o n
F M
fi br o m yal gia
G C P
G o o d Cli nical Practice 
H A D S
H os pital A n xiet y a n d De pressi o n Scale
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
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 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
I E C
I n de pe n de nt Et hics C o m mittee
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 
M C S
me ntal c o m p o ne nt s u m mar y
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
N R S
n u meric rati n g scale 
N S AI D
n o nster oi dal a nti -i nfla m mat or y dr u g
P C S
p h ysical c o m p o ne nt s u m mar y
P D
p har mac o d y na mic(s)
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(s)
P W C
P h ysicia n Wit h dra wal C hec klist 
Q D
o nce dail y 
R B C
re d bl o o d cell
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 F - 3 6
S h ort F or m 3 6 
SI D
s u bject i de ntificati o n n u m ber 
S O P
sta n dar d o perati n g pr oce d ure
S N RI
ser ot o ni n-n ore pi ne p hri ne re u pta ke i n hi bit ors 
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 e ve nt reacti o n
T E A E
treat me nt-e mer ge nt a d verse e ve nt
U L N
u p per li mit of n or mal 
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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 8
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. 
D at a S u m m ar y
1. 1. 1. 
I n vesti g ati o n al Pr o d uct(s)
1. 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, 5S , 6S )- 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.
1. 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 Ca 2 + c ha n nels a n d has bee n i de ntifie d as t he m olec ular tar get f or t he a nal gesic 
effects of pre ga bali n, c urre ntl y  mar kete d i n t he U nite d States ( U S ) f or t he ma na ge me nt of 
fi br o m yal gia ( F M), 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. 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 pai n ass ociate d wit h F M .
1. 1. 1. 4. 
N o ncli nic al St u dies
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 ustai ne d a nal gesic effect.  N o n cli 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 mmarize d i n t he D S -5 5 6 5 I n vesti gat or 
Br oc h ure.
1. 1. 1. 5. 
Cli nic al E x perie nce
F o urtee 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.   Data fr o m t hese c o m plete d 
st u dies ha ve c haracterize d t he cli nical p har mac ol o g y a n d safety pr ofile of D S -5 5 6 5 a n d 
ha ve pr o vi de d pr o of -of -c o nce pt f or D S -5 5 6 5 as a treat me nt f or c hr o nic p ai n.  
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 nvesti gat or 
Br oc h ure.
1. 2. 
St u d y R ati o n ale
D S - 5 5 6 5 is a n oral a nal gesic dr u g bei n g de vel o pe d f or c hr o nic use i n F M a n d ot her 
i n dicati o ns.  T his o pe n -la bel e xte nsi o n st u d y will pr o vi de i m p orta nt l o n g-ter m safety data 
i n s u bjects w h o will be d ose d o n D S -5 5 6 5 f or u p t o 1 y ear.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 1 9
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 a n d cli 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 .  
A ntici pate d ris 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 
ce ntral ner v o us s ys te m 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 tra 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.  
A detaile d descri pti o n of efficac y a n d safety 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 vesti gat or Broc h ure .  Safety 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 male a n d fe male s u bjects wit h a n F M dia g n osis ,
c o nfir me d acc or di n g t o A m erica n C olle ge of R he u mat ol o g y 1 9 9 0 a n d 2 0 1 0 criteria base d 
o n t he Wi des prea d Pai n I n de x a n d S y m pt o m Se verit y  Scale as well as assess me nt of 
te n der p oi nts, w h o ha ve c o m plete d partici pati o n i n a pre vi o us P hase 3 st u d y  of D S- 5 5 6 5 
i n F M (D S 5 5 6 5 - A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1 ).  I n a d diti o n s u bjects 
w h o di d n ot partici pate i n a prece di n g d o u ble- bli n d st u d y  (referre d t o as de n o v o 
s u bjects) m a y be e nr oll e d.  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.
F or all s u bjects, t he d urati o n of o pe n -la bel treat me nt ( D S-5 5 6 5 1 5 m g Q D or D S - 5 5 6 5 1 5 
m g t wice dail y [BI D] [see Secti o n 5. 1. 1 ]) will be 5 2 wee ks.
1. 5. 
C o m pli a nce St ate me nt, Et hics a n d Re g ul at or y C o m pli a nce
T his st u d y  will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he et hical pri nci ples t hat 
ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki, t he I nter nati o nal C o nfere nce o n 
Har m o ni sati o n (I C H) c o ns oli date d G ui deli ne E 6 f or G o o d Cli nical Practice ( G C P) 
( C P M P/IC H/ 1 3 5/ 9 5), a n d a p plic a ble re g ulat or y re q uire me nt(s) i ncl u di n g:

E ur o pea n C o m missi o n Directi ve ( 2 0 0 1/ 2 0/ E C A pr 2 0 0 1) a n d / or

E ur o pea n C o m missi o n Directi ve ( 2 0 0 5/ 2 8/ E C A pr 2 0 0 5) a n d/ or

F D A G C P Re g ulati o ns: C o de of Fe deral Re g ulati o ns ( C F R) Title 2 1, parts 1 1, 
5 0, 5 4, 5 6 a n d 3 1 2 as a p pr o priate 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 0
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 bse r 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 Fs) 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 [I C F]) s h o ul d be ke pt i n strict c o nfi de nce b y t he i n vesti gat or.
I n c o m plia nce wit h a p plica ble re g ulati o ns a n d I C H G C P g ui deli nes, it is re q uire d t hat t he 
i n vesti gat or a n d i nstit uti o n per mit a ut h orize d re prese n tati ves of t he c o m pa n y, of t he 
re g ulat or y a ge nc y(s), a n d t he i n de pe n de nt et hics c o m mittee (IE C) or i nstit uti o nal re vie w 
b oar d (I R B) direct access t o re vie w t he s u bject’s ori gi nal me dical rec or ds f or verificati o n 
of st u d y -relate d pr oce d ures a n d data.  T he in vesti gat or is o bli gate d t o i nf or m t he s u bject 
t hat his/ her st u d y-relate d rec or ds will be re vie we d b y t he a b o ve na me d re prese ntati ves 
wit h o ut vi olati n g t he c o nfi de ntialit y  of t he s u bject.
1. 5. 2. 
I nf or me d C o nse nt Pr oce d ure
F or r oll o ver s u bjects, t he i n vesti gat or must o btai n t he s u bject’s c o nse nt bef ore t he start of 
t he E n d- of-Ta peri n g visit ( Wee k 1 4, Visit 1 3) of o ne of t he prece di n g st u dies ( D S 5 5 6 5 -
A- E 3 0 9, D S 5 5 6 5- A- E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1), beca use i nf or mati o n fr o m t hat E n d - of-
Ta peri n g visit will als o be use d i n t he c urre nt st u d y.  F or de n o v o s u bjects, t he s u bject’s 
c o nse nt will be o btai ne d at t he Scree ni n g visit ( Visit 1).
Bef ore a s u bject’s partici pati o n i n t he st u d y , it is t he i n vesti gat or’s res p o nsi bilit y t o 
o btai n freel y gi ve n c o nse nt, i n writi n g, fr o m t he s u b ject 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 ny 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 u a 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 Decl arati o n of Helsi n ki.  T he c o nse nt f or m a n d a n y 
re visi o n(s) s h o ul d be a p pr o ve d by t he I E C or I RB pri or t o bei n g pr o vi de d t o p ote ntial 
s u bjects.
T he s u bject’s writte n i nf or me d c o nse nt s h o ul d be o btai ne d pri or t o his/ her partici pati o n i n 
t he st u d y (f or r oll o ver s u bjects, bef ore t he start of t he E n d - of-Ta peri n g visit of o ne of t he 
prece di n g st u dies) , 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 by 2 1 C F R Part 3 1 2. 6 2. T he I C F s h o ul d be si g ne d a n d pers o nall y  date d b y t he 
s u bject, an d b y  t he pers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n ( n ot 
necessaril y  t he i n vesti gat or).  T he ori gi nal si g ne d I C F s h o ul d be retai ne d i n acc or da nce 
wit h i nstit uti o nal p olic y , a n d a c o py 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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 1
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 e C R F.
S u g geste d m o del te xt f or t he I C F is pr o vi de d i n t he sp o ns or ’s I C F te m plate f or t he 
i n vesti gat or t o pre pare t he d oc u me nts t o be use d at his or her 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 all s u bjects i n t he U S, i n acc or da nce wit h t he Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI PA 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 nf o r mati o n a b o ut 
pa y me nts a n d c o m pe nsati o n a vaila ble t o t he s u bjects , a n d d oc u me ntati o n e vi de nci n g t he 
i n vesti gat or’s q ualificati o ns s h o ul d be s u b mitte d t o t he I E C or I R B f or et hical re vie w a n d 
a p pr o val acc or di n g t o l ocal re g ulati o ns, pri or t o t he st u d y  start.  T he writte n a p pr o val 
s h o ul d i de ntif y all d oc u me nts re vie we d by na me a n d versi o n.
C ha n ges i n t he c o n d uct of t he st u d y  or pla n ne d a nal ysis will be d oc u me nte d i n a pr ot oc ol 
a me n d me nt a n d/ or t he statistical a nalys is pla n ( S A P).
T he i n vesti gat or m ust s u b mit a n d, w here necessar y, o btai n a p pr o val fr o m t he I E C or I R B 
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 E C or I RB of de viati o ns fr o m t he pr ot oc ol or seri o us a d verse e ve nts ( S A Es) 
occ urri n g at t he site a n d ot her a d verse e ve nt ( A E) 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.
As re q uire d b y l ocal re g ulati o ns, t he s p o ns or’s l ocal Re g ulat or y Affairs gr o u p or 
desi g nee will e 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 2
2. 
S T U D Y O B J E C TI V E S A N D H Y P O T H E S E S
2. 1. 
St u d y O bjecti ves
T he pri mar y o bjecti ve is t o assess t he l o n g -ter m safet y of D S-5 5 6 5 i n s u bjects wit h F M .
T he sec o n da r y o bjecti ves are:

T o o bser ve t he effects of D S -5 5 6 5 o n a vera ge dail y  pai n sc ore ( A D P S) a n d 
p ai n-ass ociate d avera ge d ail y slee p interfere nce sc ore ( A D SIS) ( b ot h rec or de d 
i n a diar y). Wee kly 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 his or her w orst pai n o ver t he pre vi o us 2 4 h o urs.

T o o bser ve 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)

T o o bser ve t he effects of D S -5 5 6 5 o n de pressi o n a n d a n xiet y  as assesse d b y 
t he H os pital A n xiet y a n d De pressi o n Scale ( H A D S) 

T o o bser ve t he effects of D S -5 5 6 5 o n s u bject q ualit y  of life as assesse d b y t he 
E ur o Q o L I nstr u me nt 5 D o mai ns ( E Q -5 D) a n d t he S h ort F or m 3 6 ( S F-3 6).
2. 2. 
St u d y H y p ot hesis
T he h y p ot hesis of t his l o n g-ter m, o pe n-la bel e xte nsi o n st u d y is t hat D S -5 5 6 5 will be 
ge nerall y well t olerate d w he n a d mi nistere d f or u p t o 1 year wit h n o si g nifica nt safet y 
si g nals.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 3
3. 
S T U D Y D E SI G N
3. 1. 
O ver all Pl a n
3. 1. 1. 
St u d y T y pe
T his is a n o pe n -la bel st u d y of D S-5 5 6 5 i n s u bjects w h o eit her c o m plete d partici pati o n i n 
a prece di n g P hase 3 st u d y  of D S -5 5 6 5 i n F M (i.e. D S 5 5 6 5 - A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or 
D S 5 5 6 5 - A-E 3 1 1) or are de n o v o s u bjects. F or r oll o ver s u bjects, e nr oll me nt pr oce d ures 
are str uct ure d t o a v oi d a ga p i n treat me nt bet wee n t he prece di n g st u d y a n d t his e xte nsi o n 
st u d y (f or r oll o ver s u bjects).  T he Start -of- Treat me nt visit ( Visit 4 ) f or t his e xte nsi o n 
st u d y will occ ur o n t he sa me da y  as t he E n d - of-Ta peri n g v isit ( Visit 1 3) f or t he prece di n g
st u dies.  F or de n o v o s u bjects, scree ni n g a n d baseli ne pr oce d ures will be perf or me d at 
Visits 1 t o 3.  Eli gi ble s u bjects will be assi g ne d t o recei ve o pe n -la bel D S-5 5 6 5 f or 5 2 
wee ks.  All s u bjects will recei ve D S -5 5 6 5 1 5 m g o nce dail y ( Q D ) f or t he first t hree
wee ks of t he treat me nt peri o d .  After t hree wee ks, s u bjects ma y  be titrate d t o 1 5 m g BI D 
base d o n efficac y  a n d safet y criteria as detaile d i n Secti o n 5. 1. 1 .
3. 1. 2. 
Tr e at me nt Gr o u ps
I n t his st u d y, su bjects will i nitiall y be gi ve n o pe n -la bel D S -5 5 6 5 1 5 m g Q D.  A fter 
treat me nt at t his d ose f or 3 wee ks ( Visit 6 , Wee k 3), s u bjects ma y be titrate d t o 1 5 m g
BI D base d o n efficac y  a n d safety criteria as detaile d i n Secti o n 5. 1. 1 .  
3. 1. 3. 
St u d y E n d p oi nts
T he pri mar y  e n d p oi nt is l o n g-ter m safet y base d o n assess me nt of treat me nt-e mer ge nt 
a d verse e ve nts ( T E A Es), cli nical la b orat o r y e val uati o ns, p h ysical e xa mi nati o ns, 
electr ocar di o gra ms ( E C Gs), t he C ol u m bia-S uici de Se verit y Rati n g Scale ( C -S S R S), a n d 
t he P h ysicia n Wit h dra wal C hec klist ( P W C).
T he sec o n dar y  e n d p oi nts are:

C ha n ges fr o m baseli ne t o sc he d ule d ti me p oi nt i n A D P S a n d A D SIS

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 5 2 as 
assesse d b y P GI C

C ha n ges fr o m baseli ne t o Wee k 5 2 i n H A D S de pressi o n a n d a n xiet y sc ores 

C ha n ges i n E Q -5 D a n d S F - 3 6 para meters fr o m baseli ne t o Wee k 5 2
3. 1. 4. 
D ur ati o n of t he St u d y
T he t otal d urati o n of t he st u d y  fr o m First S u bject Scree ne d t o Last S u bject Last Visit is 
esti mate d t o be a p pr o xi matel y  3 9 m o nt hs.
3. 1. 5. 
D ur ati o n of S u bject P artici p ati o n
F or r oll o ver s u bjects, t he t otal st u d y d urati o n (f or a n i n di vi d ual s u bject’s partici pati o n) 
will be a p pr o xi matel y  5 6 wee ks, i ncl u di n g 5 2 wee ks of o pe n-la bel treat me nt a n d 4 wee ks 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 4
of p ost -treat me nt f oll o w-u p. De n o v o s u bjects will als o ha ve a scree ni n g/ baseli ne peri o d 
of u p t o 3 wee ks a n d t heref ore a t otal d urati o n of a p pr o xi matel y  5 9 wee ks.  
3. 1. 6. 
St o p pi n g R ules
3. 1. 6. 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. 6. 1. 1 or 3. 1. 6. 1. 2 , t he ass ociate d e ve nt m ust be re p orte d as a n A E or 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. 1 f or f urt her 
i nstr ucti o ns.
3. 1. 6. 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 m m 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 tra nsa 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 o o d a n d Dr u g A d mi nistrati o n
( 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. 2. 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 treat me 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 pa rtate 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 rises 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 presentati 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)
A fl o w dia gra m dis pla y i n g t he criteria f or disc o nti n ui n g treat me nt base d o n 
a mi n otra n sferase ele vati o ns is pr o vi de d i n A p pe n di x 1 7. 1 .
3. 1. 6. 1. 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. 2. 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 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) 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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 5
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 mu nicati o ns 
wit h t he patie 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,

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 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, 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 su bjects ha ve a Y E S
res p o nse t o 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 (a p pl y i n g t o Y E S res p o nses 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 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 patie nt 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 health pr ofessi 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 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 on site 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 h e 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.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 6
3. 1. 6. 2. 
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 Sect i 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
3. 2. 1. 1. 
F or t he St u d y
T he d osa ge re gi me ns of D S - 5 5 6 5 ( 1 5 m g Q D a n d 1 5 m g BI D) were selecte d base d o n t he 
res ults of t he c o m plete d P hase 2 st u d y i n t he U S of D S -5 5 6 5 i n s u bjects wit h D P N P 
( D S 5 5 6 5- A- U 2 0 1) as well as d ose o pti mizati o n m o deli n g a n d si m ulati o n.  I n t he 
D S 5 5 6 5 - A-U 2 0 1 st u d y, efficac y was o bser ve d acr oss a d ose ra n ge fr o m 1 5 m g Q D t o 
1 5 m g BI D.  T o c o nfir m t he D S 5 5 6 5 - A-U 2 0 1 e x perie nce i n s u bjects wit h F M a n d t o 
deter mi ne w het her s u bsets of s u bjects ma y  res p o n d better t o 1 5 m g Q D or 1 5 m g BI D, 
b ot h d oses are b e i n g e val uate d i n t he prece di n g P hase 3 st u dies ( D S 5 5 6 5- A-E 3 0 9 ,
D S 5 5 6 5 - A-E 3 1 0 , or D S 5 5 6 5 - A-E 3 1 1 ).
T he res ults of t he D S 5 5 6 5 - A-U 2 0 1 st u d y ( Secti o n 1. 1. 1. 5 ) s u g gest t hat 1 5 m g Q D ma y  
be t he mi ni m u m effecti ve d ose , w hile efficac y is si milar b ut n u mericall y better at t he 
1 5 m g BI D d ose c o m pare d t o 1 5 m g Q D .  O verall, t here were greater mea n re d ucti o ns 
fr o m baseli ne t o e n d- of-treat me nt ( Wee k 5) i n A D P S 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, es peciall y at t he hi g her d ose le vels.   T he mea n c ha n ges fr o m 
baseli ne t o Wee k 5 i n A D P S were -2. 0 4, - 2. 3 2, - 2. 6 6, - 2. 6 4, a n d -2. 7 9 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 vely, c o m pare d t o -1. 8 6 f or place b o.  T hese treat me nt differe nces were 
statisticall y si g nifica nt ( p < 0. 0 5) at 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 
d ose le vels.  
B ot h of t he P hase 3 d ose re gi me ns ( 1 5 m g Q D a n d 1 5 m g BI D) ha ve a safet y pr ofile t hat 
is c o nsiste nt wit h t he α2δ li ga n d class of dr u gs; A Es ha ve ge nerall y bee n mil d t o 
m o derate i n se verit y  (see t he D S - 5 5 6 5 I n vesti gat or Br oc h ure).  T he D S -5 5 6 5 3 0 m g / da y 
treat me nt ar m will be titrate d fr o m 1 5 m g / da y after t hree wee ks t o l o wer t he p ote ntial ris k 
of si de effects i n s u bjects w h o re q uire t he hi g her d ose f or effecti ve pai n relief.  N o d ose 
a dj ust me nt will be ma de f or s u bjects wit h mil d re nal i m pair me nt, as o nl y  s mall i ncreases 
i n area u n der t he c o nce ntrati o n ti me c ur ve ( A U C ) ( 1. 4-f ol d) a n d ma xi m u m plas ma 
c o nce ntrati o n (C ma x ) ( 2 4 %) were o bser ve d i n healt h y s u bjects wit h mil d re nal i m pair me nt 
( Cr Cl 5 0 t o 8 0 m L / mi n/ 1. 7 3 m 2 [refer t o D S - 5 5 6 5 I n vesti gat or Br oc h ure]).
T he data fr o m D S 5 5 6 5 - A- U 2 0 1 were als o m o dele d f or i nsi g hts i nt o d ose o pti mizati o n.  
Efficac y  was deter mi ne d usi n g wee kly A D P S .  A c o nti n u o us b o u n de d o utc o me sc ore 
met h o d ol o g y  was e m pl o ye d.2  T w o safet y e n d p oi nts, dizzi ness a n d s o m n ole nce, were 
m o dele d.  A ti me -t o-(first) a d verse e ve nt was m o dele d ( hazar d m o del) as well as se verit y 
of A E, c o n diti o nal o n ha vi n g a n e ve nt ( or dere d cate g orical).  T hese were fitte d 
i n de pe n de ntly .3  Acc or di n g t o t h is phar mac o ki netic ( P K)/ p har mac o d yna mic ( P D)
m o deli n g, t otal dail y  d oses > 2 0 m g are re q uire d t o ac hie ve a differe nce i n mea n A D P 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 7
of at least 1. 0 p oi nt bet wee n D S -5 5 6 5 a n d place b o.  T otal dail y  d oses < 2 0 m g are n ot 
pre dicte d t o ac hie ve t his le vel of res p o nse. T he pre dicte d pr o ba bilit y of ac hie vi n g a tr ue 
−1 A D P S differe nce f or 3 0 m g /d a y ( 1 5 m g BI D) is 0. 5 0 1 ( or a b o ut 5 0 %) base d o n t he 
m o del. A sec o n d d ose ( 1 5 m g Q D) was pic ke d base d o n a l o wer tar get wit h a n i m plie d 
safety ( i.e. l o wer ris k of A Es s uc h as dizzi ness) a d va nta ge.
A c o m plete d P hase 2 st u d y i n Asia (Ja pa n, K orea, a n d Tai wa n) of D S -5 5 6 5 i n s u bjects 
wit h D P N P ( D S 5 5 6 5 -A- J 2 0 2) di d n ot s h o w statisticall y si g nifica nt differe nces i n mea n 
c ha n ges i n t he pri mar y efficac y para meter, A D P S , fr o m baseli ne t o e n d-of- treat me nt 
( Wee k 7) f or t he D S- 5 5 6 5 treat me nt gr o u ps ( 5 m g BI D, 1 0 m g BI D, a n d 1 5 m g BI D) 
c o m pare d t o place b o ( Secti o n  1. 1. 1. 5 ).  T here was, h o we ver, a tre n d t o war d i m pr o ve me nt 
f or s u bjects treate d wit h D-S 5 5 6 5 i n ter ms of A D P S res p o n der rate ( i.e. pr o p orti o n of 
s u bjects wit h ≥3 0 % a n d ≥5 0 % re d ucti o n i n A D P S). T he i nci de nce of T E A Es s h o we d 
p ote ntial d ose -de pe n de nc y  ( T E A Es occ urre d i n 4 8. 9 % of s u bjects for t he 5 m g BI D 
gr o u p, 6 3. 4 % f or t he 1 0 m g BI D gr o u p, a n d 7 3. 3 % f or t he 1 5 m g BI D gr o u p).
3. 2. 1. 2. 
F or I n di vi d u al S u bjects
S u bjects will be i nitiate d at 1 5 m g Q D.  After 3 wee ks of o pe n -la bel treat me nt (i.e. at 
Visit 6 ), s u bjects ma y be titrate d t o 1 5 m g BI D base d o n efficac y  a n d safety criteria as 
detaile d i n Secti o n 5. 1. 1 .  After a s u bject has bee n u p -titrate d t o 1 5 m g BI D, t hat s u bject 
ma y be d o w n -titrate d bac k t o 1 5 m g Q D base d o n efficac y  a n d safety criteria as detaile d 
i n Secti o n  5. 1. 1.  
3. 2. 2. 
C o ntr ol Tre at me nts
N o c o ntr ol treat me nts will be use d 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 8
4. 
S T U D Y P O P U L A TI O N
4. 1. 
E nr oll me nt
S u bjects f or t his o pe n -la bel e xte nsi o n st u d y are t h ose w h o c o m plete d partici pati o n 
(t hr o u g h t he E n d- of-Ta peri n g visit) i n o ne of t he prece di n g st u dies ( D S 5 5 6 5- A-E 3 0 9, 
D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1) a n d a gree d t o r oll o ver ; I n a d diti o n s u bjects w h o 
di d n ot partici pate i n a prece di n g d o u ble -bli n d st u d y  (referre d t o as de n o vo s u bjects) 
ma y be e nr oll e d.
T he i n vesti gat or m ust i nf or m eac h pr os pecti ve s u bject of t he nat ure of t he st u d y , e x plai n 
t he p ote ntial ris ks, a n d o btai n writte n i nf or me d c o nse nt fr o m t he s u bject pri or t o 
perf or mi n g a n y st u d y- relate d scree ni n g pr oce d ures.  F or r oll o ver s u bjects, s i g nat ure of 
t he i nf or me d c o nse nt d oc u me nt f or t his st u d y s h o ul d be o btai ne d bef ore t he start of t he 
E n d - of-Ta peri n g visit ( Wee k 1 4, Visit 1 3 ) of o ne of t he prece di n g st u dies ( D S 5 5 6 5- A-
E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1) .  F or a d d iti o nal i nf or mati o n o n i nf or me d 
c o nse nt, see Secti o n  1. 5. 2.
T he s u bject i de ntificati o n n u m ber use d i n t he prece di n g st u d y s hall be retai ne d f or use i n 
t his st u d y.  S u bjects w h o di d n ot partici pate i n a prece di n g st u d y  will be assi g ne d a 
s u bject i de ntificati o n n u m ber.  T his s u bject i de ntificati o n n u m ber m ust be use d f or 
s u bject i de ntificati o n o n all st u d y-relate d d oc u me nts (e C R Fs, cli nic n otes, la b orator y  
sa m ples, etc.). 
T he user will nee d t o s u p pl y  t he I nteracti ve V oice Res p o nse/Interacti ve We b Res p o nse 
(I X R S) s yste m wit h t he i nf or mati o n re q uire d b y t he s yste m (e. g. site n u m ber, s u bject 
i de ntificati o n n u m ber).
A s u bject will be c o nsi dere d e nr olle d u p o n si g nat ure of t he i nf or me d c o nse nt d oc u me nt 
f or t his st u d y.
4. 1. 1. 
I ncl usi o n Criteri a
S u bjects w h o c o m plete d o ne of t he prece di n g P hase 3 D S -5 5 6 5 st u d y  ( D S 5 5 6 5- A-E 3 0 9 , 
D S 5 5 6 5 - A-E 3 1 0 , or D S 5 5 6 5- A-E 3 1 1 )
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 ble t o gi ve writte n i nf or me d c o nse nt
2.
C o m plete d partici pati o n ( i.e. c o m plete d t he E n d -of -Ta peri n g visi t) i n a 
prece di n g st u d y of D S -5 5 6 5 i n F M ( D S 5 5 6 5- A-E 3 0 9, D S 5 5 6 5 - A-E 3 1 0, or 
D S 5 5 6 5 - A-E 3 1 1)
3.
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 n a de q uate 
met h o d of c o ntrace pti o n (as detaile d i n Secti o n 9. 5 ) 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.
T he s u bject m ust n ot ha ve e x perie nce d a n y si g nifica nt safet y iss ues d uri n g t he 
prece di n g st u d y t hat, i n t he i n vesti gat or’s j u d g me nt, w o ul d a d versel y i m pact 
t he s u bject’s well-bei n g i n t he l o n g -ter m e xte nsi 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 2 9
5.
De N o v o S u bjects
6.
A ge ≥ 1 8 y ears
7.
A ble t o gi ve writte n i nf or me d c o nse nt
8.
A ble t o c o m plete s u bject -re p orte d q uesti o n naires per t he i n vesti gat or’s 
j u d g me nt
9.
At scree ni n g, s u bjects m ust meet t he 1 9 9 0 A merica n C olle ge of 
R he u mat ol o g y  ( A C R) criteria f or F M, i.e. wi des prea d pai n prese nt f or at least 
3 m o nt hs a n d pai n i n at least 1 1 of 1 8 s pecific te n der p oi nt sites.  I n a d diti o n, 
t he 2 0 1 0 A C R criteria m ust be met:
1 0. 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
1 1. 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
1 2. 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
1 3. 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 past 7 da ys 
pri or t o first d ose ( base d o n c o m pleti o n of at least 4 dail y  pai n diaries d uri n g 
t he 7-d a y  baseli ne peri o d)
1 4. S u bject m ust ha ve d oc u me nte d e vi de nce of a f u n d osc o pic e xa mi nati o n ( wit h 
p u pil dilati o n) or a sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n wit hi n 1 2 
m o nt hs pri or t o scree ni n g or at scree ni n g
1 5. W o me n of c hil d -beari n g p ot e ntial ( W O C B P) m ust be usi n g a n a de q uate 
met h o d of c o ntrace pti o n (as detaile d i n t he b o d y of t he pr ot oc ol) 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
All S u bjects
1.
Cli nicall y  si g nifica nt u nsta ble ne ur ol o gic, psyc hi atric, 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 yp 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) or a n y  ot her c o nc urre nt disease d uri n g t he prece di n g s t u d y (f or 
r oll o ver s u bjects) or wit hi n 1 2 m o nt hs pri or t o scree ni n g (f or de n o v o s u bjects) 
t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d i nterfere wit h st u d y partici pati o n or 
assess me nt of safet y a n d t olera bilit y
2.
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 n vesti gat or. N ote: S u bjects a ns weri n g “ yes” t o a n y of t he 
q uesti o ns a b o ut acti ve s uici dal i deati o n/i nte nt/ be ha vi ors occ urri n g wit hi n t he past 
1 2 m o nt hs m ust be e xcl u de d ( C -S S R S S uici de I deati o n secti o n – Q uesti o ns 3, 4, 
or 5; C -S S R S S uici dal Be ha vi or secti o n, a n y of t he s uici de be h a vi ors q uesti o ns).  
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. 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 0
3.
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 
4.
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
5.
S u bjects wit h pai n d ue t o ot her c o n diti o ns ( e. g. D P N P or p ost -her petic ne ural gia ) 
t hat, i n t he o pi ni o n of t he i n vesti gat or, w o ul d c o nf o u n d assess me nt or self-
e val uati o n of t he pai n ass ociate d wit h F M
6.
S u bjects wit h pai n d ue t o a n y  wi des prea d i nfla m mator y  m usc ul os keletal dis or der 
(e. g. r he u mat oi d art hritis, l u p us) or wi des prea d r he u matic disease ot her t ha n F M .
7.
A b use or de pe n de nce of prescri pti o n me dicati o ns, street dr u gs , or alc o h ol wit hi n 
t he last 1 year
8.
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 
y ears
9.
A dia g n osis of u ntreate d slee p a p nea or i nitiati o n of treat me nt f or slee p a p nea 
wit hi n t he past 3 m o nt hs
1 0. K n o w n h y perse nsiti vit y  t o α2δ 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  
1 1. 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 2. A b n or mal i n vesti gati ve tests (i.e. E C Gs) a n d la b orat or y  val ues j u d ge d by t he 
i n vesti gat or t o be cli nicall y si g nifica nt at t he E n d - of-Treat me nt visit ( Visit 1 1, 
Wee k 1 3) i n t he prece di n g st u d y (f or r oll o ver s u bjects) or at scree ni n g (f o r de 
n o v o s u bjects) , wit h partic ular f oc us o n: 

A b n or mal re nal f u ncti o n defi ne d as calc ulate d Cr Cl < 6 0 m L / mi n 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 ,4 bl o o d urea 
nitr o ge n > 1. 5 × U L N; ser u m creati ni ne > 1. 6 m g/ d L ( > 1 4 1. 4 μ m ol/ L ); or

A b n or mal li ver f u ncti o n defi ne d as A S T ( S G O T) > 2. 0 × U L N, A L T ( S G P 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.  
If a s u bject has t otal bilir u bi n > 1. 2 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 yz e 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; or

Creati ne ki nase > 3. 0 × U L N
F or De N ov o S u bjects O nly
1 3. 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 (as 
liste d i n Secti o n 5. 2. 1 of t he pr ot oc ol)  
1 4. 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 vi e w ( MI NI) i nter vie w 
( Versi o n 6. 0) at scree ni n g are e xcl u de d, b ut mil d t o m o derate maj or de pressi o n 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 1
a n xiet y dis or ders are per mitte d pr o vi de d t hat t he i n vesti gat or assesses t he patie nt 
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 5. A n y  diag n osis of lifeti me bi p olar dis or der or ps yc h otic dis or der
1 6. S u bject is c urre ntl y e nr olle d i n or has n ot yet c o m plete d at least 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 ot her 
i n vesti gati o nal a ge nts
1 7. S u bject is a n e m pl o ye e of t he st u d y ce nter, a n i m me diate fa mily me m ber * of a n 
e m pl o yee of t he st u d y ce nter, or a n e m pl o y ee of Daiic hi Sa n k yo, I N C Researc h ,
or a n y of t he st u d y ve n d ors s u p p orti n g t his st u d y. *(s p o use, pare nt, c hil d, or 
si bli n g, w het her bi ol o gical or le gally a d o pte d)
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  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 n a p pr o ve d c o ntrace pti o n met h o d 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 or s p o n ge 
wit h s per mici de , c o n d o m, i ntra uteri ne de vice or part ner’s vasect o my.  
All fe male s u bjects, re gar dless of c hil d -beari n g p ote ntial, m ust ha ve a ne gati ve ser u m 
pre g na nc y  test at all cli nic visits t hr o u g h t o t he E n d- of-Ta peri n g visit. All i nci de nce of 
b or derli ne pre g na nc y  tests (as re p orte d b y  t he ce ntral la b) at scree ni n g s h o ul d be 
f oll o we d u p t o e xcl u de pre g na nc y ( E xcl usi o n criteria 11 ).  E xcl usi o n criteria ( Secti o n 
4. 1. 2 ) ca n be satisfie d i n t he cases of 
1. 
D oc u me nte d p er ma ne nt sterilizati o n, met h o ds w hic h i ncl u de h y sterect o my,  
bilateral sal pi n gect o m y a n d bilateral o o p h orect o m y. 
2. 
C o nfir mati o n of p ost me n o pa usal stat us, wit h 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 bef ore Ra n d o mizati o n Peri o d.
A uri ne pre g na nc y  test will be perf or me d f or all W O C B P at t he F oll o w -U p cli nic visit .
Daiic hi Sa n k y o m ust be n otifie d of a n y  st u d y s ubject 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. 5 . 
4. 2. 
Re m o v al of S u bjects Fr o m T her a p y
Data fr o m all e nr olle 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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 2
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 dmi 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. 6. 1. 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 ( Secti o n  3. 1. 6. 1. 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
If a s u bject disc o nti n ues fr o m t he st u d y treat me nt f or a n y reas o n, t he reas o n f or 
disc o nti n uati o n or wit h dra wal m ust be rec or de d o n t he e C R F usi n g t he f oll o wi n g criteria: 
S u bjects w h o di d n ot c o m plete o ne of t he prece di n g P hase 3 D S - 5 5 6 5 st u dies ( D S 5 5 6 5-
A- E 3 0 9, D S 5 5 6 5 - A- E3 1 0, or D S 5 5 6 5 - A- E 3 1 1) a n d wit h dra w pri or t o start of treat me nt 
b ut after si g ni n g i nf or me d c o ns e 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
 
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
F or s u bjects disc o nti n ue d or wit h dra w n after start of treat me nt 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 efficac y

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  s u bject (i n dicate reas o n)  

Ot her (i n dicate reas o n)  
If a s u bject is wit h dra w n d ue t o re q uire me nt f or a pr o hi bite d pai n me dicati o n, t he reas o n 
ma y  be rec or de d as lac k of efficac y, as a p pr o priate.  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.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 3
A s u bject ma y  be wit h dra w n d ue t o n o n-c om 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 s h o ul d be 
wit h dra w n fr o m t he st u d y a n d earl y ter mi nati o n st u d y pr oce d ures perf or me d.
All s u bjects w h o are wit h dra w n s h o ul d c o m plete pr ot oc ol -s pecifie d wit h dra wal 
pr oce d ures (see Secti o n 4. 2. 2 a n d Secti o n 6. 4 ).
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 d ra wal, 
i ncl u di n g t he date of last treat me nt a n d t he reas o n f or wit h dra wal.
If t he s u bject is wit h dra w n d ue t o a n A 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 c o m plete all e n d- of-
treat me nt/early ter mi nati o n ( Visit 2 1 ) pr oce d ures as s o o n as p ossi ble after earl y 
wit h dra wal (Secti o n 6. 4 ).  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 ret ur n 
f or a p ost-treat me nt f oll o w-u p visit ( Secti o n 6. 5 ).  
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
Rescree ni n g of s u bjects will n ot be 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 4
5. 
T R E A T M E N T S A D MI NI S T E R E D
5. 1. 
I n vesti g ati o n al Pr o d ucts
T he I n vesti gat or m ust e ns ure t hat t he i n vesti gati o nal pr o d uct 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 uct f or t his st u d y  is:

D S -5 5 6 5 1 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
S u bjects e nteri n g i nt o t he o pe n -la bel e xte nsi o n p hase of t he st u d y will i nitiall y recei ve a 
1 5 m g Q D d ose of D S -5 5 6 5 .  After 3 wee ks o n t he 1 5 m g Q D d ose (at Visit 6 , Wee k 3), 
s u bjects will be as ke d a b o ut t he a de q uac y of t heir pai n c o ntr ol.  De pe n di n g o n t heir le vel 
of pai n c o ntr ol a n d w het her t he y  ha ve e x perie nce d a n y cli nically rele va nt T E A Es si nce 
t he pre vi o us visit, s u bjects ma y be d ose-escalate d t o D S -5 5 6 5 1 5 m g BI D.  T he d ose 
escalati o n criteria are defi ne d i n Ta ble 5. 1 .
T a ble 5. 1: 
D ose Esc al ati o n Criteri a 
P ai n C o ntr ol a
Cli nic all y Rele v a nt T E A E b
D ose I ncre ase c
I na de q uate 
N o
Yes
Yes
N o
Acce pta ble b ut n ot o pti mal  
N o
Yes
Yes
N o
O pti mal 
N o
N o
Yes
N o
a Base d u p o n t he i n vesti gat or’s j u d g me nt 
b A n y m o derate or se vere e pis o de of dizzi ness or s o m n ole nce, a n y e pis o de of e de ma or cli nicall y 
si g nifica nt wei g ht gai n, or a n y ot her cli nicall y rele va nt (i n t he j u d g me nt of t he i n vesti gat or) T E A E si nce 
t he pre vi o us visit
c Yes = s u bject ma y be d ose -escalate d t o D S -5 5 6 5 1 5 m g BI D
A b bre viati o ns: BI D = t wice dail y, T E A E = treat me nt -e mer ge nt a d verse e ve nt
O nce a s u bject has bee n d ose -escalate d t o 1 5 m g BI D, c o nti n uati o n of t he 1 5 m g BI D 
d ose will occ ur as l o n g as pai n c o ntr ol is a de q uate a n d t he s u bject e x perie nces n o 
m o derate or se vere e pis o de of dizzi ness or s o m n ole nce, e de ma, cli nicall y  si g nifica nt 
wei g ht gai n, or a n y ot her cli nical l y rele va nt (i n t he j u d g me nt of t he i n vesti gat or) A E.  If
t he s u bject d oes e x perie nce a cli nicall y rele va nt A E, t he n t he f oll o wi n g criteria will 
deter mi ne w het her disc o nti n uati o n or d o w n -titrati o n of t he d ose s h o ul d occ ur:

If t he s u bject pre vi o usl y re p orted i na de q uate pai n c o ntr ol wit h 1 5 m g Q D 
d osi n g, t he s u bject will be disc o nti n ue d fr o m t he st u d y

If t he s u bject pre vi o usl y re p orte d acce pta ble pai n c o ntr ol wit h 1 5 m g Q D 
d osi n g, t he s u bject ma y  be d ose-re d uce d t o 1 5 m g Q 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 5
N o bli n di n g will be use d .
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 plia 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 s u bject i de ntificati o n n u m ber (SI 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 ng 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.
C o ntract researc h or ga nizati o n ( C R O ) pers o n nel will re vie w eac h s u bject’s treat me nt 
c o m plia nce d uri n g i n vesti gati o nal site visits a n d at t he c o m pleti o n of t he st u d y .
5. 1. 3. 
L a beli n g a n d P ac k a gi n g
D S - 5 5 6 5 ta blets will be s u p plie d i n la bele d blister car ds ( wallets) c o ntai ni n g 1 5 m g
ta blets.  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 uct, s uc h as t he e x pirati o n 
date, ca n be f o u 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.
5. 1. 4. 
Pre p ar ati o n
St u d y  dru 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 c o ntai n 1 5 m g ta blets.
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 r ec 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 hi p me nt of dr u g s u p plies.
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) 
a n d m ust c o ntact Daiic hi Sa n k y o Cli nical S u p pl y  O perati o ns pers o n nel or desi g nee t o 
deter mi ne if t he affecte d s u p plies ca n be use d .
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 nt 
a n d c o n diti o n of t he dr u g, c hec k f or a p pr o priate l ocal la n g ua ge i n t he la bel, a n d si g n t he 
Recei pt of S hi p me nt F or m pr o vi de d.  T he ori gi nal will be retai ne d at t he site.  I n 
a d diti o n, t he In vesti gat or or desi g nee s hall c o ntact Daiic hi Sa n k y o Cli nical S u p pl y  
O perati o ns as s o o n as p ossi ble if t here is a pr o ble m wit h t he s hi p me nt.
A Dr u g Acc o u nta bilit y  Rec or d will be pr o vi de d 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) 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 6
of eac h e nr olle 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 gati 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 
n ot ta ke n), will be destr o y e d o n site or ret ur ne d t o a desi g nee as i nstr ucte d b y t he 
s p o ns or.  In vesti gati o nal pr o d uct will be 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 ntity t o be ret ur ne d.  T he ret ur n of 
i n vesti gati o nal pr o d uct m ust be d oc u me nte d a n d t he d oc u me ntati o n i ncl u de d i n t he 
s hi p me nt.  At t he e n d of t he st u d y, a fi nal i n vesti gati o nal pr o d uct rec o nciliatio n state me nt 
m ust be c o m plete d b y  t he i n vesti gat or, or desi g nee, a n d pr o vi de d t o t he s p o ns or.  U n use d 
dr u g s u p plies ma y  be destr o ye d b y t he i n vesti gat or w he n a p pr o ve d i n writi n g b y 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 ).
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 n y a ut h orize d i ns pect or 
fr o m a re g ulat or y a ge ncy.  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 efficac y a n d/ or safety 
is n ot per mitte d.  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 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 in Ta ble 5 .2 , d uri n g t he 
st u d y.  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.
De n o v o s u bjects ( i.e. s u bjects w h o di d n ot c o m plete a prece di n g st u d y) w h o are 
recei vi n g me dicati o n f or F M ( or a ny pr o hi bite d me dicati o n liste d i n  Ta ble 5. 2 ) 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 visit.  T he i n vesti 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. 2 .
De n o v o 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 dy ( base d o n t he 
res ults of t he Visit 1 assess me nts) 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 
i n vesti gat or or desi g nee.  After t he Was h o ut Peri o d is c o m plete, de n o v o s u bjects will 
ret ur n t o t he site f or t he Baseli ne visit ( Visit 3).  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 7
T a ble 5. 2: 
Pr o hi bite d Me dic ati o ns a n d Tre at me nts
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 B aseli ne P ai n Assess me nts a
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 -2 i n hi bit ors
3 da ys
Be nz o diaze pi nes
7 da ys
D o pa mi ne a g o nists
7 da ys
Tric yclic a nti de pressa nts a n d ser ot o ni n -
n ore pi ne p hri ne re u pta ke i n hi bit ors a n d ot her 
a nti de pressa nts e xce pt f or all o we d S S RIs as s h o w n 
i n Ta ble 5. 3.
7 da ys
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 (caris o pr o d ol, 
c ycl o be nza pri ne, tiza ni di ne, etc), t o pical ca psaici n, 
t o pical or i njecte d l ocal a nest hetics, te n der p oi nt 
i njecti o ns, fatt y aci d s u p ple me nts, a n d me ma nti ne
7 da ys
a Was h o ut peri o d o nl y a p plies t o de n o v o s u bjects w h o d o n ot tra nsiti o n f r o m a prece di n g st u d y.
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.
N o n p har mac ol o gical t hera pies f or F M , 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, or s ur ger y, or a n y  ot her p har mac ol o gical 
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 wit h t he e xce pti o n of t he all o wa ble me dicati o ns liste d i n S ecti o n 5. 2. 2 . Se dati n g 
a nti hista mi nes f or slee p, melat o ni n, ca n na bi n oi ds , a n d ot her se dati ves (e. g. bar bit urates )
are als o pr o hi bite d.
C ha n ge s t o n or mal dail y e xercise r o uti nes are all o we d acc or di n g t o i n vesti gat or 
j u d g me nt. S u bjects ma y  c o nti n ue wit h s o me sta ble n o n p har mac ol o gical t hera pies, s uc h 
as p h ysi ot hera p y, massa ge, c hir o pract or, a n d psyc h ol o gical t hera pies.
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. 
M ai n All o w a ble Me dic ati o ns
Use of S S RI s ( b ut n ot 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]) is all o we d 
if t he s u bject has bee n o n a sta ble d ose d uri n g t he prece di n g st u dy ( or f or ≥ 2 m o nt hs
pri or t o scree ni n g f or a de n o v o s u bject) 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.  E xa m ples of all o we d S S RI s are pr o vi de d i n Ta ble 5. 3.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 8
T a ble 5. 3: 
C o m m o n All o we d S S RIs
E x a m ples of Per missi ble S S RIs
Cital o pra m
Da p o xeti ne
escital o pra m
fl u o xeti ne
F l u v o xa mi ne
par o xeti ne
S ertrali ne
vilaz o d o ne
N ote: A n y ot her a p pr o ve d S S RI i n eac h partici pati n g c o u ntr y ( i.e. ge nerics, etc) n ot i ncl u de d i n t his list will 
als o be all o we d if mai ntai ne d at sta ble d oses o ver t he last t w o m o nt hs pri or t o st u d y e ntr y
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.  
T he use of aceta 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 ) will als o be per mitte d as all o wa ble (resc ue) me dicati o n f or brea kt hr o u g h F M.  
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 or a n y 
n o nster oi dal a nti -infla m mat or y  dr u gs (N S AI D ) 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 , if n ot li kel y relate d t o F M base d o n 
i n vesti gat or j u d g me nt, s h o ul d als o be rec or de d as a n A E 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 o ver d ose. Ot her N S AI Ds s uc h as 
i b u pr ofe n a n d na pr o xe n ma y be use d f or a n y pai n i n dicati o n (e. g. hea dac he, bac k pai n) 
e xce pt f or brea kt hr o u g h F M.  N S AI D use f or brea kt hr o u g h F M is n ot per mitte d.
A n y  n o n-pai n -relate d, 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 x perie nce, 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 a n d h or m o ne re place me nt t hera p y 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 3 9
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 A p pe n di x Secti o n 1 7. 3 .
S u bjects will recei ve o pe n -la bel treat me nt f or 5 2 wee ks f oll o we d by 4 wee ks of p ost -
treat me nt f oll o w- u p.  T he scree ni n g/ baseli ne pr ocess will de pe n d o n w het her t he s u bject 
is a r oll o ver s u bject or de n o v o s u bject.  De n o v o s u bjects will ha ve a Scree ni n g visit 
( Visit 1) a n d als o c o m plete Visits 2 a n d 3 (as detaile d i n Secti o n 6. 1. 2) bef ore recei vi n g 
st u d y treat me nt at t he Start -of- Treat me nt visit ( Visit 4) .  R oll o ver s u bjects will ha ve 
scree ni n g pr oce d ures perf or me d at t he Star t-of -Treat me nt visit ( Visit 4), w hic h will occ ur 
o n t he sa me da y  as t he E n d- of-Ta peri n g visit of t he prece di n g st u d y  (as detaile d i n 
Secti o n  6. 2. 1).  All s u bjects will visit t he cli nic t he f oll o wi n g wee k (Visit 5 , Wee k 1); 
e ver y 2 wee ks t hereafter f or t he ne xt 1 2 wee ks ( Wee ks 3, 5, 7, 9, 1 1, a n d 1 3); 3 wee ks 
t hereafter ( Wee k 1 6); e ver y 4 wee ks t hereafter f or t he re mai n der of t he st u d y ( Wee ks 2 0, 
2 4, 2 8, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 5 2 ); a n d at t he p ost-treat me nt f oll o w-u p visit ( Visit 2 3, 
Wee k 5 4 ).  P ost-treat me nt f oll o w-u p will als o i ncl u de tele p h o ne c o ntacts at 3 da y s
( Visit 2 2) a n d at 4 wee ks ( Visit 2 4 ) after t he s u bject’s last d ose of st u d y  treat me nt.
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. 6. 1. 2 ).
6. 1. 
Scree ni n g / B aseli ne f or De N o v o S u bjects
Visits 1 t o 3 are re q uire d o nl y  f or de n o v o s u bject s.
F or de n o v o s u bjects, t he Scree ni n g Peri o d will i ncl u de a Scree ni n g visit ( Visit 1), a 
tele p h o ne c o ntact pri or t o t he dr u g Was h o ut Peri o d (f or su bjects w h o are recei vi n g 
pr o hi bite d me dicati o ns) ( Visit 2), a n d a Baseli ne visit ( Visit 3). T he d urati o n of t he 
Scree ni n g Peri o d will be a p pr o xi matel y 3 wee ks, b ut n o l o n ger t ha n 3 5 da ys.  
S u bjects recei vi n g a n y 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. 2 f or mi ni m u m was h o ut re q uire me nts).  
H o we ver, t hese s u bjects 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 ( base d o n t he res ults of t he Visit 1 
assess me nts) 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 n vesti gat or, or a pers o n desi g nate d by 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 begi n t he s pecifie d Was h o ut Peri o d.  T he na me of t he pr o hi bite d 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.
T he s u bject will recei ve a n electr o nic diar y  at t he Baseli ne visit.  T he s u bject will 
c o m plete t he electr o nic diar y at h ome f or 7 da y s pri or t o i nitiati n g st u d y treat me nt.
Fasti n g is n ot re q uire d pri or t o t he Scree ni n g or Baseli ne visits.   
6. 1. 1. 
Scree ni n g Visit f or De N o v o S u bjects ( Visit 1; Wee k - 3, Pri or t o 
E nr oll me nt)
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 ys  pri or t o t he Start -of-
Treat me nt 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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 0
( 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 Secti 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 n vesti gat or is res p o nsi ble f or o btai ni n g writte n i nf or me d 
c o nse nt 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 
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 co 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 perf or me d at/ d uri n g t he Scree ni n g 
visit ( Visit 1):

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 mi nister t he W PI  a n d S S S dia g n ostic q uesti o n naires

A d mi nister t he M.I . N.I Versi o n 6. 0 i nter vie w

A d mi nister t he C -S S R S ( See Secti o n 9. 2. 1 )

Re c 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 c o m plete p h ys ical e xa mi nati o n, i ncl u di n g f u n d osc o py e xa mi nati o n 
wit h p u pil dilati o n or a sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n ( Secti o n 
9. 9. 2 )

Perf or m a 1 2 -lea d E C G ( Secti o n 9. 8 )

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 nal ys is).  T he ce ntral la b orat or y will 
perf or m a ser u m pre g na nc y  test o n all fe male s u bjects re gar dless of c hil d-
beari n g p ote ntial

S u bjects will be e xcl u de d f or scree ni n g la b orat or y  val ues j u d ge d b y t he 
i n vesti gat or t o be cli nicall y si g nifica nt, wit h a partic ular f oc us o n t he li mits i n 
Ta ble 6. 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 1
T a ble 6. 1: 
Scree ni n g L a b or at or y V al ues
Bl o o d C he mistr y
A S T (S G O T )
> 2. 0 × U L N
A L T ( S G P 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
Bl o o d urea nitr o ge n
> 1. 5 × U L N
Creati ne ki nase
> 3. 0 × U L N
Ser u m creati ni ne
> 1. 6 m g/ d L ( > 1 4 1. 4 μ m ol/ L)
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 ( S G P T) = ala ni ne a mi n otra nsferase, A S T ( S G O 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

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. 2 ; 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 lab 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 

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 f or De N o v o S u bjects ( Visit 2; Wee k - 2, 
Pri or t o E nr oll me nt )
W he n a de n o v o 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 ne. If t he s u bject is eli gi ble 
a n d d oes n ot re q uire was h o ut, t he Start of Treat me nt Visit will be sc he d ule d.   If t he
s u bject is eli gi ble a n d c urre ntl y o n a pr o hi bite d me dicati o n (see Ta ble 5. 2 ), 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 hi s tele p h o ne c o ntact: 

Assess f or a n d rec or d A Es 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 pr o hi bite d me dicati o n(s), 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. 2 )
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 2
6. 1. 3. 
B aseli ne Visit f or De N o v o S u bjects ( Visit 3; Wee k -1, Pri or t o 
E nr oll me nt )
After t he was h o ut peri o d (if a p plica ble), de n o v o s u bjects will ret ur n t o t he cli nic f or a 
Baseli ne visit.  T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d: 

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 i ncl u di n g all o wa ble 
a nal gesics

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 a n d slee p i nte rfere nce rati n gs e ver y m or ni n g a n d a n y all o wa ble 
pai n -relate d me dicati o ns. T he s u bject s h o ul d be gi n diar y  c o m pleti o n t he 
f oll o wi n g m or ni n g
6. 2. 
St art -of -Tre at me nt Visit ( Visit 4; Wee k  0)
T he pr oce d ures t o be perf or me d at t he Start -of -Treat me nt visit de pe n d o n w het her t he 
s u bject is a r oll o ver s u bject or a de n o v o s u bject.
6. 2. 1. 
St art - of-Tre at me nt Visit f or R oll o ver S u bjects
F or r oll o ver s u bjects, t he Start - of-Treat me nt visit ( Visit 4) will be c o n d ucte d o n t he sa me 
da y  of t he E n d-of -Ta peri n g visit of t he prece di n g st u d y  t o a v oi d i nterr u pti o n i n treat me nt 
wit h st u d y  dr u g.  Si g nat ure o n t he i nf or me d c o nse nt d oc u me nt f or t his st u d y s h o ul d be 
o btai ne d bef ore t he start of t he E n d - of- Ta peri n g visit ( Wee k 1 4, Visit 1 3) of t he 
prece di n g st u d y.  
It s h o ul d be n ote d t hat res ults fr o m safety la b orat or y tests fr o m t he E n d - of-Treat me nt 
visit of t he prece di n g st u d y  are re q uire d t o deter mi ne eli gi bilit y.  S u bjects will be 
e xcl u de d f or la b orat or y val ues e xcee di n g li mits liste d i n Ta ble 6. 2 .
T a ble 6. 2:   
Re q uire d L a b or at or y V al ues (fr o m t he E n d- of- Tre at me nt Visit of t he 
Prece di n g St u d y)
Bl o o d c he mistr y
A S T ( S G O T)
> 2. 0 × U L N
A L T ( S G P 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
Bl o o d urea nitr o ge n
> 1. 5 × U L N
Creati ne ki nase
> 3. 0 × U L N
Ser u m creati ni ne
> 1. 6 m g/ d L ( > 1 4 1. 4 μ m ol/ L)
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.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 3
A b bre viati o ns: A L T ( S G P T) = ala ni ne a mi n otra nsferase, A S T ( S G O 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
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 Start -of-
Treat me nt visit ( Visit 4) i n t his st u d y:

O btai n writte n i nf or me d c o nse nt ( bef ore t he start of t he E n d- of-Ta peri n g visit 
i n t he prece di n g st u dy)

Assess all a p plica ble i ncl usi o n a n d e xcl usi o n criteria

Perf or m c o m plete p h ys ical e xa mi nati o n ( Secti o n 9. 9. 2 )

Perf or m a 1 2 -lea d E C G ( Secti o n 9. 8 )

As k s u bject t o c o m plete t he H A D S , S F -3 6 a n d E Q -5 D q uesti o n naires 

C o ntact I X R S t o re gister t he s u bject a n d o btai n ne w st u d y me dicati o n wallet 
n u m ber

Dis pe nse st u d y  me dicati o n a n d re vie w d osi n g i nstr ucti o ns. 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 Start of Treat me nt visit, 
at be dti me after c o m pleti o n of t he st u d y visit.  S u bjects s h o ul d be i nstr ucte d t o 
bri n g t heir st u d y me dicati o n wallet wit h t he m t o eac h cli nic visit 
I nf or mati o n c ollecte d d uri n g t he prece di n g st u dy will als o be utilize d i n t his e xte nsi o n 
st u d y.  T his i nf or mati o n i ncl u des:

De m o gra p hic i nf or mati o n (c ollecte d at Scree ni n g of t he prece di n g st u d y)

Me di cal/s ur gical hist or y (c ollecte d at Scree ni n g of t he prece di n g st u d y )

A Es (a n y o n g oi n g A Es fr o m t he prece di n g st u d y will be tra nsferre d t o t he 
data base f or t his e xte nsi o n st u d y )

C o nc o mita nt me dicati o ns (a n y o n g oi n g c o nc o mita nt me dicati o ns fr o m t he 
prece di n g st u d y will be tra nsferre d t o t he data base f or t his e xte nsi o n st u d y) 

Vital si g ns (c ollecte d at t he E n d- of- Ta peri n g visit of t he prece di n g st u d y )

Hei g ht (c ollecte d at Scree ni n g of t he prece di n g st u d y )

Wei g ht (c ollecte d at t he E n d- of- Ta peri n g visit of t he p rece di n g st u dy)

C- S S R S (c ollecte d at t he E n d- of- Ta peri n g visit of t he prece di n g st u d y (See 
Secti o n 9. 2. 1 )

Cli nical la b orat or y  tests (c ollecte d at t he E n d-of- Ta peri n g visit of t he 
prece di n g st u d y)

Pre g na nc y  test (c ollecte d at t he E n d- of-Ta peri n g visit of t he prece di n g st u d y )

Pai n sc ores ( rec or de d f or 7 da ys pri or t o t he E n d-of -Ta peri n g visit of t he 
prece di n g 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 4

Slee p i nterfere nce sc ores ( rec or de d f or 7 da ys pri or t o t he E n d- of- Ta peri n g 
visit of t he prece di n g st u d y )
6. 2. 2. 
St art - of-Tre at me nt Visit f or De N o v o S u bjects
F or de n o v o s u bjects, t he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at t he 
Start - of-Treat me nt visit ( Visit 4; Wee k 0).

Assess f or a n d rec or d A Es 

Rec or d a n y c o nc o mita nt me dicati o ns use d si nce t he last visit 

Re vie w s u bject’s electr o nic dail y  diar y data a n d as k s u bject t o c o m plete pai n 
a n d slee p i nterfere nce rati n gs f or t o da y  ( Da y 1), if n ot yet c o m plete d

Assess s u bject eli gi bilit y  usi n g t he st u d y’s i ncl usi o n/e xcl usi o n criteria, 
i ncl u di n g Baseli ne A D P S fr o m dail y diaries (a mi ni m u m of 4 dail y pai n 
rati n gs m ust be a vaila ble) 

A d m i 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. 2. 1 )
If t he s u bject is f o u n d t o be eli gi ble base d o n t he res ults of t he A D P S a n d C-S S R S 
assess me nts, pr ocee d t o perf or m t he f oll o wi n g pr oce d ures:

Rec or d b o d y wei g ht a n 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) 

Perf or m a b bre viate d p h ysical e xa mi nati o n (see Secti o n  9. 9. 2 ) 

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).  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 Da y 1 a n d st ore d f or f urt her 
a nal ys is i n t he e ve nt of A S T or A LT ele vati o ns ≥3 X U L N d uri n g t he st u d y  
(see Secti o n 9. 2. 2 ) 

T he ce ntral la b orat or y  will perf or m a ser u m pre g na nc y test o n all fe male 
s u bjects re gar dless of c hil d -beari n g p ote ntial

A s k s u bject t o c o m plete t he H A D S, S F -3 6 a n d E Q -5 D q uesti o n naires 

Pr o vi de a d diti o nal trai ni n g o n rec or di n g of pai n a n d slee p i nterfere nce rati n gs 
f or a ny s u bjects w h o ha d err ors or missi n g i nf or mati o n d uri n g t he Baseli n e 
Peri o d

C o ntact I X R S t o o btai n t he s u bject me dicati o n wallet n u m ber

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 Start of Treat me nt visit, at be dti me after c o m pleti o n of t he st u d y visit.  
S u bjects s h o ul d be i nstr ucte d t o bri n g t heir st u d y me dicati o n wallet wit h t he m 
t o eac h cli nic 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 5
6. 3. 
O n -Tre at me nt Peri o d ( Visits 5 t o 2 0 ; Wee k s 1 t o 4 8)
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at all O n -Treat me nt v isits
(e xce pt w here ot her wise n ote d):

Assess f or a n d rec or d A Es

After 3 wee ks o n t he 1 5 m g Q D d ose (at Visit 6, Wee k 3), s u bjects will be 
as ke d a b o ut t he a de q uac y of t heir pai n c o ntr ol a n d ma y be d ose-escalate d t o
D S - 5 5 6 5 1 5 m g BI D (see Secti o n 5. 1. 1 )

Assess f or a n d rec or d c o nc o mita nt me dicati o n use i ncl u di n g all o wa ble 
a nal gesics

Re vie w i nstr ucti o ns wit h t he s u bject f or c o m pleti o n of t he pai n a n d slee p 
i nterfere nce diar y .  N ote: T hese i nstr ucti o ns nee d t o be re vie we d wit h t he 
s u bject o nl y at Visit 1 0 ( Wee k 1 1 ), Visit 1 3 ( Wee k 2 0), Visit 1 6 ( Wee k 3 2), 
Visit 1 9 ( Wee k 4 4), a n d Visit 2 0 ( Wee k 4 8)  

Re vie w electr o nic diar y  data fr o m t he pre vi o us wee k.  N ote: T hese data nee d 
t o be re vie we d o nl y at Visit 1 1 ( Wee k 1 3 ), Visit 1 4 ( Wee k 2 4), Visit 1 7 
( Wee k 3 6), Visit 2 0 ( Wee k 4 8), a n d Visit 2 1 ( Wee k 5 2)

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

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. 2. 1 )

Perf or m a n a b bre viate d p h y sical e xa mi nati o n f or all s u bjects; perf or m a 
f u n d osc o py e xa mi nati o n wit h o ut p u pil dilati o n or a sca n ni n g laser 
o p ht hal m osc o p y  e xa mi nati o n at Visit 1 4 ( Wee k 2 4) f or de n o v o s u bjects (see 
Secti o n  9. 9. 2)

C ollect n o n- fasti n g 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 safety tests (c he mistr y, he mat ol o g y, a n d uri nal ysis) . T he c e ntral 
la b orat or y will perf or m a ser u m pre g na nc y test o n all fe male s u bjects 
re gar dless of c hil d-beari n g p ote ntial  

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 (as nee de d)

Dis pe nse st u d y  me dicati o n a n d re vie w d osi n g i nstr ucti o ns.  At Visit 2 0 ( Wee k 
4 8) , s u bjects s h o ul d be i nstr ucte d t o ta ke all st u dy me dicati o n, as sc he d ule d, 
u p u ntil t he da y  of t heir E n d - of-Treat me nt v isit ( Visit 2 1 , Wee k 5 2), b ut n ot 
o n t he m or ni n g of Visit 2 1 ( i.e. s u bjects s h o ul d c o m plete d osi n g o n t he 
e ve ni n g pri or t o t heir E n d -of- Treat me nt v isit)  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 6
6. 4. 
E n d -of -Tre at me nt /E arl y Ter mi n ati o n ( Visit 2 1 ; Wee k 5 2 )
T he 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 or 
Earl y Ter mi nati o n visit ( Visit 2 1) .  N o fasti n g is re q uire d pri or t o t he E n d- of-Treat me nt
v isit.

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 i ncl u di n g all o wa ble 
a nal gesics

Re vie w electr o nic diar y  data a n d c ollect electr o nic diar y

C ollect st u d y  me dicati o n 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

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 nal ys is). T he ce ntral la b orat or y  will 
perf or m a ser u m pre g na nc y test o n all fe male s u bjects re gar dless of c hil d -
beari n g p ote ntial

As k t he s u bject t o c o m plete t he P GI C, H A D S, S F - 3 6 a n d E Q -5 D 
q uesti o n naires 

C o m plete t he C- S S R S ( See Secti o n  9. 2. 1)

Perf or m c o m plete p h ys ical e xa mi nati o n f or all s u bjects, i ncl u di n g a 
f u n d osc o py e xa mi nati o n wit h p u pil dilati o n or a sca n ni n g laser 
o p ht hal m osc o p y  e xa mi nati o n f or de n o v o s u bjects o nl y (see Secti o n 9. 9. 2)

Perf or m a 1 2 -lea d E C G ( Secti o n 9. 8 )

U p date I X R S wit h s u bject stat us
6. 5. 
F oll o w -U p
6. 5. 1. 
P ost -Tr e at me nt F oll o w- U p ( Visit s 2 2 t o 2 4 ; Wee ks 5 2 t o 5 6)
6. 5. 1. 1.  
Tele p h o ne C o nt act at D a y 3 of F oll o w -u p (Visit 2 2 ; Wee k 5 2. 5)
All s u bjects , i ncl u di n g t h ose w h o disc o nti n ue pre mat urel y , will be c o ntacte d b y  
tele p h o ne 3 da ys after t he s u bject’s last d ose of st u d y treat me nt.  T he f oll o wi n g acti vities 
a n d/ or assess me nts will be perf or me d at t his 3 -da y f oll o w -u p tele p h o ne c o ntact:

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 i ncl u di n g all o wa ble 
a nal gesics

A d mi nister t he 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 7
6. 5. 1. 2. 
Visit at Wee k 2 of F oll o w -u p ( Visit 2 3; Wee k 5 4 )
All s u bjects t he n will ret ur n t o t he cli nic f or p ost-treat me nt f oll o w-u p a p pr o xi matel y  1 4 
( ± 3 ) da ys f oll o wi n g t he last d ose of st u d y me dicati o n.  
T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d at t he F oll o w -u p cli nic 
v isit ( Visit 2 3 , Wee k 5 4):

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 i ncl u di n g all o wa ble 
a nal gesics

Re c 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 uri ne pre g na nc y test o n all W O C B P
a n d c o nfir m ne gati ve

A d mi nister t he C-S S R S ( See Secti o n  9. 2. 1)

A d mi nister t he P W C
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 E n d - of-
Treat me nt v isit s h o ul d be rec hec ke d at t he F oll o w -u p v isit.  F urt her safet y assess me nts 
ma y  be re q uire d f or cli nicall y si g nifica nt a b n or mal fi n di n gs o bser ve d at t he F oll o w-u p 
v isit.
6. 5. 1. 3. 
Tele p h o ne C o nt act at Wee k 4 of F oll o w- u p ( Visit 2 4; Wee k 5 6 )
All s u bjects will be c o ntacte d b y  tele p h o ne a p pr o xi matel y 4 wee ks f oll o wi n g t he last 
d ose of st u d y  me dicati o n.  T he f oll o wi n g acti vities a n d/ or assess me nts will be perf or me d 
at t his 4-wee k f oll o w -u p tele p h o ne c o ntact:

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 i ncl u di n g all o wa ble 
a nal gesics
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 
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 vi ati o n t o a n y pr ot oc ol pr oce d ure or wai ver t o a n y state d criteria will n ot be all o we d 
i n t his st u d y e xce pt w here necessar y t o eli mi nate i m me diate hazar d(s) t o t he s u bject.  
S p o ns or m ust be n otifie d of all i nte n de d or u ni nte n de d de viati o ns t o t he pr ot oc ol ( e. g.
i ncl usi o n/e xcl usi o n criteria, d osi n g, misse d st u d y visits) o n a n e x pe dite d basis.
T he i n vesti gat or, or pers o n desi g nate d b y t he i n vesti gat or, s h o ul d d oc u me nt a n d e x plai n 
a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 8
If a s u bject was i neli gi ble or recei ve d t he i nc orrect d ose or 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 nal pr o d uct, data s h o ul d be c ollecte d f or 
safety p ur p oses.
T he in 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 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 4 9
7. 
E F FI C A C Y A S S E S S M E N T S
7. 1. 
A v er a ge D ail y P ai n Sc ore ( A D P S )
S u bjects will rec or d t heir w orst pai n o ver t he pre vi o us 2 4 h o urs i n a n electr o nic diar y 
usi n g a n 1 1 -p oi nt n u meric rati n g scale ( 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) (refer t o t he St u d y  Ma n ual f or a c o p y of t his i nstr u me nt).  P ai n diar y sc ores 
will be rec or de d b y  t he s u bjects d uri n g t he 7 da y s pri or t o Visit 1 1 ( Wee k 13 ), Visit 1 4 
( Wee k 2 4), Visit 1 7 ( Wee k 3 6), Visit 2 0 ( Wee k 4 8), a n d Visit 2 1 ( Wee k 5 2). F or de 
n o v o s u bjects o nl y , pai n diar y sc ores will be rec or de d d uri n g t he 7 da y s pri or t o Visit 4 
(Start - of-Treat me nt ).  D uri n g t he 7 da y s pri or t o t hese visits, e ver y  da y 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 s h o ul d i n dicate t he n u m ber t hat best 
descri bes his or her w orst pai n o ver t h e pre vi o us 2 4 h o urs. 5
F or r oll o ver s u bjects, t he A D P S val ue ta ke n fr o m t he last visit of t he D S 5 5 6 5- A- E 3 0 9, 
D S 5 5 6 5 - A-E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1 st u d y  (i.e. E n d - of-Ta peri n g ) will be use d as t he 
baseli ne sc ore f or t his st u d y a n d he nce will n ot be re peate d b y t he s u bject at Visit 4 
( Start-of- Treat me nt) .
F or de n o v o s u bjects, t he baseli ne A D P S val ue will be calc ulate d base d o n t he s u bject’s 
rec or di n g of pai n diar y sc ores d uri n g t he Baseli ne peri o d.
7. 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 at t he E n d - of-Treat me nt / Earl y Ter mi nati o n visit.  
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.6  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. 
H os pit al A n xiet y a n d De pressi o n Sc ale (H A D S )
All s u bjects will c o m plete t he H A D S q uesti o n naire at t he Start -of- Treat me nt visit (Visit 
4) a n d at t he E n d -of -Treat me nt / Earl y Ter mi nati o n visit.
T he H A D S q uesti o n naire i s a relia ble, wi dely- use d self -assess me nt scale t o assess 
s ym pt o ms of a n xiet y  a n d de pressi o n.7  T he i nstr u me nt c o nsists of 7 q uesti o ns relate d t o 
a n xiet y a n d 7 relate d t o de pressi o n, eac h rate d o n a 4-p oi nt scale (sc ore of 0 t o 3). Sc ores 
f or a n xiet y a n d de pressi o n are i n de pe n de ntl y s u m me d t o c o m p ute H A DS -A n xiet y  a n d 
H A D S - De pressi o n s u bscale sc ores, wit h ra n ges fr o m 0 t o 2 1, w here hi g her sc ores 
i n dicate greater se verity.
7. 4. 
E ur o Q ol I nstr u me nt 5 Di me nsi o ns (E Q -5 D )
All s u bjects will c o m plete t he E Q - 5 D q uesti o n naire at t he Start -of -Treat me nt visit ( Visit 
4) a n d at t he E n d -of -Treat me nt / Earl y Ter mi nati o n visit.  T he E Q -5 D (refer t o 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 0
Ma n ual f or a c o p y) is a well -sta n dar dize d i nstr u me nt t hat s h o ws hi g h c o nstr uct vali dit y  
a n d res p o nsi ve ness i n patie nts wit h c hr o nic pai n 8 a n d has bee n use d s pecificall y i n F M .9  
T he E Q -5 D i ncl u des a descri pti ve secti o n wit h 5 di me nsi o ns ( m o bilit y , self-care, us ual 
acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n) t hat are c o m bi ne d i nt o a n o verall 
healt h utilities i n de x, a n d a n N R S (1 0 0 m m V A S) t hat meas ures perce pti o n of o verall 
healt h, wit h 0 i n dicati n g w orst healt h a n d 1 0 0 re prese nti n g best i ma gi na ble healt h.
7. 5. 
S h ort F or m 3 6 ( S F- 3 6)
All s u bjects will c o m plete t he S F- 3 6 q uesti o n naire at t he Start -of- Treat me nt visit (Visit 
4) a n d at t he E n d -of -Treat me nt / Earl y Ter mi nati o n visit.  T he S F -3 6 (refer t o t he St u d y  
Ma n ual f or a c o p y) is a ge neric healt h s ur ve y t hat as ks 3 6 q uesti o ns t o meas ure 
f u ncti o nal healt h a n d well-bei n g fr o m t he s u bject’s p oi nt of vie w.  It is a practical, 
relia ble, a n d vali d meas ure of p h y sical a n d me ntal healt h wi dely use d acr oss vari o us 
disease areas , i ncl u di n g F M .1 0  T he S F -3 6 pr o vi des sc ores f or 8 healt h d o mai ns ( p h y sical 
f u ncti o ni n g, r ole-p h y sical, b o dil y pai n, ge neral healt h, vitalit y, s ocial f u ncti o ni n g, r ole-
e m oti o nal, a n d me ntal healt h) as well as ps yc h o metricall y- base d p h y sical c o m p o ne nt 
s u m mar y ( P C S) a n d me ntal c o m p o ne nt s u m mar y ( M C S) sc ores. All healt h d o mai n scales 
c o ntri b ute t o t he sc ori n g of b ot h t he P C S a n d M C S meas ures.
7. 6. 
A ver a ge D ail y Slee p I nterf ere nce Sc ore ( A D SI S)
Pai n -ass ociate d slee p i nterfere nce will be assesse d usi n g electr o nic diaries usi n g a n 
1 1- p oi nt N R S ra n gi n g fr o m 0 ( pai n d oes n ot i nterfere wit h slee p) t o 1 0 ( pai n c o m pletel y  
i nterferes wit h slee p, u na ble t o slee p) (refer t o t he St u d y Ma n ual f or a c o p y of t his 
i nstr u me nt). T he slee p i nterfere nce N R S is a sta n dar d t o ol use d t o assess h o w pai n has 
i nterfere d wit h slee p d uri n g t he past 2 4 h o urs.  Slee p i nterfere nce sc ores will be rec or de d 
b y  t he s u bjects d uri n g t he 7 da y s pri or t o Visit 1 1 ( Wee k 1 3), Visit 1 4 ( Wee k 2 4), Visit 
1 7 ( Wee k 3 6), Visit 2 0 ( Wee k 4 8), a n d Visit 2 1 ( Wee k 5 2).  F or de n o v o s u bjects o nl y , 
slee p i nterfere nce sc ores will be rec or de d d uri n g t he 7 da y s pri or t o Visit 4 ( Start - of-
Treat me nt ). D uri n g t he 7 da y s pri or t o t hese visits, e ver y  da y u p o n a wa ke ni n g, pri or t o 
ta ki n g st u dy me dicati o n, t he s u bject s h o ul d c o m plete t he slee p i nterfere nce q uesti o n 
al o n g wit h t he pai n q uesti o n i n t he diar y.  
F or r oll o ver s u bjects, t he slee p i nterfere nce val ue ta ke n fr o m t he last visit of t h e D S 5 5 6 5-
A- E 3 0 9, D S 5 5 6 5- A- E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1 st u d y  (i.e. E n d - of-Ta peri n g) will be use d 
as t he baseli ne sc ore f or t his st u d y a n d he nce will n ot be re peate d b y  t he s u bject at Visit 4 
( Start- of-Treat me nt) .  
F or de n o v o s u bjects, t he baseli ne slee p i nterfere nce val ue will be calc ulate d base d o n t he 
s u bject’s rec or di n g of slee p i nterfere nce sc ores d uri n g t he Baseli ne peri o d.
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Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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8. 
P H A R M A C O KI N E TI C A S S E S S M E N T S
8. 1. 
P h ar m ac o k i netic ( P K) V ari a ble(s)
N ot a p plica ble .
8. 2. 
P h ar m ac o d y n a mic ( P D) V ari a ble(s)
N ot a p plica ble.
8. 3. 
Bi o m ar k er a n d E x pl or at or y V ari a ble(s)
N ot a p plica ble.
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Versi o n 4 U K 1 , 1 4 Mar
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Pa ge 5 2
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 ( defi ne d i n Secti o n  9. 3 ) occ urr i n g after t he s u bject has si g ne d t he I C F 
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. t he 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 b y t he s u bject, will be rec or de d o n t he 
A E e C R F pa ge.  F or s u bjects r olle d o ver fr o m a prece di n g st u d y ( D S 5 5 6 5- A-E 3 0 9 , 
D S 5 5 6 5 - A-E 3 1 0 , or D S 5 5 6 5- A-E 3 1 1 ), a n y A E t hat is o n g oi n g at t he start of t his st u d y 
will be rec or de d as a n A E i n t his st u d y , a n d all A Es ( ne w or fr o m a prece di n g st u d y) will 
be f oll o we d u ntil res ol uti o n.  F or t hese r olle d - o ver s u bjects, all A Es will be e val uate d i n 
t he c o nte xt of t heir e x perie nce i n t he prece di n g st u d y.  
All 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 b y t he i n vesti gat or as t o 
cli nical si g nifica nce.  Is olate d a b n or mal la b orat or y res ults, vital si g n fi n di n gs, or E C G 
fi n di n gs s h o ul d be re p orte d as A Es if t he y are sy m pt o matic, lea d t o st u d y  dr u g
disc o nti n uati o n, re q uire c orrecti ve treat me nt, or 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. 2 ].
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. 4 ( S A E Re p orti n g-
Pr oce d ure f or I n vesti gat ors).  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 S A E narrati ve u ntil t he dia g n osis bec o mes 
a vaila ble.  If t he si g ns a n d s y m pt o ms are disti nct a n d d o n ot s u g gest a c o m m o n dia g n osis, 
re p ort 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 
s ym pt o m re q uiri n g h os pitalizati o n).  Pre - pla n ne d ( pri or t o si g ni n g t he I C F) pr oce d ures or 
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 s h o ul d n ot be 
re p orte d as S A Es (see Secti o n 9. 3 f or Defi niti o ns).  F or deat hs, t he u n derl yi n g or 
i m me diate ca use of deat h s h o ul d al wa ys be re p orte d as a n S A E.  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 s h o ul d deter mi ne w het her a n y A Es ha ve occ urre d b y 
e val uati n g t he s u bject.  A Es ma y  be directly o bser ve d, re p orte d s p o nta ne o usl y  b y t he 
s u bject, or by q uesti o ni n g t he s u bject at eac h st u d y visit.  S u bjects s h o ul d be q uesti o ne d 
i n a ge neral wa y, wit h o ut as ki n g a b o ut t he occ urre nce of a ny s pecific s y 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. 3 .  T he I n vesti gat or’s assess me nt m ust be 
clearl y d oc u me nte d i n t he site’s s o urce d oc u me ntati o n wit h t he I n vesti gat or’s si g nat ure.
I n vesti gat ors 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.  U nres ol ve d A Es, i ncl u di n g si g nifica nt a b n or mal la b orat or y  
val ues at t he e n d of t he st u d y , s h o ul d be f oll o we d u p u ntil res ol uti o n or u ntil n o l o n ger 
cli nicall y rele va nt.
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Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 5 3
9. 2. 
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, as me nti o ne d i n Secti o n  3. 1. 6, i ncrease d he patic tra nsa mi nases have 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 E SIs .
9. 2. 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 dicatio ns, i ncl u di 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 s u bjects 
recei vi n g t hese dr u gs.1 1
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 mu nicati o ns wit h t he patie 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,

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 baseli ne 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 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:
o
P ossi ble e xce pti o n (a p pl y i n g t o yes res p o nses t o C -S S R S Q 1 a n d/ or 2 
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 ofessi 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 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 mme diatel y referre d t o a 
me ntal healt h pr ofessi o nal ( prefera bl y  a n on site 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:
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Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 5 4

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. 2. 2. 
Li ver E nz y me Ele v ati o ns/ Li ver D ysf u ncti o n
As descri be d i n Secti o n  3. 1. 6. 1. 1, i ncreases 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 by w hic h selecte d cases will be a dj u dicate d b y a li ver disease 
s pecialist ( Secti o n 1 1. 1 0 ).  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 ele vati o n ass ociate d wit h a cli nical prese ntati o n s u g gesti ve of li ver i nj ur y  
(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 osel y, 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, 
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 r et 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 ( N A S H); 
h y p 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. ser u m lactate de hy dr o ge nase, 
al kali ne p h os p hatase, ga m ma -gl uta m yl  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; 
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Pa ge 5 5
c yt o me gal o vir us; a n d E pstei n -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 criteria of a p ote ntial 
H y ’s La w case [ A L T or A S T ≥ 3 x U L N w it 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. 4. 1 ), 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/ U C M 0 7 2 2 7 8. p df) .1 2 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.
Criteria 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. 6. 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 referrals 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. 3. 
Defi niti o ns
9. 3. 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 patie nt ( or st u d y  s u bject) w h o 
has recei ve d a p har mace utical pr o d uct; a n A E 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 be a n y u nfa v ora ble or u ne x pecte d si g n (e. g.
a n a b n or mal la b orat or y fi n di n g), sy m pt o m, or disease te m p orall y ass ociate d wit h t he use 
of a me dici nal pr o d uct, w het her or n ot c o nsi dere d relate d t o t he me dici nal pr o d uct (I C H 
E 2 A G ui deli ne – Cli nical Safet y  Data Ma na ge me nt: Defi niti o ns a n d Sta n dar ds f or 
E x pe dite d Re p orti n g, Oct 1 9 9 4).
It is t he res p o nsi bilit y of eac h i n vesti gat or, base d o n his/ her k n o wle d ge a n d e x perie nce, 
t o deter mi ne w het her a si gn, s y m pt o m or a b n or mal fi n di n g s h o ul d be c o nsi dere d a n A E.
9. 3. 2. 
Seri o us A d verse E ve nt ( S A E)
A n S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose:

Res ults i n deat h

Is life-t hreate ni n g

Re q uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xist i 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
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Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
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Pa ge 5 6

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 oc e 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 C F) s ur geries or 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. 3. 3.   
A d verse E ve nt Se verit y
T he f oll o wi n g defi niti o ns s h o ul d be use d t o assess se verity of A Es :

Mil d: A ware ness of si g n or s y m 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 p acitati 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. 3. 4. 
C a us alit y Assess me nt
T he relati o ns hi p bet wee n a n A E a n d t he st u d y pr o d ucts will be deter mi ne d b y t he 
i n vesti gat or o n t he basis of his/ her clinical j u d g me nt a n d t he f oll o wi n g defi niti o ns:

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 olo g y .

2 = N ot Relate 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 7

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 d y , c o nc urre nt diseases, a n d 
c o nc o mita nt me dicati o ns).
9. 3. 5. 
Acti o n T a ke n Re g ar di n g t he I n vesti g ati o n al Pr o d uct

1 = D ose N ot C ha n ge d: N o c ha n ge i n st u d y dr u g d osa ge was ma de.

2 = Dr u g Wit h dra w n: T he st u d y  pr o d uct was per ma ne ntl y st o p pe d.

3 = D ose Re d uce d: T he d osa ge of st u d y pr o d uct was re d uce d.

4 = Dr u g I nterr u pte d: T he st u d y  pr o d uct was te m p orarily st o p pe d.
9. 3. 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 E 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 E are s till prese nt a n d o bser va ble.

I de ntif y 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. 3. 7. 
Ot her Acti o n T a ke n f or E ve nt
Ot her Acti o n Ta ke n f or E ve nt will be re p orte d as o ne of t he f oll o wi n g:

1 = N o ne.

N o treat me nt was re q uire d.

2 = Me dicati o n re q uire d.

Prescri pti o n a n d/ or o ver t he c o u nter me dicati o n was re q uire d t o treat t he 
A E.

3 = Ot her.
9. 4. 
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
9. 4. 1. 
Re p orti n g b y I n vesti g at ors
All A Es, S A Es, e n d p oi nts, a n d e ve nts of s pecial i nterest, 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 e C R F wit hi n 2 4 h o urs of a ware ness:

S A Es (see Secti o n  9. 3. 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 8

He patic e ve nts meeti n g c o m bi nati o n a b n or malities [ 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 per Secti o n 
3. 1. 6. 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 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 uld 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 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 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 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 e C R F bec o mes a vaila ble, 
please e nter S A Es re p orte d o n t he S A V E R F or m i nt o e C R F as s o o n as p ossi ble. Please 
refer t o 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 ne or y o ur st u d y  m o nit or f or a ny q uesti o ns o n S A E 
re p orti n g.
9. 4. 2. 
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 nstit uti o n al Re vie w 
B o ar ds/I nstit uti o n al Et hics C o m mittees
Daiic hi Sa n k y o a n d/ or desi g nee will i nf or m i n vesti gat ors, I R Bs/I E Cs, a n d re g ulat or y  
a ut h orities of a n y s us pecte d u ne x pecte d seri o us a d verse e ve nt reacti o ns ( S U S A Rs) 
occ urri n g i n ot her st u d y ce nters or ot her Daiic hi Sa n k yo st u dies of t he i n vesti gati o nal 
pr o d uct, as a p pr o priate p er 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 
i n vesti gati o nal pr o d uct, u nless dele gate d t o t he S p o ns or, it is t he i n vesti gat or’s 
res p o nsi bilit y t o i nf or m t he IR B per t he S p o ns or’s i n str ucti o n.
I n t he E ur o pea n Ec o n o mic Area me m ber 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 I E Cs.
9. 5. 
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.  
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 5 9
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 
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 via t he E x p os ure i n Uter o ( EI U) Re p orti n g 
f or m ( please c o ntact yo ur st u d y  m o nit or t o recei ve t he f or m).  T he i n vesti gat or s h o ul d 
ma ke e ver y  eff ort t o foll o w t he s u bject u ntil c o m pleti o n of t he pre g na nc y .  If t he o utc o me 
of t he pre g na nc y  meets t he criteria f or i m me diate classificati o n as a 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 din 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. 4.  Electe d a b orti o n is a pr oced ure 
a n d s h o ul d be re p orte d f oll o wi n g t he defi niti o ns a n d pr oce d ures f or re p orti n g A Es or 
S A Es.
9. 6. 
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 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 (see A p pe n di x 1 7. 3 ).
9. 6. 1. 
He m at ol o g y
A si n gle 2 m L  et h yl e ne dia mi netetraacetic aci d ( E D T A ) t u be of bl o o d will b
e 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 Scree ni n g/ Baseli ne v isit, Treat me nt v isits, a n d E n d - of-
Treat me nt/ Earl y Ter mi nati o n v isit.
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)
W hite bl o o d cell
( W B C) c o u nt ( wit h differe ntial)
Platelet c o u nt
9. 6. 2. 
Bl o o d C he mistr y
A 2 . 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 wil l be meas ure d fr o m sa m ples o btai ne d at t he 
Scree ni n g/ Baseli ne v isit, Treat me nt v isits, a n d E n d -of- Treat me nt / Early Ter mi nati o n v isit.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 0
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
Al kali ne p h os p hatase
Tri gl yceri des
T otal bilir u bi n a
a T otal bilir u bi n s h o ul d be fracti o nate d at baseli ne a n d w he ne ver t otal bilir u bi n > 2 x U L N
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; U L N = u p per li mit of 
n or m al
9. 6. 2. 1.  
Esti m ati o n of Cre ati ni ne Cle ar a nce
Creati ni ne cleara nce ( Cr Cl) 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 oft -Ga ult e q uati o n (A p pe n di x 1 7. 2 ).
9. 6. 3. 
Uri n al ysis
Sta n dar d uri nal ys is i ncl u 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 Scree ni n g v isit, Treat me nt v isits, a n d E n d - of-Treat me nt / Earl y Ter mi nati o n 
v isit (Ta ble 9. 3 ).
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
A b bre viati o ns: 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 re d 
bl o o d cells ( R B Cs), w hite bl o o d cells ( W B Cs), bacteria, a n d casts s h o ul d be perf or me d.
9. 6. 4. 
Pre g n a nc y Testi n g
A ser u m pre g na nc y  test will als o be perf or me d f or all w o me n at all cli nic visits t hr o u g h 
t he E n d - of-Treat me nt / Earl y Ter mi nati o n visit.  A uri ne pre g na nc y test will be perf or me d 
f or all W O C B P at t he F oll o w -u p cli nic 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 1
9. 7. 
Vit al Si g ns
Vital si g ns will be rec or de d at all visits 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 bjects 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 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 pi 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 hat was 
use d i n t he prece di n g st u d y.  F or s u bjects n ot c o m pleti n g a prece di n g st u d y, 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 
s yst 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 ur e 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. 8. 
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 v isit ( Visit 1) f or de n o v o s u bjects, 
a n d at Start - of-Treat me nt visi t ( Visit 4) a n d at t he E n d - of-Treat me nt / Early Ter mi nati o n 
v isit ( Visit 2 1) f or all s u bjects.  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 nical l y si g nifica nt or 
si g nifica nt.  Cli nically 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).  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. 9. 
P h ysic al Fi n di n gs
9. 9. 1. 
B o d y Hei g ht a n d Wei g ht
F or de n o v o s u bjects o nl y, meas ure me nt of hei g ht will be perf or me d at t he Scree ni n g 
v isit ( Visit 1) 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 yes f or war d.
Meas ure me nt of wei g ht s h o ul d be perf or me d at e ver y  visit, e xce pt t he Baseli ne visit 
( Visit 3) f or de n o v o s u bjects, wit h t he s u bject dresse d i n i n d o or cl ot hi n g, s h oes re m o ve d.  
S u bjects s h o ul d be wei g he d o n t he sa me scale at all visits.
9. 9. 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 Scree ni n g 
v isit ( Visit 1) f or de n o v o s u bjects or at t he Start-of -Treat me nt visit ( Visit 4) f or r oll o ver 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 2
s u bjects a n d E n d - of-Treat me nt / Earl y Ter mi nati o n visit ( Visit 2 1) f or all s u bjects.  A n 
a b bre viate d p h ys ical e xa mi nati o n will be perf or me d at t he Treat me nt v isits.  
T he f ull p h ysical 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.
F or de n o v o s u bjects, a f u n d osc o p y e xa mi nati o n of t he e yes, wit h p u pil dilati o n or a 
sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n, will be c o n d ucte d at t he Scree ni n g visit 
( Visit 1) a n d E n d of Treat me nt visit ( Visit 2 1) d uri n g t he f ull p hys ical e xa mi nati o n.  At 
Visit 1 4 ( Wee k 2 4), t he a b bre viate d p h ys ical e xa mi nati o n will i ncl u de a f u n d osc o p y 
e xa mi nati o n wit h o ut p u pil dilati o n or a sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n .  
T he a b bre viate d p h ys ical 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 heart a n d l u n gs. A d diti o nal s y ste ms ma y be e xa mi ne d base d o n a ny s y m pt o ms 
e x hi bite d b y t he s u bject.
9. 1 0. 
Ot her S afet y Assess me nts
9. 1 0. 1. 
C ol u m bi a - S uici de Se verit y R ati n g Sc ale ( C-S S R S)
F or r oll o ver s u bjects, t he C -S S R S assess me nt ta ke n fr o m t he last visit of t he D S 5 5 6 5 - A-
E 3 0 9, D S 5 5 6 5- A- E 3 1 0, or D S 5 5 6 5 - A-E 3 1 1 st u d y  (i.e. E n d - of- Ta peri n g) will be use d as 
t he baseli ne assess me nt f or t his st u d y a n d he nce will n ot be re peate d b y t he s u b ject at 
Visit 4 ( Start -of- Treat me nt) .
F or all ot her cli nic visits ( n ot i ncl u di n g tele p h o ne visits), 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.
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 uici dal i deati o n a n d be ha vi or . 1 3  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 p arat or y 
be ha vi or; a n d n o ns 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 n t or di nal scale. 
9. 1 0. 2. 
P h ysici a n Wit h dr a w al C hec klist ( P W C)
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 P ost -treat me nt F oll o w- u p visit.  I n a d diti o n, t he P W C will be a d mi nistere d 
b y  tele p h o ne 3 da ys after t he s u bject’s last d ose of me dicati o n.  
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 4
t he P W C als o has bee n use d i n st u dies of pre ga bali n. 1 5 ,1 6 ,1 7  T he P W C rates 2 0 c o m m o n 
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 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 3
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 ntesti nal.   
Eac h of t he 2 0 i n di vi d ual ite ms o n t he P W C are 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 rate 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 ularl y  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 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 4
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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 5
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 nalys 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 e nr olle d a nal ys is 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 e nr olle d i nt o t he st u d y 

T he safet y a nal ys is 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.
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 a n d fi g ures a n d data listi n gs.  
Ra w data will be prese nte d wit h t he sa me precisi o n wit h w hic h t he y were c ollecte d.
F or s u m mar y  statistics, mea ns a n d me dia ns will be dis pla ye d t o o ne m ore deci mal place 
t ha n was deter mi ne d f or ra w data, dis persi o n statistics will ha ve t w o m ore deci mal 
places, a n d t he mi ni m u m a n d ma xi m u m will be dis pla y e d t o t he sa me n u m ber of deci mal 
places as t he ra w data.  
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, 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 perce nt, 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 
descri 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 e nr olle d a nal ys is set acc or di n g 
t o treat me nt assi g n me nt i n t he prece di n g st u d y (as a p plica ble).  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 d y  mass i n de x) f or all e nr olle 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 ( ge n der, race, et h nicit y , 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.
S u bject dis p ositi o n will be s u m marize d f or t he e nr olle d a nalys is set acc or di n g t o 
treat me nt assi g n me nt i n t he prece di n g st u d y (as a p plica ble).  T he n u m ber of s u bjects 
scree ne d, t he n u m ber e nr olle d , a n d t he n u m ber a n d perce nt of t h ose w h o c o m plete d t he 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a

Pr ot oc ol A me n d me nt D S 5 5 6 5 - A-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 6
o pe n -la bel e xte nsi o n peri o d or wit h dre w ( wit h t he latter s u m marize d b y reas o n f or 
wit h dra wal) will be s u m marize d .
C o nc o mita nt me dicati o ns will be s u m m arize d b y n u m ber a n d perce nt 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
F or A D P S , a bs ol ute val ues a n d c ha n ges fr o m baseli ne will be s u m marize d usi n g t he 
safet y a nal ysis set.
F or P GI C , 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” ( i.e. sc ore ≤ 2) will be 
s u m marize d usi n g t he safet y a nalys is set.  
F or t he H A D S, a bs ol ute val ues a n d c ha n ges fr o m baseli ne f or t he De pressi o n a n d 
A n xiet y  s u bscales will be s u m marize d usi n g t he safety a nal ysis set.
F or t he E Q-5 D, a bs ol ute val ues a n d c ha n ges fr o m baseli ne f or t he E Q-5 D si n gle 
s u m mar y i n de x ( base d o n t he 5 d o mai n q uesti o ns) a n d t he E Q V A S will be s u m marize d 
usi n g t he safet y a nal ys is set.
F or t he S F - 3 6, a bs ol ute val ues a n d c ha n ges fr o m baseli ne f or ei g ht d o mai ns (i.e. p h y sical 
f u ncti o ni n g, r ole-p h y sical, b o dil y pai n, ge neral healt h, vitalit y, s ocial f u ncti o ni n g, r ole-
e m oti o nal, a n d me ntal healt h ) as well as P C S a n d M C S sc ores will be s u m marize d usi n g 
t he safety a nal ys is set.  
1 1. 5. 
P h ar m ac o k i netic/ P h ar m ac o d y n a mic A n al yses
N ot a p plica ble .  
1 1. 6. 
S afet y A n al yses
T he safet y a nal ys is set will be use d f or all safet y a nal 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 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, t he C-S S R S e val uati o n, a n d t he P W C
e val uati o ns will be s u m marize d.   Prece di n g st u d y a n d e xte nsi o n st u d y data wi ll be 
s u m marize d se parately a n d als o ma y be c o m bi ne d.  
1 1. 6. 1. 
A d verse E ve nt A n al yses
A Es will be ta b ulate 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.  F or 
s u bjects w h o tra nsfer directl y i nt o t his st u d y fr o m a prece di n g st u d y ( D S 5 5 6 5- A-E 3 0 9 , 
D S 5 5 6 5 -A- E 3 1 0 , D S 5 5 6 5- A-E 3 1 1 ), a n A E t hat starte d i n t he prece di n g st u d y will n ot be 
c o nsi dere d treat me nt -e mer ge nt i n t his st u d y u nless t he A E w orse ns i n se verit y d uri n g t his 
st u d y.  T he fre q ue nc y  of s u bjects e x perie nci n g a s pecific T E A E will be ta b ulate d b y  
s yste m or ga n class, preferre d ter m, seri o us ness (see Secti o n 9. 3. 2 ), w orst se verit y (see 
Secti o n 9. 3. 3 ), a n d relati o ns hi p t o st u d y dr u g (see Secti o n 9. 3. 4 ).  A Es of s pecial i nterest 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 7
( defi ne d i n t he S A P ) will be s u m marize d se paratel y.  I n t he by -s u bject a nal ysis, 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 d i 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 E v al u ati o n 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.  S hift ta bles (i n cate g ories of l o w, n or mal, a n d hi g h, w he n 
a p pr o priate) will be pr o vi de d.  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
Vita l 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.
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  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 ar m 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 ns
Cli nicall y  si g nifica nt a b n or mal p h 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 y sical e xa mi nati o ns will be liste d a n d s u m marize d b y  visit.
1 1. 6. 6. 
C ol u m bi a -S uici de Se verit y R ati n g Sc ale ( C -S S R S)
C- S S R S data will be liste d a n d s u m marize d b y  visit.  
1 1. 6. 7. 
P h ysici a n Wit h dr a w al C hec klist ( P W C)
P W C data will be liste d a n d s u m marize d. 
1 1. 7. 
Ot her A n al yses
N o t a p plica ble.
1 1. 8. 
I nteri m A n al yses
T he s p o ns or e x pects t hat a p pr o xi matel y  5 0 0 s u bjects acr oss t he de vel o p me nt pr o gra m f or 
D S -5 5 6 5 will nee d t o be e x p ose d t o D S -5 5 6 5 f or at least 5 2 wee ks t o s u p p ort re gistrati o n.  
If t his o pe n-la bel e xte nsi o n st u d y ( D S 5 5 6 5- A-E 3 1 2) is still o n g oi n g w he n t he a b o ve 
c o n diti o n is met, t he s p o ns or i nte n ds t o ta ke a s na ps h ot of t he data base of t his o pe n -la bel 
e xte nsi o n st u d y t o s u p p ort re gistrati o n.  T he t otalit y of t he st u dy data f or D S - 5 5 6 5- A-
E 3 1 2 will be a nal yz e d at t he c o ncl usi o n o f 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 6 8
1 1. 9. 
D at a a n d 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 pr o vi di n g i n de pe n de nt rec o m me n dati o ns 
t o t he s p o ns or a b o ut e v ol vi n g ris k-be nefit o bser ve d i n t he c o urse of t he d o u ble -bli n d 
prece di n g st u dies a n d t his o pe n-la bel e xte nsi o n st u d y.  T he D S M B will re vie w safety 
data i n a n o n g oi n g ma n ner t o m o nit or a n d ass ure o verall safet y  of t he st u d y s u bjects.  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 ny e m er 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 nt 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 safety 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 t he IC F

S us pe n d t he st u d y  ( or a c o h ort) 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 priately ma na gi n g acti ve 
st u d y s u bjects

Ter mi nate t he st u d y ( or a c o h ort) 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 a 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 Cli nical Safet y a n d P har mac o vi gila nce) 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 n s 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 yo f or arc hi vi n g.
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 wo q ualifie d he pat ol o gists, w h o are n ot i n vesti gat ors 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.  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 la b orat or y re p orts.
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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C o n v ert t o P D F/ A- 1 a

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Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 6 9
1 1. 1 1. 
S a m ple Size Deter mi n ati o n
S u bjects w h o c o m plete t he d o u ble -bli n d st u dies are eli gi ble t o r oll o ver t o t his o pe n -la bel 
e xte nsi o n st u d y. Alt h o u g h it’s u n k n o w n h o w ma n y s u bjects will c o m plete t he d o u ble-
bli n d st u dies, t he n u m ber is a ntici pate d t o be bet wee n 2 1 0 0 a n d 2 5 0 0. I n a d diti o n s u bjects 
w h o di d n ot partici pate i n a prece di n g d o u ble -bli n d st u d y  (referre d t o as de n o v o 
s u bjects) m a y be e nr oll e d. O verall, t he g oal of t he o pe n -la bel e xte nsi o n st u dy is t o c ollect 
l o n g-ter m safety data o n a p pr o xi matel y 5 0 0 s u bjects e x p ose d t o D S -5 5 6 5 f or at least 5 2 
wee ks.  D uri n g t he c o n d uct of t he o pe n -la bel st u dy , s u bject wit h dra wal rates will be 
cl osel y m o nit ore d. E ntr y i nt o t he o pe n -la bel st u d y will be st o p pe d w he n t he s p o ns or 
a ntici pates t hat t he desire d n u m ber of s u bjects c o m pleti n g 5 2 wee ks ca n be ac hie ve 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 7 0
1 2. 
D A T A I N T E G RI T Y A N D Q U A LI T Y A S S U R A N C E
T he i n vesti gat or/i n vesti gati o nal site will per mit st u d y -relate d m o nit ori n g, a u dits, 
I RB/I E C re vie w, a n d re g ulat or y  i ns pecti ons 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 in vesti gat or f or t he p ur p ose of i ns pecti n g t he facilities a n d, 
u p o n re q uest, i ns pecti n g t he vari o us rec or ds of t he st u d y  (e. g. eC R Fs, 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  
acc or di n g t o t he cli nical m o nit ori n g pla n 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 dhere nce t o I C H G C P a n d 
l ocal re g ulati o ns o n t he c o n d uct of cli nical researc h.  T he m o nit or is res p o nsi ble f or 
i ns pecti n g t he eC R Fs a n d e ns uri n g c o m plete ness of t he st u d y  esse ntial d oc u me nts.  T he 
m o nit or s h o ul d ha ve access t o s u bject me dical 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 eC R Fs.
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 in vesti gat or a n d will e ns ure t hat a p pr o priate acti o n desi g ne d t o pre ve nt 
rec urre nce of t he detecte d de viati o ns is ta ke n a n d d oc u me nte d.
B y  si g ni n g t his pr ot oc ol, 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 t he 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) 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 assess me 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 but n ot e nr olle d, mi ni mal data will 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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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.
S u bjects will be pr o vi de d wit h a n electr o nic de vice t o ca pt ure t heir daily pai n i nte nsit y  
rati n g, slee p i nterfere nce sc ore. T he data fr o m t hese diaries will be i nte grate d i nt o t he 
e C R F. Q uesti o n naires will be a d mi nistere d via electr o nic de vices at eac h site visit, a n d 
data c ollecte d o n t hese de vices will be i nte grate d i nt o t he e C R F.
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 nically 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 SI D.
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 p licati 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.
S A Es i n t he cli nical data base will be rec o ncile d wit h t he safety data base.
All me dical hist or y  (e xce pt ter ms pre-s pecifie d o n t he e C R F) 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 g ate 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 e C R F will be i ncl u de d o n t he Si g nat ure L ist.
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 
e C R F data are o btai ne d.  T hese i ncl u de b ut are n ot li mite d t o h os pital rec or ds, cli nical 
a n d office c harts, la b orat or y a n d p har mac y rec or ds, diaries, micr ofic hes, X-ra ys, a n d 
c orres p o n de 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 7 2
T he i n vesti gat or a n d st u d y  staff are res p o nsi ble f or mai ntai ni n g a c o m pre he nsi ve a n d 
ce ntralize d fili n g s ys te m ( Trial Master File) of all st u d y-relate d (esse ntial) 
d oc u me ntati o n, s uita ble f or i ns pecti o n at a n y ti me b y  re prese ntati ves fr o m t he s p o ns or 
a n d/ or a p plica ble re g ulat or y a ut h orities.  Esse ntial d oc u me nts i ncl u de t he f oll o wi n g:

S u bject files c o ntai ni n g c o m pl ete d 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, I n vesti gat or 
Br oc h ure, c o pies of rele va nt esse ntial d oc u me nts re q uire d pri or t o 
c o m me nci n g a cli nical st u d y, a n d all c orres p o n de nce t o a n d fr o m t he I E C/I R B 
a n d t he S p o ns or.

Rec or ds relate d t o t he I n vesti gati o nal Pr o d uct(s), i ncl u di n g ac k n o wle d g me nt 
of recei pt at site, acc o u nta bilit y  rec or ds a n d fi nal rec o nciliati o n, a n d 
a p plica ble c orres p o n de nce.
I n a d diti o n, all ori gi nal s o urce d oc u me nts s u p p orti n g e ntries i n t he eC R Fs m ust be 
mai ntai ne d a n d be rea dil y  a vaila ble.
All esse ntial d oc u me ntati o n will be retai ne d b y t he i 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 n vesti gat or wis h t o assi g n t he st u d y rec or ds t o 
a n ot her part y or 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 n vesti gat ors 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, 
eC R Fs, i n ve nt or y  of st u d y pr o d uct, re g ulat or y d oc u me nts (e. g. pr ot oc ol a n d a me n d me nts, 
I RB/ E C c orres p o n de nce a n d a p pr o vals, a p pr o ve d a n d si g ne d I 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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Pa ge 7 3
1 3. 
FI N A N CI N G A N D I N S U R A N C E
1 3. 1. 
Fi n a nces
Pri or t o starti n g t he st u d y, t he Pri nci pal I n vesti gat or a n d/ or i nstit uti o n will si g n a cli nical 
st u d y a gree me nt wit h 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

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Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
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1 5. 
S T U D Y A D MI NI S T R A TI V E I N F O R M A TI O N
1 5. 1. 
Pr ot oc ol A me n d me nts
A n y  a me n d me nts t o t he st u d y pr ot oc ol t hat see m t o be a p pr o priate as t he st u d y 
pr o gresses wil l 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/ IE C, 
a n d w here rele va n t b y t he re g ulat or y a ut h orities, 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/IE C wit hi n fi ve w or ki n g da y s.  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 da te 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 6
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 -d e 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 H ut mac her M M, Fre nc h J L, Kris h nas wa mi S, Me n o n S. Esti mati n g tra nsf or mati o ns f or re peate d meas ures 
m o deli n g of c o nti n u o us b o u n de d o utc o me data. Statistics i n me dici ne. 2 0 1 1; 3 0( 9): 9 3 5 -4 9.
3 Fra m e B, Miller R, H ut mac her M M. J oi nt m o deli n g of dizzi ness, dr o wsi ness, a n d dr o p o ut ass ociate d wit h 
pre ga bali n a n d place b o treat me nt of ge neralize d a n xiet y dis or der. J o ur nal of p har mac o ki netics a n d 
p har mac o d y na mics. 2 0 0 9; 3 6( 6): 5 6 5 -8 4.
4 C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n. 
1 9 7 6; 1 6( 1): 3 1 -4 1.
5 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.
6 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.
7 Bjella n d I, Da hl A A, Ha u g T T, Nec kel ma n n D. T he vali dit y of t he H os pital A n xiet y a n d De pressi o n 
Scale: a n u p date d literat ure re vie w. J o ur nal of ps yc h os o matic researc h. 2 0 0 2; 5 2( 2): 6 9 -7 7.
8 O bra d o vic M, Lal A, Lie d ge ns H. Vali dit y a n d res p o nsi ve ness of E ur o Q ol -5 di m e nsi o n ( E Q-5 D) vers us 
S h ort F or m -6 di m e nsi o n ( S F -6 D) q uesti o n naire i n c hr o nic pai n. Healt h a n d q ualit y of life o utc o mes. 
2 0 1 3; 1 1: 1 1 0.
9 C uatrecasas G, Ale gre C, Fer na n dez -S ola J, G o nzalez MJ, Garcia -Fr uct u os o F, P oca -Dias V, et al. 
Gr o w t h h or m o ne treat me nt f or s ustai ne d pai n re d ucti o n a n d i m pr o ve me nt i n q ualit y of life i n se vere 
fi br o m yal gia. Pai n. 2 0 1 2; 1 5 3( 7): 1 3 8 2-9.
1 0 H off ma n D L, D u kes E M. T he healt h stat us b ur de n of pe o ple w it h fi br o m yal gia: a re vie w of st u dies t hat 
assesse d healt h stat us wit h t he S F -3 6 or t he S F -1 2. I nter nati o nal j o ur nal of cli nical practice. 
2 0 0 8; 6 2( 1): 1 1 5 - 2 6.
1 1 U. S. F o o d a n d Dr u g A d mi nistrati o n. I nf or mati o n f or Healt hcare Pr ofessi o nals: S uici dal Be ha vi or a n d 
I deati o n a n d A ntie pile ptic Dr u gs 2 0 0 8 [ u p date d A u g ust 1 5, 2 0 1 3; cite d 2 0 1 3 Dece m ber 3, 2 0 1 3]. A vaila ble 
fr o m: 
htt p:// w w w.f da. g o v/ Dr u gs/ Dr u g Saf et y/ P ost mar ket Dr u g Safet yI nf or mati o nf or Patie ntsa n d Pr o vi ders/ uc m 1 0 0
1 9 2. ht m .
1 2 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.
1 3 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 b ia-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 4 Ric kels K, Garcia -Es pa na F, Ma n d os 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 5 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 6 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 or 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 7 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 7
1 7. 
A P P E N DI C E 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

1 7. 1. 
A mi n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
Disc o nti n u ati o n
Fi g ure 1 7 . 1: A m i n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
Disc o nti n u ati o n
a 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
ras h, a n d/ or e osi n o p hilia
b E val uati o ns f or p ote ntial viral eti ol o gies will i ncl u de: He p A A b b y I g M ac ute, H Bs A g, H Be A g, a nti
H Bc, He p C A b, He p C R N A b y P C R, He p E I g G A b, He p E I g M A b, E B V I g G A b, E B V I g M A b, a n d 
C M V D N A b y P C R
A b bre viati o ns: 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; C M V = c yt o me gal o vir us, E B V = E pstei n
gl uta m yltra nsferase, L D H = lactate de h y dr o ge nase, L F T = li ver f u ncti o n test, P T = p
U L N = u p per li mit of n or mal
Pr ot oc ol A me n d me nt D S 5 5 6 5
Versi o n 4 U K 1 , 
Pr o prietar y  a n d C o nfi de ntial
Pa ge 7 8
A mi n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
Disc o nti n u ati o n
A m i n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
Disc o nti n u ati o n
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, 
E val uati o ns f or p ote ntial viral eti ol o gies will i ncl u de: He p A A b b y I g M ac ute, H Bs A g, H Be A g, a nti
H Bc, He p C A b, He p C R N A b y P C R, He p E I g G A b, He p E I g M A b, E B V I g G A b, E B V I g M A b, a n d 
A b bre viati o ns: 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; C M V = c yt o me gal o vir us, E B V = E pstei n-Barr vir us, G G T = ga m ma -
gl uta m yltra nsferase, L D H = lactate de h y dr o ge nase, L F T = li ver f u ncti o n test, P T = p r ot hr o m bi n ti me, 
D S 5 5 6 5 - A-E 3 1 2
, 1 4 Mar
2 0 1 7
A mi n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
A m i n otr a nsfer ase Ele v ati o ns: M o nit ori n g a n d Tre at me nt 
pai n or te n der ness, fe ver, 
E val uati o ns f or p ote ntial viral eti ol o gies will i ncl u de: He p A A b b y I g M ac ute, H Bs A g, H Be A g, a nti -
H Bc, He p C A b, He p C R N A b y P C R, He p E I g G A b, He p E I g M A b, E B V I g G A b, E B V I g M A b, a n d 
A b bre viati o ns: 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 
r ot hr o m bi n ti me, 
All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D 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-E 3 1 2
Versi o n 4 U K 1 , 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. 2. 
C oc k cr oft-G a ult E q u ati o n
T he esti mate d Cr Cl rate ( m L / mi n) will be calc ulate d usi n g t he C oc kcr oft-Ga ult e q uati o n 
base d o n act ual wei g ht i n kil o gra ms ( 1 kil o gra m = 2. 2 p o u n ds):
C o n ve nti o n al – ser u m cre ati ni ne i n m g/ d L:
Male:
Cr Cl ( m L / mi n) = 
7 2
 x 
m g/ d L)
(i n 
creati ni ne
ser u m
k g)
(i n 
 x wei g ht 
ye ars)]
(i n 
a ge
-
[ 1 4 0
Fe male:
Cr Cl ( m L / mi n) = 
7 2
 x 
m g/ d L)
(i n 
creati ni ne
ser u m
k g)
(i n 
 x wei g ht 
ye ars)]
(i n 
a ge
-
[ 1 4 0
0. 8 5
I nter n ati o n al S yste m of U nits ( SI) – ser u m cre ati ni ne i n μ m ol/ L:
Male:
Cr Cl ( m L / mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
m ol/ L )
(i n 
creati ni ne
ser u m
k g)
(i n 
 x wei g ht 
ye ars)]
(i n 
a ge
-
[ 1 4 0

Fe male:
Cr Cl ( m L / mi n) = 
0. 0 1 1 3
 x 
7 2
 x 
m ol/ L )
(i n 
creati ni ne
ser u m
k g)
(i n 
 x wei g ht 
ye ars)]
(i n 
a ge
-
[ 1 4 0

0. 8 5
S o urce: C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m ser u m creati ni ne. Ne p hr o n 
1 9 7 6; 1 6: 3 1 -4 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 0
1 7. 3. 
Sc he d ule of E ve nts
T a ble 1 7. 1: 
Sc he d ule of E ve nts
St u d y Peri o d
Scree ni n g/ B aseli ne 
( De N o v o O nl y)
St art 
of T x
o n -Tre at m e nt
E n d of 
T x/ Et
F oll o w -U p a
Visit 
1  
2  
3  
4  
5  
6- 1 1  
1 2  
1 3 -2 0 
2 1  
2 2  
2 3  
2 4
Tele p h o ne C o nt act 
-- 
X 
--  
--  
--  
--  
--  
--
-- 
X
X
Wee k
- 3  
- 2  
- 1  
0  
1 
3, 5, 7, 
9, 1 1, 1 3
1 6 
2 0, 2 4, 2 8, 
3 2, 3 6, 4 0, 
4 4, 4 8
5 2 
5 2. 5 
5 4   
5 6
Visit Wi n d o w ( D a ys) 
--  
--  
--  
-- 
± 3  
± 3  
± 3  
± 7
± 7  
± 1  
± 3  
± 7
I nf or me d c o nse nt   
D N
X b
I ncl usi o n/e xcl usi o n  
D N
X
De m o gra p hic 
i nf or mati o n
D N
X b
Me dical/s ur gical hist or y
D N
X b
A d verse e ve nt re p orti n g 
D N   
D N
X c
X   
X   
X   
X
X   
X   
X   
X
Was h o ut i nstr ucti o ns
D N
C o nc o mita nt 
me dicati o ns
D N   
D N   
D N 
X c
X   
X   
X   
X
X   
X   
X   
X
Vital si g ns
D N
X d
X   
X   
X   
X
X
X
Hei g ht
D N
X b
Wei g ht
D N
X d
X   
X   
X   
X
X
X
P h y sical e xa mi nati o ne
D N
X   
X   
X   
X   
X
X
F u n d osc o p y e
D N
D N ( V. 1 4) 
D N
C- S S R S
D N
X d
X   
X   
X   
X
X
X
W PI/ S S S
D 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 1
St u d y Peri o d
Scree ni n g/ B aseli ne 
( De N o v o O nl y)
St art 
of T x
o n -Tre at m e nt
E n d of 
T x/ Et
F oll o w -U p a
Visit 
1  
2  
3  
4  
5  
6- 1 1  
1 2  
1 3 -2 0 
2 1  
2 2  
2 3  
2 4
Tele p h o ne C o nt act 
-- 
X 
--  
--  
--  
--  
--  
--
-- 
X
X
Wee k
- 3  
- 2  
- 1  
0  
1 
3, 5, 7, 
9, 1 1, 1 3
1 6 
2 0, 2 4, 2 8, 
3 2, 3 6, 4 0, 
4 4, 4 8
5 2 
5 2. 5 
5 4   
5 6
Visit Wi n d o w ( D a ys) 
--  
--  
--  
-- 
± 3  
± 3  
± 3  
± 7
± 7  
± 1  
± 3  
± 7
M.I. N.I
D N
1 2 -lea d 
electr ocar di o gra m
D N
X
X
Cli nical la b orat or y tests 
D N
X d
X   
X   
X   
X
X
Pre g na nc y test f
D N
X d
X   
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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 2
T a ble 1 7. 1: 
Sc he d ule of E ve nts ( C o nti n ue d)
St u d y Peri o d
Scree ni n g/ B aseli ne 
( De N o v o O nl y)
St art 
of T x
o n -Tre at m e nt
E n d of 
T x/ Et
F oll o w -U p a
Visit 
1  
2  
3  
4  
5  
6- 1 1  
1 2  
1 3 -2 0 
2 1  
2 2  
2 3  
2 4
Tele p h o ne C o nt act 
-- 
X 
--  
--  
--  
--  
--  
--
-- 
X
X
Wee k
- 3  
- 2  
- 1  
0  
1 
3, 5, 7, 
9, 1 1, 1 3
1 6 
2 0, 2 4, 2 8, 
3 2, 3 6, 4 0, 
4 4, 4 8
5 2 
5 2. 5 
5 4   
5 6
Visit Wi n d o w ( D a ys) 
--  
--  
--  
-- 
± 3  
± 3  
± 3  
± 7
± 7  
± 1  
± 3  
± 7
P W C 
X   
X
St u d y dr u g c o m plia nce
X   
X   
X   
X
X
C o ntact I X R S
D N
X   
X   
X   
X   
X
X
St u d y dr u g dis pe nsi n g g
X   
X   
X   
X   
X h
P GI C
X
H A D S
X
X
E Q -5 D  a n d S F -3 6 
X
X
Pr o vi de dail y diar y
D N
Re vie w/c ollect dail y 
diar y
X i
X i
X i
X i
Pai n i nte nsit y rati n g
X i
X i
X i
X i
Slee p i nterfere nce sc ore
X i
X i
X i
X i
D N de n otes visits a n d assess me nts f or de n o v o s u bjects o nl y.
a: T he f oll o w -u p peri o d w ill c o m prise a tele p h o ne c o ntact 3 da ys after t he last d ose, a cli nic visit at 2 wee ks after t he last d ose ( Wee k 54 if t he s u bject 
c o m pletes   treat me nt), a n d a tele p h o ne c o ntact at 4 wee ks after t he s u bject’s last d ose of st u d y treatme nt ( Wee k 5 6 if t he s u bject c o m pletes treat me nt).
b: F or r oll o ver s u bjects, i nf or me d c o nse nt will be o btai ne d bef ore t he start of t he E n d -of -Ta peri n g visit i n t he prece di n g st u d y a n d de m o gra p h y, hei g ht, 
a n d me dical hist or y will be use d fr o m t he prece di n g st u d y a n d will n ot be re peate d.  F or de n o v o s u bjects, t hese assess me nts are n ot a p plica ble at Visit 
4.
c: F or r oll o ver s u bjects, a n y o n g oi n g a d verse e ve nts a n d c o nc o mita nt me dicati o ns s h o ul d be rec or de d fr o m t he prece di n g st u d y
d: F or r oll o ver s u bjects, v al ues f or vital si g ns, wei g ht, C -S S R S, cli nical safet y la b orat or y tests, a n d pre g na nc y test will be ta ke n fr o m t he E n d -of -
Ta peri n g visit of t he prece di n g st u d y a n d he nce will n ot be re peate 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-E 3 1 2
Versi o n 4 U K 1 , 1 4 Mar
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
Pa ge 8 3
e: A f ull p h ysical e xa mi nati o n will be perf or me d at Visit 1 (f or de n o v o s u bjects) or Visit 4 (f or r oll o ver s u bjects) a n d at Visit 2 1 (f or all s u bjects).  A n 
a b bre viate d p h ysical e xa mi nati o n will be perf or me d at Visits 5 t o 2 0. Refer t o Secti o n  9. 9. 2 f or details. F u n d osc o p y (f or de n o v o s u bjects) will be 
perf or me d at Visit 1 ( wit h p u pil dilati o n) or a sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n, Visit 1 4 ( w it h o ut p u pil dilati o n) or a sca n ni n g laser 
o p ht hal m osc o p y e x a mi nati o n, a n d Visit 2 1 ( wit h p u pil dilati o n) or a sca n ni n g laser o p ht hal m osc o p y e xa mi nati o n.  
f: A ser u m pre g na nc y test will als o be perf or me d f or all w o m e n at all cli nic visits (e xce pt as n ote d i n f o ot n ote d) t hr o u g h t he E n d -of -Treat m e nt/ Earl y 
Ter m i natio n visit.  A uri ne pre g na nc y test will be perf or me d f or all W O C B P at t he F oll o w -u p cli nic visit.
g: S u bjects recei vi n g 1 5 m g Q D w ill be dis pe nse d a 1-m o nt h s u p pl y ( 1 car d).  S u bjects recei vi n g 1 5 m g BI D ca n be dis pe nse d e ver y 2 wee ks ( 1 car d) or 
m o nt hl y ( 2 car ds).  
h: At Visit 2 0 ( Wee k 4 8), s u bjects s h o ul d be i nstr ucte d t o ta ke all st u d y me dicati o n, as sc he d ule d, u p u ntil t he da y of t heir E n d-of -Treat me nt visit ( Visit 
2 1, Wee k 5 2), b ut n ot o n t he m or ni n g of Visit 2 1 (i.e. s u bjects s h o ul d c o m plete d osi n g o n t he e ve ni n g pri or t o t heir E n d -of -Treat m e nt visit).
i: F or r oll o ver s u bjects, pai n a n d slee p i nterf ere nce sc ores fr o m t he E n d -of -Ta peri n g visit i n t he prece di n g st u d y will be use d as t he baseli ne val ues f or 
t his st u d y.  I n t his st u d y, t he pai n a n d slee p i nterfere nce sc ores will be rec or de d d uri n g t he 7 da ys pri or t o Visit 1 1 ( Wee k 1 3), Visit 1 4 ( Wee k 2 4 ), 
Visit 1 7 ( Wee k 3 6), Visit 2 0 ( Wee k 4 8), a n d Visit 2 1 ( Wee k 5 2).  F or de n o v o s u bjects o nl y, pai n diar y sc ores will be rec or de d d uri n g t he 7 da ys pri or 
t o Visit 4 ( Start-of -Treat m e nt).  D uri n g t he 7 da ys pri or t o t hese visits, e ver y da y u p o n a wa ke ni n g, p ri or t o ta ki n g st u d y me dicati o n, t he s u bject s h o ul d 
i n dicate t he n u m ber t hat best descri bes his or her w orst pai n o ver t he pre vi o us 2 4 h o urs a n d c o m plete t he slee p i nterfere nce q uesti 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, D N = de n o v o, E T = earl y ter mi nati o n, I X R S = i nteracti ve v oice/ we b res p o nse 
s yste m, P GI C = Patie nt Gl o bal I m pressi o n of C ha n ge, P W C = P h ysicia n Wit h dra wal C hec klist, H A D S = H os pital A n xiet y a n d De pressi o n Scale, E Q-
5 D = E ur o Q o L I nstr u me nt 5 D o mai ns, S F -3 6 = S h ort F or m 3 6, 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, S S S = S y m pt o m Se verit y 
Scale, W PI = Wi des prea d 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