Conditions: Fibromyalgia
Keywords: chronic kidney disease . α2δ ligands mirogabalin pain relief kidney metabolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
DS-5565 (mirogabalin) is being studied as treatment for fibromyalgia (FM) pain. Because it is excreted through the kidneys, people who have reduced kidney function will not process the drug as well as with those with normal kidney function, so the dose must be reduced. This study will test two reduced dose levels for both moderately reduced and severely reduced kidney function. The study will test the hypothesis that the drug will be safe and well-tolerated in people who have both fibromyalgia and chronic kidney disease.

Detailed description:
The main objective of the trial is to determine the safety and tolerability of subjects with FM and moderate to severe renal dysfunction during 13 weeks of renally-adjusted dosing of DS-5565 compared to placebo, followed by a short-term (4-week) safety follow-up.

This trial is conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation (ICH) Harmonised Tripartite Guidelines. An independent Data Safety Monitoring Board (DSMB) is created to further protect the rights, safety, and well-being of subjects who participate in this study by monitoring their progress and results. The independent DSMB is composed of qualified scientists who are not investigators in the study and not otherwise directly associated with the sponsor.

Additional protection is provided by special monitoring of liver enzyme elevations and liver dysfunction performed by a Hepatic Adjudication Committee (HAC), comprised of three qualified hepatologists who are not investigators in the study and not otherwise directly associated with the sponsor. The HAC completes assessments on an ongoing basis. Adjudication of hepatic events is based on evaluation of electronic case report forms (eCRFs) and source documents, as available, including but not limited to hospital discharge summaries, diagnostic imaging, histopathology, consultation, and laboratory reports.

Arms:
arm 1: Patients with moderate chronic kidney disease (M-CKD) randomized to receive DS-5565 BID during the treatment period. arm 2: Fibromyalgia patients with severe chronic kidney disease (S-CKD) randomized to receive a DS-5565 7.5 mg tablet once per day (QD), and a placebo tablet (no drug) QD, for a total of 7.5 mg DS-5565 arm 3: Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period. arm 4: Patients with S-CKD randomized to receive placebo once daily (QD) during the treatment period.

Interventions: intervention 1: DS-5565 intervention 2: Placebo
Intervention descriptions: intervention 1: DS-5565 7.5 mg tablet for oral use intervention 2: Placebo tablet for oral use to match DS-5565 7.5 mg tablet

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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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


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