Conditions: Pain Associated With Fibromyalgia
Keywords: pain fibromyalgia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2485
Healthy volunteers: no

Brief summary:
This is an open-label study of DS-5565 in subjects who either completed participation in a preceding Phase 3 study of DS-5565 in fibromyalgia (FM); i.e. DS5565-A-E309 (NCT02146430), DS5565-A-E310 (NCT02187471), or DS5565-A-E311 (NCT02187159) or are de novo subjects. Eligible subjects will be assigned to receive open-label DS-5565 for 52 weeks. All subjects will receive DS-5565 15 mg once daily (QD) for the first three weeks of the treatment period. After three weeks, subjects may be titrated to 15 mg twice daily (BID) based on protocol-specified criteria.

Detailed description:

Arms:
arm 1: Participants receive 15 mg DS-5565 administered once or twice daily. Each participant's dose can be titrated up or down based on the investigator's decision. Analysis will be based on the dose modality at the time of data collection.

Interventions: intervention 1: DS-5565
Intervention descriptions: intervention 1: DS-5565 15 mg tablet for oral administration

Protocol document:
Prot_SAP_000.pdf: 
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.
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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
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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
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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
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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
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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
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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
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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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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
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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
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
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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
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
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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
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
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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
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
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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
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
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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
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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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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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Versi o n 4 U K 1 , 1 4 Mar
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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
2 0 1 7
Pr o prietar y  a n d C o nfi de ntial
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
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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Pr ot oc ol 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 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
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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
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
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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
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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
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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
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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
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Versi o n 4 U K 1 , 1 4 Mar
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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
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Versi o n 4 U K 1 , 1 4 Mar
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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
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
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All pr o bl e ms acc or di n g t o Pr efli g ht pr ofil e
C o n v ert t o P D F/ A- 1 a
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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
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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
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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