A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
Phase: PHASE3
Conditions: Chronic Kidney Disease, Autosomal Dominant Polycystic Kidney Disease
Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Pr ot oc ol: 1 5 6 -1 3 -2 1 0  
Co nfi d e ntial - Pr o priet ar y I nf or mati o n  
• Prot o c ol n u m ber : 1 5 6- 1 3- 2 1 0 
• D o c u me nt title:  A P hase 3 b, M ulti -ce nter, Ra n d o mize d - wit h dra wal, 
Place b o -c o ntr olle d, D o u ble - blin d, P arallel -gr o u p Trial t o C o m pare t he 
Efficac y a n d Safet y of T olva pta n ( 4 5 t o 1 2 0 m g/ da y, S plit -d ose) in S u bjects 
wit h C hr o nic Kid ne y Disease Bet wee n Late Sta ge 2 t o Early Sta ge 4 D ue t o 
Aut os o mal D o mina nt P olyc ystic Kid ne y Disease  
• Versi o n n u m ber : A me n d me nt 3  
• D ate of t h e d o c u me nt : 2 6 Marc h 2 0 1 5  
• N C T n u m ber : N C T 0 2 1 6 0 14 5 

Ots u ka P har mace utical
De vel o p me nt & C o m mercializati o n, I nc.
I n vesti gati o nal Me dici nal Pr o d uct
T ol va pta n ( O P C - 4 1 0 6 1)
R E VI S E D C LI NI C A L P R O T O C O L
A P hase 3 b, M ulti- ce nter, Ra n d o mize d -wit h dra wal, Place b o -c o ntr olle d, D o u ble -bli n d, 
Parallel -gr o u p Trial t o C o m pare t he Efficac y  a n d Safet y of T ol va pta n (4 5 t o 1 2 0 m g/ da y , 
S plit -d ose) i n S u bjects wit h C hr o nic Ki d ne y  Disease B et wee n Late Sta ge 2 t o Earl y 
Sta ge 4 D ue t o A ut os o mal D o mi na nt P ol y c ystic Ki d ne y Disease
Pr ot oc ol N o. 1 5 6- 1 3- 2 1 0
I ND N o. 7 2, 9 7 5 E u dra C T N o. 2 0 1 4- 0 0 0 2 2 6- 3 8
C O N FI D E N TI A L – P R O P RI E T A R Y I N F O R M A TI O N
Cli nical De vel o p me nt P hase:
3 b
S p o ns or:
Ots u ka P har mace utical De vel o p me nt &
C o m mercializati o n, I nc.
2 4 4 0 Researc h B o ule var d
R oc k ville, Mar y la n d 2 0 8 5 0 , U S A
S p o ns or Re prese ntati v es:
P h o ne :  
Fa x:  
E -mail: 
P h o ne:  
Fa x:  
E- mail: 
P h o ne:  
Fa x:  
E- mail: 
I m me diatel y Re p orta ble E ve nt  
Cli nical Safet y a n d P har mac o vi gila n ce
P h o ne:  
; Fa x:  
Iss ue Date:
1 2 Fe b r uar y 2 0 1 4
Date of A d mi nistrati ve C ha n ge 1:
2 1 Fe br uar y  2 0 1 4
Date of A me n d me nt 1 :
3 1 Marc h 2 0 1 4
Date of A d mi nistrati ve C ha n ge 2: 
2 5 J u ne 2 0 1 4

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2
2 6 Mar 2 0 1 5 
Date of A me n d me nt 2:
2 6 N o ve m ber 2 0 1 4
Date of A me n d me nt 3:
2 6 Marc h 2 0 1 5

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
3
2 6 Mar 2 0 1 5 
Pr ot o c ol S y n o p si s 
Na me of S p o ns or:  Ots u ka P har mace utical 
De vel o p me nt & C o m mercializati o n, I nc.
Na me of I n vesti gati o nal Me dici nal Pr o d uct:  
T ol va pta n ( O P C - 4 1 0 6 1)
Pr ot oc ol # 1 5 6- 1 3- 2 1 0
I ND # 7 2, 9 7 5
E u dra C T #  2 0 1 4- 0 0 0 2 2 6- 3 8
Pr ot oc ol Title:
A P hase 3 b, M ulti -ce nter, Ra n d o mize d -wit h dra wal, Place b o -
c o ntr olle d, D o u ble-bli n d, Parallel -gr o u p Trial t o C o m pare t he 
Efficac y  a n d Safety of T ol va pta n ( 4 5 t o 1 2 0 m g/ da y, 
S plit -d ose) i n S u bjects wit h C hr o nic Ki d ne y Disease Bet wee n 
Late Sta ge 2 t o Earl y Sta ge 4 D ue t o A ut os o mal D o mi na nt 
P ol y c ystic Ki d ne y Disease
Cli nical P hase/ Trial 
T y pe:
P hase 3 b/ T hera pe utic use
Treat me nt I n dicati o n: 
A ut os o mal D o mi na nt P ol yc ystic Ki d ne y  Disease ( A D P K D)
O bjecti ve(s):
Pri mar y : T o c o m pare t he efficac y  of t ol va pta n treat me nt i n 
re d uci n g t he c ha n ge i n esti mate d gl o mer ular filtrati o n rate 
(e G F R ) fr o m pre-treat me nt baseli ne t o p ost-treat me nt 
f oll o w-u p, as c o m pare d wit h place b o, i n s u bjects wit h late -
sta ge c hr o nic ki d ne y disease (C K D ) d ue t o A D P K D w h o 
t olerate t ol va pta n d uri n g a n i nitial r u n-i n peri o d.
Sec o n dar y :  T o c o m pare t he efficac y  of t ol va pta n treat me nt i n 
re d uci n g t he decli ne of a n n ualize d e G F R sl o pe, as c o m pare d 
wit h place b o, i n s u bjects wit h late -sta ge C K D d ue t o A D P K D
w h o t olerate t ol va pta n d uri n g a n i nitial r u n -i n peri o d.
T o c o m pare o verall a n d he patic safet y of t ol va pta n wit h
place b o a n d t o c o m pare i nci de nce of A D P K D c o m plicati o ns 
( o utc o mes) d uri n g t he trial.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
4
2 6 Mar 2 0 1 5 
Trial Desi g n:
M ulti -ce nter, ra n d o mize d -wit h dra wal, place b o -c o ntr olle d, 
d o u ble -bli n d, parallel -gr o u p trial:
Scree ni n g peri o d ( 1- 2 wee k s):  Scree ni n g peri o d ma y  be 
e xte n de d u p t o a n a d diti o nal 8 wee ks f or s u bjects w h o re q uire 
m o dificati o n of me dical ca re s pecificall y f or t his trial.  T his 
ma y  i ncl u de, f or exa m ple, sta bilizi n g a nti -h y perte nsi ve 
re gi me ns f or s u bjects disc o nti n ui n g di uretics or “ was h-o ut” of 
ot her i n vesti gati o nal a ge nts. Preli mi nar y  eli gi bilit y f or t he 
trial will be i nitiall y assesse d usi n g t he s u bjects’ hist orical 
la b orat or y or i ma gi n g data. Eli gi bilit y  will be c o nfir me d b y 
t he mea n of e G F R calc ulate d fr o m t he s u bjects’ 2 pre-
treat me nt, ce ntral-la b ser u m creati ni ne assess me nts (c ollecte d 
at least 2 4 h o urs a part). T he fi nal scree ni n g visit o n Da y  - 4 3 
will n ot be sc he d ule d u ntil la b orat or y  res ults fr o m t he sec o n d 
scree ni n g visit ( V 2) are recei ve d a n d e val uate d.  T he e G F R 
val ues will be esti mate d base d o n t he C hr o nic Ki d ne y  Disease-
E pi de mi ol o g y  ( C K D-E PI) f or m ula (e G F RC K D- E PI , hereafter
referre d t o as e G F R). C o nfir mati o n of A D P K D dia g n osis 
( usi n g t he m o difie d Pei-Ra vi ne criteria) ma y  re q uire 
c o nfir mat or y i ma gi n g.
Place b o r u n -i n peri o d ( 1 wee k):  Su bjects will be gi ve n 
place b o (as a si n gle-bli n d “s ha m” 1 5/ 1 5 m g d ose) in a dail y  
s plit d ose of a si n gle 0 m g ta blet u p o n a wa ke ni n g a n d a n ot her 
0 m g ta blet a p pr o xi matel y  8 t o 9 h o urs later (a b bre viate d 0/ 0 
m g), i n a f or m i de ntical t o t ol va pta n ta blets.  B l o o d will be 
dra w n o nce o n t he last da y of t he r u n-i n peri o d ( Da y - 3 6) f or 
efficac y a n d safety meas ures .  S u bjects u na ble t o t olerate t he 
place b o d ose re gi me n will be c o nsi dere d “ R u n -i n fail ures”,
will c o m plete a n e n d of treat me nt ( E o T x) visit a n d be f oll o we d 
u p after 7 da y s b y p h o ne call t o assess a ny o n g oi n g a d verse 
e ve nts (A Es ).
T ol va pta n titrati o n peri o d ( 2 wee ks):  S u bjects will be gi ve n a 
s plit d ose of 3 0/ 1 5 m g t ol va pta n (si n gle-bli n d) wit h u p war d 
titrati o n e ver y 3 t o 4 da ys t o 4 5/ 1 5 m g, 6 0/ 3 0 m g, u p t o a 
ma xi m u m d ose of 9 0/ 3 0 m g per da y  o ver 2 wee ks.  S u bjects 
w h o are u na ble t o t olerate at least 6 0/ 3 0 m g of dail y  t ol va pta n 
will be c o nsi dere d “ R u n-i n fail ures” a n d will co m plete a n 
E o T x visit a n d be f oll o we d u p after 7 d a ys b y p h o ne call t o 
assess a n y o n g oi n g A Es .  S u bjects will ha ve bl o o d dra w n o n 
t he last da y of t his peri o d f or efficac y a n d safety meas ures.
Trial Desi g n, c o nt.:
T ol va pta n r u n -i n peri o d ( 3 wee ks):  S u bjects w h o t olerate t he 
t ol va pta n 6 0/ 3 0 m g or 9 0/ 3 0 m g daily d ose re gi me n will e nter 
t he t ol va pta n r u n-i n peri o d (si n gle-bli n d) at t he t olerate d d ose 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
5
2 6 Mar 2 0 1 5 
f or 3 a d diti o nal wee ks.  E xce pt f or ma na ge me nt of A Es, n o 
d ose a dj ust me nt will be per mitte d.  S u bject s u na ble t o t olerate 
at least 3 wee ks of dail y t ol va pta n treat me nt at 6 0/ 3 0 m g or 
hi g her will be c o nsi dere d “ R u n -i n fail ures” a n d will c o m plete 
a n E o T x visit a n d be f oll o we d u p after 7 d a y s b y p ho ne call t o 
assess a n y o n g oi n g A Es .  D uri n g t he last 2 wee ks of t his 
peri o d, bl o o d will be dra w n 2 ti mes o n se parate da ys (at least 
2 4 h o urs a part) , i ncl u di n g t he last da y of t he r u n-i n peri o d, f or 
efficac y a n d safety meas ures.
D o u ble- bli n d, r a n d o mize d treat me nt peri o d ( 1 2 m o nt hs) :  O nl y  
s u bjects w h o reac h t he e n d of t he t ol va pta n r u n -i n peri o d a n d 
are able t o t olerate t ol va pta n 6 0/ 3 0 m g or 9 0/ 3 0 m g dail y “f or 
t he rest of t heir li ves” are eli gi ble t o e nter t his peri o d.   
Ra n d o mizati o n will be 1: 1, t ol va pta n t o place b o.   Su bjects will 
be stratifie d b y t heir baseli ne eG F R , at a t hres h ol d of 
 
, a n d b y a ge (5 5 or > 5 5 y ears ol d).  
S u bjects will als o be stratifie d b y  t hree t otal ki d ne y v ol u me 
( T K V) criteria 
.  
P ost -ra n d o mizati o n, t he ma xi mall y-t olerate d d ose of t ol va pta n 
esta blis he d d uri n g t he r u n- i n peri o d, or t he e q ui vale nt as 
matc hi n g place b o ta blets, will be dis pe nse d acc or di n g t o t he 
s u bject’s ra n d o mizati o n o utc o me.  If c o nti n ue d t olera bilit y 
bec o mes a n iss ue, s u bjects ma y  titrate d o w n war d t o 4 5/ 1 5 m g 
(or 3 0/ 1 5 m g , wit h me dical m o nit or a p pr o val) or te m p orarily 
i nterr u pt treat me nt as nee de d.  Ret ur n t o hi g her d oses is als o 
all o we d.  S u bjects w h o disc o nti n ue I M P bef ore t he M o nt h 1 2 
visit will c o m plete a n E o T x visit, w hic h s h o ul d be sc he d ule d 
as s o o n as p ossi ble after t he s u bject’s last d ose of 
i n vesti gati o nal me dici nal pr o d uct (I M P) a n d c o m plete t he 
f oll o w-u p peri o d .
F oll o w -u p peri o d ( 3 wee ks):   F or all ra n d o mize d s u bjects t he 
f oll o w-u p peri o d starts i m me diatel y after t he last d ose of I M P.  
N o f oll o w - u p assess me nts will be ta ke n d uri n g t he first wee k 
of t his peri o d . D uri n g t he last 2 wee ks, Da y s 8 t hr o u g h 2 1, 
i ncl usi ve, 3 f oll o w- u p visits will be sc he d ule d. T he last 
f oll o w- u p visit will i ncl u de meas ure me nts of efficac y  a n d 
safety.  S u bjects will ha ve bl o o d dra w n at eac h visit .  

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
6
2 6 Mar 2 0 1 5 
S u bject P o p ulati o n:
T his trial will ra n d o mize a p pr o xi matel y  1 3 0 0 t ol va pta n naï ve 
s u bjects wit h A D P K D.  Male a n d fe male a d ults will be 
e nr olle d, fr o m 1 8- 5 5 ye ars of a ge wit h e G F R bet wee n 2 5 a n d 
6 5 m L / mi n/ 1. 7 3 m2 or 5 6 t o < 6 6 y ears of a ge wit h e G F R 
bet wee n 2 5 a n d 4 4 m L / mi n/ 1. 7 3 m2 ( wit h e vi de nce of A D P K D 
pr o gressi o n a n d me dical m o nit or a p pr o val).
O nl y s u bjects 
t olerati n g a si n gle-bli n d r u n -i n peri o d of t ol va pta n ( 6 0/ 3 0 m g 
per da y  or 9 0/3 0 m g  per da y) will be ra n d o mize d, t o li mit 
s u bse q ue nt wit h dra wal d ue t o lac k of t olera bilit y.
I ncl usi o n/ E xcl usi o n 
Criteria:
Mai n i ncl usi o n criteria:

e G F R bet wee n 2 5 a n d 6 5 m L/ mi n/ 1. 7 3 m2 ( 1 8 t o 5 5 ye ars
of a ge ) or e G F R bet wee n 2 5 a n d 4 4 m L / mi n/ 1. 7 3 m2 ( 5 6 t o 
< 6 6 ye ars of a ge w it h e vi de nce of A D P K D pr o gressi o n, 
ie, e G F R decli ne of > 2. 0 m L/ mi n/ 1. 7 3 m 2 per ye ar
b ase d o n hist oric al e G F R d at a a n d me dic al m o nit or 
discreti o n .

T ol va pta n naï ve .

Dia g n osis of A D P K D b y m o difie d Pei - Ra vi ne criteria

Wit h fa mil y  hist or y: se veral c ysts per ki d ne y ( 3 if b y 
s o n o gra p hy, 5 if b y c o m p ute d t o m o gra p h y or ma g netic 
res o na nce i ma gi n g).

Wit h o ut fa mil y  hist or y: 1 0 c ysts per ki d ne y ( by a n y 
ra di ol o gic met h o d a b o ve ) a n d e xcl usi o n of ot her c ystic 
ki d ne y diseas es. C o n diti o ns t o be e xcl u de d i ncl u de: 
m ulti ple si m ple re nal c ysts, re nal t u b ular aci d osis, 
c ystic d ys plasia of t he ki d ne y, m ultic ystic ki d ne y, 
m ultil oc ular c y sts of t he ki d ne y, me d ullar y c ystic 
ki d ne y  a n d ac q uire d c ystic disease of t he ki d ne y.

Dis tri b uti o n a n d n u m ber of c ysts c o nsiste nt wit h t he 
o bser ve d le vel of re nal f u ncti o n deficit.
Mai n e xcl usi o n criteria:

Nee d f or c hr o nic di uretic use.

He patic i m pair me nt or li ver f u ncti o n a b n or malities ot her 
t ha n t hat e x pecte d f or A D P K D wit h t ypical c ystic li ver 
disease d uri n g t he pre -ra n d o mizati o n peri o d.

S u bjects wit h a d va nce d dia betes (e g, gl yc os y late d 
he m o gl o bi n [ H g b A 1c ] > 7. 5, a n d/ or gl yc os uria b y di pstic k, 
si g nifica nt pr otei n uria, reti n o pat h y), e vi de nce of a d diti o nal 
si g nifica nt re nal disease(s) (ie, c urre ntly acti ve gl o mer ular 
ne p hriti des ), re nal ca ncer, si n gle ki d ne y, or rece nt ( wit hi n 
last 6 m o nt hs ) re nal s ur ger y, or ac ute ki d ne y i nj ur y.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
Trial Site(s):
A p pr o xi matel y 2 2 0 e nr olli n g sites i ncl u d i n g, b ut n ot li mite d 
t o, t he f oll o wi n g re gi o ns:  N ort h A merica, S o ut h A merica, 
Easter n E ur o pe, Wester n E ur o pe , Asia, a n d A ustralia .
I n vesti gati o nal 
Me dici nal Pr o d uct(s), 
D ose, D osa ge 
re gi me n, Treat me nt 
peri o d, F or m ulati o n, 
M o de of 
A d mi nistrati o n:
T ol va pta n ta blets ( 1 5 or 3 0 m g) or matc hi n g place b o will be 
self-a d mi nistere d orall y as s plit-d ose re gi me ns, o nce u p o n 
a wa ke ni n g a n d a n ot her a p pr o xi matel y 8 t o 9 h o urs later.
D oses will be e x presse d as earl y d ose/ late d ose (e g, 6 0/ 3 0 m g ).  
Place b o will be a d mi nistere d t o all s u bjects d uri n g t he place b o 
r u n-i n peri o d as a si n gle - bli n d “s ha m” 1 5/ 1 5 m g d ose.  
T ol va pta n r e gi me ns i ncl u de 3 0/ 1 5, 4 5/ 1 5, 6 0/ 3 0 a n d 9 0/ 3 0 m g 
a n d will be titrate d t o t olera bilit y d uri n g t he t ol va pta n titrati o n 
peri o d , a n d t he n c o nti n ue d at t he ma xi mall y t olerate d d ose 
t hr o u g h t he t ol va pta n r u n-i n peri o d , a n d t hr o u g h o ut t he 
d o u ble -bli n d, ra n d o mize d treat me nt peri o d f or t h ose s u bjects 
ra n d o mize d t o recei ve t ol va pta n ( place b o s u bjects will recei ve 
matc hi n g place b o ta blets ).
Trial Assess me nts:
Scree ni n g:   M e dical hist or y, c o m plete p h y sical e xa mi nati o n, 
uri ne pre g na nc y  test (w o me n of c hil d -beari n g p ote ntial o nl y ), 
a n d la b orat or y tests t o deter mi ne i nitial eli gi bilit y.
Efficac y : Ser u m creati ni ne f or deter mi nati o n of e G F R, 
p ol y c ystic ki d ne y disease (P K D ) outc o mes s ur ve y.
Safet y : V ital si g ns, directe d p h y sical e xa mi nati o n, self-
assesse d t olera bilit y, A Es , he mat ol o g y , uri nal ysis, a n d ser u m 
c he mistr y tests (i ncl u din g ser u m tra nsa mi nase s, al kali ne 
p h os p hatase, bilir u bi n, ser u m s o di u m), bi o mar ker plas ma a n d 
uri ne sa m ples , a n d D N A bl o o d sa m ples (f or c o nse nti n g 
s u bjects).
P har mac o ki netic ( P K) : S parse b l o o d sa m ples f or a p ossi ble 
p o p ulati o n P K a nal ysis, w hic h w o ul d be re p orte d se paratel y, 
a n d c o nfir mati o n of c o m plia nce .
P har mac o d y na mic ( P D): Uri ne os m olalit y  ( Uos m ), uri ne 
s pecific gra vit y.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
Criteria f or 
E val uati o n:
Pri m ar y Effic ac y E n d p oi nt:
Treat me nt differe nce i n t he c ha n ge of e G F R fr o m 
pre -treat me nt baseli ne t o p ost-treat me nt f oll o w-u p, a n n ualize d
( di vi de d) by eac h s u bject ’s I MP treat me nt d urati o n .
Sec o n d ar y E n d p oi nts:
K e y  Sec o n dar y Efficac y E n d p oi nt:
Treat me nt differe nce i n a n n ualize d sl o pe of e G F R calc ulate d 
f or i n di vi d ual s u bjects usi n g a n a p pr o priate baseli ne a n d 
a vaila ble p ost -ra n d o mizati o n, o n-treat me nt assess me nts.
S afet y E n d p oi nts :
1)
A Es  
2)
Vital si g ns
3)
Cli nical la b orat or y  tests, i ncl u di n g ser u m 
tra nsa mi nases, t otal bilir u bi n ( B T), al kali ne 
p h os p hatase ( A L P), a n d ser u m s o di u m.
P K E n d p oi nts :  Plas ma t ol va pta n a n d meta b olite(s), i ncl u di n g
D M - 4 1 0 3 plas ma c o nce ntrati o ns.
P D E n d p oi nts :  U os m a n d uri ne s pecific gra vity.
E x pl or at or y E n d p oi nts:
 
 
 
 
 
 
 
 
 
 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
Statistical Met h o ds:
Sa m ple size :  Base d o n a Mi xe d M o del Re peate d 
Meas ure me nts a nal ys is of t he 
C K D - 3 su bjects 
fr o m trial 
, t he treat me nt differe nce i n re nal 
f u ncti o n at M o nt h 1 2 is 1. 0 7 i n o ur sa m ple size calc ulati o n.  It 
is e x pecte d t hat t he i ntra-s u bject varia nce is 1 4. 2 a n d i nter-
s u bject varia nce is 2 8. 0 5 at M o nt h 1 2.  Wit h 3 re peate d 
meas ures at pre -treat me nt baseli ne a n d p ost-treat me nt 
f oll o w-u p, res pecti vel y, t he p o wer calc ulati o n esti mates t hat, 
f or a 2-si de d al p ha set at 0. 0 5 f or a p o wer of 9 0 %, a n d wit h a n 
ass u m pti o n of 1 0 % dr o p o ut rate i n t he trial , a t otal sam ple size 
of a p pr o xi matel y 1 3 0 0 s u bjects is nee de d.
K e y  Datasets f or a nal ys is:  T he f oll o wi n g datasets are defi ne d 
f or t his trial:

 
 
 
 
  
 
 
Pri mar y  efficac y a nalys is:
 
 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0
2 6 Mar 2 0 1 5 
Statistical Met h o ds, 
c o nt.:
K e y  sec o n dar y efficac y a nal ysis:  
 
 
 
 
 
 
 
Safet y  a nalys es:  
 
 
 
 
 
 
Trial D urati o n:
T he d urati o n of t he d o u ble- bli n d, ra n d o mize d treat me nt peri o d 
will be 1 2 m o nt hs.  T he t otal d urati o n f or eac h s u bject e ntere d 
i nt o t he trial is a p pr o xi matel y 1 5-1 7 m o nt hs (i ncl u di n g t he pre-
ra n d o mizati o n a n d f oll o w-u p peri o ds , a n d a n a d diti o nal 
8 wee ks f or e xte nsi o n of t he scree ni n g peri o d i n s u bjects f or 
w h o m t his is necessar y ).

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1
2 6 Mar 2 0 1 5 
T a bl e of C o nt e nt s 
Pr ot oc ol S y n o psis ...........................................................................................3
T a ble of C o nte nts .........................................................................................1 1
List of I n -te xt T a bles ...................................................................................1 6
List of I n -te xt Fi g ures..................................................................................1 7
List of A p pe n dices ........................................................................................1 8
List of A b bre vi ati o ns a n d Defi niti o ns of Ter ms .......................................1 9
1
I ntr o d ucti o n ........................................................................................2 2
1. 1
N o ncli nical Data ................................................................................................ 2 3
1. 2
Cli nical Data...................................................................................................... 2 3
1. 3
P har mac o ki netics/ P har mac o d y na mics ..............................................................2 4
1. 4
K n o w n a n d P ote ntial Ris ks a n d Be nefits .......................................................... 2 6
2
Tri al R ati o n ale a n d O bjecti ves ..........................................................2 7
2. 1
Trial Rati o nale ................................................................................................... 2 7
2. 2
D osi n g Rati o nale ...............................................................................................2 9
2. 3
Trial O bjecti ves ................................................................................................. 3 1
3
Tri al Desi g n .........................................................................................3 1
3. 1
T y pe/ Desi g n of Trial ......................................................................................... 3 1
3. 2
Treat me nts ......................................................................................................... 3 2
3. 2. 1
Pre -ra n d o mizati o n........................................................................................... 3 3
3. 2. 1. 1
Scree ni n g Peri o d ( u p t o Da y  - 4 3)................................................................ 3 3
3. 2. 1. 2
Place b o R u n -i n Peri o d ( Da y -4 2 t o Da y  - 3 6)..............................................3 4
3. 2. 1. 3
T ol va pta n Titrati o n Peri o d ( Da y  -3 5 t o Da y  - 2 2) ....................................... 3 4
3. 2. 1. 4
T ol va pta n R u n -i n Peri o d ( Da y -2 1 t o Da y  - 1)............................................3 4
3. 2. 2  
D o u ble- bli n d Ra n d o mize d Treat me nt Peri o d ( Da y  0 t o M o nt h 1 2)...............3 5
3. 2. 3
F oll o w -u p Peri o d ( Da y  + 7 t o Da y + 2 1)..........................................................3 6
3. 3
Trial P o p ulati o n ................................................................................................. 3 6
3. 4
Eli gi bilit y  Criteria..............................................................................................3 7
3. 4. 1
I nf or me d C o nse nt ...........................................................................................3 7
3. 4. 2
I ncl usi o n Criteria................................ ............................................................3 8
3. 4. 3
E xcl usi o n Criteria ...........................................................................................3 8

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2
2 6 Mar 2 0 1 5 
3. 5
O utc o me E n d p oi nts ...........................................................................................3 9
3. 5. 1
Pri mar y  O utc o me E n d p oi nt............................................................................ 3 9
3. 5. 1. 1
Pri mar y  Efficac y E n d p oi nt.......................................................................... 3 9
3. 5. 2
Sec o n dar y  O utc o me E n d p oi nts....................................................................... 3 9
3. 5. 2. 1
K e y  Sec o n dar y Efficac y E n d p oi nt..............................................................3 9
3. 5. 2. 2
Safet y  E n d p oi nts ......................................................................................... 4 0
3. 5. 2. 3
P har mac o ki netic/ P har mac o d y na mic E n d p oi nts .......................................... 4 0
3. 5. 3
E x pl orat or y  O utc o me E n d p oi nts .................................................................... 4 0
3. 5. 3. 1
E x pl orat or y  Efficac y E n d p oi nt ................................................................... 4 0
3. 5. 3. 2
E x pl orat or y  Safety E n d p oi nts ..................................................................... 4 0
3. 6
Meas ures t o Mi ni mize/ A v oi d Bias .................................................................... 4 0
3. 7
Trial Pr oce d ures ................................................................................................ 4 1
3. 7. 1
Sc he d ule of Assess me nts ................................................................................ 4 6
3. 7. 1. 1
Pre -ra n d o mizati o n Peri o d............................................................................ 4 6
3. 7. 1. 1. 1
Scree ni n g Peri o d ( u p t o Da y  - 4 3)............................................................ 4 6
3. 7. 1. 1. 2
Place b o R u n -i n Peri o d ( Da ys -4 2 t o - 3 6)................................................ 4 8
3. 7. 1. 1. 3
T ol va pta n Titrati o n Peri o d ( Da y s -3 5 t o -2 2) .......................................... 4 9
3. 7. 1. 1. 4
T ol va pta n R u n -I n Peri o d ( Da ys -2 1 t o -1) .............................................. 4 9
3. 7. 1. 2
D o u ble- bli n d, Ra n d o mize d Treat me nt Peri o d ( Da y 0 t o M o nt h 1 2).......... 5 0
3. 7. 1. 3
F oll o w -u p Peri o d ( M o nt h 1 2/ E n d of Treat m e nt t o Da y 2 1 
P ost -treat me nt)............................................................................................ 5 2
3. 7. 2
Efficac y  Assess me nts ..................................................................................... 5 3
3. 7. 2. 1
Ser u m Creati ni ne f or Esti mate d Gl o mer ular Filtrati o n Rate ...................... 5 3
3. 7. 2. 2
P ol y c ystic Ki d ne y Disease Hist or y a n d O utc o mes S ur ve ys ....................... 5 4
3. 7. 3
Safet y  Assess me nts......................................................................................... 5 5
3. 7. 3. 1
A d verse E ve nts ............................................................................................5 5
3. 7. 3. 2
Cli nical L a b orat or y Assess me nts................................................................5 5
3. 7. 3. 3
P h y sical E xa mi nati o n a n d Vital Si g ns........................................................ 5 7
3. 7. 3. 4
Assess me nt of L i ver Sy m pt o ms, Si g ns or Test A b n or malities ...................5 7
3. 7. 3. 4. 1
Re q uire me nts f or Re peate d L i ver Testi n g............................................... 5 8
3. 7. 3. 4. 1. 1
Re peate d Li ver Testi n g i n S u bjects wit h N or mal Val ues at 
Scree ni n g ..............................................................................................5 8

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 3
2 6 Mar 2 0 1 5 
3. 7. 3. 4. 1. 2
Re peate d Li ver Testi n g i n S u bjects wit h A b n or mal Val ues at 
Scree ni n g ..............................................................................................5 8
3. 7. 3. 4. 2 
Li ver Test A b n or malities a n d I nterr u pti o n/ Disc o nti n uati o n of 
I n vesti gati o nal Me dici nal Pr o d uct........................................................... 5 8
3. 7. 3. 4. 3
Re q uire me nts f or S pecial Re p orti n g Usi n g t he Li ver Disease 
Electr o nic Case Re p ort F or m a n d I m me diatel y Re p orta ble E ve nt 
F or m ........................................................................................................ 5 9
3. 7. 3. 5
Ot her Safet y Assess me nts ........................................................................... 6 0
3. 7. 3. 5. 1
Bi o mar ker Plas ma Sa m ples ..................................................................... 6 0
3. 7. 3. 5. 2
Bi o mar ker Uri ne Sa m ples ....................................................................... 6 0
3. 7. 3. 5. 3
D N A Bl o o d Sa m ples ............................................................................... 6 1
3. 7. 4
P har mac o ki netic/ p har mac o d y na mic Assess me nts ......................................... 6 1
3. 7. 4. 1
P har mac o ki netic Bl o o d Sa m ples ................................................................. 6 1
3. 7. 4. 2
P har mac o d y na mic Uri ne Sa m ples ..............................................................6 2
3. 7. 5
E n d of Treat me nt/ E n d of Trial ....................................................................... 6 2
3. 7. 6
I n de pe n de nt Data M o nit ori n g C o m mittee ...................................................... 6 3
3. 8
St o p pi n g R ules, Wit h dra wal Criteria, a n d Pr oce d ures...................................... 6 3
3. 8. 1
E ntire Trial or Treat me nt Ar m(s) ................................................................... 6 3
3. 8. 2
I n di vi d ual Site................................................................................................. 6 3
3. 8. 3
I n di vi d ual S u bject Disc o nti n uati o n................................................................ 6 3
3. 8. 3. 1
S u bjects Disc o nti n ue d Pri or t o Ra n d o mizati o n .......................................... 6 3
3. 8. 3. 2
Treat me nt I nterr u pti o n ................................................................................ 6 4
3. 8. 3. 3
Treat me nt Disc o nti n uati o n .......................................................................... 6 5
3. 8. 3. 4
D oc u me nti n g Reas o ns f or Treat me nt I nterr u pti o n/ Disc o nti n uati o n........... 6 6
3. 8. 3. 5
Wit h dra wal of C o nse nt
............................................................................... 6 6
3. 8. 3. 5. 1
Pr oce d ures t o E nc o ura ge C o nti n ue d Trial Partici pati o n......................... 6 7
3. 8. 3. 5. 2 
Pr oce d ures t o Pre ve nt “ L ost t o F oll o w- u p”................................ .............6 8
3. 9
Scree n Fail ures .................................................................................................. 6 9
3. 1 0
Defi niti o n of C o m plete d S u bjects................................ .....................................6 9
3. 1 1
Defi niti o n of S u bjects L ost t o F oll o w - u p..........................................................7 0
3. 1 2
S u bject C o m plia nce ...........................................................................................7 0
3. 1 3
Pr ot oc ol De viati o ns ...........................................................................................7 0
4
Restricti o ns ..........................................................................................7 1
4. 1
Pr o hi bite d or Restricte d Me dicati o ns ................................................................ 7 1

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4
2 6 Mar 2 0 1 5 
4. 2
Dietar y  Restricti o ns a n d Rec o m me n dati o ns .....................................................7 2
5
Re p orti n g of A d verse E ve nts .............................................................7 3
5. 1  
Defi niti o ns......................................................................................................... 7 3
5. 2
Eliciti n g a n d Re p orti n g A d verse E ve nts........................................................... 7 5
5. 3
I m me diatel y Re p orta ble E ve nts ........................................................................ 7 5
5. 4
Pre g na nc y .......................................................................................................... 7 6
5. 5
Pr oce d ure f or Brea ki n g t he Bli n d ...................................................................... 7 7
5. 6
F oll o w -u p of A d verse E ve nts ............................................................................ 7 7
5. 6. 1
F oll o w -u p of N o n -seri o us A d verse E ve nts..................................................... 7 8
5. 6. 2
F oll o w -u p of P ost -Trial Seri o us A d verse E ve nts........................................... 7 8
5. 6. 3
F oll o w -u p a n d Re p orti n g of Seri o us A d verse E ve nts Occ urri n g after 
Last Sc he d ule d C o ntact .................................................................................. 7 8
6
P h ar m ac o k i netic a n d P h ar m ac o d y n a mic A n al ysis.........................7 9
6. 1
P har mac o ki netic ................................................................................................ 7 9
6. 2
P har mac o d y na mic ............................................................................................. 7 9
7
St atistic al A n al ysis ..............................................................................7 9
7. 1
Sa m ple Size ....................................................................................................... 7 9
7. 1. 1
Sa m ple Size Esti mati o n .................................................................................. 7 9
7. 1. 2
Bli n de d Sa m ple Size Re -esti mati o n ...............................................................8 2
7. 2
Datasets f or A nal ys is......................................................................................... 8 2
7. 3
Ha n dli n g of Missi n g Data................................................................................. 8 3
7. 4
Pri mar y  a n d Sec o n dar y O utc o me A nalys is....................................................... 8 4
7. 4. 1
Pri mar y  Efficac y O utc o me A nalys is ..............................................................8 4
7. 4. 1. 1
Pri mar y  E n d p oi nt A nalys is......................................................................... 8 4
7. 4. 1. 2
Se nsiti vit y  A nalys is of t he Pri mar y E n d p oi nt .............................................8 5
7. 4. 1. 3
Se nsiti vit y  A nalys is I ncl u di n g Data fr o m S u bjects W h o Disc o nti n ue 
I M P.............................................................................................................. 8 6
7. 4. 2
Sec o n dar y  O utc o me A nal yses ........................................................................8 6
7. 4. 2. 1
K e y  Sec o n dar y E n d p oi nt A nal ysis..............................................................8 6
7. 4. 2. 2
Se nsiti vit y  A nalys is of t he Ke y Sec o n dar y E n d p oi nt.................................8 7
7. 4. 2. 3
Se nsiti vit y  A nalys is I ncl u di n g Data fr o m S u bjects W h o Disc o nti n ue 
I M P.............................................................................................................. 8 7
7. 4. 2. 4
Se nsiti vit y  A nalys is I ncl u di n g I m p utati o n of Missi n g Data....................... 8 7

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5
2 6 Mar 2 0 1 5 
7. 4. 3
S u b gr o u p Efficac y  A nalysis ...........................................................................8 8
7. 4. 4
E x pl orat or y  A nalys es ...................................................................................... 8 8
7. 4. 4. 1
A nal y sis of Efficac y Base d o n M o dal D oses.............................................. 8 8
7. 4. 4. 2
A D P K D O utc o mes ...................................................................................... 8 8
7. 4. 4. 3
D N A a n d Uri ne a n d Plas ma Bi o mar kers .................................................... 8 9
7. 4. 5
I nteri m A nalys is..............................................................................................8 9
7. 5
A nal y sis of De m o gra p hic a n d Baseli ne C haracteristics.................................... 9 0
7. 6
Safet y  A nalys is.................................................................................................. 9 0
7. 6. 1
A d verse E ve nts ...............................................................................................9 0
7. 6. 2
Cli nical L a b orat or y Data ................................................................................ 9 1
7. 6. 3
P h y sical E xa mi nati o n a n d Vital Si g ns Data ................................................... 9 1
8
M a n a ge me nt of I n vesti g ati o n al Me dici n al Pr o d uct ........................9 1
8. 1
Pac ka gi n g a n d La beli n g .................................................................................... 9 1
8. 2
St ora ge ............................................................................................................... 9 2
8. 3
Acc o u nta bilit y ................................................................................................... 9 2
8. 4
Ret ur ns a n d Destr ucti o n.................................................................................... 9 2
9
Rec or ds M a n a ge me nt .........................................................................9 3
9. 1
S o urce D oc u me nts ............................................................................................. 9 3
9. 2
Data C ollecti o n .................................................................................................. 9 3
9. 3
File Ma na ge me nt at t he Trial Site ..................................................................... 9 4
9. 4
Rec or ds Rete nti o n at t he Trial Site .................................................................... 9 4
1 0
Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce ...........................................9 4
1 0. 1
M o nit ori n g ......................................................................................................... 9 4
1 0. 2
A u diti n g ............................................................................................................. 9 5
1 1
Et hics a n d Res p o nsi bilit y ...................................................................9 5
1 2
C o nfi de nti alit y ....................................................................................9 5
1 3
A me n d me nt P olic y ..............................................................................9 6
1 4
Refere nces ............................................................................................9 7

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 6
2 6 Mar 2 0 1 5 
Li st of I n- t e xt T a bl e s
Ta ble 1. 2 - 1  
Vas o pressi n Bl oc ka de Acr oss Differi n g Se verities of 
A D P K D: Effect o n Rate of Esti mate d Gl o mer ular Filtrati o n 
Decli ne i n C hr o nic Ki d ne y  Disease Sta ges 1- 3............................. 2 4
Ta ble 3. 2. 2- 1  
D osi n g Sc he d ule............................................................................ 3 5
Ta ble 3. 4. 2 -1
I ncl usi o n Criteria ........................................................................... 3 8
Ta ble 3. 4. 3 -1
E xcl usi o n Criteria .......................................................................... 3 9
Ta ble 3. 7- 1
Sc he d ule of Assess me nts ...............................................................4 2
Ta ble 3. 7. 3. 2 - 1
Cli nical L a b orat or y Assess me nts................................................... 5 6
Ta ble 4. 1 - 1
C Y P 3 A 4 I n hi bit ors ( Partial L ist)................................................... 7 2
Ta ble 7. 1 - 1 
T otal Sa m ple Size wit h C ha n ge = 1. 0 7 a n d 1 0 % Dr o p o ut 
Rate ( Al p ha = 0. 0 5) ....................................................................... 8 1

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 7
2 6 Mar 2 0 1 5 
Li st of I n- t e xt Fi g ur e s
Fi g ure 3. 1 - 1
Trial Desi g n Sc he matic .................................................................. 3 2

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 8
2 6 Mar 2 0 1 5 
Li st of A p p e n di c e s
A p pe n di x 1
Na mes of S p o ns or Pers o n nel ......................................................... 9 9
A p pe n di x 2
I nstit uti o ns C o ncer ne d Wit h t he Trial.......................................... 1 0 0
A p pe n di x 3
Ha n dli n g a n d S hi p me nt of Bi oa nal y tical Sa m ples ...................... 1 0 2
A p pe n di x 4
A d mi nistrati ve C ha n ges/ Pr ot oc ol A me n d me nts .......................... 1 0 4

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 9
2 6 Mar 2 0 1 5 
Li st of A b br e vi ati o n s a n d D efi niti o n s of T er m s
A b bre vi ati o n
Defi niti o n
A D P K D
A ut os o mal d o mi na nt p ol yc ystic ki d ne y  disease
A D R
A d verse dr u g reacti o ns
A E
A d verse e ve nt
A L P  
A l kali ne p h os p hatase
A L T  
Ala ni ne a mi n otra nsferase
A N C O V A
A nal y sis of c o varia nce
A S T
A s partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n-ti me c ur ve
A U C 0 -2 4
area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me zer o t o 2 4 h o urs
A U C 
A rea u n der t he c o nce ntrati o n-ti me c ur ve calc ulate d t o t he last 
o bser va ble c o nce ntrati o n
A V P
Ar gi ni ne vas o pressi n
B T
B ilir u bi n, t otal
B U N
Bl o o d urea nitr o ge n
c A M P
C yclic a de n osi ne m o n o p h os p hate
C K D
C hr o nic ki d ne y  disease
C K D -E PI
C hr o nic Ki d ne y  Disease-E pi de mi ol o g y
C L / F
A p pare nt cleara nce of dr u g fr o m plas ma after e xtra vasc ular 
a d mi nistrati o n
C ma x
M a xi m u m ( pea k) plas ma c o nce ntrati o n
Cr C L
Creati ni ne cleara nce
C R O
Cli nical Researc h Or ga nizati o n
C S R
Cli nical st u d y  re p ort
C T
C o m p ute d t o m o gra p h y
C Y P
C y t oc hr o me P 4 5 0
DI LI
Dr u g -i n d uce d li ver i nj ur y
DI LI N
Dr u g -I n d uce d Li ver I nj ur y Net w or k
D N A
D e o x yri b o n ucleic aci d
D S M C
Data Safet y a n d M o nit ori n g C o m mittee
eC R F
Electr o nic c ase re p ort f or m
e G F R
Esti mate d gl o mer ular filtrati o n rate
e G F R C K D -E PI
Esti mate d gl o mer ular filtrati o n rate calc ulate d usi n g t he C hr o nic 
Ki d ne y  Disease-E pi de mi ol o g y  f or m ula
E M A
E ur o pea n Me dici nes A ge nc y
E o T x
E n d of treat me nt
E S R D
E n d- sta ge re nal disease
E U
E ur o pea n U ni o n
F D A
(U nite d States ) F o o d a n d Dr u g A d mi nistrati o n
G C P
G o o d Cli nical Practice
G G T
G a m ma gl uta m yl tra nsferase
H A C
He patic a dj u dicati o n c o m mittee
H g b A 1c
Gl y c os yl ate d he m o gl o bi n
I A
I nteri m a nalys is

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 0
2 6 Mar 2 0 1 5 
A b bre vi ati o n
Defi niti o n
I B
I n vesti gat or’s br oc h ure
I CF
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 D
I de ntificati o n n u m ber
I D M C
I n de pe n de nt Data M o nit ori n g C o m mittee
I D M S
Is ot o pe dil uti o n mass s pectr o metr y
I E C
I n de pe n de nt et hics c o m mittee
I M P
I n vesti gati o nal me dici nal pr o d uct
IN D
I n vesti gati ve ne w dr u g
I N R
I nter nati o nal n or malize d rati o
I RB 
I nstit uti o nal re vie w b oar d
I R E
I m me diatel y re p orta ble e ve nt
I T T
I nte nt-t o-treat
I V R S
Interacti ve v oice res p o nse s y ste m
L D H
L actate de h ydr o ge nase
M A R
M issi n g at ra n d o m
M C H C
Mea n c or p usc ular he m o gl o bi n
M C V
M ea n c or p usc ular v ol u me
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
M M R M
Mi xe d M o del Re peate d Meas ure me nts
M N A R
M issi n g n ot at ra n d o m
M RI
M a g netic res o na nce i ma gi n g
N R C
Nati o nal Researc h C o u ncil
N S AI D
N o n- ster oi dal a nti-i nfla m mat or y dr u gs
O C
O bser ve d cases
O P D C
Ots u ka P har mace utical De vel o p me nt & C o m mercializati o n, I nc.
P D
P har mac o d y na mic
P K
P har mac o ki netic
P K D
P ol y c ystic ki d ne y disease
P T
Pr ot hr o m bi n ti me
Q D
O nce dail y
R B C
Re d bl o o d cell
R N A
Ri b o n ucleic aci d
S A E
Seri o us a d verse e ve nt
S A P
Statistical a nal y sis pla n
S D
Sta n dar d de viati o n
S U S A R
S us pecte d u ne x pecte d seri o us ad verse reacti o n
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
t1/ 2,z
Eli mi nati o n half -life
T K V
T otal ki d ne y v ol u me
tma x
T i me t o ma xi m u m ( pea k) plas ma c o nce ntrati o n
U os m
Uri ne os m olalit y
U L N
U p per li mit of n or mal
U S or U S A
U nite d States or U nite d States of A merica
V 2
Vas o pressi n t y pe 2 (rece pt or)

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 1
2 6 Mar 2 0 1 5 
A b bre vi ati o n
Defi niti o n
W B C
W hite bl o o d cell
W O C B P
W o me n
of c hil d beari n g p ote ntial

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 2
2 6 Mar 2 0 1 5 
1
I ntr o d u cti o n
T ol va pta n ( O P C - 4 1 0 6 1) is a selecti ve ar gi ni ne vas o pressi n ( A V P) ty pe 2 ( V 2) rece pt or 
a nta g o nist t hat is c urre ntl y a p pr o ve d i n t he U nite d States ( U S), E ur o pe, A u stralia, 
Ca na da, C hi na, H o n g K o n g, I n d o nesia, Ja pa n, P hili p pi nes, Re p u blic of K orea, Ta i wa n, 
T haila n d, a n d T ur ke y , f or vari o us f or ms of hy p o natre mia, a n d i n Ja pa n als o f or v ol u me 
o verl oa d i n heart fail ure or li ver cirr h osis .
T ol va pta n is als o bei n g i n vesti gate d f or t he use i n a d ults t o treat a ut os o mal d o mi n a nt 
p ol y c ystic ki d ne y disease ( A D P K D), a n i n herite d c o n diti o n w hic h lea ds t o pr o gressi ve 
destr ucti o n of n or mal ki d ne y  str uct ure lea di n g t o e n d-sta ge re nal disease ( E S R D).  T he 
disease affects t he str uct ure of t he ki d ne y s t hr o u g h pr oliferati o n a n d gr o wt h of n u mer o us 
fl ui d-fille d c ysts.  T he e x pa n di n g c ysts c o m press n or mal tiss ue a n d bl o o d vessels 
res ulti n g i n isc he mia, i nfla m mati o n a n d fi br osis lea di n g t o pr o gressi ve ne p hr o n l oss.  T he 
re mai ni n g ne p hr o ns are i nitiall y a ble t o c o m pe nsate t hr o u g h gl o mer ular h yperfiltrati o n u p 
t o a p oi nt w he n ne p hr o n l oss is s o great t hat c o m pe nsati o n is n o l o n ger a de q uate a n d 
re nal f u ncti o n be gi ns t o decli ne.  Cli nical ma nifestati o ns of ki d ne y disease ma y be 
s p ora dic ( he mat uria, i nfecti o ns, pai n) or c hr o nic ( h y perte nsi o n, al b u mi n uria, re nal 
i ns ufficie nc y) a n d i n dicate o n g oi n g a n d c u m ulati ve da ma ge t o t he ki d ne y.
T he n u m ber of dia g n ose d A D P K D cases was esti mate d at 1 1 6, 2 2 8 i n t he U S i n 2 0 0 9. 
T he esti mate d pre vale nce of dia g n ose d A D P K D is si milar i n E ur o pe a n d esti mate d t o be 
< 5 per 1 0, 0 0 0. 1 T h o u g h a rare ge netic disease, it ra n ks as t he 6 t h lea di n g ca use of E S R D 
i n t he U S ( 2. 3 % of t he ne w E S R D cases).2   A n esti mate d 4 5 % t o 7 0 % of patie nts wit h 
A D P K D pr o gress t o E S R D b y  a ge 6 5.3   O ver t he past 3 0 y ears, t he a ge of o nset f or 
E S R D a m o n g A D P K D patie nts has re mai ne d t he sa me ( me dia n a ge of 5 4).  I n c o ntrast, 
effecti ve t hera p y has dela y e d t he o nset of E S R D i n patie nts wit h ne p hr o pat h y d ue t o 
h y perte nsi o n, dia betes , a n d gl o mer ul o ne p hritis.
T here are c urre ntl y  n o t hera pies w hic h ca n sl o w c yst gr o wt h or t he deteri orati o n of 
ki d ne y  f u ncti o n i n A D P K D.  C urre nt ma na ge me nt f oc uses o n a meli orati n g s y m pt o ms of 
pai n, c o ntr ol of bl o o d press ure, a n d treat me nt of i nfecti o ns wit h a nti bi otics.  N o ne of 
t hese treat me nts tar get t he u n derlyi n g ca use of t he disease.   Ofte n, t he o nl y  defi niti ve 
i nter ve nti o n f or re nal c o m plicati o ns i n A D P K D is ki d ney tra ns pla ntati o n, w hic h t y picall y 
occ urs after ye ars of he m o dial ysis.
I n t he U S, t he de vel o p me nt pr o gra m f or tol va pta n f or A D P K D was gra nte d Fast -trac k 
desi g nati o n o n 2 0 Ja n 2 0 0 6 a n d or p ha n dr u g desi g nati o n o n 0 6 A pr 2 0 1 2.  T ol va pta n was 
desi g nate d as a n or p ha n dr u g f or pre ve nti o n of t he pr o gressi o n of A D P K D i n Ja pa n o n 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 3
2 6 Mar 2 0 1 5 
1 1 A u g 2 0 0 6.  T he E ur o pea n Me dici nes A ge nc y  ( E M A) gra nte d or p ha n desi g nati o n f or 
t he use of t ol va pta n f or t he treat me nt of A D P K D o n 5 A u g 2 0 1 3.
If a p pr o ve d, t ol va pta n w o ul d be t he first a vaila ble t hera p y t o sl o w ki d ne y disease 
pr o gressi o n i n a d ults wit h A D P K D. 4, 5   Refer t o t he T ol va pta n I n vesti gat or’s Br oc h ure 
(I B) f or m ore i nf or mati o n.4
1. 1
N o n cli ni c al D at a
R o de nt m o dels of A D P K D a n d e x -vi v o h u ma n A D P K D cell a n d tiss ue c ult ures ha ve 
i m plicate d A V P as a pr o m oter of ki d ne y c yst gr o wt h.6 ,7   A V P -i n d uce d c yclic a de n osi ne 
m o n o p h os p hate (c A M P) i ncreases pr oliferati o n of A D P K D re nal t u b ular e pit heli u m a n d 
c hl ori de-me diate d, i ntra -c ystic, fl ui d secreti o n.  T his lea ds t o c yst e x pa nsi o n w hic h 
disr u pts re nal arc hitect ure lea di n g t o isc he mia, ki d ne y  fi br osis, a n d irre versi ble da ma ge 
t o t he ki d ne y, ulti mately i m pairi n g its f u ncti o n.  T ol va pta n i n hi bits c A M P pr o d ucti o n b y 
bl oc ki n g A V P bi n di n g t o t he re nal A V P - V2 rece pt or.  F or i nf or mati o n o n no ncli nical 
t o xic ol o g y a n d a bs orp ti o n, distri b uti o n a n d meta b olis m data o n tol va pta n please refer t o 
t he m ost c urre nt versi o n of t he I n vesti gat or's Br oc h ure.4
1. 2
Cli ni c al D at a
T ol va pta n was cli nicall y  effecti ve i n dela yi n g decli ne of re nal f u ncti o n, as deter mi ne d b y 
c ha n ges i n ser u m creati ni ne c o nce ntrati o ns o ver 3 years, i n a n i nter nati o nal, m ultice nter, 
cli nical trial i n s u bjects wit h c hr o nic ki d ne y  disease ( C K D) sta ge 1 t o 3 d ue t o A D P K D.8   
T hese effects were c o nsiste nt acr oss eac h of t hese C K D sta ges, s u p p orti n g t ol va pta n’s 
p ote ntial utilit y  i n early t o mi d -sta ge disease (Ta ble 1. 2- 1 ), a n d creati n g a c o m pelli n g 
ar g u me nt f or l o n g-ter m effecti ve ness i n t h ose initiati n g t hera p y at a n earl y sta ge a n d 
a d heri n g t o t hera p y as t he disease pr o gresses.  T his trial als o de m o nstrate d a n ac ute a n d 
persiste nt re d ucti o n o n rate of ki d ne y  c ystic gr o wt h.  T he re d ucti o ns i n rate of ki d ne y 
gr o wt h c orrelate d wit h re d ucti o ns i n k i d ne y pai n a n d wit h preser vati o n of re nal f u ncti o n.  
Si milar c orrelati o ns were o bser ve d i n a s maller, matc he d -c o ntr ol st u d y (St u d y 1 5 6- 0 9-
2 8 3). 9   T h us, t he cli nical data ha ve c o nfir me d t he n o n- clinical effects see n i n a ni mals (see
Secti o n 1. 1 ) a n d s u p p ort a p pr o val of t ol va pta n as t he first a ge nt t o sl o w t he pr o gressi o n 
of A D P K D. 9   T his trial will ser ve t o c o nfir m pri or res ults a n d e xte n d o ur u n dersta n di n g 
of t he safet y a n d efficac y of t ol va pta n i nt o later sta ges of disease, s pecificall y  C K D 
sta ges 3 b a n d 4.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 4
2 6 Mar 2 0 1 5 
T a ble 1. 2 - 1
V as o pressi n Bl oc k a de Acr oss Differi n g Se verities of 
A D P K D: Effect o n R ate of Esti m ate d Gl o mer ul ar Filtr ati o n 
Decli ne i n C hr o nic Ki d ne y Dise ase St a ges 1 - 3
C K D S t a ge
b y e G F R C K D- E PI
( mL/ mi n/ 1. 7 3 m 2)
N
( T ol v a pt a n/
Pl ace b o )
e G F R Sl o pe
T ol v a pt a n
e G F R Sl o pe
Pl ace b o
Effect Size
Rel ati ve 
Effect Size
Sta ge 1 ( 9 0)
3 3 0/ 1 7 3
-1. 9 3
-2. 8 6 
0. 9 4 a
3 3 %
Sta ge 2 ( 6 0 -9 0)
4 6 5/ 2 2 4
-2. 6 4
-3. 8 5 
1. 2 1 a
3 1 %
Sta ge 3 b
( 3 0-6 0 )
3a ( 4 5 -6 0)
1 3 5/ 7 0
-3. 5 1
-5. 2 3 
1. 7 2
3 3 %
3 b ( 3 0 -4 5)
2 8/ 1 4
-3. 9 2
-5. 9 9 
2. 0 7
3 5 %
e G F R C K D- E PI = esti mate d gl o mer ular filtrati o n rate calc ulate d b y t he C hr o nic Ki d ne y Disease -
E pi de mi ol o g y ( C K D -E PI) f or m ula 
aAll p < 0. 0 0 5
b C K D Sta ge 3: relati ve effect size ( 3 3 %); N (t ol va pta n/ place b o; 1 6 3/ 8 4)
S o urce:  Trial 
cli nical st u d y re p ort ( C S R ); D ata o n file
1. 3
P h ar m a c o ki n eti c s/ P h ar m a c o d y n a mi c s
F oll o wi n g si n gle oral d oses t o healt h y  s u bjects, t ol va pta n ma xi m u m ( pea k) plas ma 
c o nce ntrati o n (C ma x ) val ues s h o w less t ha n d ose -pr o p orti o nal i ncrease s fr o m 3 0 t o 
2 4 0 m g wit h mea n val ues i ncreasi n g fr o m a b o ut 2 3 5 t o 1 0 0 0 n g/ m L ; val ues platea u at 
d oses ra n gi n g fr o m 2 4 0 t o 4 8 0 m g. Foll o wi n g m ulti ple o nce -dail y ( Q D) d osi n g, 
t ol va pta n p har mac o ki netic ( P K) val ues were als o n o nli near.  M ea n C ma x a n d area u n der 
t he c o nce ntrati o n-ti me c ur ve calc ulate d t o t he last o bser va ble c o nce ntrati o n ( A U C ) 
val ues were 4. 2 - a n d 6. 4-f ol d hi g her f or t he 3 0 0 m g  d ose c o m pare d wit h t he 3 0 m g d ose.  
Acr oss all d oses, t he me dia n ti me t o me dia n ( pea k) plas ma c o nce ntrati o n (tma x ) val ue was 
2 h o urs (ra n ge 1 t o 1 2 h o urs).   F or 6 0 - a n d 9 0-m g  ta blets, d osi n g wit h a hi g h-fat meal 
i ncreases t ol va pta n Cma x b ut has n o effect o n t ol va pta n area u n der t he c o nce ntrati o n -ti me 
c ur ve ( A U C) .
T ol va pta n c o nce ntrati o ns d o n ot si g nifica ntl y acc u m ulate f oll o wi n g Q D d osi n g, 
i n dicati n g t hat t ol va pta n has a s h ort eli mi nati o n half-life (t1 / 2,z).  F oll o wi n g si n gle oral 
d oses, t he t1 / 2,z of t ol va pta n i ncrease s wit h i ncreasi n g d ose , wit h mea n val ues ar o u n d 
3 h o urs f or a 1 5 m g d ose a n d 1 2 ho urs f or 1 2 0 t o 4 8 0 m g d oses.
T ol va pta n e xcreti o n i n uri ne is < 1 % of t he d ose a n d i n feces a b o ut 1 9 % of t he d ose.  
T ol va pta n is eli mi nate d pri maril y  b y c yt oc hr o me P 4 5 0 (C Y P ) 3 A-me diate d meta b olis m 
a n d is c o nsi dere d t o be a wea k s u bstrate as t he t ol va pta n A U C was i ncrease d a b o ut 
3. 5- f ol d a n d t he a p pare nt cleara nce of dr u g fr o m plas ma after e xtra vasc ular 
a d mi nistrati o n ( C L / F) was decrease d b y 8 7 % w he n c o -a d mi nistere d wit h ket oc o naz ole.  

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 5
2 6 Mar 2 0 1 5 
Mea n C
ma x a n d A U C val ues i n s u bjects wit h A D P K D a n d preser ve d re nal f u ncti o n 
 ra n ge fr o m 1 5 t o 6 0 % hi g her w he n 
c o m pare d wit h healt h y  s u bject val ues, b ut rates of C L/ F ra n ge fr o m 1 4 % sl o wer t o 2 7 % 
faster, i n dicati n g t hat t ol va pta n P K i n A D P K D s u bjects wit h preser ve d re nal f u ncti o n is 
si milar t o t hat i n healt h y  s u bjects.  F oll o wi n g m ulti ple Q D a n d s plit -d ose re gi me ns 
ra n gi n g fr o m 3 0 t o 1 2 0 m g/ da y, acc u m ulati o n of t ol va pta n c o nce ntrati o ns is ne gli gi ble. 
F or s plit -d ose re gi me ns of 3 0, 6 0 a n d 1 2 0 m g/ da y , t ol va pta n P K a p pears t o be li near as 
mea n val ues of A U C fr o m ti me zer o t o 2 4 h o urs p ost -d ose ( A U C 0- 2 4 h ) a p pr o xi matel y 
d o u ble wit h a d o u bli n g of dail y  d ose.
Re nal i m pair me nt re d uces t ol va pta n cleara nce a n d c o nse q ue ntly plas ma c o nce ntrati o ns 
i ncrease.  F oll o wi n g a si n gle 6 0 m g d ose, t ol va pta n A U C i n s u bjects wit h 
 
 hi g her c o m pare d t o s u bjects wit h 
  
T ol va pta n is hi g hl y b o u n d t o plas ma pr otei ns ( > 9 8 %) a n d bi n di n g was u naffecte d b y  
re nal i m pair me nt.
P har mac o d y na mic ( P D) res p o nses t o t ol va pta n were o bser ve d f or s u bjects wit h A D P K D 
at C K D sta ges 1 t o 4. At t he rec o m me n de d s plit-d ose re gi me ns of 4 5/ 1 5 m g  t o 9 0/ 3 0 m g 
dail y , t ol va pta n bl oc ke d A V P acti o n at t he V 2 rece pt or (ie, i ncrease d uri ne e xcreti o n rates 
a n d s u p presse d U os m ) f or al m ost t he e ntire 2 4- h o ur da y  i n s u bjects wit h A D P K D ( C K D 
Sta ge 1 t o 2).  T he lar ge i ncrease i n uri ne o ut p ut t hat res ulte d fr o m t his i n hi biti o n was 
ass ociate d wit h t he 5 m ost fre q ue ntl y re p orte d a d verse e ve nts ( A Es; p ol y u ria, p olla ki uria, 
n oct uria, t hirst, a n d dr y  m o ut h) i n cli nical p har mac ol o g y or cli nical efficac y trials.  I n 
2 cli nical p har mac ol o g y  trials i n s u bjects wit h A D P K D a n d esti mate d gl o mer ular 
filtrati o n rates (e G F R ) > 6 0 m L / mi n/ 1. 7 3 m2 a d mi nistere d a 9 0/ 3 0 m g  d ose re gi me n f or at 
least 7 d a y s, mea n (sta n dar d de viati o n [S D ]) 2 4-h o ur uri ne v ol u mes were 7 .4 6 4 ( 2 . 1 0 3) L 
a n d 6.5 3 2 ( 2 .0 3 6) L. As re nal f u ncti o n decli ne d, t he v ol u me of uri ne pr o d uce d f or a 
gi ve n d ose of t ol va pta n decrease d ; f oll o wi n g a 9 0/ 3 0 m g s plit -d ose re gi me n, mea n ( S D) 
2 4- h o ur uri ne v ol u mes f or s u bjects wit h A D P K D a n d e G F R 3 0 t o 6 0 a n d 
< 3 0 m L / mi n/ 1. 7 3 m2 were 6 .2 3 3 ( 1 .3 0 7) L a n d 5 .0 2 4 ( 1 .7 6 7) L, res pecti vel y .  T heref ore, 
des pite a n i ncrease i n t ol va pta n c o nce ntrati o n, t he cli nical effects of t ol va pta n o n t he 
m ost c o m m o n a d verse e ve nts are di mi nis he d. Ot her a d verse reacti o ns, s uc h as i di o pat hic 
li ver i nj ur y, d o n ot a p pear t o be c o nce ntrati o n-de pe n de nt.
S u bjects wit h A D P K D are a ble t o mai ntai n a ne utral fl ui d bala nce s o i ncreases i n ser u m 
s o di u m a n d plas ma os m olalit y were s mall, f oll o wi n g t ol va pta n treat me nt. Ser u m 
c o nce ntrati o ns of cr eati ni ne, c ystati n C, a n d uric aci d were hi g her f oll o wi n g t ol va pta n 
treat me nt as t ol va pta n re d uce d t he eG F R a p pr o xi matel y 6 t o 8 %, Cr C L a p pr o xi matel y 
8 t o 1 0 %, a n d uric aci d cleara nce a p pr o xi matel y 2 0 t o 2 5 %; t he c ha n ges a p peare d t o 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
2 6
2 6 Mar 2 0 1 5 
i n de pe n de nt of baseli ne re nal f u ncti o n f or C K D sta ges 1 t o 4. Uri nar y  e xcreti o n of 
a q ua p ori n 2 a n d c A M P were l o wer f oll o wi n g t ol va pta n treat me nt, s u p p orti n g t he 
h y p ot hesis t hat t ol va pta n i n hi biti o n of t he V 2 rece pt or is s uccessf ul i n re d uci n g cell ular 
c A M P c o nce ntrati o ns. 
F oll o wi n g m ulti ple oral d oses, t he t ol va pta n meta b olite D M- 4 1 0 3 acc u m ulates , as its 
half -life is a p pr o xi matel y 1 8 0 h o urs. T his meta b olite has n o p har mac ol o gical acti vit y  at 
t he c o nce ntrati o ns e x pecte d t o be ac hie ve d f oll o wi n g t he d oses use d i n t his trial a n d has 
s h o w n a n acce pta ble t o xicit y pr ofile. T he meta b olite has n ot bee n s h o w n t o acc u m ulate 
i n n o ncli nical t o xic o ki netic trials; h o we ver, i n a 2 6-wee k trial i n rats, D M -4 1 0 3 plas ma 
c o nce ntrati o ns at a b o ut 8 0 % of t h ose e x pecte d t o be ac hie ve d i n t his trial r e veale d n o 
e vi de nce of ti me- de pe n de nt t o xic ol o gical effects. 
F or a d diti o nal i nf or mati o n o n P K/ P D res p o nses fr o m t ol va pta n treat me nt, please refer t o 
t he In vesti gat or's Br oc h ure. 4
1. 4
K n o w n a n d P ot e nti al Ri s k s a n d B e n efit s
A D P K D is a de vastati n g, pr o gressi ve disease t hat places a tre me n d o us b ur de n o n patie nts 
a n d t heir fa milies.  T he ris k a patie nt is willi n g t o acce pt is a pers o nal decisi o n base d o n 
his/ her i n di vi d ual a n d fa milial e x perie nce wit h t he disease.  T ol va pta n is p ote ntiall y  t he 
first t hera py t hat offers patie nts a treat me nt o pti o n t o sl o w t heir disease pr o gressi o n ; 
h o we ver, as of Ja n uar y 2 0 1 4, it has n ot y et bee n a p pr o ve d f or t his i n dicati o n .  T he 
treat me nt ris ks are well c haracterize d, ma na gea ble, a n d m ust be weig he d a gai nst t he 
c o nse q ue nces of n o treat me nt.
T he m ost c o m m o n o bser ve d ris ks of t ol va pta n t hera p y i ncl u de t h ose arisi n g fr o m 
a q uaresis (e g, p oly uria, p olla ki uria, n oct uria, t hirst, dr y m o ut h) , de h ydrati o n, electr ol yt e 
a b n or malities, a n d g o ut.  W hile a q uar etic e ve nts di d n ot c o ntri b ute t o si g nifica nt patie nt 
m or bi dit y  o ver 3 years of st u d y i n t he pi v otal place b o-c o ntr olle d trial ( Trial 
), 
t he y d o re prese nt a d verse dr u g reacti o ns ( A D Rs) w hic h occ ur earl y  ( wit hi n da ys t o 
wee ks) a n d are m ost li kel y  to li mit a s u bject’s a bilit y t o c o nti n ue t hera p y o ver a d urati o n 
of treat me nt t hat is li kel y t o pr o vi de be nefit.   Aq uaretic A D Rs are als o li kel y  t o li mit t he 
efficac y of a n u n pr o ve n, yet ofte n rec o m me n de d , t hera pe utic strate g y of i ncreasi n g water 
i n gesti o n.
W hile t he pr o p osal of
i ncrease d water i n gesti o n as a mec ha nis m of a meli orati n g C K D 1 0
has n ot reac he d me dical e q ui p oise, i n t his trial we belie ve a ge neral rec o m me n dati o n t o 
d o s o is reas o na ble a n d w o ul d rec o m me n d i n gesti o n o f water a de q uate t o a v oi d t hirst. 
T y picall y , t his w o ul d re prese nt a mi ni m u m of 2 t o 3 liters of water per da y  i n s u bjects 
wit h relati vel y  i ntact re nal f u ncti o n, a n d lesser a m o u nts i n t h ose wit h m ore i m paire d 

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f u ncti o n. Ser u m s o di u m s h o ul d be m o nit ore d d ur i n g t he trial t o e ns ure a te n de nc y 
t o war d hy p o natre mia (s y m pt o matic or as y m pt o matic) is n ot pr o d uce d.
T he m ost n ota ble safet y i ss ue ass ociate d wit h c hr o nic t ol va pta n use, ne wly i de ntifie d i n 
Trial 
 is t he p ote ntial f or i di os yncratic he patic t o xi cit y.  Wit h a o nce e ver y  4-
m o nt h m o nit ori n g sc he me , a n i m bala nce i n t he pr o p orti o n of s u bjects wit h ele vate d 
tra nsa mi nases (t ol va pta n > place b o) le d t o i de ntificati o n of 3 s u bjects (t otal fr o m b ot h 
Trial 
 a n d its o pe n-la bel e xte nsi o n trial, 1 5 6- 0 8- 2 7 1) wit h la b orat or y a n d 
cli nical e vi de nce of p ote ntiall y  seri o us dr u g -i n d uce d li ver i nj ur y ( DI LI). Base d o n t he 
a vaila ble data fr o m t he af ore- me nti o ne d trials, t he s p o ns or pr o p oses t hat a p pr o priate 
patie nt m o nit ori n g a n d ma na ge me nt be i m ple me nte d t o miti gate t his p ote ntial ris k i n t he 
A D P K D p o p ulati o n .  F or t his trial, sta n dar d li ver para meters will be meas ure d at baseli ne 
a n d t he n m o nt hl y t hereafter.
S i g nifica nt e ve nts relate d t o gla uc o ma a n d s ki n ne o plas ms were als o o bser ve d; h o we ver 
t he ca usal relati o ns hi p t o t ol va pta n re mai ns u ncertai n.  T hese a d verse e ve nts a n d t he 
a b o ve attri b uta ble a d verse reacti o ns s h o ul d be c o nsi dere d i n li g ht of t he be nefits of a 
re d uce d ris k of A D P K D ki d ne y  c o m plicati o ns, i ncl u di n g re nal pai n, uri nar y  tract 
i nfecti o n, hemat uria, a ne mia, a n d ne p hr olit hiasis .5
T he treat me nt ris ks of t ol va pta n are well c haracterize d, ma na gea ble, a n d m ust be 
wei g he d a gai nst t he c o nse q ue nces of n o a de q uate treat me nt.  Wit h s ufficie nt k n o wle d ge 
of t he be nef its a n d ris ks a n d ris k miti gati o n strate gies, patie nts a n d t heir p h ysicia ns ma y 
ma ke i nf or me d decisi o ns a b o ut t ol va pta n treat me nt.  I n t he fi nal assess me nt, t he o verall 
be nefit -ris k pr ofile of t ol va pta n f or t he treat me nt of A D P K D a p pears fa v ora ble, offeri ng 
a real o p p ort u nit y t o fill a l o n gsta n di n g u n met me dical nee d.
2
Tri al R ati o n al e a n d O bj e cti v e s
2. 1
Tri al R ati o n al e
T he c urre nt trial will e xte n d t he u n dersta n di n g of t he efficac y  a n d safety of t ol va pta n 
treat me nt i n A D P K D patie nts wit h late sta ge 2 t o early st a ge 4 C K D.  F oc usi n g o n t he 
e G F R calc ulate d b y t he C hr o nic Ki d ne y  Disease-E pi de mi ol o g y  ( C K D-E PI) f or m ul a
(e G F R C K D -E PI , hereafter referre dt o as “e G F R”)1 1 , t his trial is e x pecte d t o pr o vi de ki d ne y  
f u ncti o n data t hat are c o m ple me ntar y t o t he data de m o nstrati n g t he be nefits pre vi o usl y 
o bser ve d pri maril y  i n A D P K D s u bjects wit h earlier sta ges of disease.
Trial 
utilize d a p ost -ra n d o mizati o n baseli ne t o acc o u nt f or t ol va pta n’s ac ute 
he m o d y na mic effect o n e G F R.  T his he m o d y na mic effect has bee n well c haracterize d i n 
pri or trials of u p t o 3 -ye ars d urati o n.  It has als o bee n e xa mi ne d i n s u bjects wit h ki d ne y  

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f u ncti o n ra n gi n g fr o m n or mal t o se verely d ys f u ncti o nal d ue t o A D P K D or ot her 
dis or ders. 1 2 ,1 3   T he o nset of he m o d y na mic effect is ac ute, it persists as l o n g as treat me nt 
c o nti n ues a n d is ra pi dl y re versi ble u p o n disc o nti n uati o n of treat me nt. A c o m paris o n of 
t ol va pta n a n d place b o s u bjects a ble t o c o m plete T rial 
 i n dicate d t hat t he 
relati ve preser vati o n of e G F R d uri n g treat me nt was s ustai ne d i n t he p ost-treat me nt 
f oll o w-u p p hase a n d at baseli ne f or Trial 1 5 6- 0 8- 2 7 1 (e xte n di n g t o at least 3 m o nt hs). I n 
a n i nteri m a nal ys is of e G F R i n t he e xte nsi o n trial, b ot h t he pri or-place b o a n d 
pri or -t ol va pta n gr o u ps e x hi bite d t his he m o d yna mic effect wit h o pe n- la bel treat me nt wit h 
differe nces bet wee n gr o u ps bei n g s ustai ne d f or a f urt her 2 y ears of treat me nt. ( Data o n 
file).
H o we ver, i n Trial 
, a n early a n d i m bala nce d wit h dra wal of t ol va pta n s u bjects 
le d t o missi n g baseli ne data f or ~ 5 % of t ol va pta n s u bjects, c o m plicati n g t he i nter pretati o n 
of t hese res ults .  T he c urre nt trial will utilize t ol va pta n treat me nt titrati o n a n d t olera bilit y 
r u n-i n peri o ds t o e xcl u de, pri or t o ra n d o mizati o n, t h ose s u bjects w h o re p ort t he y are 
u nli kel y  t o be a ble t o t olerate t ol va pta n’s a q uaretic effects d uri n g l o n g -ter m treat me nt.  
T his , a n d a place b o r u n -i n peri o d, will be use d t o esta blis h a pre -ra n d o mizati o n baseli ne 
e G FR f or eac h p ote ntial treat me nt assi g n me nt, t here b y  facilitati n g a strai g htf or war d 
calc ulati o n of t he ke y sec o n dar y e n d p oi nt of e G F R sl o pe f or all s u bjects.
T he trial’s pri mar y  e n d p oi nt is defi ne d as t he a bs ol ute c ha n ge i n e G F R fr o m 
pre -treat me nt t o p ost-treat me nt, n or malize d b y t he s u bject’s d urati o n of treat me nt.  T o 
decrease varia bilit y , m ulti ple ser u m creati ni ne meas ure me nts (is ot o pe dil uti o n mass 
s pectr o metr y [ID M S] -tracea ble) will be ta ke n b ot h pre - a n d p ost-treat me nt f or eac h 
s u bject, a n d t he e G F R values will t he n be a vera ge d.   A d diti o nall y , sta n dar dizati o n of 
diet, e xercise , a n d ti mi n g of ser u m c ollecti o n a n d a nal ys is of sa m ples f or ser u m 
creati ni ne are e x pecte d t o re d uce i ntra -s u bject varia bilit y.
I n t his trial, e ver y eff ort will be ma de t o a v oi d mis si n g data by e nc o ura gi n g c o m plia nce 
a n d c o nti n uati o n of I M P. F urt her m ore, all s u bjects w h o d o n ot s pecifically wit h dra w 
t heir c o nse nt will be f oll o we d as c o m pletel y as p ossi ble f or la b orat or y , healt h a n d vital 
stat us. T his eff ort will be gi n d uri n g t he i nf or me d c o nse nt pr ocess.  I n vesti gat ors, site 
pers o n nel , a n d s u bjects will be pr o vi de d wit h i nf or mati o nal t o ols a n d e d ucate d re gar di n g 
t he i m p orta nce of partici pati o n i n cli nical trials a n d a d here nce t o all pr ot oc ol s pecifie d 
visits a n d assess me nts.  T his will i ncl u de trai ni n g o n rele va nt c o nce pts fr o m t he Nati o nal 
Aca de m y of Scie nces Nati o nal Researc h C o u ncil (N R C ) g ui deli ne o n pre ve nti o n a n d 
ha n dli n g of missi n g data. 1 4   T he i nf or me d c o nse nt f or m (I C F) will i ncl u de a secti o n 
c o dif yi n g t his u n dersta n di n g bet wee n t he pri nci pal i n vesti gat or a n d t he pr os pecti ve 
s u bject a n d ca n be wit h dra w n i n sta ges acc o m m o dati n g eac h s u bject ’s willi n g ness t o 

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pr o vi de f oll o w - u p of t heir me dical i nf or mati o n. H o me n ursi n g vis its or l ocal la b orat or y  
visits will als o be a vaila ble at m ost sites f or c ollecti o n of f oll o w- u p bl o o d sa m ples a n d t o 
c o nti n ue healt h-stat us f oll o w-u p e ve n if I MP is per ma ne ntl y  disc o nti n ue d.
T hr o u g h m ore fre q ue nt (e g, m o nt hl y ) m o nit ori n g of li ver tra nsa mi nases (as partate 
a mi n otra nsferase [ A S T] , ala ni ne a mi n otra nsferase [ A LT] ), al kali ne p h os p hatase ( A L P),
a n d bilir u bi n (t otal; B T), t he c urre nt trial will m ore precisel y  defi ne t he p ote ntial f or DI LI 
pre vi o usl y  o bser ve d i n Trial 
.  Fre q ue nt m o nit ori n g will als o detect s maller 
ele vati o ns earlier per mitti n g cl oser a n d m ore t h or o u g h e val uati o n a n d i nter ve nti o n 
(i ncl u di n g dr u g i nterr u pti o n or disc o nti n uati o n). T his is e x pecte d t o miti gate t he ris k of 
seri o us or irre versi ble i nj ur y.
Uri ne a n d plas ma sa m ples f or p ote ntial bi o mar ker testi n g a n d a n o pti o nal bl o o d sa m ple 
f or ge netic de o x y ri b o n ucleic aci d ( D N A) testi n g will be c ollecte d a n d st ore d f or a 
ma xi m u m of 1 5 ye ars after t he trial has e n de d .  P ote ntial a nal ysis ma y i ncl u de 
disease -relate d ge nes a n d ge nes i n v ol ve d i n h o w t ol va pta n is pr ocesse d wit hi n t he b o d y.  
T heref ore, t he i nf or mati o n gat here d t hr o u g h ge netic / bi o mar ker a nal ys is s h o ul d i m pr o ve 
t he s p o ns or’s u n dersta n di n g of t he disease, its dia g n osis, pr o g n osis, a n d p ossi bl y 
treat me nt o utc o me.  T his ca n be acc o m plis he d b y  i de ntif yi n g w hic h s u bjects are m ore 
li kel y t o res p o n d t o t ol va pta n, a n d/ or pre dicti n g w hic h s u bjects are li kely t o pr o gress t o 
m ore se vere disease states, a n d/ or pre dicti n g w hic h s u bjects ma y  ha ve a n a d verse e ve nt 
s uc h as DI LI, a n d/or lea d t o ne w o p p ort u nities f or t hera pies. T he ai m of t he 
ge netic / bi o mar ker testi n g is t o f urt her u n dersta n d t he ca uses a n d pr ocesses of A D P K D 
a n d t he i m pact treat me nt wit h t ol va pta n has o n t he pr o gressi o n of t he disease a n d safet y 
of t he s u bject a n d f uture ge nerati o ns of patie nts .
2. 2
D o si n g R ati o n al e
S uccessf ul treat me nt of A D P K D a p pears t o re q uire early, c o nsta nt i n hi biti o n of t he 
vas o pressi n V 2 rece pt or.  T his treat me nt para di g m pr o d uce d decrease d rates of gr o wt h i n 
ki d ne y  size i n a ni mal m o dels.  T he cli nical f or m ulati o n of t ol va pta n was o pti mize d t o 
i ncrease bi oa vaila bilit y w hic h necessitates s plit d osi n g t o mai ntai n s u p pressi o n of A V P 
acti o n acr oss 2 4 h o urs .  A hi g her d ose is use d earl y i n t he da y, wit h a l o wer d ose 
a p pr o xi matel y 8 t o 9 h o urs later i n or der t o pr o d uce a ma xi mal i n hi biti o n o n wa ki n g wit h 
a gra d ual fall -off of effect d uri n g t he ni g ht w he n fre q ue nt uri nati o n c o ul d lea d t o 
i nterr u pti o n of slee p.
Uri ne os m olalit y  ( Uos m ) has bee n use d as a s urr o gate of vas o pressi n V2 rece pt or 
i n hi biti o n i n Trials 1 5 6-0 3 -2 4 8 a n d 1 5 6 - 0 3- 2 4 9 t o refi ne t hese d oses.  N or mall y, Uos m
o nl y  i ncreases a b o ve plas ma os m olalit y (a p pr o xi matel y 2 9 0 m Os m/ L) w he n vas o pressi n 

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is acti n g at t he ki d ne y’s distal c ollecti n g d ucts.  W he n tr o u g h s p ot U os m re mai ns bel o w 
3 0 0 m Os m, effecti ve V 2 rece pt or i n hi biti o n ca n be ass u me d.  T hese trials als o c o nfir me d 
a p he n o me n o n w here t he first da y’s t hera p y pr o d uces t he m ost r o b ust a q uaresis, w hic h 
t he n decreases a p pr o xi matel y 2 0 % b y  t he 5t h d a y  of re peate d d osi n g.1 5
S plit d ose re gi me ns of 3 0/ 1 5, 4 5/ 1 5, 6 0/ 3 0 , a n d 9 0/ 3 0 m g were a vaila ble i n t he titrati o n 
p hase of t he o n g oi n g o pe n -la bel e xte nsi o n trial i n A D P K D (Trial 1 5 6- 0 4- 2 5 0).  D uri n g 
t his trial, b ot h t he t olera bilit y of t ol va pta n re gi me ns a n d efficac y (as meas ure d b y 
s u p pressi o n of U os m ) were deter mi ne d i n 4 6 s u bjects.  Res ults of t his trial c o nfir m t hat 
s u p pressi o n of tr o u g h U os m i m pr o ves wit h eac h hi g her d ose of t ol va pta n, a n d t hat 
“ brea kt hr o u g h” occ urre d less fre q ue ntl y wit h eac h re gi me n ( brea kt hr o u g h of 6 1 %, 3 9 %, 
2 6 %, 1 5 % f or 3 0/ 1 5, 4 5/ 1 5, 6 0/ 3 0 , a n d 9 0/ 3 0 m g d oses, res pecti vel y ).1 6
W hile o pti mal efficac y  ( 0 % brea kt hr o u g h at tr ou g h ) c o ul d n ot be ac hie ve d at a n y of t he 
d ose re gi me ns use d i n t he titrati o n f or Trial 1 5 6 -0 4 -2 5 0, t he li mit of t olera bilit y  was 
reac he d wit h o nl y 4 1 % of s u bjects stati n g t hat t he y  c o ul d t olerate a 9 0/ 3 0 m g d ose. 1 6
T his tr ial will als o i m ple me nt a titrati o n strate g y i n t he pre-ra n d o mizati o n peri o d t o 
esta blis h, b y self-re p ort, a ma xi mall y t olerate d d ose of t olva pta n f or eac h s u bject .
I n t he t ol va pta n titrati o n peri o d, all s u bjects will be give n a s plit d ose of 3 0/ 1 5 m g 
t ol va pta n wit h u p war d titrati o n e ver y 3 t o 4 da y s t o 4 5/ 1 5 m g, 6 0/ 3 0 m g, u p t o a 
ma xi m u m d ose of 9 0/ 3 0 m g per da y  o ver 2 wee ks.  All s u bjects will be e nc o ura ge d t o 
pr o gress t o 9 0/ 3 0 m g per da y , as a hi g her d ose is li kel y t o be m ost effecti ve.  All s u bjects
w h o t olerate t ol va pta n at t he 6 0/ 3 0 m g or 9 0/ 3 0 m g dail y d ose re gi me n ma y e nter t he 
t ol va pta n r u n-i n peri o d at o ne of t hese d oses f or 3 a d diti o nal wee ks.  E xce pt f or 
ma na ge me nt of A Es, n o d ose a dj ust me nt will be per mitte d d uri n g t he t ol va pta n r u n -i n 
peri o d .  S u bjects u na ble t o t olerate at least 3 wee ks of dail y  t ol va pta n treat me nt at 
6 0/ 3 0 m g or 9 0/ 3 0 m g  d uri n g t he t ol va pta n r u n -i n peri o d will n ot be eli gi ble f or 
ra n d o mizati o n.  T his is e x pecte d t o mi ni mize p ost -ra n d o mizati o n wit h dra wal d ue t o 
i na bilit y t o t olerate acute si de effects of t ol va pta n.
D uri n g t he d o u ble -bli n d ra n d o mize d treat me nt peri o d, s u bjects will eit her be mai ntai ne d 
o n t heir ma xi mall y  t olerate d s plit d ose of t ol va pta n at 6 0/ 3 0 m g or 9 0/ 3 0 m g or 
ra n d o mize d t o place b o.  T o ma na ge a d diti o nal t olera bilit y iss ues d uri n g t his peri o d, 
s u bjects ma y d o w n-titrate bli n de d treat me nt t o 4 5/ 1 5 m g or e ve n 3 0/ 1 5 m g wit h me dical 
m o nit or a p pr o val.  S u bjects will be e nc o ura ge d t o mai ntai n ma xi mall y  t olerate d d ose t o 
o pti mize a n d mai ntai n desire d s u p pressi o n. If d o w n-titrati o n occ urs, s u bjects will be 
e nc o ura ge d t o ret ur n t o pre vi o us ma xi mal t olerate d d ose, if p ossi ble.

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2. 3
Tri al O bj e cti v e s
Pri mar y :

T o c o m pare t he efficac y  of t ol va pta n treat me nt i n re d uci n g t he c ha n ge i n e G F R fr o m 
pre -treat me nt baseli ne t o p ost-treat me nt f oll o w- u p, as c o m pare d wit h place b o, i n 
s u bjects wit h late-sta ge C K D d ue t o A D P K D w h o t olerate t ol va pta n d uri n g a n i nitial 
r u n-i n peri o d.
Sec o n dar y :

T o c o m pare t he efficac y of t ol va pta n treat me nt i n re d uci n g t he decli ne of a n n ualize d 
e G F R sl o pe, a s c o m pare d wit h place b o, i n s u bjects wit h late-sta ge C K D d ue t o 
A D P K D w h o t olerate t ol va pta n d uri n g a n i nitial r u n- i n peri o d.

T o c o m pare o verall a n d he patic safet y of t ol va pta n wit h t hat of place b o a n d t o 
c o m pare i nci de nce of A D P K D c o m plicati o ns ( o utc o mes) d uri n g t he trial .
3
Tri al D e si g n
3. 1
T y p e/ D e si g n of Tri al
T his is a p hase 3 b , m ulti-ce nter, ra n d o mize d -wit h dra wal, place b o -c o ntr olle d, 
d o u ble -bli n d, parallel -gr o u p trial t o c o m pare t he efficac y  a n d safety of t ol va pta n i n 
s u bjects wit h A D P K D a n d baseli ne ki d ne y f u ncti o n as d oc u me nte d by a n e G F R b et wee n 
2 5 - 6 5 m L / mi n/ 1. 7 3 m2 , i ncl usi ve. T he o verall desi g n is ill ustrate d i n Fi g ure 3. 1- 1 .

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Fi g ure 3. 1- 1
Tri al Desi g n Sc he m atic
3. 2
Tr e at m e nt s
All s u bjects will be gi ve n i n vesti gati o nal me dici nal pr o d uct (I M P; t ol va pta n a n d/ or 
place b o, acc or di n g t o trial peri o d a n d ra n d o mizati o n gr o u p) i n a dail y s plit d ose, o nce 
u p o n a wa ke ni n g a n d a n ot her a p pr o xi matel y  8 t o 9 h o urs later.  E xact ti mi n g of d osi n g 
ma y  be a dj uste d base d o n wa ke/slee p ha bits (e g, sta n dar d 8 A M a n d 5 P M ma y  be 
s witc he d t o 1 0 P M a n d 7 A M if w or ki n g a ni g ht s hift).  H o we ver, d osi n g ti mes s h o ul d be 
c o nsiste nt f or eac h i n di vi d ual’s dail y d ose t o ma xi mize rece pt or s u p pressi o n.  D oses will 
be e x presse d as earl y d ose/ late d ose (e g, 6 0/ 3 0 m g ).  Place b o will be a d mi nistere d t o 
s u bjects ra n d o mize d t o t hat treat me nt i n a f or m i de ntical t o t he c orres p o n di n g d ose of 
t ol va pta n ta blets.
U p o n c o nse nt, all s u bjects s h o ul d recei ve t he rec o m me n dati o n f or i n gesti o n of at least
2 t o 3 liters of fl ui d (i ncl u di n g i n s oli d, se mi -s oli d, a n d li q ui d f o o ds) per da y, u nless 
ot her wise directe d b y t he i n vesti gat or. T his rec o m me n dati o n s h o ul d start d uri n g 
scree ni n g a n d c o nti n ue t hr o u g h t he e n d of t he trial.

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W hile ta ki n g I M P, all s u bjects s h o ul d be i nstr ucte d t o i n gest fl ui ds i n a ntici pati o n of, or 
at t he first si g n of t hirst i n or der t o a v oi d e xcessi ve t hirst or de h y drati o n.  A d diti o nall y , 
s u bjects s h o ul d i n gest 1 t o 2 c u ps of water bef ore be dti me re gar dless of percei ve d t hirst 
a n d re ple nis h fl ui ds o ver ni g ht wit h eac h e pis o de of n oct uria.
3. 2. 1
Pr e -r a n d o mi z ati o n
S u bjects w h o pr o vi de i nf or me d c o nse nt a n d f or w h o m preli mi nar y  eli gi bilit y is 
esta blishe d will e nter a n 8 -wee k r u n -i n peri o d .  T his re prese nts “ pre-ra n d o mizati o n”.  
T his p re-ra n d o mizati o n peri o d c o nsists of a scree ni n g peri o d (t ypicall y 1- 2 wee k s;
h o we ver, l o n ger peri o ds u p t o 8 a d diti o nal wee ks are acce pta ble f or s u bjects nee di n g 
sta bilizati o n after c ha n gi n g ot her treat me nts, es peciall y a nti-h y perte nsi ves a n d di uretics ,
or w h o re q uire a d diti o nal assess me nts f or q ualificati o n); a place b o r u n -i n peri o d
( 1 wee k), a t ol va pta n titrati o n peri o d ( 2 wee ks), a n d a tol va pta n r u n -i n peri o d ( 3 wee ks) .
D uri n g t his peri o d, s u bjects s h o ul d be t ol d “ Y o u will recei ve place b o or acti ve treat me nt 
(t ol va pta n) d uri n g t he treat me nt p hase, b ut yo u will n ot k n o w w hic h.”  T he s u bjects 
s h o ul d n ot be t ol d t hat t here is a se parate r u n-i n p hase a n d ra n d o mizati o n p hase, a n d t he y 
s h o ul d n ot be t ol d w he n f or mal ra n d o mizati o n will occ ur.  T he y s h o ul d als o be t ol d 
“ Y o ur eli gi bilit y f or c o nti n ue d partici pati o n will be assesse d i nter mitte ntl y d uri n g t he 
treat me nt peri o d.”
3. 2. 1. 1
S cr e e ni n g P eri o d ( u p t o D a y -4 3)
N o i n vesti gati o nal treat me nts will be a d mi nistere d d uri n g t he scree ni n g peri o d.  D uri n g 
t his peri o d, t he s u bject’s eli gi bilit y f or t he trial will be c o nfir me d usi n g hist orical i ma gi n g 
data t o s u p p ort a dia g n osis of A D P K D a n d t o verif y  t he le vel of C K D pri maril y d ue t o 
A D P K D a n d n ot t o ot her re nal ( h y p o plasia) or meta b olic ( dia betic or h y p erte nsi ve 
ne p hr o pat h y) dis or ders.   I n a d diti o n, eli gi bilit y will be c o nfir me d b y t he mea n of e G F R 
calc ulate d fr o m t he s u bjects’ 2 pre -treat me nt, ce ntral-la b, ser u m creati ni ne assess me nts.  
S u bjects will be t ol d t hat t he y will recei ve t ol va pta n or place b o d uri n g vari o us 
s u bse q ue nt peri o ds of t he trial a n d t hat t he ne xt peri o d i n v ol ves a d ose escalati o n wit h 
m ulti ple efficac y , safety, a n d t olera bilit y assess me nts.
Trial me dicati o n will be dis pe nse d 
o n Da y  -4 3 after s u bject eli gi bilit y  is c o nfir me d.  I n e xce pti o nal circ u msta nces, trial 
me dicati o n ma y  be pr o vi de d at t he sec o n d scree ni n g visit wit h i nstr ucti o n n ot t o ta ke a n y  
me dicati o n u ntil c o nfir mati o n o n Da y  -4 3 b y  t he i n vesti gat or.  If trial me dicati o n is
dis pe nse d at t he sec o n d scree ni n g visit, c o nfir mati o n of eli gi bilit y a n d i nstr ucti o ns t o ta ke 
me dicati o n will be pr o vi de d b y  tele p h o ne o n Da y - 4 3.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
3 4
2 6 Mar 2 0 1 5 
3. 2. 1. 2
Pl a c e b o R u n -i n P eri o d ( D a y -4 2 t o D a y  -3 6)
I n t he first wee k after t he scree ni n g peri o d, all s u b jects will be gi n t he si n gle-bli n d, 
p lace b o r u n-i n peri o d w it h place b o i n a dail y  s plit d ose of 0 m g (a b bre viate d 0/ 0 m g), i n a 
f or m i de ntical t o t ol va pta n ta blets at t he 1 5/ 1 5 m g d ose .  T he s u bject will re mai n bli n de d 
t o treat me nt, ha vi n g recei ved a b ottle of trial dr u g d uri n g t he scree ni n g peri o d w hic h t he y  
u n derst o o d c o ul d be eit her t ol va pta n or place b o. T h ose s u bjects u na ble t o t olerate t he 
place b o d ose re gi me n wi ll be c o nsi dere d “ R u n-i n fail ures”, t he y will c o m plete e n d of 
treat me nt ( E o T x) visit assess me nts a n d be f oll o we d u p after 7 da y s b y p h o ne call t o 
assess a n y o n g oi n g A Es.
3. 2. 1. 3
T ol v a pt a n Titr ati o n P eri o d ( D a y -3 5 t o D a y -2 2)
D uri n g t he si n gle -bli n d , tol va pta n titrati o n peri o d ( 2 wee k d urati o n) , all s u bjects will 
recei ve 2 cart o ns of t ol va pta n, 1 cart o n c o ntai ni n g 2 b ottles of 1 5 m g ta blets a n d t he ot her 
cart o n c o ntai ni n g 2 b ottles of 3 0 m g ta blets. T he t ol va pta n ta blets will a p pear i de ntical t o 
t he place b o ta blets dis pe nse d i n t he pri or peri o d, a n d s u bjects will be t ol d t hat t he y  c o ul d 
be eit her t ol va pta n or place b o.  S u bjects will be i nstr ucte d t o ta ke t ol va pta n starti n g at a 
s plit d ose of 3 0/ 1 5 m g (as 2 ta blets u p o n wa ki n g a n d 1 ta blet a p pr o xi matel y 8 t o 9 h o urs 
later) a n d t o titrate u p e ver y 3 t o 4 da y s; first t o 4 5/ 1 5 m g, t he n 6 0/3 0 m g, t he n u p t o t he 
ma xi m u m d ose of 9 0/ 3 0 m g.  Titrati o n will be acc o m plis he d b y  i ncreasi n g t he n u m ber of 
ta blets/ d ose a n d/ or s witc hi n g fr o m 1 5 m g ta blets t o 3 0 m g ta blets, as detaile d i n 
Ta ble 3. 2. 2- 1 , bel o w.  Pri or t o eac h u p war d titrati o n, t he s u bject’s t olera bilit y  t o t he 
c urre nt d ose will be assesse d b y  as ki n g, “ C o ul d yo u t olerate t his d ose of trial me dicati o n 
f or t he rest of y o ur life?”  T h ose s u bjects u na bl e t o reac h a n d t olerate at least a 6 0/ 3 0 m g 
t ol va pta n d ose re gi me n wi ll be c o nsi dere d “ R u n -i n fail ures”, t he y will c o m plete e n d of 
E o T x visit assess me nts a n d be f oll o we d u p after 7 da ys b y p h o ne call t o assess a n y 
o n g oi n g A Es .
3. 2. 1. 4
T ol v a pt a n R u n -i n P eri o d ( D a y -2 1 t o D a y  -1)
S u bjects t olerati n g at least 6 0/ 3 0 m g t ol va pta n ma y e nter t he si n gle-bli n d, tol va pta n r u n -
i n peri o d ( 3 wee k d urati o n).  S u bjects will c o nti n ue o n a sta ble 6 0/ 3 0 m g or 9 0/ 3 0 m g 
t ol va pta n d ose t o c o nfir m t olera bilit y o ver a l o n ger peri o d a n d t o esta blis h a t ol va pta n 
pre -ra n d o mizati o n baseli ne.
At t he e n d of t he tol va pta n r u n -i n peri o d, s u bjects n ot t olerati n g at least 6 0/ 3 0 m g 
t ol va pta n will be c o nsi dere d “ R u n -i n fail ures”. T he y  will c o m plete E o T x visit
assess me nts a n d be f oll o we d u p after 7 da ys b y p h o ne call t o assess a n y o n g oi n g A Es.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
3 5
2 6 Mar 2 0 1 5 
3. 2. 2
D o u bl e -bli n d R a n d o mi z e d Tr e at m e nt P eri o d ( D a y 0 t o M o nt h 1 2)
S u bjects c o m pleti n g t he t ol va pta n r u n -i n peri o d t olerati n g at least 6 0/ 3 0 m g of t ol va pta n 
will be ra n d o mize d u p o n e ntr y  t o t his d o u ble-bli n d per i o d. Asi de fr o m t he first re q uire d 
cli nic visit a n d dis pe nsi n g ne w b ottle s of I M P, n o disti ncti o n bet wee n t he pri or r u n -i n 
peri o d a n d t he r a n d o mizati o n peri o d s h o ul d be ma de f or t he s u bject.
After stratifie d ra n d o mizati o n, b y  baseli ne 
 
, a n d by t hree T K V criteria 
, s u bjects will e nter t he d o u ble-bli n d, ra n d o mize d 
treat me nt peri o d recei vi n g eit her t ol va pta n or place b o i n a 1: 1 rati o.  T ol va pt a n, or 
matc hi n g place b o , will be a d mi nistere d at 6 0/ 3 0 or 9 0/ 3 0 m g , as s plit d oses, wit h d o w n-
titrati o ns t o 4 5/ 1 5 m g a n d 3 0/ 1 5 m g as nee de d f or t olera bili t y. Pla n ne d d o w n titrati o n t o 
3 0/ 1 5 m g re q uires c o ns ulta ti o n wit h t he me dical m o nit or.
S u bjects ra n d o mize d t o t ol va pta n will c o nti n ue t o ta ke t he sa me d ose t hat t he y recei ve d 
d uri n g t he t ol va pta n r u n-i n peri o d .  S u bjects ra n d o mize d t o place b o will recei ve place b o 
ta blets matc hi n g t heir t olerate d t ol va pta n d ose d uri n g t he t ol va pta n r u n-i n peri o d.
T he treat me nt d urati o n of t hese s u bjects will be 1 2 m o nt hs fr o m t heir date of 
ra n d o mizati o n.  S u bjec ts n ot c o nti n ui n g i n t his trial will c o m plete E o T x visit assess me nts 
a n d be f oll o we d f or 2 1 d a y s t o assess a n y o n g oi n g A Es.
T a ble 3. 2. 2- 1
D osi n g Sc he d ule
Tri al D a y
N o m i n al Ti me
D ose
1 t o 2 we e ks
(t o Da y −4 3 )
Scree ni n g
1- 2 we e ks ( N o dr u g)
D a y  −4 2 t o -3 6
8: 0 0 a m/
4: 0 0 t o 5: 0 0 p m
Pl ace b o r u n -i n
Place b o ( matc hi n g e q ui vale nt t o t ol va pta n ) 0 m g
D a y  −3 5 t o −2 2
8: 0 0 a m/
4: 0 0 t o 5: 0 0 p m
T ol v a pt a n t itr ati o n
T ol va pta n s plit -d ose titrati o n ( usi n g 1 5 or 3 0 m g ta blets)
3 0/ 1 5, 4 5/ 1 5, 6 0/ 3 0 t he n 9 0/ 3 0 m g 
( gi ve n as 2 x 1 5/ 1 x 1 5; 3 x 1 5/ 1 x 1 5; 2 x 3 0/ 1 x 3 0 or 
3 x 3 0/ 1 x 3 0 m g ta blets, res pecti vel y)
D a y  −2 1 t o −1
8: 0 0 a m/
4: 0 0 t o 5: 0 0 p m
T ol v a pt a n r u n -i n
T ol va pta n sta ble d ose (sa me as ma xi m u m t olerate d d ose 
fr o m t ol va pta n titrati o n, eit her 6 0/ 3 0 or 9 0/ 3 0 m g ) f or 
3 we e ks, usi n g 3 0 m g ta blets
Ra n d o mizati o n 1: 1 - t ol va pta n: place b o ( Da y -1)

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
T a ble 3. 2. 2 - 1
D osi n g Sc he d ule
Tri al D a y
N o m i n al Ti me
D ose
D a y  1 t o M o nt h 1 2
8: 0 0 a m/
4: 0 0 t o 5: 0 0 p m
D o u ble -bli n d r a n d o mize d tre at me nt
T ol va pta n or p lace b o at a n e q ui vale nt d ose gi ve n at last 
da y of t ol va pta n r u n-i n (ie, Da y −1, eit her 6 0/ 3 0 or 
9 0/ 3 0 m g) usi n g 3 0 m g or matc hi n g place b o 0 m g ta blets.
3 0 m g or matc hi n g place b o 0 m g ta blets gi ve n 2 u p o n 
wa ki n g / 1 at 8 -9 h o urs later or 3 u p o n w a ki n g / 1 at 8 -9 
h o urs later.
T ol va pta n (s u bject c o nti n ue d at sa me d ose as Da y −1, b ut 
ma y d o w n -titrate t o 4 5/ 1 5 [or 3 0/ 1 5 m g , wit h me dical 
m o nit or a p pr o val] usi n g 1 5 m g ta blets a n d ret ur n t o 
pre vi o us ma xi mal t olerate d d ose , if p ossi ble)
Place b o (s u bject c o nti n ue d at sa me d ose as Da y −1, b ut
usi n g matc hi n g place b o 0 m g ta blets)
3. 2. 3
F oll o w - u p P eri o d ( D a y + 7 t o D a y + 2 1)
F or ra n d o mize d s u bjects, a 3- wee k f oll o w -u p peri o d will be gi n i m me diatel y  after 
treat ment cessati o n (earl y or pla n ne d). N o I M P will be a d mi nistere d d uri n g t his peri o d.
3. 3
Tri al P o p ul ati o n
T his trial will c o nse nt a n d scree n t ol va pta n naï ve s u bjects wit h A D P K D dia g n ose d by t he 
prese nce of bilateral c y sts per t he Pei- Ra vi ne criteria 1 8 ,1 9 ( m o difie d f or c o m p ute d 
t o m o gra p hy [ C T ] or ma g netic res o na nce i ma gi n g [ M RI ], if nee de d). I n or der t o 
ma xi mize p o wer a n d mi ni mize t he p ossi bilit y  of T ype 2 err or, trial e nr oll me nt will 
c o nti n ue u ntil a p pr o xi matel y 1 3 0 0 s u bjects are ra n d o mize d.
A d ult s u bjects wit h m ore a d va nce d A D P K D -re nal d ysf u ncti o n p he n ot ype will be 
e nr olle d. S u bjects w h o ha ve a d va nce d t o a n e G F R < 6 0 m L / mi n/ 1. 7 3 m2 b y a ge 5 5 or 
< 4 5 m L / mi n/ 1. 7 3 m2 b y  a ge 6 5 re mai n at a si g nifica nt ris k of pr o gressi o n t o E S R D 
bef ore re ac hi n g a vera ge life e x pecta nc y .  Re nal f u ncti o n will be c o nfir me d d uri n g 
scree ni n g b y  t he mea n of e G F R calc ulate d fr o m t he s u bjects’ first 2 pretreat me nt, 
ce ntral-la b ser u m creati ni ne assess me nts.  See Ta ble 3. 4. 2- 1 f or a d diti o nal i ncl usi o n 
criteria.
C o nsiste nt wit h t his trial’s pre -s pecifie d efficac y esti ma n d, onl y  s u bjects t oleratin g t he
si n gle-bli n d r u n -i n peri o d of t ol va pta n ( 6 0/ 3 0 or 9 0/ 3 0 m g per da y ) will be ra n d o mize d t o 
t he d o u ble-bli n d treat me nt peri o d , t o li mit s u bse q ue nt wit h dra wal d ue t o lac k of 
t olera bilit y.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
3 7
2 6 Mar 2 0 1 5 
3. 4
Eli gi bilit y  Crit eri a
3. 4. 1 
I nf or m e d C o n s e nt
Eac h i n vesti gat or has b ot h et hical a n d le gal res p o nsi bilit y t o e ns ure t hat s u bjects bei n g 
c o nsi dere d f or i ncl usi o n i n t his trial are gi ve n a f ull e x pla nati o n of t he pr ot oc ol ( wit h o ut 
re veali n g details of its i nitial si n gle-bli n d nat ure) a n d of t heir r ole a n d res p o nsi bilities i n 
t he pr o p ose d researc h .  T his s hall be d oc u me nte d o n a writte n I C F t hat s hall be a p pr o ve d 
b y  t he sa me i nstit uti o nal re vie w b oar d/i n de pe n de nt et hics c o m mittee (IR B/I E C) 
res p o nsi ble f or a p pr o val of t his pr ot oc ol.  I n a d diti o n, t he pr ot oc ol e x pla nati o n ma y 
i ncl u de rec or de d or electr o nic mea ns of e d ucati o n, w hic h will als o meet IR B/I R C 
a p pr o val.  Eac h I C F s hall i ncl u de t he ele me nts re q uire d b y  t he I nter nati o nal C o nfere nce 
o n Har m o nizati o n ( I CH) G o o d Cli nical Practice ( G C P) G ui deli ne 2 0 a n d l ocal re g ulat or y 
re q uire me nts a n d m ust a d here 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 i n vesti gat or a grees t o o btai n a p pr o val fr o m t he s p o ns or of 
a n y writte n I C F use d i n t he trial, pri or t o s u b missi o n t o t he I R B/I E C. Tra nslati o ns of t he 
I CF i nt o t he s u bject p o p ulati o ns’ nati ve la n g ua ge s h o ul d be certifie d a n d ha ve bee n bac k 
tra nslate d wit h s p o ns or a p pr o val of t he bac k tra nslati o n.
Writte n i nf or me d c o nse nt will be
o btai ne d fr o m all s u bjects ( or t heir g uar dia n or le gal 
re prese ntati ve, as a p plica ble f or l ocal la ws).  I n vesti gat ors ma y disc uss t he a vaila bilit y of 
t he trial a n d t he p ossi bilit y f or e ntr y wit h a p ote ntial s u bject wit h o ut first o btai ni n g 
c o nse nt.  H o we ver, i nf or me d c o nse nt m ust be o btai ne d a n d d oc u me nte d pri or t o i nitiati o n 
of a n y pr oce d ures t hat are perf or me d s olel y f or t he p ur p ose of deter mi ni n g eli gi bilit y  f or 
t his trial, i ncl u di n g wit h dra wal fr o m c urre nt me dicati o n(s).  W he n t his is d o ne i n 
a ntici pati on of, or i n pre parati o n f or, t he researc h, it is c o nsi de re d t o be part of t he 
researc h.
O nce t he a p pr o priate esse ntial i nf or mati o n has bee n pr o vi de d t o t he s u bject a n d f ull y  
e x plai ne d i n la yma n’s la n g ua ge b y t he i n vesti gat or ( or a q ualifie d desi g nee) a n d i t is felt 
t hat t he s u bject u n dersta n ds t he i m plicati o ns of partici pati n g, t he I R B/I E C-a p pr o ve d 
writte n I C F s hall be si g ne d a n d date d b y  all s u bjects ( or t heir g uar dia n or le gal 
re prese ntati ve, as a p plica ble f or l ocal la ws), a n d t he pers o n o btai ni n g c o nse nt
(i n vesti gat or or desi g nee), a n d b y a n y ot her parties re q uire d by t he I RB/I E C.  T he s u bject 
s hall be gi ve n a c o py of t he si g ne d I C F; t he ori gi nal s hall be ke pt o n file b y t he 
i n vesti gat or.  All of t he a b o ve me nti o ne d acti vities m ust be c o m plete d pri or t o the 
s u bject’s partici pati n g i n t he trial.
S u bjects will ha ve t he o pti o n of c o nse nti n g o n t he writte n I C F f or c ollecti o n of D N A 
sa m ples.  S u bjects d o n ot nee d t o c o nse nt t o t he D N A sa m ple c ollecti o n i n or der t o be 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
3 8
2 6 Mar 2 0 1 5 
c o nsi dere d as a p ote ntial s u bject i n t he tri al.  S u bjects w h o c o nse nt t o t he D N A sa m ple 
c ollecti o n m a y  wit h dra w t heir c o nse nt t o t he s p o ns or’s f ut ure a nalys is of t hat sa m ple ( b y 
writte n re q uest, as detaile d i n t he I C F) .
3. 4. 2 
I n cl u si o n Crit eri a
S u bjects are re q uire d t o meet t he f oll o wi n g i ncl usi o n criteria:
T a ble 3. 4. 2 - 1 
I ncl usi o n Criteri a
1.
Male a n d fe male s u bjects a ge 1 8 t o 5 5 years
of a ge (i ncl usi ve) wit h e G F R bet wee n 2 5 a n d 
6 5 m L / mi n/ 1. 7 3 m2 -O R -
2.
Male a n d fe male s u bjects a ge 5 6 t o < 6 6 years of a ge wit h e G F R b et wee n 2 5 a n d 
4 4 m L / mi n/ 1. 7 3 m2 wit h e vi de nce of A D P K D pr o gressi o n , ie, e G F R decli ne of 
> 2. 0 m L/ mi n/ 1. 7 3
m 2 per ye ar , b ase d o n hist oric al e G F R d at a a n d me dic al m o nit or 
discreti o n .
3.
Male a n d fe male s u bjects w h o are t ol va pta n
naï ve .
4.
Dia g n osis of A D P K D b y m o difie d Pei -Ra vi ne criteria 1 8 1 9 :

Wit h fa mil y hist or y: se veral c ysts per ki d ne y ( 3 if b y s o n o gra p h y, 5
if b y C T or M RI )

Wit h o ut fa mil y hist or y: 1 0 c ysts per ki d ne y ( b y a n y ra di ol o gic met h o d, a b o ve ) a n d e xcl usi o n 
of ot her c ystic ki d ne y diseases. C o n diti o ns t o be e xcl u de d i ncl u de: m ulti ple si m ple re nal 
c ysts, re nal t u b ular aci d osis, c ystic d ys plasia of t he ki d ne y, m ultic ystic ki d ne y, m ultil oc ular 
c ysts of t he ki d ne y, me d ullar y c ystic ki d ne y a n d ac q uire d c ystic disease of t he ki d ne y .

Distri b uti o n a n d n u m ber of c ysts c o nsiste nt wit h t he o bser ve d le vel of re nal f u ncti o n deficit.
3. 4. 3
E x cl u si o n Crit eri a
S u bjects will be e xcl u de d if t he y  meet a n y of t he f oll o wi n g e xcl usi o n criteria d uri n g t he 
pre -ra n d o mizati o n peri o d.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
T a ble 3. 4. 3 - 1 
E xcl usi o n Criteri a
1.
W o m e n of c hil d beari n g p ote ntial ( W O C B P) w h o d o n ot a gree t o practice 2 differe nt met h o ds of 
birt h c o ntr ol or re mai n a bst i ne nt d uri n g t he trial a n d f or 3 0 d a ys after t he last d ose of I M P. If 
e mpl o y i n g birt h c o ntr ol, 2 of t he f oll o wi n g preca uti o ns m ust be use d: vasect o m y of  part ner, t u bal 
li gati o n, va gi nal dia p hra g m, i ntra uteri ne de vice, birt h c o ntr ol pill, birt h c o ntr ol i m pla nt, birt h 
c o ntr ol de p ot i njecti o n, c o n d o m, or s p o n ge wit h s per mici de.
2.
W o m e n w h o are breast -fee di n g a n d/ or w h o ha ve a p ositi ve pre g na nc y test res ult pri or t o recei vi n g
I M P.
3.
Nee d f or c hr o nic di uretic use .
4.
He patic i m pair me nt or li ver f u ncti o n a b n or malities ot her t ha n t hat e x pecte d f or A D P K D wit h 
t ypical c ystic li ver disease d uri n g t he pre-ra n d o mizati o n peri o d.
5.
S u bjects wit h a d va nce d dia betes (e g, gl yc os ylate d he m o gl o bi n [H g b A 1c ] > 7. 5 , a n d/ or gl yc os uria 
b y di pstic k, si g nifica nt pr otei n uria, reti n o pat h y), e vi de nce of a d diti o nal si g nifica nt re nal 
disease(s) (ie, c urre ntl y acti ve gl o mer ular ne p hriti des ), re nal ca ncer, si n gle ki d ne y, or rece nt 
( wit hi n last 6 m o nt hs ) re nal s ur ger y or ac ute ki d ne y i nj ur y .
6.
S u bjects wit h c o ntrai n dicati o ns t o re q uire d trial assess me nts. 
7.
S u bjects w h o, i n t he o pi ni o n of t he trial i n vesti gat or or me dical m o nit or, ha ve a me dical hist or y or 
me dical fi n di n gs i nc o nsiste nt wit h safet y or c o m plia nce wit h trial assess me nts .
8.
T ol va pta n is c o ntrai n dicate d i n patie nts w h o: are k n o w n t o ha ve h y perse nsiti vit y t o t ol va pta n or 
o ne of t he e xci pie nts, are h y p o v ole mic ( v ol u me de pleti o n), ca n n ot percei ve t hirst.  A d diti o nall y, 
s u bjects wit h baseli ne scree ni n g a b n or malities of ser u m s o di u m c o nce ntrati o ns ( h y p o natre mia or 
h y per natre mi a) ma y n ot be e nr olle d i n t he trial u ntil t hese a b n or malities res ol ve a n d t he n m ust be 
m o nit ore d acc or di n gl y.  
N o n -c hil d beari n g p ote ntial i n w o me n is defi ne d as fe male s u bjects w h o are s ur gicall y 
sterile (ie, ha ve u n der g o ne bilateral o o p h orect o my or h y sterect o my) or fe male s u bjects 
w h o ha ve bee n p ost me n o pa usal f or at least 1 2 c o nsec uti ve m o nt hs.
S u bjects ma y  be re-scree ne d, at t he discreti o n of t he me dical m o nit or, if t he e xcl usi o n 
c haracteristic has c ha n ge d or res ol ve d.  I n t he e ve nt t hat a s u bject is r e-scree ne d, a ne w 
I CF m ust be si g ne d a n d a ne w scree ni n g n u m ber assi g ne d a n d scree ni n g pr oce d ures 
re peate d.
3. 5
O ut c o m e E n d p oi nt s
3. 5. 1
Pri m ar y  O ut c o m e E n d p oi nt
3. 5. 1. 1
Pri m ar y  Effi c a c y  E n d p oi nt
Treat me nt differe nce i n t he c ha n ge of e G F R fr o m pre-treat me nt baseli ne t o p ost-
treat me nt f oll o w- u p, a n n ualize d ( di vi de d) b y eac h s u bject’s I M P treat me nt d urati o n .
3. 5. 2
S e c o n d ar y  O ut c o m e E n d p oi nt s
3. 5. 2. 1
K e y  S e c o n d ar y Effi c a c y E n d p oi nt
Treat me nt differe nce i n a n n ualize d sl o pe of e G F R calc ulate d f or i n di vi d ual s u bjects 
usi n g e G F R data o bser ve d i n t he place b o r u n -i n, t ol va pta n r u n-i n ( n ot i ncl u di n g t ol va pta n 

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titrati o n), d o u ble-bli n d treat me nt, a n d p ost -treat me nt f oll o w-u p ( n ot i ncl u di n g data 
c ollecte d i n t he first wee k after t he last I M P d ose) peri o d s.
3. 5. 2. 2
S af et y  E n d p oi nt s
Safet y  e n d p oi nts t o be a nal yze d will i ncl u de a descri pti ve s u m mar y of:
1)
A E s
2)
Vital si g ns
3)
Cli nical la b orat or y  tests, i ncl u di n g ser u m tra nsa mi nases, B T, A LP, a n d ser u m 
s o di u m
3. 5. 2. 3
P h ar m a c o ki n eti c/ P h ar m a c o d y n a mi c E n d p oi nt s
P K E n d p oi nts :  Deter mi nati o n of plas ma t ol va pta n a n d meta b olite (s), i ncl u di n g D M - 4 1 0 3 
c o nce ntrati o ns.
P D E n d p oi nts :  U os m a n d uri ne s pecific gra vity
3. 5. 3
E x pl or at or y O ut c o m e E n d p oi nt s
3. 5. 3. 1
E x pl or at or y  Effi c a c y E n d p oi nt
 
 
 
3. 5. 3. 2
E x pl or at or y  S af et y E n d p oi nt s

 
 
 
 
 
3. 6
M e a s ur e s t o Mi ni mi z e/ A v oi d Bi a s
O nl y  s u bjects w h o reac h Da y - 1 a n d are w h o ha ve i n dicate d t hat t he y  w o ul d li kel y be 
a ble t o t olerate a d ose of t ol va pta n “f or t he rest of t heir li ves” at a le vel of 6 0/ 3 0 m g or 
9 0/ 3 0 m g will be eli gi ble t o e nter t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d.  I n t his 

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peri o d, neit her t he s u bject n or t he i n vesti gat or or his/ her staff will k n o w w hic h treat me nt 
is assi g ne d.  I m me diately pri or t o ra n d o mizati o n, a n d at all s u bse q ue nt visits or site -
s u bject c o ntacts, t he s u bject will be re mi n de d of t he i m p orta nce of t heir c o m mit me nt t o 
c o nti n ue partici pati o n i n t he trial, h o we ver t he s u bject will n ot be t ol d t hat t his da y is t he 
p oi nt at w hic h ra n d o mizati o n t o l o n g -ter m t hera py occ urs.
Ra n d o mizati o n will be 1: 1, t ol va pta n ( 6 0/ 3 0 m g or 9 0/ 3 0 m g) t o place b o, a n d will utilize 
a n i nteracti ve v oice res p o nse s y ste m (I VR S) t o e ns ure a p pr o priate stratificati o n .  
Esti mate d G F R is a n i m p orta nt pre dict or of t he ra te of re nal f u ncti o n decli ne; theref ore, 
s u bjects will be stratifie d b y t heir baseli ne e G F R at a t hres h ol d of 
 
a n d b y a ge (5 5 or > 5 5 y ears ol d).  S u bjects will als o be stratifie d 
b y  t hree T K V criteria 
.
T he p rescri pti o n of a d diti o nal fl ui d t o s u bjects i n t his trial ma y  ser ve t o c o nf o un d s u bject 
u n bli n di n g, b ut it is ac k n o wle d ge d t hat, wit h a ra n d o mize d wi t h dra wal desi g n, a 
li mitati o n of t he mai n a n d e x pl orat or y a nalys es mi g ht i ncl u de t he s u bject’s perce pti o n of 
t heir treat me nt assi g n me nt. N ote, h o we ver , t hat calc ulati o n of e G F R is a n o bjecti ve 
meas ure a n d is e x pecte d t o be u naffecte d b y s uc h perce pti o ns.
3. 7
Tri al Pr o c e d ur e s
Trial assess me nt ti me p oi nts are s u m marize d i n Ta ble 3. 7- 1 .

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T a ble 3. 7- 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1) ( D a y 0)
Visits:
m o nt hl y
( ± 2 
d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt a
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 8 t o + 2 1 
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
V 1  
V 2  
V 3
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n
X
D e m o gr a p hic/ Me dic al hist or y
X
Vit al si g ns c
X
X 
X
X
X
( X)c
X
X
P h ysic al e x a mi n ati o n d
X
( X)d
X
Uri ne pre g n a nc y test ( W O C B P 
o nl y) e
X
X
( X)e
X
X
C he mistr y Bl o o d S a m ple c,f:
   Ser u m C he mistr y Pa nel
X
X
X
   Li ver F u ncti o n Pa nel
X  
X
X
X  
X
X  
X
X
   Creati ni ne
X
X 
X
X  
X  
X
X  
X  
X  
X  
X
   S o di u m
X  
X
X
X
X
X  
X
X
H e m at ol o g y a n d c o a g ul ati o n
X
P K pl as m a s a m ple
X
( X)g
X
X

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T a ble 3. 7- 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1) ( D a y 0)
Visits:
m o nt hl y
( ± 2 
d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt a
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 8 t o + 2 1 
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
V 1  
V 2  
V 3
Bi o m ar ker pl as m a s a m ple
X
X
X
X
( X)g
X
X
D N A bl o o d s a m ple h
X
Uri n al ysis
X
X 
X
X
X
P D a n d Bi o m ar ker uri ne 
s a m ple
X g
X g
X g
X g
( X)g
X g
X g
St art ne wl y dis pe nse d I M P
X  
X
X
X
T oler a bilit y/ D osi n g re vie w
X  
X  
X  
X  
X
X
X  
X
R a n d o miz ati o n
X
Dr u g dis pe ns ati o n i
X  
X
X
X
X
Dr u g rec o ncili ati o n i
X
X
X
X  
X
I V R S e ntr yj
X  
X  
X
X
X
X  
X
X
E x pl or at or y P K D o utc o m es k
X
X
X  
X
A d verse e ve nts
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>
C o nc o m it a nt me dic ati o ns
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>

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aT he scree ni n g peri o d s h o ul d be c o m plete d wit hi n 1 -2 w ee ks bef ore t he start of t he place b o r u n -i n peri o d.  T he scree ni n g peri o d ma y be e xte n de d u p t o a n 
a d diti o nal 8 wee ks f or s u bjects w h o re q uire m o dificati o n of me dical care s pecificall y f or t his trial. V isits d uri n g t he scree ni n g a n d f oll o w-u p peri o ds m ust 
be sc he d ule d at least 2 4 h o urs ( 1 da y) a part.  T he Da y -4 3 visit ca n n ot occ ur u ntil la b orat or y val ues fr o m V 2 are recei ve d.  F or t w o visits ( V 1, V 2) d uri n g 
t he scree ni n g peri o d, bl o o d will be c ollecte d a n d a nal yze d ce ntrall y f or ser u m creati ni ne c o nce ntrati o ns, i n a d diti o n t o a n y ot her assess me nts liste d.  A 
visiti n g n urse h o use call or l ocal la b orat or y visit ma y be s u bstit ute d f or visits w here o nl y bl o o d/ uri ne will be c ollecte d d u ri n g t he f oll o w- u p ( F/ U) peri o d.  
T hree visits i n t he F/ U peri o d s h o ul d be sc he d ule d bet wee n Da y 8 a n d Da y 2 1 (i ncl usi ve) after t he last d ose of I M P .  N o F/ U assess me nts will be ta ke n 
d uri n g t he first wee k of t his peri o d.  Bl o o d sa m ples will be dra w n at eac h visit f or ser u m creati ni ne ( V 1, V 2) a n d ser u m creat i ni ne a n d ot her safet y, 
efficac y, P K a n d P D meas ure me nt s ( V 3).  
b If I M P treat me nt is i nterr u pte d f or 7 da ys d uri n g t his peri o d, pr oce d ures s h o ul d be f oll o we d as detaile d i n Secti o n 3. 8. 3. 2 .
cT he f oll o w i n g visits (a n d all assess me nts re q uire d d uri n g t h ose visits) s h o ul d be perf or me d i n-cli nic: scree ni n g ( V 1, V 2, Da y -4 3), e n d of place b o r u n -i n, e n d 
of t ol va pta n titrati o n, e n d of t ol va pta n r u n-i n, q uarterl y visits d uri n g t he ra n d o mize d, d o u ble-bli n d treat me nt peri o d (e g, M o nt hs 3, 6, 9), M o nt h 1 2/e n d of 
treat me nt ( E o T x) visit, a n d t he last f oll o w-u p visit.  Vital si g ns at eac h of t he a b o ve visits i ncl u de sitti n g heart rate a n d bl o o d press ure.  P ost -v oi d b o d y 
wei g ht s h o ul d be meas ure d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit o nl y.  Hei g ht s h o ul d be assesse d at t he fi rst scree ni n g visit o nl y.  Eit her 
hei g ht or wei g ht ma y be c ollecte d as a n u nsc he d ule d meas ure me nt if the pla n ne d assess me nt was misse d .  Wei g ht ma y be assesse d as necessar y t o assess 
c ha n ges i n b o d y wei g ht.
d A f ull p h ysical e xa mi nati o n is re q uire d at scree ni n g ( V 1) a n d t he M o nt h 1 2/ E o T x visit.  A “ directe d p h ysical e xa mi nati o n” is perf or me d at t he q uarterl y visits 
(e g, M o nt hs 3, 6, 9) f or assess me nt of si g ns or s y m pt o ms re p orte d b y t he s u bject t hat mi g ht re q uire f urt her e val uati o n.
eD uri n g t he trial, a pre g na nc y test s h o ul d be c o m plete d at scree ni n g, e n d of place b o r u n -i n a n d at t he q uarterl y visits.  O n s us pici o n of pre g na nc y, 
u nsc he d ule d uri ne or ser u m pre g na nc y testi n g will be perf or me d.  P ositi ve uri ne pre g na nc y tests s h o ul d be c o nfir me d wit h a se r u m pre g na nc y test.
fAll ser u m creati ni ne sa m ples will be a nal yze d b y t he ce ntral la b orat or y.  T he s pecifics a n d ti mi n g f or all cli nical la b orat or y sa m ples f or ce ntral a n d l ocal 
la b orat or y a nal yses are as f oll o ws:
All visits:
O ne or m ore t u bes of bl o o d ma y be c ollecte d t o acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 1 -2 w ee ks of t he scree ni n g pe ri o d, bl o o d will be dra w n 2 ti mes o n se parate da ys ( V 1, V 2) at least 2 4 h o urs a part.  T he 
s u bject’s eli gi bilit y will be c o nfir me d b y t he mea n of e G F R calc ulate d fr o m t he s u bjects’ 2 pre-treat me nt ( V 1, V 2), ce ntral la b orat or y ser u m creati ni ne 
assess me nts a n d e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  S u bjects will ha ve 1 bl o o d dra w  at t he e n d of 1 wee k wit h t he sa m ple bei n g o btai ne d o n Da y -3 6.
T ol v a pt a n titr ati o n peri o d:   S u bjects will ha ve 1 bl o o d dra w at t he e n d of 2 wee ks wit h t he sa m ple bei n g o btai ne d o n Da y -2 2.
T ol v a pt a n r u n -i n peri o d:  D uri n g t he last 2 wee ks of t his peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys (at least 2 4 h o urs a part) wit h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt peri o d:   Sa m ples will be c ollecte d f or ce ntral la b a nal ysis m o nt hl y a n d at t he M o nt h 1 2/ E o T x visit.  L ocal sta n dar d of care 
la b orat or y tests will be perf or me d m o nt hl y per t he s u bject’s i n di vi d ual cli nical ma na ge me nt nee ds.  L ocal li ver f u ncti o n pa nel a nal yses will als o be 
perf or me d m ore fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects will ha ve bl o o d dra w n o n 3 visits at least 2 4 h o urs a part d uri n g t he 3 -wee k F/ U peri o d , w hic h starts after t he last d ose of I M P .  
Visits s h o ul d be sc he d ule d bet wee n Da ys 8 a n d 2 1 , i ncl usi ve.
    F ull C he mistr y pa nel will be o btai ne d d uri n g t he f oll o wi n g visits: Scree ni n g ( V 1), q uarterl y visit ( M 3, M 6, M 9, M 1 2/ E o T x, F/ U peri o d ( V 3). 

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    Ser u m creati ni ne, ser u m s o di u m: Scree ni n g ( V 2) , e n d of place b o peri o d, e n d of t ol va ptan tit rati o n, 2 ti mes d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g 
d o u ble - bli n d treat me nt peri o d, 3 ti mes f or ser u m creati ni ne a n d 1 ti me f or ser u m s o di u m ( V 3) d uri n g t he F/ U peri o d .  N ote t hat t he first F/ U visit will 
occ ur at least 7 da ys ( Da y 8) after t he last d ose of I M P.
    Li ver f u ncti o n pa nel:
Scree ni n g ( V 2), e n d of place b o peri o d , e n d of t ol va pta n titrati o n, 1 ti me d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d ( V 3).
g D uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d, P K plas ma sa m ples, P D uri ne sa m ples, a n d bi o mar ker uri ne/ plas ma sa m ples will be c ollecte d 
q uarterl y (e g, M o nt hs 3, 6, 9, 1 2/ E o T x).   Uri ne bi o mar ker sa m ples s h o ul d be c ollecte d as a mi d -strea m, clea n-catc h sa m ple d uri n g t he sec o n d m or ni n g v oi d 
pri or t o t he s u bject eati n g brea kfast.  W here necessar y, s u p plies f or c ollecti o n s h o ul d be dis pe nse d pri or t o t he visit wit h i nstr ucti o ns t o c ollect t he uri ne 
sa m ple o n t he da y of t he visit.
h D N A sa m ples are o pti o nal a n d ma y be c ollecte d at s u bse q ue nt visits wit h s u bject’s c o nse nt.
iDr u g dis pe nsi n g a n d rec o nciliati o n will be d o ne m o nt hl y (e xce pti o ns t o all o w dis pe nsi n g/rec o nciliati o n at eac h 3 -m o nt h cli nic visit ma y be ma de b y t he 
me dical m o nit or i n e xce pti o nal circ u msta nces, wit h i nstr ucti o ns t o ta ke o nl y o ne m o nt h’s s u p pl y a n d start t he ne xt m o nt h o nl y after acce pta ble safet y la b 
res ults are c o nfir me d b y t he i n vesti gat or).  I nstr ucti o ns t o be gi n ta ki n g t he ne xt m o nt h’s trial me dicati o n will be gi ve n d uri n g t he ti me of I M P dis pe nsat io n 
at eac h m o nt hl y visit or b y tele p h o ne c o ntact after t he m o nt hl y L F T sa m ple s are c ollecte d.  If L F T res ults are a b n or mal, t he site will c o n d uct a tele p h o ne 
c o ntact wit h t he trial s u bject t o i nf or m t he m t hat pr o m pt i m me diate retesti n g (ie, wit hi n 7 2 h o urs) ma y be necessar y (see Secti o n 3. 7. 3. 4 f or g ui da nce) a n d
to arra n ge f or f oll o w -u p a n d a dj ust me nt of me dicati o n (as nee de d) ; if a d o w n titrati o n is re q uire d, t he s u bject ma y nee d t o ret ur n t o t he site or ha ve ne w 
dr u g deli vere d.   S u bjects will be re mi n de d of t he i m p orta nce of t heir c o m mit me nt t o c o nti n ue partici pati o n i n t he trial.  At t he c o m pleti o n of t he scree ni n g 
peri o d, trial me dicati o n wi ll be dis pe nse d at Da y -4 3 after s u bject eli gi bilit y is c o nfir me d.  I n e xce pti o nal circ u msta nces, trial me dicati o n ma y be dis pe nse d 
at V 2, wit h t he i nstr ucti o n n ot t o ta ke a n y trial me dicati o n u ntil eli gi bilit y is c o nfir me d b y t he i n vesti gat or.  I n t hese cases, c o nfir mati o n of eli gi bilit y a n d 
i nstr ucti o ns f or ta ki n g trial me dicati o n will be pr o vi de d b y tele p h o ne o n Da y -4 3.
jAt t he e n d of t he titrati o n peri o d, t he s u bject’s hi g hest t olerate d d ose will be utilize d f or t he 3 -we e k t ol va pta n r u n -i n peri o d.
k E x p l orat or y P K D o utc o mes will be c o m plete d eit her m o nt hl y o ver t he p h o ne or i n pers o n d uri n g q uarterl y cli nic visits.

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3. 7. 1
S c h e d ul e of A s s e s s m e nt s
3. 7. 1. 1
Pr e -r a n d o mi z ati o n P eri o d
After o btai ni n g c o nse nt a n d u p o n esta blis hi n g i nitial eli gi bilit y usi n g i ncl usi o n/e xcl usi o n 
criteria, s u bjects will e nter a n i nitial 8 -wee k, si n gle -bli n d, pre -ra n d o mizati o n peri o d pri or 
t o act ual ra n d o mizati o n w hic h will c o nsist of:

scree ni n g peri o d ( 1- 2 wee ks; l o n ger d urati o ns of u p t o 8 a d diti o nal wee ks ma y  be 
re q uire d acc ordi n g t o t he i n vesti gat or’s j u d g me nt, as descri be d bel o w )

place b o r u n -i n peri o d ( 1 wee k) 

t ol va pta n titrati o n peri o d ( 2 wee ks)

t ol va pta n r u n-i n peri o d ( 3 wee ks)
T here are 2 g oals of t his pre -ra n d o mizati o n peri o d: 1) t o esta blis h t he de gree t o w hic h a 
he m o d y na mic e G F R s hift ma y  occ ur f or eac h p ote ntial treat me nt assi g n me nt ( place b o 
a n d t ol va pta n); a n d 2) t o deter mi ne t he ma xi mall y t olerate d d ose of t ol va pta n f o r eac h 
s u bject b y self-re p ort.
Pre -ra n d o mizati o n e G F R val ue(s) will be calc ulate d b y C K D-E PI f or eac h p ote ntial 
treat me nt assi g n me nt f or all s u bjects.  Ha vi n g t hese data pre -ra n d o mizati o n will all o w f or 
t he f oll o wi n g:  e q ui vale nt e val uati o n of baseli ne c haracteristics, i ncl u di n g t he ac ute 
he m o d y na mic res p o nse t o t ol va pta n i n all s u bjects w h o will c o ntri b ute t o t he pri mar y  a n d 
ke y  sec o n dar y e n d p oi nt; facilitate baseli ne assess me nts w hic h a p pr o priatel y acc o u nts f or 
place b o effect a n d t ol va pta n he m o d y na mic o ns et effect of all ra n d o mize d s u bjects w h o 
ha ve a p ost -ra n d o mizati o n e G F R.  It als o all o ws f or c o m paris o n of ra n d o mize d, 
c o m pleter a n d n o n -c o m pleter p o p ulati o ns i n ter ms of t heir he m o d y na mic res p o nse t o 
t ol va pta n.
T o esta blis h t he pre -ra n d o mizati o n e G F R, m ulti ple ser u m creati ni ne val ues 
(I D M S-tracea ble) will be o btai ne d u n der sta n dar dize d c o n diti o ns (see Secti o n 3. 7. 2. 1 ), 
eac h se parate d b y o ne ( mi ni m u m of 2 4 h o urs) t o se veral da y s d uri n g t he scree ni n g peri o d 
a n d place b o r u n-i n f or t he pri mar y e n d p oi nt, a n d d uri n g eac h treat me nt’s r u n-i n peri o d 
f or t he ke y sec o n dar y e n d p oi nt.  T he e G F R f or eac h ser u m creati ni ne assess me nt will be 
calc ulate d a n d t he n a vera ge d , wit h t he me dia n of assess me nt dates bei n g set as t he 
s u bject’s e G F R val ue’s date.
3. 7. 1. 1. 1
S cr e e ni n g P eri o d ( u p t o D a y -4 3)
T he scree ni n g peri o d will be f or 1- 2 wee ks, b ut m a y  be e xte n de d u p t o a n a d diti o nal 
8 wee ks f or s u bject s w h o re q uire m o dificati o n of me dical care or f urt her me dical 
e val uati o n s pecificall y f or t his trial.  T his ma y i ncl u de, f or e xa m ple, sta bilizi n g 

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a nti-h y perte nsi ve re gi me ns f or s u bjects disc o nti n ui n g di uretics or “ was h - o ut” of ot her 
i n vesti gati o nal a ge nts. As part of t his sta bilizati o n or was h -o ut peri o d, li ver f u ncti o n 
a n d/ or ot her la b safet y tests ma y be perf or me d , as nee de d.
T he scree ni n g peri o d s h o ul d be c o m plete d wit hi n 1-2 wee ks of t he place b o r u n -i n peri o d, 
( u nless e xte n de d as descri be d a b o ve).  Bl o o d will be d ra w n 2 ti mes o n se parate da ys 
( visit 1 a n d visit 2), at least 2 4 h o urs a part.  T he Da y  -4 3 visit will n ot be sc he d ule d u ntil 
la b orat or y res ults fr o m t he sec o n d visit are recei ve d a n d e val uate d, s o t hat t he calc ulate d 
mea n e G F R res ult is a vaila ble f or eli gi bilit y assess me nt o n Da y  - 4 3.
Assess me nts d uri n g t he scree ni n g peri o d will i ncl u de ( See Ta ble 3. 7- 1 ):
1)
C o nfir m dia g n osis a n d deter mi ne w het h er t he s u bject meets i ncl usi o n a n d 
e xcl usi o n criteria (first visit)
2)
Rec or d me dical/ P K D hist or y , i ncl u di n g de m o gra p hic i nf or mati o n (first visit)
3)
Rec or d c o nc o mita nt me dicati o ns a n d e ns ure s u bject's treat me nt meets c urre nt 
sta n dar d of care i ncl u di n g lifestyl e a n d dietar y rec o m me n dati o ns, es peciall y f or 
i n gesti o n of at least 2-3 liters of fl ui d per da y  as a p pr o priate, u nless ot her wise 
directe d b y y o ur st u d y d oct or. (all visits)
4)
Assess A Es (if re p orte d; all visits) 
5)
Perf or m a f ull p h ys ical e xa mi nati o n (first visit)
6)
Assess vital si g ns (i ncl u de sitti n g heart rate a n d bl o o d press ure [first a n d sec o n d 
visits])
7)
Assess p ost -v oi d b o d y  wei g ht a n d hei g ht (first visit)
8)
Uri ne pre g na nc y  test f or W O C B P (first visit)
9)
C ollect uri nal y sis sa m ples (first a n d sec o n d visits)
1 0) C ollect bl o o d f or ser u m creati ni ne f or e G F R calc ulati o n ( 2 c ollecti o ns: first a n d 
sec o n d visits, at least 2 4 h o urs a part)
1 1) C ollect bl o o d f or ce ntral cli nical la b orat or y  a nalys es (s o di u m [first a n d sec o n d 
visits]), he mat ol o g y , ser u m c he mistr y, a n d li ver f u ncti o n panel [first visit] - see 
Secti o n 3. 7. 3. 2).  If s o di u m, ser u m c he mistr y  a n d/ or li ver f u ncti o n pa nel are 
c ollecte d at t he sa me visit, a si n gle t u be of bl o o d s h o ul d be dra w n f or all 
assess me nts.
1 2) C ollect P D uri ne sa m ple (sec o n d visit)
1 3) C ollect bi o mar ker plas ma a n d uri ne sa m ples (sec o n d visit, see Secti o n 3. 7. 3. 5)
1 4) C o m plete P K D hist or y  a n d o utc o mes s ur ve ys
1 5) Re gister s u bject stat us i n I V R S
1 6) C ollect bl o o d f or D N A sa m ple (sec o n d visit, f or c o nse nti n g s u bjects o nl y) .  D N A 
sa m ples ma y be c ollecte d at a s u bse q ue nt visit if s u bjects c o nse nt at a later date.

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1 7) Dis pe nse I M P f or ne xt peri o d (last visit)
Preli mi nar y  eli gi bilit y f or t he trial will be i nitiall y assesse d usi n g t he s u bjects’ hist orical 
la b orat or y or i ma gi n g data.  Eli gi bilit y will be c o nfir me d b y t he mea n of e G F R calc ulate d 
fr o m t he s u bjects’ 2 pre-treat me nt, ce ntral-la b ser u m creati ni ne assess me nts.
C o nfir mati o n of A D P K D di a g n osis ( usi n g t he m o difie d Pei- Ra vi ne criteria) ma y  re q uire 
c o nfir mat or y i ma gi n g.  S u bjects will be t ol d t hat t he y will recei ve b ot h t ol va pta n a n d 
place b o d uri n g vari o us s u bse q ue nt peri o ds of t he trial a n d t hat t he ne xt peri o d i n v ol ves a 
d ose escalati o n wit h m ulti ple efficac y , safety, a n d t olera bilit y assess me nts.  Trial 
me dicati o n will be dis pe nse d at Da y  -4 3 after s u bject eli gi bilit y  is c o nfir me d.  I n 
e xce pti o nal circ u msta nces, trial me dicati o n ma y be dis pe nse d at t he sec o n d visit, wit h t he 
i nstr ucti o n n ot t o ta ke a n y trial me dicati o n u ntil eli gi bilit y is co nfir me d b y t he 
i n vesti gat or.  I n t hese cases, co nfir mati o n of eli gi bilit y  a n d i nstr ucti o ns f or ta ki n g trial 
me dicati o n will be pr o vi de d b y  tele p h o ne o n Da y - 4 3.
3. 7. 1. 1. 2
Pl a c e b o R u n -i n P eri o d ( D a ys -4 2 t o -3 6)
T he place b o r u n -i n peri o d will be 1 wee k (1 da y) a n d will be c o n d ucte d i n a 
si n gle-bli n de d fas hi o n . Su bjects will be gi ve n place b o i n a dail y s plit d ose of a si n gle 
0 m g ta blet u p o n a wa ke ni n g a n d a n ot her 0 m g ta blet a p pr o xi matel y 8 t o 9 h o urs later 
(a b bre viate d 0/ 0 m g), i n a f or m i de ntical t o 1 5/ 1 5 m g t ol va pta n ta blets.
Assess me nts d uri n g t he place b o r u n -i n peri o d will i ncl u de ( See Ta ble 3. 7- 1 ):
1)
Rec or d c o nc o mita nt me dicati o ns at all visits
2)
Assess A Es at all visits
3)
Assess vital si g ns ( i ncl u de sitti n g heart rate a n d bl o o d press ure ) o n Da y  - 3 6
4)
C ollect uri nal y sis sa m ple o n Da y  - 3 6
5)
Uri ne pre g n a nc y test f or W O C B P ( Da y - 3 6)
6)
C ollect bl o o d f or ser u m creati ni ne f or e G F R calc ul ati o n a n d f or assess me nt of 
s o di u m a n d li ver f u ncti o n pa nel o n Da y  - 3 6 (see Secti o n 3. 7. 3. 2 ).
7)
C ollect P D uri ne sa m ple o n Da y  - 3 6
8)
C ollect bi o mar ker plas ma a n d uri ne sa m ples (see Secti o n 3. 7. 3. 5 ) o n Da y  - 3 6
9)
As k s u bject “ Ca n y o u t olerate t his d ose of trial me dicati o n f or t he rest of y o ur 
life?” o n Da y  - 3 6
1 0) U p date s u bject stat us i n I V R S o n Da y  - 3 6
1 1) I M P rec o nciliati o n o n Da y -3 6
1 2) Dis pe nse I M P f or ne xt peri o d o n Da y - 3 6
1 3) S u bjects f o u n d t o be i neli gi ble t o c o nti n ue i n t his trial after recei vi n g I M P m ust 
ha ve a 7 -d a y  f oll o w-u p visit (see Secti o n 3. 8. 3. 1 ).

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3. 7. 1. 1. 3 
T ol v a pt a n Titr ati o n P eri o d ( D a ys -3 5 t o -2 2 )
T he t ol va pta n titrati o n peri o d will be a si n gle - bli n d peri o d t hat will last f or 2 wee ks 
(1 d a y ).  All s u bjects will be gi ve n a s plit d ose of 3 0/ 1 5 m g of t ol va pta n wit h u p war d 
titrati o n e ver y 3 t o 4 da ys t o 4 5/ 1 5 m g, 6 0/ 3 0 m g, u p t o a ma xi m u m d ose of 9 0/ 3 0 m g per 
da y  o ver 2 wee ks.  T his titrati o n will be m o nit ore d wit h tele p h o ne or cli nic visits at eac h 
escalati o n le vel t o assess t olera bilit y .
Assess me nts d uri n g t he t ol va pta n titrati o n peri o d will i ncl u de ( See Ta ble 3. 7 - 1):
1)
Rec or d c o nc o mita nt me dicati o ns at all visits
2)
Assess A Es at all visits
3)
Assess vital si g ns ( i ncl u de sittin g heart rate a n d bl o o d press ure ) o n Da y -2 2
4)
C ollect bl o o d f or ser u m creati ni ne f or e G F R calc ulati o n a n d f or  assess me nt of 
s o di u m a n d li ver f u ncti o n pa nel o n Da y  - 2 2 (see Secti o n 3. 7. 3. 2 ).  If s o di u m a n d 
li ver f u ncti o n pa nel are c ollecte d at t he sa me visit, a si n gle t u be of bl o o d s h o ul d 
be dra w n f or all assess me nts.
5)
C ollect P D uri ne sa m ple o n Da y  - 2 2
6)
C ollect bi o mar ker plas ma a n d uri ne sa m ples ( see Secti o n 3. 7. 3. 5 ) o n Da y  - 2 2
7)
As k s u bject “ Ca n y o u t olerate t his d ose of trial me dicati o n f or t he rest of y o ur 
life?” at eac h u p war d titrati o n visit
8)
U p date s u bject stat us i n I V R S o n Da y -2 2
9)
I M P rec o nciliati o n o n Da y  - 2 2
1 0) S u bjects n ot t olerati n g at least 6 0/ 3 0 m g d ose s h o ul d be i nf or me d t he y  di d n ot 
meet eli gi bilit y criteria f or c o nti n uati o n
1 1) Dis pe nse I M P f or ne xt peri o d o n Da y  - 2 2
1 2) S u bjects f o u n d t o be i neli gi ble t o c o nti n ue i n t his trial m ust ha ve a 7 -d a y  
f oll o w-u p visit (see Secti o n 3. 8. 3. 1 ).
3. 7. 1. 1. 4
T ol v a pt a n R u n -I n P eri o d ( D a ys -2 1 t o -1)
All s u bjects w h o t olerate t ol va pta n at t he 6 0/ 3 0 m g or 9 0/ 3 0 m g dail y d ose re gi me n will 
e nter t he t ol va pta n r u n-i n peri o d at o ne of t hese d oses f or 3 wee ks ( 1 da y ).  E xce pt f or 
ma na ge me nt of A Es , n o d ose a dj ust me nt will be per mitte d d uri n g t his peri o d.  S u bjects 
u n a ble t o t olerate at least 3 wee ks of dail y t ol va pta n treat me nt at 6 0/ 3 0 m g or 9 0/ 3 0 m g
will n ot be eli gi ble f or ra n d o mizati o n.
S u bjects w h o reac h Da y  -1 a n d are a ble t o t olerate a gi ve n d ose of t ol va pta n “f or t he rest 
of t heir li ves” at a le vel of 6 0/ 3 0 m g or 9 0/ 3 0 m g will be eli gi ble t o e nter t he 
d o u ble -bli n d, ra n d o mize d treat me nt peri o d. Ra n d o mizati o n ( Da y -1) will be stratifie d b y 
mea n e G F R ser u m creati ni ne meas ure me nts ta ke n d uri n g t he scree ni n g peri o d a n d 

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place b o r u n -i n peri o d .  S u bjects will be stratifie d i n a 1: 1 rati o t o eac h treat me nt gr o u p as 
f oll o ws:

C K D 2 t o 3a sta ges [ > 4 5 m L / mi n/ 1. 7 3 m2 ] or

C K D 3 b t o 4 sta ges [ 4 5 m L / mi n/ 1. 7 3 m2 ]
I deall y, a distri b uti o n of half of s u bjects bei n g a b o v e or bel o w t his c ut-off will be 
tar gete d. T heref ore , e nr ollme nt ma y  be a dj uste d if t his rati o be gi ns t o var y b y m ore t ha n 
a 6 0: 4 0 rati o.  
 
Assess me nts d uri n g t he t ol va pta n r u n-i n peri o d will i ncl u de ( See Ta ble 3. 7- 1 ):
1)
Rec or d c o nc o mita nt me dicati o ns at all visits
2)
Assess A Es at all visits
3)
Assess vital si g ns ( i ncl u de sitti n g heart rate a n d cali brate d bl o o d press ure ) o n 
D a y - 1
4)
C ollect uri nal y sis sa m ple o n Da y - 1
5)
C ollect bl o o d ( 2 ti mes o n se parate da y s d uri n g t he last 2 wee ks of t he peri o d, wit h 
t he last sa m ple dra w n o n Da y  -1) f or ser u m creati ni ne f or e G F R calc ulati o n a n d 
f or 1 assess me nt of s o di u m a n d li ver f u ncti o n pa nel (see Secti o n 3. 7. 3. 2 ).  If 
s o di u m a n d li ver f u nctio n pa nel are c ollecte d at t he sa me visit, a si n gle t u be of 
bl o o d s h o ul d be dra w n f or all assess me nts.
6)
C ollect P K plas ma sa m ple a n d P D uri ne sa m ple o n Da y  - 1 
7)
C ollect bi o mar ker plas ma a n d uri ne sa m ples (see Secti o n 3. 7. 3. 5 ) o n Da y  - 1
8)
C o m plete P K D o utc o mes s ur ve y o n Da y  - 1
9)
As k s u bject “ Ca n y o u t olerate t his d ose of trial me dicati o n f or t he rest of y o ur 
life?” o n Da y  - 1
1 0) U p date s u bject stat us i n I V R S o n Da y  - 1
1 1) I M P rec o nciliati o n o n Da y  - 1
1 2) Re mi n d t he s u bject of t he i m p orta nce of t heir c o m mit me nt t o c o nti n ue 
partici pati o n i n t he trial o n Da y  - 1
1 3) Ra n d o mizati o n o n Da y  - 1
1 4) Dis pe nse I M P f or ne xt peri o d o n Da y -1
1 5) S u bjects f o u n d i neli gi ble t o be ra n d o mize d a n d c o nti n ue i n t his trial m ust ha ve a 
7- d a y  f ollo w -u p visit (see Secti o n 3. 8. 3. 1 ).
3. 7. 1. 2
D o u bl e -bli n d, R a n d o mi z e d Tr e at m e nt P eri o d ( D a y 0 t o 
M o nt h
1 2 )
D a y  0 is t he be gi n ni n g of t he d o u ble-bli n d, ra n d o mize d treat me nt peri o d.  O nl y  s u bjects 
w h o reac h Da y - 1 a n d are a ble t o t oler ate a gi ve n d ose of t ol va pta n “f or t he rest of t heir 

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li ves” at a le vel of 6 0/ 3 0 m g or 9 0/ 3 0 m g will be eli gi ble t o e nter t his p eri o d.  In t his 
peri o d, neit her t he s u bject n or t he i n vesti gat or or his/ her staff will k n o w wit h certai nt y 
w hic h treat me nt is ass i gne d.  I m me diatel y pri or t o ra n d o mizati o n, a n d at eac h s u bse q ue nt 
visit or site c o ntact, t he s u bject will be re mi n de d of t he i m p orta nce of t heir c o m mit me nt 
t o c o nti n ue partici pati o n i n t he trial; h o we ver , t he s u bject will n ot be t ol d t hat t his da y is 
t he p oi nt at w hic h ra n d o mizati o n t o l o n g -ter m t hera py occ urs.
P ost -ra n d o mizati o n, the ma xi mall y -t olerate d d ose of t ol va pta n esta blis he d d uri n g t he 
r u n-i n peri o d, or t he e q ui vale nt as matc hi n g place b o ta blets, will be dis pe nse d acc or di n g 
t o t he s u bject’s ra n d o mizati o n o utc o me .  S u bjects m ust ret ur n a n y u n use d I M P fr o m t he 
pre -ra n d o mizati o n peri o d bef ore c o nti n ui n g i n t he d o u ble - bli n d, ra n d o mize d treat me nt 
peri o d.
Fr o m t his p oi nt f or war d, e ver y  eff ort t o mai ntai n a d here nce a n d c o nti n uati o n of t he 
s u bjects u ntil t he e n d of t he trial s h o ul d be u n derta ke n.  If c o nti n ue d t olera bilit y  bec o mes 
a n iss ue, s u bjects m a y  titrate d o w n war d t o 4 5/ 1 5 m g or 3 0/ 1 5 m g ( wit h me dical m o nit or 
a p pr o val) or te m p oraril y i nterr u pt treat me nt as nee de d. Ret ur n t o hi g her d oses is als o 
all o we d.
Assess me nts d uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d will i ncl u de ( See
Ta ble 3. 7- 1 ):
1)
Re mi n d t he s u bject of t he i m p orta nce of t he ir c o m mit me nt t o c o nti n ue 
partici pati o n i n t he trial at all visits
2)
Rec or d c o nc o mita nt me dicati o ns at all visits
3)
Assess A Es at all visits
4)
Assess vital si g ns ( i ncl u di n g sitti n g heart rate a n d bl o o d press ure ) at M o nt h 3, 6, 
9, 1 2/ E o T x visits ; i ncl u de assess me nt of p ost -v oi d b o d y  wei g ht at t he 
M o nt h
1 2/ E o T x visit o nl y
5)
Perf or m a f ull p h ys ical e xa mi nati o n at M o nt h 1 2 / Eo T x visit o nl y ( directe d 
p h y sical e xa m ma y be perf or me d at M o nt h 3, 6, 9 visits, if dee me d necessar y b y 
t he i n vesti gat or)
6)
Uri ne p re g na nc y test f or W O C B P at M o nt h 3, 6, 9, 1 2/ E o T x visits ( or if 
i n dicate d)
7)
C ollect uri nal y sis sa m ple at t he M o nt h 1 2/ E o T x visit
8)
C ollect bl o o d f or ser u m creati ni ne f or e G F R calc ulati o n a n d f or assess me nt of 
s o di u m a n d li ver f u ncti o n pa nel (see Secti o n 3. 7. 3. 2 ) m o nt hl y  a n d at t he 
M o nt h
1 2 / Eo T x visit .  Ser u m s o di u m a n d li ver f u ncti o n pa nel s h o ul d be 
deter mi ne d fr o m t he sa me bl o o d sa m ple.
9)
C ollect bl o o d f or ser u m c he mistr y  assess me nt at t he M o nt h 1 2/ E o T x visit. T he 
s o di u m, ser u m c he mistr y a n d li ver f u ncti o n pa nel s h o ul d be deter mi ne d fr o m a 
si n gle t u be of bl o o d.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
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2 6 Mar 2 0 1 5 
1 0) C ollect plas ma sa m ples f or P K a nal ys is a n d P D uri ne sa m ples at M o nt h 3, 6, 9, 
1 2 / Eo T x visits
1 1) C ollect plas ma a n d uri ne sa m ples f or p ote ntial bi o mar ker a nal ys is at M o nt h 3, 6, 
9, 1 2/ E o T x visits (see Secti o n 3. 7. 3. 5 )
1 2) C o m plete P K D o utc o mes s ur ve y ( m o nt hl y a n d at t he M o nt h 1 2 / Eo T x visit)
1 3) As k s u bject “ Ca n y o u t olerate t his d ose of trial me dicati o n f or t he rest of y o ur 
life?” at eac h visit
1 4) U p date s u bject stat us i n I V R S ( m o nt hl y a n d at t he M o nt h 1 2 / Eo T x visit)
1 5) Dis pe nse I M P at m o nt hl y vi sits u p t o a n d i ncl u di n g M o nt h 1 1.  I n certai n 
circ u msta nces, wit h me dical m o nit or a p pr o val, a 3 -m o nt h dr u g s u p pl y ma y be 
pr o vi de d; h o we ver, i nitiati o n of t he ne xt m o nt h’s s u p pl y m ust be directe d b y t he 
site.
1 6) I M P rec o nciliati o n ( m o nt hl y a n d at t he M o nt h 1 2 / Eo T x visit)
1 7) S u bjects n ot c o nti n ui n g i n t his trial m ust ha ve a 2 1-d a y  f oll o w-u p peri o d (see 
Secti o n 3. 8. 3. 3 ).
Visits d uri n g t he treat me nt peri o d will be sc he d ule d m o nt hl y  (2 da y s), wit h a fi nal visit 
at M o nt h 1 2 / Eo T x.
Re gar dless of disc o nti n uati o n of I M P, t he s u bjects are e x pecte d t o c o m plete all m o nt hl y  
visits a n d assess me nts i ncl u di n g t he M o nt h 1 2 visit (see Secti o n 3. 8. 3. 3 ).
All s u bjects ha ve t he ri g ht t o wit h dra w t heir c o nse nt fr o m f urt her partici pati o n i n t he trial 
at a n y ti me wit h o ut prej u dice.   I n all cases of i m pe n di n g I M P disc o nti n uati o n or c onse nt 
wit h dra wal, t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures o utli ne d i n Secti o n 3. 8. 3. 5. 1 t o 
deter mi ne if t he s u bject ca n c o nti n ue partici pati o n i n t he trial if m o dificati o ns t o his/ her 
treat me nt a n d/ or sc he d ule of assess me nts ca n be acc o m m o date d.
3. 7. 1. 3
F oll o w - u p P eri o d (M o nt h 1 2/ E n d of Tr e at m e nt t o D a y  2 1 
P o st -tr e at m e nt)
F or all ra n d o mize d s u bjects, t he 3- wee k f oll o w -u p peri o d starts i m me diatel y  after t he last 
d ose of I M P.  N o f oll o w - u p assess me nts will be ta ke n d uri n g t he first wee k of t his peri o d.  
D uri n g t he last 2 wee ks, Da y s 8 t hr o u g h 2 1, i ncl usi ve, 3 f oll o w-u p visits will be 
sc he d ule d.  T he visits m ust occ ur at least 2 4 h o urs a part.  Bl o o d sa m ples will be c ollecte d 
at eac h visit f or ser u m creati ni ne meas ure me nts.  T he bl o o d sa m ple c ollecte d at t he last 
f oll o w- u p visit will al s o i ncl u de meas ureme nt s of p ost-treat me nt efficac y a n d safety .
T he se visit s ma y  be visiti n g n urse h o use call s or l ocal la b orat or y  visits w he n o nl y  bl o o d 
sa m ples will be c ollecte d, wit h t he e xce pti o n of t he last visit, w hic h will be a cli nic visit.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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5 3
2 6 Mar 2 0 1 5 
Assess m e nts d uri n g t he last 2 wee ks of t he f oll o w-u p peri o d will i ncl u de
( See Ta ble 3. 7- 1 ):
1)
Rec or d c o nc o mita nt me dicati o ns at eac h visit
2)
Assess A Es at eac h visit
3)
Assess vital si g ns ( i ncl u di n g sitti n g heart rate a n d bl o o d press ure ) at t he last visit
4)
Uri ne pre g na nc y  test f or W O C B P at t he last visit
5)
C ollect bl o o d f or ce ntral la b orat or y a nalys is of ser u m creati ni ne f or e G F R 
calc ulati o n s at eac h visit
6)
C ollect bl o o d f or assess me nt of s o di u m le vels at t he last visit (see Secti o n 3. 7. 3. 2 )
7)
C o llect bl o o d f or li ver f u ncti o n pa nel assess me nts at t he last visit (see 
Secti o n 3. 7. 3. 2 )
8)
C ollect plas ma sa m ples f or P K a nal ys is a n d P D uri ne sa m ples at t he last visit
9)
C ollect plas ma a n d uri ne sa m ples f or p ote ntial bi o mar ker a nal ys is at t he last visit 
(see Secti o n 3. 7. 3. 5 )
1 0) U p date s u bject stat us i n I V R S at t he last visit
T he a b o ve f oll o w- u p assess me nts will als o be perf or me d f or a s u bject w h o i nterr u pts 
I M P f or 7 da y s, i n or der t o c ollect t heir data i n t he e ve nt t hat t he y ne ver restart I M P 
treat me nt (see Secti o n 3. 8. 3. 2 ).
3. 7. 2
Effi c a c y  As s e s s m e nt s
3. 7. 2. 1
S er u m Cr e ati ni n e f or E sti m at e d Gl o m er ul ar Filtr ati o n R at e
T he ser u m creati ni ne c o nce ntrati o n is relate d t o e G F R a n d is c o m m o nl y  use d t o esti mate 
re nal f u ncti o n i n cli nical practice.  Alterati o n i n meta b olis m of creati ni ne a n d 
met h o d ol o gical i nterfere nce i n its meas ure me nts ma y i m pact acc urac y  of t he ser u m 
creati ni ne a n d re nal f u ncti o n esti mati o n.  Bel o w are s u g geste d meas ures t o decrease 
ser u m creati ni ne varia bilit y pri or t o t he m o nt hly bl o o d dra ws re q uire d b y t his pr ot oc ol.  
All trial s u bjects s h o ul d:

Mai ntai n a sta ble dietar y pr otei n i nta ke a n d a v oi d ver y  differe nt or hi g h c o o ke d meat 
pr otei n meals t he da y  bef ore eac h sc he d ule d ser u m creati ni ne assess me nt.

Mai ntai n a sta ble e xercise
r o uti ne a n d a v oi d ver y differe nt or hea vy p h ys ical 
acti vit y/e xercise t he da y bef ore eac h sc he d ule d ser u m creati ni ne assess me nt.

Mai ntai n a sta ble water i nta ke, ai me d at a v oi di n g t hirst c o nsiste ntl y  t hr o u g h o ut t he 
trial - rec o m me n de d i n gesti o n of at least 2 -3 liters of fl ui d (i ncl u di n g i n s oli d, 
se mi-s oli d, a n d li q ui d f o o ds) per da y, u nless ot her wise directe d b y  yo ur st u d y  d oct or.

Pla n t o arri ve at t he sa me ti me f or eac h bl o o d- dra w a n d cli nic visit t o better
sta n dar dize ti me of t he sa m ple c ollecti o n t hr o u g h o ut t he trial.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
5 4
2 6 Mar 2 0 1 5 

S o me me dicati o ns ma y i ncrease ser u m creati ni ne le vels (e g, ci meti di ne, n o n -ster oi dal 
a nti-i nfla m mat or y dr u gs [N S AI D] me dicati o ns li ke as piri n or i b u pr ofe n, 
c he m ot hera p y dr u gs, ce p hal os p ori n ). S u bjects s h o ul d a lert t heir trial d oct or, a n d a n y
ot h er healt h-care pr o vi ders, t o ta ke t his i nt o c o nsi derati o n w he n c o nsi deri n g c ha n ges
i n t heir prescri be d or o ver -t he-c o u nter me dicati o ns , a n d all me dicati o n c ha n ges 
s h o ul d be re p orte d t o t heir trial d oct or or his/ her staff.
Ser u m creati ni ne is sta ble w he n st ore d fr oze n ; t heref ore, t w o sa m ples/ali q u ots of bl o o d 
will be c ollecte d f or its a nal y sis. W hile o ne bl o o d sa m ple will be a nal yz e d b y t he ce ntral 
la b orat or y as s o o n as it is recei ve d a n d accessi o ne d, t he f or mal efficac y a nal yses will be 
base d o n d u plicate sa m ples/ali q u ots w hic h are c ollecte d c o nte m p ora ne o usl y a n d fr oze n 
f or later batc he d a nal ys is t o eli mi nate i nter-d a y varia bilit y  of t he assa y . O n g oi n g, 
batc he d a nal ys is will be c o n d ucte d f or eac h s u bject u p o n his/ her i n di vi d ual c o m pleti o n of 
all t heir assess me nts wit hi n t he trial ( n ot at t he e n d of t he trial).
T he e G F R val ues will be calc ulate d b y  C K D- E PI fr o m t he ce ntral-la b orat or y ser u m 
creati ni ne c o nce ntrati o ns ta ke n at scree ni n g a n d d uri n g e ver y trial visit.  I n t he scree ni n g 
peri o d, ser u m creati ni ne assess me nts ma y  n ot be re peate d; t he first t w o assess me nts m ust 
be use d t o deter mi ne t he e G F R val ues t hat will be a vera ge d f or deter mi nati o n of meeti n g 
i ncl usi o n criteria.  F urt her detail re gar di n g e G F R calc ulati o ns will be pr o vi de d i n t he 
statistical a nal ysis pla n ( S A P).
3. 7. 2. 2
P ol y c y sti c Ki d n e y Di s e a s e Hi st or y  a n d O ut c o m e s S ur v e ys
A s h ort P K D hist or y  sur ve y  will be c o m plete d o nce d uri n g scree ni n g t o ca pt ure 
i nf or mati o n fr o m t he s u bject’s rec ollecti o n, a n d d oc u me nte d past me dical hist or y w here 
a vaila ble. T he s ur ve y s h o ul d be u p date d at eac h visit if ne w i nf or mati o n re gar di n g past 
hist or y  bec omes a vaila ble .
T he P K D o utc o mes s ur ve y  will c ollect i nf or mati o n rele va nt t o t he me dical, s ocial a n d 
ec o n o mic c o nse q ue nces of ne w a n d o n g oi n g P K D -relate d m or bi dities. Ne w cli nicall y  
rele va nt i nf or mati o n a n d s pecific q uesti o ns a b o ut o utc o mes will be c ollecte d at t he 
f oll o wi n g visits : scree ni n g, e n d of t ol va pta n r u n-i n, a n d d uri n g t he d o u ble -bli n d 
ra n d o mize d treat me nt peri o d eit her m o nt hl y (o ver t he p h o ne or i n pers o n ) or d uri n g 
q uarterl y cli nic visits (i n pers o n).
If a s u bject w h o has bee n ra n d o mize d disc o nti n ues t he use of I M P, P K D o utc o mes will 
be c ollecte d at t he n or mall y sc he d ule d trial visits, or b y tele p h o ne c o ntact, t o t he date of 
t he ori gi nally pla n ne d M o nt h 1 2 visit , if t he s u bject a grees.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
5 5
2 6 Mar 2 0 1 5 
3. 7. 3
S af et y  As s e s s m e nt s
3. 7. 3. 1
A d v er s e E v e nt s
Refer t o Secti o n 5 , Re p orti n g of A d verse E ve nts .
3. 7. 3. 2
Cli ni c al L a b or at or y  As s e s s m e nt s
Bl o o d a n d/ or uri ne sa m ples will be c ollecte d as i n dicate d i n t he sc he d ule of assess me nts,
(Ta ble 3. 7- 1 ). It is prefera ble t o c ollect t he cli nical la b orat or y sa m ples fr o m eac h s u bject 
at a c o nsiste nt ti me of da y t hr o u g h o ut t he trial , a n d t o rec o m me n d t hat t he s u bject ha ve a 
si milar diet, a v oi di n g variati o n i n pr otei n i nta ke (es peciall y c o o ke d meat pr otei n ), a n d 
e xercise patter n d uri n g t hese peri o ds , i n or der t o re d uce varia bilit y i n t he sa m ples o ver 
ti me (see Secti o n 3. 7. 2. 1 ).
A list of t he s pecific cli nical la b orat or y  assess me nts is prese nte d i n Ta ble 3. 7. 3. 2 -1 .
C li nical la borat or y  sa m ples f or a nal ysis b y t he ce ntral la b orat or y will be c ollecte d at t he 
f oll o wi n g visits:

d uri n g scree ni n g ( 2 visits at least 2 4 h o urs a part t hat occ ur d uri n g t he 1- 2 wee ks pri or 
t o place b o r u n-i n) - creati ni ne (first a n d sec o n d visits), s o di u m a n d uri nal ysis (first 
a n d sec o n d visits), he mat ol o g y  a n d c oa g ulati o n pa nel, ser u m c he mistr y pa nel, a n d 
li ver f u ncti o n pa nel (first visit)

d uri n g place b o r u n -i n - uri nal y sis, li ver fu ncti o n pa nel, creati ni ne, a n d s o di u m o n 
D a y  - 3 6)

d uri n g t ol va pta n titrati o n - li ver f u ncti o n pa nel, creati ni ne, a n d s o di u m (Da y  - 2 2)

d uri n g t ol va pta n r u n-i n - li ver f u ncti o n pa nel ( Da y -8), uri nal ys is ( Da y -1), creati ni ne, 
( 2 ti mes o n se parate da ys d uri n g t he last 2 wee ks of t he peri o d, wit h t he last sa m ple 
dra w n o n Da y -1), a n d s o di u m ( Da y  - 1)

at m o nt hl y cli nic visits d uri n g t he d o u ble -bli n d , ra n d o mize d treat me nt peri o d - li ver 
f u ncti o n pa nel, creati ni ne, a n d s o di u m

at t he M o nt h 1 2 / Eo T x visit - ser u m c he mistr y pa nel, uri nal y sis, li ver f u ncti o n pa nel, 
creati ni ne, a n d s o di u m

d uri n g t he 3- wee k f oll o w-u p peri o d ( 3 visits t hat occ ur bet wee n Da y s 8 a n d 2 1, 
i ncl usi ve, after t he last d ose of I M P, a n d at least 2 4 h o urs a part ) - creati ni ne ( 3 visits), 
s o di u m (last visit ), li ver f u ncti o n pa nel a n d ser u m c he mistr y pa nel (last visit)

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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5 6
2 6 Mar 2 0 1 5 
T a ble 3. 7. 3. 2 - 1
Cli nic al L a b or at or y Assess me nts
H e m at ol o g y a n d c o a g ul ati o n p a nel:

h e mo gl o b i n,

mea n c or p usc ular he m o gl o bi n ( M C H C)

mea n c or p usc ular v ol u me ( M C V)

re d bl o o d cell ( R B C) c o u nt

w hite bl o o d cell ( W B C) c o u nt w it h differe ntial

platelet c o u nt

pr ot hr o m bi n ti me ( P T) as i nter nati o nal 
n or m alize d rati o (I N R)

acti vate d partial t hr o m b o plasti n ti me
Ser u m c he mistr y p a nel:

al b u mi n

bl o o d urea nitr o ge n ( B U N)

ser u m calci u m

ser u m c hl ori de

car b o n di o xi de ( C O 2)

ga m ma -gl uta m yl tra ns pe pti dase ( G G T)

gl uc ose

lactate de h y dr o ge nase ( L D H)

p h os p h or us

p otassi u m

t otal c h olester ol

t otal pr otei n

uric aci d
Li ver f u ncti o n p a nel:

al kali ne p h os p hatase ( A L P)

ala ni ne tra nsa mi nase ( A L T)

as partate a mi n otra nsferase ( A S T)

direct bilir u bi n

t otal bilir u bi n ( B T)
Uri n al ysis p a nel:

ap peara nce

c ol or

bl o o d

gl uc ose

micr osc o pic a nal ysis (i ncl u di n g W B C/ R B C 
c o u nts per hi g h -p o w ere d fiel d)

p H

pr otei n

os m olalit y

s pecific gra vit y

uri ne creati ni ne
Cre ati ni ne
S o di u m
L i ver pa nels will be a nal yze d m ore fre q ue ntl y  d uri n g t he d o u ble -bli n d , ra n d o mize d 
treat me nt peri o d if A L T > t wice t he u p per li mit of n or mal ( 2 × U L N ), usi n g b ot h ce ntral 
a n d l ocal la b orat orie s, as nee de d, a n d per sta n dar d of care acc or di n g t o t he s u bject’s 
i n di vi d ual me dical nee ds.  If li ver f u ncti o n pa nel, s o di u m a n d/ or ser u m c he mistr y 
assess me nts are sc he d ule d at t he sa me visit, all val ues s h o ul d be deter mi ne d fr o m t he 
sa me bl o o d sa m ple.
Uri ne pre g na nc y  testi n g will be perf or me d wit h c o m merciall y a vaila ble, hi g h-se nsiti vit y 
kits s u p plie d t o t he s u bject b y  t he site (ac q uire d b y t he s p o ns or or t hr o u g h t he ce ntral 
la b orat or y f or u nif or mit y). Fe male s u bjects w h o are ca pa ble of bea ri n g c hil dre n will 
ha ve t heir uri ne teste d i n cli nic pri or t o trial e ntry (scree ni n g peri o d ) a n d at visits f or 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
5 7
2 6 Mar 2 0 1 5 
M o nt hs 3, 6, a n d 9 d uri n g t he d o u ble -bli n d ra n d o mize d treat me nt peri o d . O nce e nr olle d 
i nt o t he trial, the s u bject s h o ul d c o ntact t he cli nic i m me diatel y  o n s us pici o n of pre g na nc y, 
a n d u nsc he d ule d uri ne or bl o o d pre g na nc y  testi n g will be perf or me d.  P ositi ve uri ne 
pre g na nc y  tests s h o ul d be c o nfir me d wit h a ser u m pre g na nc y test.
T he f oll o wi n g ser u m c he mistr y  la b orat or y tests ma y be perf or me d b y t he ce ntral
la b orat or y at the re q uest a n d a p pr o val of t he m e dical m o nit or:  calci u m, p h os p h or us, 
parat h yr oi d h or m o ne, vita mi n D, a n d bicar b o nate le vels. If perf or me d, t he res ults fr o m 
t hese tests will be i ncl u de d i n t he cli nical data base.
3. 7. 3. 3
P h y si c al E x a mi n ati o n a n d Vit al Si g n s
A f ull p h y sical e xami nati o n will be perf or me d a n d d oc u me nte d at t he first scree ni n g visit 
a n d t he M o nt h 1 2 / Eo T x visit .  At ot her visits, a directe d p hys ical e xa mi nati o n ma y  be 
perf or me d t o f oc us o n A D P K D -relate d si g ns a n d s ym pt o ms .  I n s o me ge o gra p hic 
re gi o ns, m ore fre q ue nt s u bject visits ma y be t he n or m; h o we ver vital si g ns a n d cli nicall y 
si g nifica nt p hys ical fi n di n gs will be rec or de d as a n u nsc he d ule d visit i n t he electr o nic 
case re p ort f or m ( eC R F ) as a p plica ble. A n y c ha n ges i n me dicati o n or A Es will be 
rec or de d i n t he eC R F.
B o d y wei g ht will be ta ke n p ost -v oi d.  I t is prefera ble t o use t he sa me scale f or eac h 
meas ure me nt.  Cli nic scales s h o ul d be cali brate d at least y earl y. T he i n vesti gat or or 
his/ her a p p oi nte d desi g nee is pri maril y  res p o nsi ble t o perf or m t he p h ysical e xa mi nati o n.  
If t he a p p oi nte d desi g nee is t o perf or m t he p hys ical e xa mi nati o n, he/s he m ust be 
per mitte d t o d o s o b y  l ocal re g ulati o ns a n d his/ her na me m ust be i ncl u de d o n a n y 
gl o ball y a n d l ocall y re q uire d d oc u me nts (e g, i n di vi d ual m ust be a d de d f or all site s o n a 
U S F D A F or m 1 5 7 2, w here l ocal re g ulati o ns all o w, w hile l ocal re g ulati o ns deter mi ne 
t heir bei n g na me d i n t he I C F).  W he ne ver p ossi ble, t he sa me i n di vi d ual s h o ul d perf or m 
all p h ysical e xa mi nati o ns.  A n y u n desira ble c o n diti o n prese nt at a p ost -treat me nt p h ysical 
e xa mi nati o n t hat was n ot prese nt at t he baseli ne e xa mi nati o n s h o ul d be d oc u me nte d as a n 
A E a n d f oll o wed t o a satisfact or y  c o ncl usi o n.
Vital si g n data , i ncl u di n g seate d bl o o d press ure, heart rate , te m perat ure, hei g ht, a n d 
wei g ht, will be ta ke n at t he visits i de ntifie d i n t he Sc he d ule of Assess me nts (Ta ble 3. 7- 1 ).
3. 7. 3. 4
A s s e s s m e nt of Li v er S y m pt o m s, Si g n s or T e st A b n or m aliti e s
Testi n g f or he patic tra nsa mi nase ( A L T/ A S T) , al kali ne p h os p hatase, a n d B T will be 
perf or me d d uri n g scree ni n g/r u n -i n a n d at eac h m o nt hl y visit.  Ma na ge me nt of li ver 
a b n or malities is disc usse d i n t he para gra p hs bel o w. 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
5 8
2 6 Mar 2 0 1 5 
3. 7. 3. 4. 1
R e q uir e m e nt s f or R e p e at e d Li v er T e sti n g
3. 7. 3. 4. 1. 1
R e p e at e d Li v er T e sti n g i n S u bj e ct s wit h N or m al V al u e s at 
S cr e e ni n g
T he a p peara nce of a n y s us pici o us s y m pt o m or si g n s h o ul d tri g ger pr o m pt testi n g of 
he patic f u ncti o n (ie, wit hi n 7 2 h o urs). L o cal la b orat or y testi n g is acce pta ble, i deally wit h 
a c o nc urre nt ce ntral la b orat or y  sa m ple f or c o nfir mati o n.
A n y  tra nsa mi nase or bilir u bi n val ues w hic h e xcee d 2 × U L N s h o ul d als o pr o m pt 
i m me diate retesti n g wit hi n 7 2 h o urs.  W hile val ues re mai n i n a n a b n or mal ra n ge, testi n g 
fre q ue nc y s h o ul d be i ncrease d t o at least wee kly f or t he first m o nt h, gra d uall y  ret ur ni n g 
t o m o nt hl y as i n dicate d b y t he res ults.
S u bjects e x hi biti n g s uc h a n i ncrease d uri n g t he t ol va pta n titrati o n/r u n -i n p hases will be 
dis q ualifie d fr o m ra n d o mizati o n o n safet y  gr o u n ds a n d s h o ul d n ot be ra n d o mize d. 
S h o ul d t he ca use of t he a b n or malit y  be deter mi ne d t o be u nrelate d t o t ol va pta n e x p os ure 
(e g, ha vi n g i de ntifie d a pla usi ble alter nati ve e x pla nati o n) s uc h a s u bject ma y be 
re-scree ne d o nly wit h me dical m o nit or a p pr o val.
3. 7. 3. 4. 1. 2
R e p e at e d Li v er T e sti n g i n S u bj e ct s wit h A b n or m al V al u e s at 
S cr e e ni n g
S u bjects f o u n d t o ha ve li ver la b orat or y  a b n or malities at scree ni n g or w h o ha ve a hist or y 
of n o n -A D P K D -relate d li ver disease will re q uire f urt her e val uati o n. T hese s u bjects will 
nee d t o ha ve t he s pecial li ver e C R F ( see Secti o n 3. 7. 3. 4. 3 ) c o m plete d a n d a d diti o nal 
testi n g will be re q uire d d uri n g scree ni n g (t o c o nfir m t he sta bilit y of t he a b n or malit y) a n d 
d uri n g t he t ol va pta n r u n -i n p hase at least 1 wee k pri or t o ra n d o mizati o n (t o c o nfir m 
eli gi bilit y f or ra n d o mizati o n). 
Ma na ge me nt of s uc h s u bjects s h o ul d be cl osel y 
c o or di nate d wit h t he trial’s Me dical M o nit or.  I n t hese s u bjects, f urt her c ha n ges i n li ver 
test le vels of > 2 x u p per li mit of t heir hi g hest scree ni n g val ue at a n y p oi nt p ost -scree ni n g 
s h o ul d pr o m pt re-testi n g wit hi n 7 2 h o urs. S h o ul d s uc h a n i ncrease occ ur i n t he t ol va pta n 
titrati o n/r u n-i n p hase, t he s u bject will be dis q ualifie d fr o m ra n d o mizati o n.
3. 7. 3. 4. 2
Li v er T e st A b n or m aliti e s a n d I nt err u pti o n/ Di s c o nti n u ati o n of 
I n v e sti g ati o n al M e di ci n al Pr o d u ct
Li ver tra nsa mi nase or bilir u bi n le vels reac hi n g or e xcee di n g 2 × U L N t hat ha ve a n 
u ncertai n or ra pi dl y i ncreasi n g traject or y s h o ul d pr o m pt at least te m p orar y I M P 
i nterr u pti o n. I MP s h o ul d n ot be res u m e d u ntil m o nit ori n g i n dicates a b n or malities ha ve 
res ol ve d, are sta ble or are n ot ra pi dl y i ncreasi n g, a n d t he n o nl y wit h a n i ncrease d 
fre q ue nc y of m o nit ori n g.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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5 9
2 6 Mar 2 0 1 5 
S u bjects w o ul d n ot t y picall y  be all o we d t o res u me treat me nt wit h I M P if t he y ha ve:

tra nsa mi nase le vels rise a b o ve 8 × U L N, 

tra nsa mi nase le vels are > 5 × U L N f or m ore t ha n 2 wee ks, or

c o nc urre nt ele vati o ns of tra nsa mi nase > 3 × U L N a n d B T > 2 × U L N .
S u bjects wit h t hese le vels of a b n or malit y  m a y be re-c halle n ge d wit h I M P if a b n or malities 
were a dj u dic ate d as ha vi n g a < 5 0 % li keli h o o d of bei n g relate d t o I M P ( per DI LI net w or k 
[ DILI N] pr o ba bilit y criteria 1 7 ) b y  a n i n de pe n de nt he patic a dj u dicati o n c o m mittee ( H A C)
(see Secti o n 3. 7. 3. 4. 3 ) a n d t he i n vesti gat or a n d me dical m o nit or a gree t o a n i nte nsi ve 
m o nit ori n g pla n t o miti gate ris k. All ele vati o ns will be assesse d b y  t he me dical 
m o nit ori n g tea m.  T he s u bject m ust als o be willi n g t o c o m pl y wit h t hese m o nit ori n g 
meas ures, be i nf or me d of t he p ote ntial ris ks , a n d c o nse nt t o IM P re -c halle n ge.
3. 7. 3. 4. 3
R e q uir e m e nt s f or S p e ci al R e p orti n g U si n g t h e Li v er Di s e a s e 
El e ctr o ni c C a s e R e p ort F or m a n d I m m e di at el y  R e p ort a bl e 
E v e nt F or m
T he p ur p ose of t he li ver disease e C R F a n d o pti o nal a d diti o nal testi n g is t o facilitate 
re vie w of eac h s u bject w h o prese nts wit h, or de vel o ps a li ver a b n or mality d uri n g t he trial 
or a n d t o deter mi ne t he pr o ba ble ca use(s) of t hese a b n or malities. T he re vie w will be 
perf or me d b y a bli n de d, i n de pe n de nt H A C usi n g DI LI N pr o ba bilit y  criteria 
( < 2 5 % = u nli kel y, 2 5 % t o 5 0 % = p ossi bl y , 5 1 % t o 7 5 % = pr o ba bl y, 7 6 % t o 9 5 % = ver y  
li kel y, > 9 5 % = defi nite). 1 7   T he H A C will i n de pe n de ntl y  deci de attri b uti o n a n d will 
c o m m u nicate wit h t he I nde pe n de nt Data M o nit ori n g C o m mittee ( I D M C) t hat o versees 
t he trial.  T he res ult of t hese a nal ys es ma y be prese nte d se parately fr o m t he C S R.
T he i n vesti gat or m ust c o m plete a s peci al li ver disea se e C R F f or a n y s u bject w h o: 
1)
disc o nti n ues trea t me nt d ue t o a li ver-relate d A E,
2)
re p orts a seri o us li ver-relate d A E, 
3)
wit h n or mal scree ni n g le v els de vel o ps A L T or A S T le vels 3 × U L N, 
4)
wit h n or mal scree ni n g le vels de vel o ps B T le vels 2 × U L N, or
5)
wit h a n a b n or mal scree ni n g li ver test le vel de vel o ps a b n or malities i n t hat test t hat 
are > 2 × t he u p per li mit of t heir hi g hest scree ni n g val ue.
All s u bjects meeti n g a n y o ne of t he a b o ve criteria will als o be as ke d t o pr o vi de a n 
a d diti o nal set of bl o o d a n d uri ne bi o mar ker sa m ples at t he ti me of t he e ve nt.  A d diti o nal 
cli nical testi n g (s uc h as testi n g f or he patitis ser ol o g y ) ma y als o be i n dicate d a n d t heir 
res ults re p orte d acc or di n g t o l ocal g ui deli nes.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
6 0
2 6 Mar 2 0 1 5 
T he li ver e C R F a n d I m me diate l y Re p orta ble E ve nt (IR E) f or m (see Secti o n 5. 3 ) s h o ul d 
be u p date d as ne w i nf or mati o n bec o mes a vaila ble.
3. 7. 3. 5
Ot h er S af et y  As s e s s m e nt s
3. 7. 3. 5. 1
Bi o m ar k er Pl a s m a S a m pl e s
Bl o o d sa m ples ( 1 0 m L) f or p ote ntial bi o mar ker a nal ysis will be c ollecte d at t he f oll o wi n g 
ti mes:

sec o n d visit of t he scree ni n g peri o d

e n d of t h e place b o r u n-i n peri o d ( Da y - 3 6)

e n d of t he t ol va pta n titrati o n peri o d ( Da y - 2 2)

e n d of t he t ol va pta n r u n -i n peri o d (Da y  - 1)

d uri n g t he d o u ble -bli n d , ra n d o mize d treat me nt peri o d at M o nt hs 3, 6, 9, 1 2 / Eo T x

at t he last f oll o w-u p peri o d visit

d uri n g a n e pis o de of i ncrease d li ver s ur veilla nce ( d ue t o A E or la b a b n or malit y  a b o ve 
set t hres h ol ds)
T he bl o o d sa m ple will b e ta ke n f oll o wi n g t he P K sa m ple at visits w here b ot h are 
c ollecte d, a n d pr ocesse d si milarl y t o t he P K bl o o d sa m ple. Date a n d ti me of t he bl o o d 
sa m ple, as well as t he date a n d ti me of t he last prece di n g d ose s h o ul d be n ote d i n t he 
e C R F.
All plas ma sa m ples wi ll be s hi p pe d t o t he ce ntral cli nical la b orat or y f or st ora ge. Detaile d 
ha n dli n g a n d s hi p pi n g i nstr ucti o ns are i n A p pe n di x 3 .
3. 7. 3. 5. 2
Bi o m ar k er Uri n e S a m pl e s
A s p ot uri ne sa m ple will be o btai ne d at t he f oll o wi n g ti mes:

sec o n d visit of t he scree ni n g peri o d

e n d of t h e place b o r u n -i n peri o d ( Da y - 3 6)

e n d of t he t ol va pta n titrati o n peri o d ( Da y - 2 2)

e n d of t he t ol va pta n r u n -i n peri o d ( Da y - 1)

d uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d at M o nt hs 3, 6, 9, 1 2 / Eo T x

at t he last f oll o w-u p peri o d visit

d uri n g a n e pis o de of i ncrease d li ver s ur veilla nce ( d ue t o A E or la b a b n or malit y  a b o ve 
set t hres h ol ds) 
T his sa m ple s h o ul d be o btai ne d pri or t o t he s u bject eati n g brea kfast , fr o m t he uri ne v oi d 
ta ke n after t he first m or ni n g’s v oi d, a n d will i deall y be pr o vi de d as a mi d -strea m, 
clea n-catc h sa m ple. T o e ns ure a fasti n g uri ne sa m ple is c ollecte d, s u bjects will be 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
6 1
2 6 Mar 2 0 1 5 
pr o vi de d wit h a sterile uri ne c u p o n t he visit prece di n g t he date of uri ne sa m ple 
c ollecti o n.  S u bjects will be i nstr ucte d t o c ollect a uri ne sa m ple pri or t o eati n g brea kfast ,
a n d t o st ore t he sa m ple i n t he refri gerat or u ntil t heir cli nic visit.  Date a n d ti me of t he 
uri ne sa m ple, as well as t he date a n d ti me of t he last prece di n g d ose of I M P, s h o ul d be 
n ote d i n t he e C R F.  T his sa m ple s h o ul d be o btai ne d fr o m t he sa me v oi d as c ollecte d f or 
t he P D uri ne sa m ple, w he n b ot h sa m ples are c ollecte d at t he sa me visit.
All uri ne sa m ples will be s hi p pe d t o t he ce ntral cli nical la b orat or y f or st ora ge. Detaile d 
ha n dli n g a n d s hi p pi n g i nstr ucti o ns are i n A p pe n di x 3 .
3. 7. 3. 5. 3
D N A  Bl o o d S a m pl e s
A bl o o d sa m ple f or D N A c ollecti o n will be o btai ne d fr o m e ver y c o nse nti n g s u bject at t he 
sec o n d visit of t he scree ni n g peri o d .  Sa m ples ma y be c ollecte d at a s u bse q ue nt visit if 
s u bjects pr o vi de c o nse nt after t he sec o n d visit of t he scree ni n g peri o d.
All s a m ples will be s hi p pe d t o t he ce ntral cli nical la b orat or y. Detaile d ha n dli n g a n d 
s hi p pi n g i nstr ucti o ns are i n A p pe n di x 3 .
3. 7. 4
P h ar m a c o ki n eti c/ p h ar m a c o d y n a mi c A s s e s s m e nt s
3. 7. 4. 1
P h ar m a c o ki n eti c Bl o o d S a m pl e s
S parse sa m ples will be ta ke n f or deter mi nati o n of plas ma t ol va pta n a n d meta b olite (s), 
i ncl u di n g D M -4 1 0 3 c o nce ntrati o ns. A 4 m L  sa m ple will be c ollecte d at t he f oll o wi n g 
ti mes:

e n d of t he t ol va pta n r u n-i n peri o d ( Da y - 1)

d uri n g t he d o u ble -bli n d , ra n d o mize d treat me nt peri o d at M o nt hs 3, 6, 9, 1 2 / Eo T x

at t he last f oll o w-u p visit
T he date a n d ti me of c ollecti o n of t he P K sa m ple a n d t he date a n d ti me of a d mi nistrati o n 
of t he last prece di n g d ose of I M P m ust be rec or de d o n t he eC R F f or all o n-treat me nt a n d 
E o T x sa m ples. T he last d ose ti me f or t he off -treat me nt f oll o w-u p sa m ple will be 
ass u me d t o be t he sa me as f or t he M o nt h 1 2/ E o T x sa m ple.  T he e xact ti me of sa m pli n g 
relati ve t o t he pre vi o us I M P d ose is n ot cr itical a n d ca n var y as m uc h as is o perati o nally 
practical.
All plas ma sa m ples will be s hi p pe d t o t he ce ntral cli nical la b orat or y  f or st ora ge. Detaile d 
ha n dli n g a n d s hi p pi n g i nstr ucti o ns are i n A p pe n di x 3 .

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
6 2
2 6 Mar 2 0 1 5 
3. 7. 4. 2
P h ar m a c o d y n a mi c Uri n e S a m pl e s 
A s p ot uri ne sa m ple f or deter mi nati o n of U os m a n d s pecific gra vit y will be o btai ne d at 
t he f oll o wi n g ti mes:

sec o n d visit of t he scree ni n g peri o d

e n d of t h e place b o r u n-i n peri o d ( Da y - 3 6)

e n d of t he t ol va pta n titrati o n peri o d ( Da y - 2 2)

e n d of t he t ol va pta n r u n -i n peri o d ( Da y - 1)

d uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d at M o nt hs 3, 6, 9, a n d 1 2 / E o T x

at t he last f oll o w-u p visit
T his sa m ple s h o ul d be o btai ne d pri or t o t he s u bject eati n g brea kfast , fr o m t he uri ne v oi d 
ta ke n after t he first m or ni n g’s v oi d, a n d will i deall y be pr o vi de d as a mi d -strea m, 
clea n-catc h sa m ple. T o e ns ure a fasti n g uri ne sa m ple is c ollecte d, s u bjects will be 
pr o vi de d wit h a sterile uri ne c u p o n t he visit prece di n g t he d ate of uri ne sa m ple 
c ollecti o n. S u bjects will be i nstr ucte d t o c ollect a uri ne sa m ple pri or t o eati n g brea kfast ,
a n d t o st ore t he sa m ple i n t he refri ger at or u ntil t heir cli nic visit.
Date a n d ti me of t he uri ne sa m ple, as well as t he date a n d ti me of t he last prece di n g d ose 
of I M P f or all o n -treat me nt a n d Eo T x sa m ples, s h o ul d be n ote d i n t he eC R F.
T he last 
d ose date f or t he off -treat me nt sa m ple will be ass u me d t o be t he sa me as f or t he M o nt h 
1 2/ E o T x P D uri ne sa m ple.
All uri ne sa m ples will be s hi p pe d t o t he ce ntral cli nical la b orat or y  f or a nalysis.  Detaile d 
ha n dli n g, i ncl u di n g v ol u me of sa m ple nee de d, a n d s hi p pi n g i nstr ucti o ns is pr o vi de d i n 
A p pe n di x 3 .
3. 7. 5
E n d of Tr e at m e nt/ E n d of Tri al
Ra n d o mize d s u bjects will ha ve t heir last sc he d ule d treat me nt 1 2 m o nt hs fr o m t he ir date 
of ra n d o mizati o n.
If a s u bject disc o nti n ues I M P bef ore M o nt h 1 2 , t he last date t hat t he s u bject recei ve d I M P 
will be rec or de d as E o T x .  See Secti o n 3. 8. 3 a n d Secti o n 3. 1 0 f or m ore i nf or mati o n o n 
E o T x r ules f or t his trial.
T he en d of trial d ate is defi ne d as t he last d ate of last co ntact wit h t he s u bject .  T his d oes 
n ot refer t o o verall trial d urati o n.  T he e n d of trial date a n d ti mi n g f or f oll o w - u p 
assess me nts will be i n di vi d ualize d f or eac h s u bject.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
6 3
2 6 Mar 2 0 1 5 
3. 7. 6
I n d e p e n d e nt D at a M o nit ori n g C o m mitt e e
F or trials i n hi g h m or bi dit y  a n d/ or hi g h m ortality disease, w here efficac y  e n d p oi nts c o ul d 
be s u bject t o e x pe dite d re p orti n g, t he i nte grit y of t he cli nical trial ma y be c o m pr o mise d if 
t he bli n d is br o ke n. F or t his trial , a n I D M C, als o k n o w n as a Data Saf et y a n d M o nit ori n g 
C o m mittee [ D S M C]) will be esta blis he d. T he r ole of t he I D M C s hall be deli neate d i n a 
se parate I D M C C harter d oc u me nt, b ut i n ge neral t his gr o u p will meet o n a re g ular basis 
t o e ns ure t he safe a n d et hical treat me nt of trial s u bjects, e ns ure t he scie ntific i nte grit y  of 
t he trial, a n d t o e ns ure t he trial is c o n d ucte d wit hi n t he b o u n ds of et hical me dical 
practice. A dj u dicati o n res ults as deter mi ne d b y t he H A C will be re p orte d t o t he I D M C 
o n a q uarterl y  basis or more fre q ue ntl y as necessa r y.  T his I D M C ma y  ma ke 
rec o m me n dati o ns t o t he s p o ns or a n d trial steeri n g c o m mittee t o a me n d or ter mi nate t he 
trial base d o n gr o u n ds of safety, f utilit y , or greater t ha n e x pecte d efficac y  as defi ne d b y 
t he acce pte d statistical practices a n d pr oce d ures detaile d i n t heir C harter.
3. 8
St o p pi n g R ul e s, Wit h dr a w al Crit eri a, a n d Pr o c e d ur e s
3. 8. 1
E ntir e Tri al or Tr e at m e nt A r m( s)
If t he s p o ns or ter mi nates or s us pe n ds t he trial f or safety or u na ntici pate d ot her reas o ns, 
pr o m pt n otificati o n will be gi ve n t o i n vesti gat ors, I R Bs/ I E Cs, a n d re g ulat or y a ut h orities 
i n acc or da nce wit h re g ulat or y re q uire me nts.
3. 8. 2
I n di vi d u al Sit e
T he i n vesti gat or will n otif y  t he s p o ns or pr o m ptl y if t he trial is ter mi nate d b y t he 
i n vesti gat or or t he I R B/I E C at t he site. If t he i n vesti gat or, I R B/I E C or s p o nsor deci des t o 
ter mi nate or s us pe n d t he trial’s c o n d uct at a partic ular ce nter f or safety , n o n-e nr oll me nt 
of s u bjects, n o n -c o m plia nce wit h t he pr ot oc ol , or u na ntici pate d ot her reas o ns, t he a b o ve 
a n d ot her parties, as re q uire d b y t he a p plica ble re g ulat or y re q uire me nts, will be pr o m ptl y  
n otifie d.
3. 8. 3
I n di vi d u al S u bj e ct Di s c o nti n u ati o n
3. 8. 3. 1
S u bj e ct s Di s c o nti n u e d Pri or t o R a n d o mi z ati o n
S u bjects disc o nti n ue d d uri n g t he pre -ra n d o mizati o n peri o d will be desi g nate d as eit her a 
“ Scree n fail ure” or “ R u n -i n fail ure”.  D uri n g t he scree ni n g peri o d, if a s u bject wit h dra ws 
t heir c o nse nt or fails t o meet all of t he re q uire me nts t o c o nti n ue i n t he trial, t hat s u bject 
will be c o nsi dere d a “ Scree n fail ure”.  S u bjects w h o fail t o meet trial re q uire me nts d uri n g 
t he scree ni n g peri o d ma y be rescree ne d at a later date.

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Scree n fail ure s u bjects will be rec or de d as s uc h o n t he e C R F.  Scree n fail ure s u bjects d o 
n ot re q uire f oll o w -u p a n d ca n be c o nsi dere d f or rescree ni n g if t he reas o n f or t he scree n 
fail ure was n ot t hat t he s u bject wit h dre w t heir c o nse nt .  If rescree ne d, t he s u bject will 
si g n a ne w i nf or me d c o nse nt, will be assi g ne d a ne w scree ni n g n u m ber, a n d will re peat 
all scree ni n g pr oce d ures.
D u ri n g t he re mai n der of t he pre -ra n d o mizati o n peri o d (place b o r u n -i n, t ol va pta n titrati o n, 
or t ol va pta n r u n -i n peri o ds), if a s u bject disc o nti n ues or is disc o nti n ue d t hat s u bject will 
be c o nsi dere d a “ R u n -i n fail ure”.  A s u bject ma y be c o nsi dere d a “ R u n-i n fail ure” f or a ny 
of t he f oll o wi n g reas o ns :

S u bject d oes n ot meet e ntr y  re q uire me nts (ie, s u bject ca n n ot t olerate I M P treat me nt 
as s pecifie d f or a partic ular pr e-ra n d o mizati o n peri o d - see Secti o n 3. 2. 1 ),

S u bject deci des t o f or mall y wit h dra w c o nse nt a n d/ or fails t o ret ur n f or s u bse q ue nt 
a p p oi nt me nts at t he trial site, or

I n vesti gat or c o nsi ders t he s u bject u ns uita ble f or f urt her partici pati o n.
R u n -i n fail ure s u bjects will be rec or de d as s uc h o n t he e C R F. R u n -i n fail ure s u bjects will 
c o m plete a n E o T x visit u p o n wit h dra wal fr o m t he trial.  T he E o T x visit assess me nts will 
i ncl u de: c ollect vital si g ns, p h ysical e xa mi nati o n, ser u m creati ni ne assess me nt, cli nical 
la b orat or y assess me nts, c ollect P K/ P D sa m ples a n d bi o mar ker uri ne/ plas ma sa m ples .  
R u n -i n fail ure s u bjects will t he n be f oll o we d u p after 7 d a y s wit h a p h o ne call t o rec or d 
a n y o n g oi n g A Es (as s pecifie d i n Secti o n 5. 6 ); u nless t he s u bject f ully wit h dra ws c o nse nt 
t o a n y f urt her f oll o w-u p b y  writte n d oc u me ntati o n.
3. 8. 3. 2
Tr e at m e nt I nt err u pti o n
I n t his ye ar-l o n g trial, it is e x pecte d t hat s u bjects ma y ha ve o ne or m o re treat me nt
i nterr u pti o ns d uri n g t he d o u ble- bli n d, ra n d o mize d treat me nt peri o d .  If a s u bject’s I M P 
treat me nt m ust be i nterr u pte d f or me dical or s ur gical reas o ns; li ver test a b n or malities; use 
of a pr o hi bite d c o nc o mita nt me dicati o n; or ot her reas o ns (e g, h os pital a d missi o n f or a n 
i n vasi ve pr oce d ure, a maj or me dical c o n diti o n, s ur ger y; de ntal w or k, or a te m p orar y 
sit uati o n t hat pre ve nts s u bject c o m plia nce wit h t he I M P a d mi nistrati o n sc he d ule ), t he 
s u bject’s I M P s h o ul d be res u me d as early as t he sit uati o n al l o ws (see Secti o n 3. 8. 3. 4 ).
A n y  I MP i nterr u pti o n of < 7 c o nsec uti ve da ys will be rec or de d as misse d d oses rat her 
t ha n as a te m p orar y i nterr u pti o n of I MP.  T he s u bject s h o ul d i m me diatel y i nf or m t he 
i n vesti gat or of a ny misse d d oses reac hi n g or e x pecte d t o be 2 da y s or m ore s o t hat t he 
i n vesti gat or ca n c o nti n ue t o m o nit or t he s u bject’s treat me nts a n d pre pare f or a p ossi ble 
7- d a y  I M P i nterr u pti o n.

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A n I MP i nterr u pti o n t hat lasts 7 c o nsec uti ve da ys will be rec or de d as a “ 7 -d a y  
Treat me nt I nterr u pti o n” o n t he e C R F a n d t he s u bject will visit t he cli nic t o c ollect vital 
si g ns, p hys ical e xa m, ser u m creati ni ne assess me nt, cli nical la b orat or y assess me nts, 
P K/ P D sa m ples, a n d bi o mar ker urine/ plas ma sa m ples.  It is ass u me d t hat a n i nterr u pti o n 
of t his d urati o n ma y  bec o me per ma nent, t heref ore t he s u bject will ha ve a t otal of 
3 sa m ples c ollecte d f or ser u m creati ni ne meas ure me nts (i n t he 2- wee k peri o d be gi n ni n g 
o n t he 7t h da y  a n d i ncl u di n g t he a b o ve-me nti o ne d ser u m creati ni ne assess me nt). 
Treat me nt ma y  still be restarte d d uri n g or after t hese assess me nts are c o m plete d ; a ny 
re mai ni n g ser u m creati ni ne assess me nts will n ot nee d t o be c o m plete d if treat me nt is 
restarte d d uri n g t his peri o d.  If treat me nt is restarte d, a n d t he s u bject c o nti n ues t o 
M o nt h
1 2, t he s u bject will c o m plete t he M o nt h 1 2 visit a n d sc he d ule d f oll o w - u p 
assess me nts; t he 7 -d a y  Interr u pti o n assess me nts will be c o nsi dere d as u nsc he d ule d.   T his 
pr oce d ure is ai me d at e ns uri n g data f or t he pri mar y e n d p oi nt will be c ollecte d fr o m all 
s u bjects.
3. 8. 3. 3
Tr e at m e nt Di s c o nti n u ati o n
After ra n d o mizati o n, a s u bject ma y st o p treat me nt per ma ne ntly bef ore M o nt h 1 2 f or a 
variet y of reas o ns.  Treat me nt disc o nti n uati o ns ma y  be i nitiate d b y a s u bject w h o is n ot 
satisfie d wit h treat me nt or ma y bec o me me dicall y nece ssar y d ue t o A Es or ot her iss ues, 
as deter mi ne d b y t he i n vesti gat or (see Secti o n 3. 8. 3. 4 ).  H o we ver, eac h i n vesti gat or m ust 
c o m pre he nsi vel y re vie w t he circ u msta nces a n d offer t he s u bject o pti o ns f or c o nti n ue d 
treat me nt t o t he de gree p ossi ble as descri be d i n Secti o n 3. 8. 3. 5. 1 .
A s u bject w h o per ma ne ntl y  disc o nti n ue s treat me nt will be rec or de d as a n I M P 
disc o nti n uati o n o n t he e C R F.  T he y  will ha ve a n E o T x v isit, w hic h s h o ul d be sc he d ule d 
as s o o n as p ossi ble after t he s u bject’s last d ose of I M P, t o c ollect vital si g ns, p h ysical 
e xa m, ser u m creati ni ne assess me nt, cli nical la b orat or y assess me nts, P K/ P D sa m ples, a n d 
bi o mar ker uri ne/ plas ma sa m ples.  T he s u bject ’s f oll o w-u p peri o d will be 3 wee ks, as 
t h o u g h t h e y h ad r e a c h e d t h e M o nt h 1 2 visit , a n d t h e f oll o w-u p p eri o d will st art aft er t h e 
l ast d a y of tr e at m e nt, w hi c h m a y b e a diff er e nt d a y fr o m t h e E o T x visit.  N o f oll o w -u p 
ass ess m e nts will b e t a k e n d uri n g t h e first w e e k of t his p eri o d.   T h er e will b e t hr e e visits 
in t h e f oll o w-u p p eri o d b et w e e n D a y 8 a n d D a y 2 1.  T h e first t w o will b e f or t h e 
c oll e cti o n of s er u m cr e ati ni n e m e as ur e m e nt a n d t h e t hir d will h a v e a d diti o n al s af et y , 
effi c a c y, P K, a n d P D m e as ur e m e nts.
After t he f oll o w -u p peri o d, t he s u bject will 
c o nti n ue wit h all assess me nts u p t o a n d i ncl u di n g t h ei r s c h e d ul e d M o nt h 1 2 visit, 
b ut will n ot b e r e q uir e d t o c o m pl et e f oll o w -u p b e y o n d t h at visit .

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3. 8. 3. 4
D o c u m e nti n g R e a s o n s f or Tr e at m e nt
I nt err u pti o n/ Di s c o nti n u ati o n
A s u bject ma y  te m p oraril y i nterr u pt or disc o nti n ue IM P
f or a n u m ber of reas o ns 
i ncl u di n g t h ose liste d bel o w:

Reas o ns r elate d t o A E:

S u bject c o ul d n ot t olerate I M P d ue t o a n A E w hic h is a n n o y i n g or 
u nc o mf orta ble b ut n ot seri o us or hazar d o us

P h y sicia n deter mi ne d t hat t here are p ote ntial I M P relate d safety c o ncer n or 
S A E placi n g s u bject at u n d ue hazar d

Seri o us a d verse e ve nt ( S A E )

Pr o gressi o n of disease lea di n g t o dial ys is, tra ns pla ntati o n or e G F R decli ne as 
deter mi ne d b y t he i n vesti gat or

Li ver test a b n or malities meeti n g criteria f or per ma ne nt disc o nti n uati o n (s ee 
Secti o n 3. 7. 3. 4 )

Cli nical si g ns of DI LI (e g, ja u n dice, ri g ht u p per q ua dra nt pai n)

Deat h

Reas o ns u nrelate d t o me dical c o n diti o n ( e g, pre g na nc y , trial t o o b ur de ns o me)

Wit h dra wal of i nf or me d c o nse nt
(partial relate d t o I M P or c o m plete fr o m t he trial )

L ost t o f oll o w -u p ( Detaile d pr oce d ures t o pre ve nt s u bjects fr o m bec o mi n g “l ost t o 
f oll o w- u p will be pr o vi de d i n t he o perati o ns ma n ual.  T hes e pr oce d ures m ust be 
f oll o we d by t he i n vesti gat or, t heir staff or ot her desi g nate d trial pers o n nel.)

Ter mi nati o n of all or part of t he trial b y t he s p o ns or

Ta ki n g mar kete d pr o d uct f or t ol va pta n ( disc o nti n ue d s u bjects o nl y )
If t he s u bject te m p orarily i nter r u pts or disc o nti n ues IM P d ue t o a n A E, t he i n vesti gat or , 
or ot her trial pers o n nel, will ma ke e ver y  eff ort t o f oll o w t he e ve nt u ntil it has res ol ve d or 
sta bilize d.  F oll o w u p pr oce d ures i n Secti o n 3. 8. 3. 2 a n d/ or Secti o n 3. 8. 3. 3 m ust be 
f oll o we d.  If t he s u bject’s IM P is i nterr u pte d f or a li ver test a b n or malit y or li ver 
s ym pt o ms , pr oce d ures o utli ne d i n Secti o n 3. 7. 3. 4 s h o ul d be f oll o we d.
3. 8. 3. 5
Wit h dr a w al of C o n s e nt
All s u bjects ha ve t he r i ght t o wit h dra w t heir c o nse nt fr o m f urt her partici pati o n i n t he trial 
at a n y ti me wit h o ut prej u dice.  T he i n vesti gat or ca n als o disc o nti n ue a s u bject’s 
partici pati o n i n t he trial at a n y  ti me if me dicall y necessar y.  U nless t he s u bject pr o vi des 
t heir writte n wit h dra wal of c o nse nt or t here is ot her writte n d oc u me ntati o n b y t he 
i n vesti gat or c o nfir mi n g t he s u bject’s ver bal i nte nt t o c o m pletel y wit h dra w fr o m t he trial,
s u bjects s h o ul d be f oll o we d f or all pr ot oc ol-s pecifie d e val uati o ns a n d assess me nts.

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C o m p lete wit h dra wal of c o nse nt re q uires a s u bject’s ref usal of A L L of t he f oll o wi n g 
met h o ds of f oll o w u p (t hese met h o ds of f oll o w u p will als o be n ote d i n t he trial I C F):

Partici pati o n i n all f oll o w - u p pr oce d ures s pecifie d i n t he pr ot oc ol ( w het her i n-cli nic, 
b y tele p h o ne, or b y a n i n -h o me visit).

Partici pati o n i n a s u bset of pr ot oc ol s pecifie d f oll o w -u p pr oce d ures ( b y  a fre q ue nc y 
sc he d ule a n d met h o d as a gree d by s u bject a n d staff) .

Partici pati o n i n all re g ularl y  sc he d ule d, st u d y-relate d f oll o w-u p visits a n d E o T x
visits .

C o ntact of t he s u bject b y trial pers o n nel, e ve n if o nl y  b y tele p h o ne, t o assess c urre nt 
me dical c o n diti o n a n d o btai n necessar y  me dical or la b orat or y re p orts rele va nt t o t he 
trial’s o bjecti ves.

C o ntact of alter nati ve pers o n(s) w h o ha ve bee n desi g n ate d i n s o urce rec or ds as bei n g 
a vaila ble t o disc uss t he s u bject’s me dical c o n diti o n, e ve n if o nl y b y tele p h o ne, mail 
or e -mail (e g, fa mil y, s p o use, part ner, le gal re prese ntati ve, frie n d, nei g h b or, 
p h y sicia n).

Access t o me dical i nf or mati o n fr o m alter nati ve s o urces (e g, h os pital/cli nic me dical 
rec or ds, referri n g d oct or’s n otes, p u blic rec or ds, dial ysis, tra ns pla ntati o n or vital 
re gistries, s ocial me dia s o urces). 
Wit h dra wal of c o nse nt is a critical trial e ve nt a n d t heref ore s h o ul d be a p pr oac he d wit h 
t he sa me de gree of i m p orta nce a n d care as is use d i n i nitiall y o btai ni n g i nf or me d c o nse nt.  
T he reas o ns f or a s u bject’s i nte n de d wit h dra wal nee d t o be c o m pletel y  u n derst o o d, 
d oc u me nte d a n d ma na ge d t o pr otect t he ri g hts of t he s u bject a n d t he i nte grit y  of t he trial.  
A s u bject ma y  i nitiall y e x press t heir desire t o i nterr u pt or disc o nti n ue I M P 
a d mi nistrati o n, w hic h is n ot e q ui vale nt t o a c o m plete wit h dra wal of c o nse nt f or f urt her 
partici pati o n (see Secti o n 3. 8. 3. 2 t hr o u g h Secti o n 3. 8. 3. 4 ).  A s u bject ma y, h o we ver, 
i n dicate t hat f urt her trial partici pati o n is creati n g a b ur de n o n t heir w or k or s ocial 
sc he d ule.  T heref ore, t he i n vesti gat or s h o ul d f oll o w t he pr oce d ures o utli ne d i n 
Secti o n 3. 8. 3. 5. 1 t o deter mi ne if t he s u bject ca n c o nti n ue partici pati o n i n t he trial if 
m o dificati o ns t o his/ her treat me nt a n d/ or sc he d ule of assess me nts ca n be acc o m m o date d.
O nl y  s u bjects w h o wit h dra w t heir per missi o n f or all of t he a b o ve de grees of f oll o w- u p 
are c o nsi dere d t o ha ve c o m pletel y  wit h dra w n t heir c o nse nt t o partici pate i n t he st u d y.
3. 8. 3. 5. 1
Pr o c e d ur e s t o E n c o ur a g e C o nti n u e d Tri al P arti ci p ati o n
I n all cases of i m pe n di n g I MP disc o nti n uati o n or c o nse nt wit h dra wal, i n vesti gat ors will 
be gi ve n i nstr ucti o ns t o meet a n d disc uss wit h t he s u bject t heir o pti o ns of c o nti n ui n g i n 
t he trial, prefera bly o n t hera p y.  T he i n vesti gat or s h o ul d e ns ure u n dersta n di n g a n d 
d oc u me ntati o n of t he reas o ns f or t he s u bject’s desire t o wit h dra w c o nse nt .

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If a s u bject i n t he d o u ble-bli n d, ra n d o mize d treat me nt peri o d wis hes t o wit h dra w fr o m 
t he trial:
1)
T he i n vesti gat or s h o ul d first see k t o u n dersta n d t he s u bject’s m oti vati o n a n d 
w here ve r p ossi ble ma ke acc o m m o dati o n s t o pre ve nt treat me nt disc o nti n uati o n or 
c o m plete wit h dra wal of c o nse nt a n d mai ntai n t he f ullest c o m plia nce wit h t he 
pr ot oc ol assess me nts (e g, pr o vi de necessar y  tra vel rei m b urse me nt, i n-h o me visits, 
alter nate visit sc he d uli n g , i ncl u di n g d uri n g wee ke n ds). If t he s u bject’s wis h is t o 
disc o nti n ue st u d y  me dicati o n o nl y, pr ocee d t o Ste p 2.
2)
As k t he s u bject, “ W o ul d y o u be willi n g t o c o nti n ue if y o ur d ose of me dicati o n 
was l o were d?”  I f t he a ns wer is “ Yes” titrate t he s u bject’s d ose do w n 1 le vel (e g, 
fr o m 9 0/ 3 0 t o 6 0/ 3 0, fr o m 6 0/ 3 0 t o 4 5/ 1 5, or fr o m 4 5/ 1 5 t o 3 0/ 1 5 [ wit h me dical 
m o nit or a p pr o val]).  Re peat t his ste p if t he s u bject c o nti n ues t o re q uest 
wit h dra wal of c o nse nt.  If t he a ns wer is “ N o” or if, o nce t he 3 0/ 1 5 d ose is 
reac he d, the s u bject c o nti n ues t o re q uest wit h dra wal of c o nse nt, g o t o Ste p 3.
3)
As k t he s u bject , “If we te m p oraril y i nterr u pt yo ur trial me dicati o n w o ul d y o u be 
willi n g t o later res u me me dicati o n a n d c o nti n ue wit h all visits a n d sa m ple 
c ollecti o ns?”  If t he a ns wer is “ Yes”, i nterr u pt I MP b ut c o nti n ue t o f oll o w all 
ot her trial pr oce d ures f or t he s u bject u ntil t he s u bject restarts treat me nt.  If t he 
s u bject d oes n ot res u me treat me nt wit h I M P after 7 da ys, perf or m 7- d a y  
I nterr u pti o n assess me nts a n d f oll o w-u p (see Secti o n 3. 8. 3. 2 ) a n d t he n res u me 
I M P a n d c o nti n ue wit h all ot her m o nt hl y assess me nts t o t he e n d of t he trial.  If t he 
s u bject still wishes t o wit h dra w fr o m t he trial, g o t o Ste p 4.
4)
As k t he s u bject , “If we disc o nti n ue yo ur trial me dicati o n per ma ne ntl y , w o ul d yo u 
c o nti n ue wit h all visits a n d sa m ple c ollecti o ns?”  If t he a ns wer is “ Yes”, 
disc o nti n ue I M P, perf or m a n E o T x visit, c o m plete t he foll o w -u p peri o d, a n d t he n 
c o nti n ue wit h all ot her m o nt hl y assess me nts t o t he e n d of t he trial (see 
Secti o n 3. 8. 3. 3 ).  If t he a ns wer is “ N o” g o t o Ste p 5.
5)
If f urt her trial s u p p ort or i nterr u pti o n or per ma ne nt disc o nti n uati o n of st u d y 
me dicati o n d oes n ot res ol ve t he s u bject’s iss ues, f urt her acc o m m o dati o ns s uc h as 
less fre q ue nt visits or bl o o d dra ws m a y  be use d (s o l o n g as a de q uate safety 
m o nit ori n g ca n be e ns ure d f or t h ose c o nti n ui n g I M P).  Less fre q ue nt visits or 
pr oce d ures m ust be offere d o nl y  if t he y are re q uire d t o mai ntai n access t o t he 
s u bject’s me dical i nf or mati o n a n d / or t o e nc o ura ge t he s u bject t o c o nti n ue i n t he 
trial.
3. 8. 3. 5. 2 
Pr o c e d ur e s t o Pr e v e nt “ L o st t o F oll o w -u p ”
T he i n vesti gat or m ust ma ke e ver y eff ort t o c o ntact s u bjects w h o fail t o ret ur n f or 
sc he d ule d visits s o t hat t he y will n ot be declare d “l ost t o f oll o w-u p”. T he f oll o wi n g 
pr oce d ures s h o ul d be f oll o we d at a mi ni m u m, wit h a d diti o nal meas ures ta ke n if 
u ns uccessf ul.

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
C o ntact all n u m bers f or t he s u bject a n d t heir liste d c o ntacts (t o be c ollecte d i n s o urce 
at t he s u bject’s e ntr y i nt o t he trial). T his incl u des ma ki n g calls after n or mal b usi ness 
h o urs or o n h oli da y s a n d wee ke n ds.

C o ntact t he s u bject’s pri mar y  care p h ysicia n, referri n g s pecialist, p har macist or ot her 
healt h -care pr ofessi o nal ( usi n g t he c o ntacts pr o vi de d b y  t he s u bject at e ntr y t o t he 
trial).

Se n d a te xt, e -mail a n d p ostal mail wit h certifie d (ret ur n -recei pt re q ueste d) letters t o 
all t he s u bject’s a d dresses a n d all c o ntacts (as pr o vi de d b y  t he s u bject at e ntr y t o t he 
trial).

I n-h o me visit at last a d dress gi ve n.

Re vie w a vaila ble me dical rec or ds/ n otes f or details of h os pitalizati o ns, cli nic visits or 
ot her pr oce d ures w hic h ma y  i n dicate t he stat us of s u bjects (as all o we d t hr o u g h 
release of me dical rec or d f or ms t o be c o m plete d b y patie nt at trial e ntr y).

Utilize t he i nter net t o searc h f or a d diti o nal c o ntact i nf or mati o n (e g, re verse direct or y  
f or p h o ne n u m bers or ne w a d dress i nf or mati o n; Face b o o k , Li n ke d-I n, or ot her s ocial 
me dia f or stat us u p dates) .

C hec k l ocal, re gi o nal a n d nati o nal p u blic rec or ds t o l ocate t he s u bject or searc h f or 
m ortalit y  stat us as all o we d b y la w.
O nce all t hese acti o ns ha ve bee n e x ha us te d (a n d d oc u me nte d), t he n t he s p o ns or cli nical 
researc h ass ociate or me dical m o nit or s h o ul d be c o ntacte d f or a d diti o nal g ui da nce.
3. 9
S cr e e n F ail ur e s
A scree n fail ure is a s u bject fr o m w h o m i nfor me d c o nse nt is o btai ne d a n d is d oc u me nte d 
i n writi n g (ie, s u bject si g ns a n IC F), b ut w h o wit h dra ws c o nse nt fr o m t he trial or d oes n ot 
meet all of t he re q uire me nts, d uri n g t he scree ni n g peri o d , t o c o nti n ue i n t he trial 
(ie, s u bject d oes n o t e nter t he place b o r u n -i n peri o d).
S cree n fail ure s u bjects are per mitte d t o be re -scree ne d.  I n t he e ve nt t hat t he s u bject is 
re-scree ne d, a ne w I C F m ust be si g ne d.
3. 1 0
D efi niti o n of C o m pl et e d S u bj e ct s
T he treat me nt peri o d is defi ne d as t he ti me peri o d d uri n g w hic h s u bjects are e val uate d f or 
pri mar y  a n d/ or sec o n dar y o bjecti ves of t he trial irres pecti ve of w het her or n ot t he s u bject 
act uall y c o ns u mes all d oses of t he I M P.
F or p ur p oses of t his trial, s u bjects w h o are ra n d o mize d, ta ke I MP u p t o M o nt h 1 2 
(-7/ + 2 d a y s), a n d c o m plete s o me or all of t heir re q uire d trial visits/assess me nts t o t he e n d 
of t he trial (i ncl u di n g t he M o nt h 1 2 visit A N D at least 1 f oll o w-u p ser u m creati ni ne 
assess me nt) will be defi ne d as “ O n -treat me nt c o m pleters ”.

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S u bjects w h o are ra n d o mize d, ta ke I M P b ut disc o nti n ue treat me nt pri or t o Da y  3 5 8 ( or 
ne ver be gi n treat me nt) , a n d c o m plete s o me or all of t heir re q uire d trial visits/assess me nts 
t o t he e n d of t he trial (i ncl u di n g t he M o nt h 1 2 visit A N D at least 1 f oll o w-u p ser u m 
creati ni ne assess me nt) will be d efi ne d as “ Off -treat me nt c o m pleters”.
S u bjects w h o are ra n d o mize d, ta ke I M P
( or ne ver be gi n treat me nt), b ut D O N O T 
c o m plete t he M o nt h 1 2 visit A N D at least 1 E o T x f oll o w- u p ser u m creati ni ne assess me nt 
will be defi ne d as “ N o n -c o m pleters”.
B ot h O n -treat me nt c o m pleters a n d Off -treat me nt c o m pleters will ha ve t he o p p ort u nit y t o 
e nr oll i n a t ol va pta n e xte nsi o n trial f oll o wi n g t heir c o m pleti o n of t his c urre nt trial.  
N o n -c o m pleters w h o t o o k I M P m a y  o nly e nr oll i n t he t ol va pta n e xte nsi o n trial wit h 
me dical m o nit or a p pr o val.   N o n -c o m pleters w h o ne ver t o o k I M P d uri n g t he d o u ble- bli n d, 
ra n d o mize d peri o d ma y n ot e nr oll i n t he t ol va pta n e xte nsi o n trial.
3. 1 1
D efi niti o n of S u bj e ct s L o st t o F oll o w -u p
S u bjects w h o ca n n ot be c o ntacte d o n or bef ore t heir last trial visit a n d w h o d o n ot ha ve a 
k n o w n reas o n f or disc o nti n uati o n (e g, wit h dre w c o nse nt or A E) will be classifie d as “l ost 
t o f oll o w-u p” as t he reas o n f or wit h dra wal .
E ver y  eff ort will be ma de b y t he i n vesti gat or, or trial pers o n nel, t o c o ntact t he s u bject 
bef ore t he s u bject is declare d l ost t o f oll o w- u p (see Secti o n 3. 8. 3. 5. 2 ).
3. 1 2
S u bj e ct C o m pli a n c e
Dis pe nsi n g of I M P a n d rec o nciliati o n will be d o ne m o nt hl y d uri n g t he ra n d o mize d 
treat me nt peri o d.  S u bject c o m plia nce will be m o nit ore d b y  pill c o u nts as dr u g is 
ret ur ne d.  I n a d diti o n, t ol va pta n meta b olite D M-4 1 0 3 c o nce ntrati o ns wil l be deter mi ne d 
a n d e val uate d f or c o nsiste nc y  wit h re p orte d d osi n g.
A n y  s u bject w h o, wit h o ut t he i nstr ucti o n of t he i n vesti gat or, disc o nti n ues i n vesti gati o nal 
pr o d uct f or 3 0 c o nsec uti ve da y s or misses > 3 0 % of t he d oses i nte n de d f or a peri o d 
( w hic he ver is greater) will be dee me d n o n-c o m plia nt.  De pe n di n g o n t he circ u msta nces 
lea di n g t o n o n-c o m plia nce, t he s u bject ma y  be disc o nti n ue d fr o m I M P a d mi nistrati o n b y 
t he in vesti gat or a n d/ or s p o ns or.  A s u bject w h o pr oacti vel y wis hes t o disc o nti n ue I MP
a d mi nist rati o n, or has I M P disc o nti n ue d b y  t he in vesti gat or, will be e nc o ura ge d t o 
c o nti n ue li mite d partici pati o n i n t he trial, as descri be d i n Secti o n 3. 8. 3. 3 .
3. 1 3
Pr ot o c ol D e vi ati o n s
I n t he e ve nt of a si g nifica nt de viati o n fr o m t he pr ot oc ol d ue t o a n e mer ge nc y, acci de nt, or 
mista k e (e g, vi olati o n of i nf or me d c o nse nt pr ocess, IM P dis pe nsi n g or s u bject d o si n g 

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err or, treat me nt assi g n me nt err or, s u bject e nr olle d i n vi olati o n of eli gi bilit y  criteria or 
c o nc o mita nt me dicati o n criteria), t he i n vesti gat or or desi g nee will c o ntact t he me dical 
m o nit or at t he earliest p o ssi ble ti me b y tele p h o ne.  T he in vesti gat or a n d s p o ns or will 
c o me as q uic kl y as p ossi ble t o a j oi nt decisi o n re gar di n g t he s u bject’s c o nti n uati o n i n t he 
trial.  T his decisi o n will be d oc u me nte d by t he i n vesti gat or a n d t he s p o ns or, a n d re vie we d 
b y  t he site m o nit or. 
4
R e stri cti o n s
4. 1
Pr o hi bit e d or R e stri c t e d M e di c ati o n s
Me dicati o ns or s ur gical t hera pies use d f or t he p ur p ose or p ote ntial f or m o dif y i n g t he 
pr o gressi o n of P K D c yst gr o wt h or de vel o p me nt will be pr o hi bite d. T hese i ncl u de, b ut 
are n ot restricte d t o, s o mat ostati n a g o nists, ra pa m u ne (sir oli m us), a nti-se nse ri b o n ucleic 
aci d (R N A ) t hera pies, t ol va pta n, a n d ot her vas o pressi n a nta g o nists e g, O P C- 3 1 2 6 0 
( m oza va pta n), Va pris ol (c o ni va pta n), or a go nists (e g, des m o pressi n ) a n d c yst 
dec o m pressi o n s ur ger y . 
C o nti n u o us or s h ort -ter m use of ot her me dicati o ns, w hile n ot pr o hi bite d, ma y be 
restricte d by t he i n vesti gat or beca use of t heir p ote ntial f or i nterfere nce wit h meta b olis m 
or efficac y  e n d p oi nts.  T his i ncl u des t he use of di uretics w hic h m a y be use d 
i nter mitte ntl y, b ut n ot wit h i n 7 da ys of a uri ne assess me nt.  D i uretics are n ot ge nerally 
rec o m me n de d i n A D P K D d ue t o t heir te n de nc y t o i ncrease A V P le vels t hr o u g h relati ve 
de h y drati o n or v ol u me de pleti o n ; t h us, chr o nic use of di uretics (e g, f or hy p erte nsi o n) will
be pr o hi bite d d ue t o p ote ntial e n d p oi nt i nterfere nce a n d is a n e xcl usi o nar y criteri o n f or 
t his trial.  S u bjects ta ki n g s uc h a ge nts m ust first si g n a n I CF a n d t he n a gree t o be 
s witc he d t o a n alter nate f or m of t hera py i n or der t o be eli gi ble f or t he trial.  S o me dr u gs 
are k n o w n t o alter creati ni ne c o nce ntrati o ns s o, w hile n ot pr o hi bite d, s u bjects s h o ul d alert 
t heir trial d oct or, a n d a ny ot her healt h -care pr o vi ders, t o ta ke t his i nt o c o nsi derati o n w he n 
c o nsi deri n g c ha n ges i n t heir prescri be d or o ver -t he-c o u nter me dicati o ns.  A b rief list 
w o ul d i ncl u de:  ci meti di ne, N S AI D me dicati o ns li ke as piri n or i b u pr ofe n, c he m ot hera p y 
dr u gs, a n d ce p hal os p ori n.
Si nce t ol va pta n is a wea k c yt oc hr o me P 4 5 0 (C Y P ) 3 A 4 s u bstrate, p ote nt C Y P 3 A 4 
i n hi bit ors s h o ul d be a v oi de d d uri n g t he trial, wit h t he exce pti o n of a mi o dar o ne , w hic h 
was f o u n d t o ha ve n o effect o n t ol va pta n.  A partial list of ot her C Y P 3 A 4 i n hi bit ors ca n 
be f o u n d i n Ta ble 4. 1 - 1.

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T a ble 4. 1 - 1
C Y P 3 A 4 I n hi bit ors ( P arti al L ist)
b oce pre vir
clarit hr o m yci n
cl otri maz ole (if use d 
orall y)
i n di na vir
itrac o naz ole
ket oc o naz ole (if use d 
orall y)
l o pi na vir
mi befra dil
nefaza d o ne
nelfi na vir
p osac o naz ole
rit o na vir
sa q ui na vir
tela pre vir
telit hr o m yci n
v oric o naz ole
4. 2
Di et ar y  R e stri cti o n s a n d R e c o m m e n d ati o n s
Restricti o n of e xcess dietar y  s o di u m a n d c o o ke d meat pr otei n ma y  pr o ve be neficial t o 
s u bjects wit h a hist or y of, or pre dis p ositi o n f or, h y perte nsi o n or ki d ne y disease i n ge neral 
a n d s h o ul d be a p plie d t o all s u bjects dia g n ose d wit h a d va nce d A D P K D, partic ularl y if 
t here is e vi de nce f or a pr o pe nsit y f or ra pi d pr o gressi o n.  In t he a bse nce of alter nate 
re gi o nal practices, restricti o ns of dietar y  salt < 5 g/ da y a n d dietar y c o o ke d meat pr otei n 
< 1 g/ k g/ da y  a n d t o li mit caffei nate d dri n ks/f o o ds s h o uld als o be gi ve n ( n o m ore t ha n 
2 c offee e q ui vale nts per da y). 
A d diti o nall y , fl ui d i nta ke is ge nerally e nc o ura ge d i n s u bjects wit h P K D.  Gi ve n t he 
p ote ntial f or de h y drati o n wit h t ol va pta n treat me nt, all s u bjects s h o ul d be i nstr ucte d t o 
i n gest fl ui ds i n a ntici pati o n of, or at t he first si g n of t hirst i n or der t o a v oi d e xcessi ve 
t hirst or de h ydrati o n.  U p o n c o nse nt, all s u bjects s h o ul d recei ve t he rec o m me n dati o n t o 
i n gesti o n of at least 2- 3 liters of fl ui d (i ncl u di n g i n s oli d, se mi -s oli d, a n d li q ui d f o o ds) per
da y , u nless ot her wise directe d b y yo ur st u d y  d oct or.  T his rec o m me n dati o n s h o ul d start 
d uri n g scree ni n g a n d c o nti n ue t hr o u g h t he e n d of t he trial.  A d diti o nall y , s u bjects s h o ul d 
i n gest 1 t o 2 c u ps of water bef ore be dti me re gar dless of percei ve d t hirst a n d re ple nis h 
fl ui ds o ver ni g ht wit h eac h e pis o de of n oct uria.  De h y drati o n will be m o nit ore d b y  s u bject 
self-assess me nt of c ha n ges i n b o d y  wei g ht a n d re p orti n g of sy m pt o ms.  Ac ute c ha n ges of 
> 3 % of b o d y wei g ht (i ncrease or decrease) o ver a n y 7 -d a y  peri o d s h oul d be n ote d.  
S u bjects s h o ul d be i nstr ucte d t o re p ort ac ute c ha n ges i n b o d y wei g ht t o t he trial p h ysicia n 
f or f urt her e val uati o n a n d rec o m me n dati o ns.
S u bjects s h o ul d be a d vise d t hat t he i n gesti o n of p o mel o, gra pefr uit , or Se ville ora n ge 
pr o d ucts w o ul d be e x pecte d t o i ncrease t ol va pta n c o nce ntrati o ns a n d t hese s h o ul d be 
a v oi de d.  I n t he e ve nt of a n u ni nte nti o nal i n gesti o n of s uc h pr o d ucts, t he i n vesti gat or ma y  
as k t he s u bject t o te m p oraril y i nterr u pt I M P.  S u bjects s h o ul d be i nf or me d of re gi o nall y 
a p pr o priate rec o m me n dati o ns i n t he trial IC F .

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5
R e p orti n g of A d v er s e E v e nt s
T he f oll o wi n g descri bes t he met h o ds a n d ti mi n g f or assessi n g, rec or di n g, a n d a nal yz i n g 
safety para meters, as well as t he pr oce d ures f or elic iti n g re p orts of a n d rec or di n g a n d 
re p orti n g A Es a n d i nterc urre nt ill nesses a n d t he ty pe a n d d urati o n of t he f oll o w -u p of 
s u bjects after A Es.
A D P K D is a pr o gressi ve dis or der i n v ol vi n g t he ki d ne y , li ver a n d occasi o nall y ot her 
or ga n s ys te ms. A n u m ber of A Es m a y  be ass ociate d wit h t his dis or der a n d are e n d p oi nts 
i n t his trial, i ncl u di n g uri ne c o nce ntrati o n defects, h yperte nsi o n, re nal pai n, re nal 
i nfecti o n, ne p hr olit hiasis, h e mat uria, a n d E S R D. As s uc h, t hese e ve nts are c o nsi dere d 
“e x pecte d” i n t his trial p o p ulati o n a n d will n ot q ualif y  f or t he p ur p oses of re g ulat or y 
e x pe dite d re p orti n g (e g, S us pecte d U ne x pecte d Seri o us A d verse Reacti o n [ S U S A R] a n d 
i n vesti gati o nal ne w dr u g [I ND ] safety re p orts). 
T hese bli n de d e ve nts will be e val uate d o n a re g ular basis b y  t he trial’s Me dical M o nit or 
a n d t he s p o ns or’s Safet y gr o u p.  T he trial’s I D M C will i ncl u de a se parate statistical 
s u p p ort gr o u p w h o will be pr o vi de d t he ra n d o mizati o n c o des s o t hat partiall y or f ull y 
u n bli n de d re vie w of data ma y  occ ur i n cl ose d sessi o n t o be tter assess ris k/ be nefit i n t he 
trial p o p ulati o n.
5. 1
D efi niti o n s
A n A E is defi ne d as a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g 
i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d.
A s us pecte d a d verse reacti o n mea ns a n y  A E f or w hic h t here is a reas o na ble p ossi bilit y 
t hat t he dr u g ca use d t he A E. F or t he p ur p ose of I N D safety re p orti n g, “reas o na ble 
p ossi bilit y ” mea ns t here is e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d 
t he A E. S us pecte d a d verse reacti o n i m plies a lesser de gree of certai nt y  a b o ut ca usalit y.  
A S A E i ncl u des a n y e ve nt t hat res ults i n a n y  of t he f oll o wi n g o utc o mes:
1.
deat h
2.
life-t hreate ni n g, ie, t he s u bject was, i n t he o pi ni o n of t he i n vesti gat or, at 
i m me diate ris k of deat h fr o m t he e ve nt as it occ urre d.  It d oes n ot i ncl u de a n 
e ve nt t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.
3.
persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o 
c o n d uct n or mal life f u ncti o ns.
4.
re q uires i n-patie nt h os pitalizati o n or pr ol o n gs h o s pitalizati o n
N O T E: A pre -sc he d ule d h os pitalizati o n is n ot c o nsi dere d a n S A E.
5.
c o n ge nital a n o mal y/ birt h defect

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6.
ot her me dicall y si g nifica nt e ve nts t hat, base d u p o n a p pr o priate me dical 
j u d g me nt, ma y je o par dize t he s u bject a n d ma y re q uire me dical or s ur gical 
inter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d a b o ve, e g, aller gic 
br o nc h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge nc y  r o o m or h o me, 
bl o o d d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n, or t he 
de vel o p me nt of dr u g de pe n de nc y  or dr u g a b use.
N o n -seri o us A Es are all A E s t hat d o n ot meet t he criteria f or a “seri o us” A E .
I m me diatel y Re p orta ble E ve nt (I R E):

A n y  S A E

A n y  A E ( w het her seri o us or n o n-seri o us) t hat necessitates disc o nti n uati o n of 
I M P.

A n y  s u bject wit h a ne w li ver test a b n or malit y meeti n g t he A E ( w het her seri o us or 
n o n-seri o us) or la b orat or y  t hres h ol d criteria ( w het her c o nsi dere d a n A E or n ot) 
f or he patic e C R F re p orti n g.

A n y  s u bject re p orti n g a n A E of s pecial i nterest (e g, s ki n ne o plas ms or gla uc o ma).

Pre g na ncies are als o defi ne d as I R Es . A lt h o u g h n or mal pre g na nc y is n ot a n A E , 
it will ma n date IM P disc o nti n uati o n a n d m ust be re p orte d o n a n I R E f or m t o 
Ots u ka P har mace utical De vel o p me nt & C o m mercializati o n, I nc. (O P D C ).  
Pre g na nc y  will o nl y be d oc u me nte d o n t he A E eC R F if t here is a n a b n or malit y or 
c o m plicati o n.

A d diti o nall y , i n t he E U re gi o n, e ve nts i n v ol vi n g o ver d ose, mis use a n d a b use as 
well as re p orte d lac k of efficac y  m ust als o be re p orte d as I R Es.
Cli nical L a b orat or y C ha n ges:  It is t he i n vesti gat or’s res p o nsi bilit y t o re vie w t he res ults 
of all la b orat or y  tests as t he y bec o me a vaila ble.  T his re vie w will be d oc u me nte d b y t he 
i n vesti gat or’s date d si g nat ure o n t he la b orat or y re p ort.  F or eac h a b n or mal la b orat or y test 
res ult, t he i n vesti gat or nee ds t o ascertai n if t his is a n a b n or mal (ie, cli nicall y  si g nifica nt) 
c ha n ge fr o m baseli ne f or t hat i n di vi d ual s u bject. ( T his deter mi nati o n, h o we ver, d oes n ot 
necessaril y  nee d t o be ma de t he first ti me a n a b n or mal val ue is o bser ve d.  T he 
i nvesti gat or ma y  re peat t he la b orat or y test or re q uest a d diti o nal tests t o verif y t he res ults 
of t he ori gi nal la b orat or y tests).  If t his la b orat or y  val ue is deter mi ne d b y t he i n vesti gat or 
t o be a n a b n or mal c ha n ge fr o m baseli ne f or t hat s u bject, t his is c o nsi dere d a n A E. 
Se verit y :  A d verse e ve nts will be gra de d o n a 3- p oi nt scale a n d re p orte d as i n dicate d o n 
t he eC R F .  T he i nte nsity of a n a d verse e x perie nce is defi ne d as f oll o ws:
1 = Mil d:
Disc o mf ort n otice d, b ut n o disr u pti o n t o dail y  acti vit y.
2 = M o der at e:
Disc o mf ort s ufficie nt t o re d uce or affect n or mal dail y  acti vity.
3 = Se vere:
I na bilit y t o w or k or perf or m n or mal dail y acti vit y.

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I M P Ca usality: Assess me nt of ca usal relati o ns hi p of a n A E t o t he use of t he I M P
Rel ate d : 
T here is a reas o na ble p ossi bilit y of a ca usal relati o ns hi p.
P ossi bl y rel ate d : T here is a reas o na ble ca usal relati o ns hi p bet wee n t he I M P a n d t he 
A E.  Dec halle n ge is lac ki n g or u nclear.
U nli kel y rel ate d : T here is a te m p oral relati o ns hi p t o I M P a d mi nistrati o n, b ut t here is 
n ot a reas o na bl e ca usal relati o ns hi p bet wee n t he I M P a n d t he A E.
N ot Rel ate d : 
T here is n o te m p oral or reas o na ble relati o ns hi p t o t he I M P 
a d mi nistrati o n.
5. 2
Eli citi n g a n d R e p orti n g A d v er s e E v e nt s
T he i n vesti gat or will peri o dicall y  assess s u bjects f or t he occ urre nce of A Es.  In or der t o 
a v oi d bias i n eliciti n g A Es, s u bjects s h o ul d be as ke d t he f oll o wi n g n o n -lea di n g q uesti o n: 
“H o w ha ve y o u felt si nce y o ur last visit? ”  All A Es (seri o us a n d n o n -seri o us) re p orte d by 
t he s u bject m ust be rec or de d o n t he s o urce d oc u me nts a n d e C R Fs pr o vi de d b y  t he 
s p o ns or.
I n a d diti o n, t he s p o ns or m ust be n otifie d i m me diatel y by t ele p h o ne or fa x of a n y 
i m me diatel y re p orta ble e ve nts acc or di n g t o t he pr oce d ure o utli ne d bel o w i n Secti o n 5. 3 .  
S pecial atte nti o n s h o ul d be pai d t o rec or di n g h os pitalizati o n a n d c o nc o mita nt 
me dicati o ns.
5. 3
I m m e diat el y  R e p ort a bl e E v e nt s
T he i n vesti gat or m ust i m me diatel y re p ort wit hi n 2 4 h o urs after eit her t he i n vesti gat or or 
site pers o n nel bec o me a ware of a n y S A E , ne w li ver la b a b n or malit y  re q uiri n g s pecial 
li ver e C R F c o m pleti o n, or c o nfir me d pre g na nc y , b y  tele p h o ne or b y fa x t o Q ui ntiles dr u g 
safety ser vices as o utli ne d i n A p pe n di x 1.  A n I R E f or m m ust be c o m plete d a n d se nt by 
fa x or o ver ni g ht c o urier t o t he sp o ns or.  ( Please n ote t hat t he I R E f or m is N O T t he A E 
eC R F .)
N o n -seri o us e ve nts t hat re q uire di sc o nti n uati o n of I M P (i ncl u di n g la b orat or y  
a b n or malities) s h o ul d be re p orte d t o t he sp o ns or wit hi n 3 w or ki n g da y s.  T he IR E f or m 
m ust be c o m plete d a n d se nt b y  fa x or o ver ni g ht c o urier t o t he s p o ns or.
S u bjects e x perie nci n g S A Es s h o ul d be f oll o we d cli nicall y u ntil t heir healt h has ret ur ne d 
t o baseli ne stat us, or u ntil all para meters ha ve ret ur ne d t o n or mal, or ha ve ot her wise bee n 
e x plai ne d.  It is e x pecte d t hat t he i n vesti gat or will pr o vi de or arra n ge a p pr o priate 
s u p p orti ve care f or t he s u bject.

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F or s u bjects disc o nti n ue d fr o m I M P, vital stat us a n d sc he d ule d la b orat or y  data will 
c o nti n ue t o be c ollecte d at sc he d ule d m o nt hl y  visits a n d at trial ter mi nati o n.
5. 4
Pr e g n a n c y
W o me n of c hil d be ari n g p ote ntial w h o are se x uall y acti ve m ust use a n effecti ve met h o d of 
birt h c o ntr ol d uri n g t he c o urse of t he trial a n d f or 3 0 da y s after t he last d ose of I M P i n a 
ma n ner s uc h t hat ris k of fail ure is mi ni mize d.  U nless t he s u bject is sterile (ie, w o me n 
w h o ha ve ha d a bilateral o o p h or ect o m y a n d/ or h ys terect o my or ha ve bee n 
p ost me n o pa u sal f or at least 1 2 c o nsec uti ve m o nt hs) or re mai ns a bsti ne nt, 2 of t he 
f oll o wi n g preca uti o ns m ust be use d: vasect o my, t u bal li g ati o n, i ntra uteri ne de vice, birt h 
c o ntr ol pills, birt h c o ntr ol de p ot i njecti o n, birt h c o ntr ol i m pla nt, c o n d o m or occl usi ve ca p 
( dia p hra g m or cer vical/ va ult ca ps) wit h s per mici de.  A n y  si n gle met h o d of birt h c o ntr ol, 
i ncl u di n g vasect o m y a n d t u bal li gati o n, ma y fail, lea di n g t o pre g na nc y.
Bef ore e nr olli n g W O C B P i n t his cli nical trial, i n vesti gat ors m ust re vie w g ui deli nes a b o ut 
trial partici pati o n f or W O C B P.  T he t o pics s h o ul d ge nerall y i ncl u de:

Ge neral i nf or mati o n .

I CF.

Pre g na nc y  pre ve nti o n i nf or mati o n.

Dr u g i nteracti o ns wit h h or m o nal c o ntrace pti ves.

C o ntrace pti ves i n c urre nt use.

G ui deli nes f or t he f oll o w -u p of a re p orte d pre g na nc y .
Pri or t o trial e nr oll me nt, W O C B P m ust be a d vise d of t he i m p orta nce of a v oi di n g 
pre g na nc y  d uri n g trial partici pati o n a n d t he p ote ntial ris k fact ors f or a n u ni nte nti o nal 
pre g na nc y .  T he s u bject m ust si g n a n i nf or me d c o nse nt f or m stati n g t hat t he a b o ve-
me nti o ne d ris k fact ors a n d t he c o nse q ue nces were disc usse d wit h her.
D uri n g t he trial, all W O C B P s h o ul d be i nstr ucte d t o c o ntact t he i n vesti gat or i m me diatel y  
if t he y s us pect t he y mi g ht be pre g na nt (e g, misse d or late me nstr ual c ycle).
If a s u bject or i n vesti gator s us pects t hat t he s u bject ma y  be pre g na nt pri or t o 
a d mi nistrati o n of t he i n vesti gati o nal pr o d uct, a d mi nistrati o n m ust be wit h hel d u ntil t he 
res ults of bl o o d ser u m pre g na nc y tests are a vaila ble.  If t he pre g na nc y is c o nfir me d, t he 
s u bject m ust n ot recei ve I M P or be e nr olle d i n t he trial.  If pre g na nc y  is s us pecte d w hile 
t he s u bject is recei vi n g treat me nt, I M P m ust be wit h hel d i m me diatel y  (if reas o na ble, 
ta ki n g i nt o c o nsi derati o n a n y p ote ntial wit h dra wal ris ks) u ntil t he res ult of a ser u m
pre g na nc y  test is k n o w n.  If pre g na nc y is c o nfir me d, IM P will be i nterr u pte d or wit h hel d 
i n a n a p pr o priate ma n ner (e g, d ose ta peri n g if necessar y f or s u bject safety) a n d t he 

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s u bject will c o nti n ue t o be m o nit ore d f or t he d urati o n of t he re mai n der of t he trial or of 
t heir pre g na nc y. S u bjects w h o per ma ne ntl y disc o nti n ue I M P d ue t o pre g na nc y  m a y 
c o nti n ue t o be m o nit ore d i n t he sa me ma n ner as ot her s u bjects t o t heir 1 2 -m o nt h visit a n d 
will be c o nsi dere d trial O ff-treat me nt c o m pleters.
T he i n vesti gat or m ust i m me diatel y  n otif y t he sp o ns or of a n y  pre g na nc y ass ociate d wit h 
I M P e x p os ure d uri n g t he trial a n d for 3 0 da y s after t he last d ose of I M P a n d rec or d t he 
e ve nt o n t he I R E f or m a n d f or war d it t o t he s p o ns or.  T he s p o ns or will f or war d 
Pre g na nc y  S ur veilla nce F or m(s) f or m o nit ori n g t he o utc o me of t he pre g na nc y. 
Pr ot oc ol re q uire d pr oce d ures f or I MP disc o nti n uati o n a n d f oll o w -u p m ust be perf or me d 
o n t he s u bject u nless c o ntrai n dicate d b y pre g na nc y (e g, x -ra y st u dies).  Ot her a p pr o priate 
pre g na nc y  f oll o w-u p pr oce d ures s h o ul d be c o nsi dere d if i n dicate d.  I n a d diti o n, t he 
in vesti gat or m ust re p ort t o t he s p o ns or, o n a p pr o priate Pre g na nc y  S ur veilla nce f or m(s), 
f oll o w-u p i nf or mati o n re gar di n g t he c o urse of t he pre g na nc y , i ncl u di n g peri natal a n d 
ne o natal o utc o me.  I nfa nts will be f oll o we d f or a mi ni m u m of 6 m o nt hs.
5. 5
Pr o c e d ur e f or Br e a ki n g t h e Bli n d
T he i n vesti gat or is e nc o ura ge d t o c o ntact t he s p o ns or/ Cli nical Researc h Or ga nizati o n 
( C R O) me dical a d vis or t o disc uss t heir rati o nale f or u n bli n di n g.  H o we ver, t o pre ve nt 
dela y s t o t he i n vesti gat or or me dical pers o n nel res p o n di n g t o a p ote ntiall y e mer ge nt 
sit uati o n, u n bli n di n g of I M P will n ot be de pe n de nt u p o n t he i n vesti gat or recei vi n g 
a p pr o val fr o m t he s p o ns or/ C R O me dical a d vis or (ie, t he i n vesti gat or will be a ble t o 
o btai n t he c o de brea k i nf or mati o n i n de pe n de nt of t he s p o ns or/ C R O me dical a d vis or).  
T he i n vesti gat or m ust c o ntact t he s p o ns or/C R O m e dical a d vis or b y  tele p h o ne wit h a n 
e x pla nati o n of t he nee d f or o pe ni n g t he treat me nt assi g n me nt c o de wit hi n 2 4 h o urs of 
o pe ni n g t he c o de. If t he bli n d is br oke n , t he s p o ns or’s Cli nical Safet y a n d 
P har mac o vi gila nce de part me nt (c o ntact i nf or mati o n pr o vi de d i n A p pe n di x 1) will be 
n otifie d i m me diatel y .  D oc u me ntati o n of brea ki n g t he bli n d s h o ul d be rec or de d i n t he 
s u bject’s me dical rec or d wit h t he date a n d ti me t he bli n d was br o ke n a n d t he na mes of 
t he pers o n nel i n v ol ved.  O nce t he bli n d is br o ke n f or a gi ve n s u bject, t hat s u bject ma y  n ot 
rei nitiate treat me nt wit h I M P.
5. 6
F oll o w -u p of A d v er s e E v e nt s
F or t his trial, A Es will be f oll o we d u p f or 7 da y s i n s u bjects w h o disc o nti n ue d pri or t o 
ra n d o mizati o n a n d f or 2 1 da y s after t he last d ose of I M P has bee n a d mi nistere d
(f oll o w-u p peri o d) i n s u bjects w h o were ra n d o mize d.

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S u bjects e x perie nci n g S A Es s h o ul d be f oll o we d cli nicall y u ntil t heir healt h has ret ur ne d 
t o baseli ne stat us, or u ntil all para meters ha ve ret ur ne d t o n or mal, or ha ve ot her wise bee n 
e x plai ne d.
F or s u bjects w h o ha ve disc o nti n ue d I M P b ut ha ve n ot wit h dra w n fr o m t he trial , vital 
stat us, A Es, c o nc o mita nt me dicati o ns, E S R D stat us, a n d sc he d ule d la b orat or y data
(incl u di n g ser u m creati ni ne data) are pla n ne d t o be c ollecte d re gar dless of I M P 
disc o nti n uati o n u ntil t he sc he d ule d e n d of t he trial.
5. 6. 1
F oll o w -u p of N o n -s eri o u s A d v er s e E v e nt s
N o n -seri o us A Es t hat are i de ntifie d o n t he last sc he d ule d c o ntact m ust be rec or de d on t he 
A E eC R F wi t h t he c urre nt stat us n ote d.  All n o n -seri o us e ve nts t hat are o n g oi n g at t his 
ti me will be rec or de d as o n g oi n g o n t he e C R F.
5. 6. 2
F oll o w -u p of P o st -Tri al S eri o u s A d v er s e E v e nt s
Seri o us A Es t hat are i de ntifie d o n t he l ast sc he d ule d c o nt act m ust be rec or de d o n t he 
A E eC R F pa ge a n d re p orte d t o t h e sp o ns or acc or di n g t o t he re p orti n g pr oce d ures o utli ne d 
i n Secti o n 5. 3 .  T his ma y i ncl u de u nres ol ve d pre vi o usl y re p orte d S A Es , or ne w S A Es .  
T he i n vesti gat or will f oll o w S A Es u ntil t he e ve nts are res ol ve d, or t he s u bject is l ost t o 
f oll o w- u p.  Res ol uti o n mea ns the s u bject has ret ur ne d t o t he baseli ne state of healt h, or 
t he i n vesti gat or d oes n ot e x pect a n y f urt her i m pr o ve me nt or w orse ni n g of t he s u bject’s 
c o n diti o n.  T he i n vesti gat or will c o nti n ue t o re p ort a n y  si g nifica nt f oll o w-u p i nf or mati o n 
t o O P D C u p t o t he p oi n t t he e ve nt has bee n res ol ve d.
5. 6. 3
F oll o w -u p a n d R e p orti n g of S eri o u s A d v er s e E v e nt s O c c urri n g 
aft er L a st S c h e d ul e d C o nt a ct
A n y  ne w S A Es re p orte d b y t he s u bject t o t he i n vesti gat or t hat occ ur after t he l ast 
sc he d ule d c o nt act, a n d are deter mi ne d by t he i n ve sti gat or t o be reas o na bl y ass ociate d 
wit h t he use of t he I M P, s h o ul d be re p orte d t o O P D C.  T his ma y  i ncl u de S A Es t hat are 
ca pt ure d o n f oll o w- u p tele p h o ne c o ntact or at a n y ot her ti me p oi nt after t he defi ne d trial 
peri o d (ie, u p t o last sc he d ule d c o ntact). T he i n vesti gat or s h o ul d f oll o w p ote ntiall y  
I M P-relate d S A Es i de ntifie d after t he last sc he d ule d c o ntact u ntil t he e ve nts are res ol ve d, 
or t he s u bject is l ost t o f oll o w - u p.  T he i n vesti gat or s h o ul d c o nti n ue t o re p ort a n y 
si g nifica nt f oll o w-u p i nf or mati o n t o O P D C u p t o t he p oi n t t he e ve nt has bee n res ol ve d.

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6
P h ar m a c o ki n eti c a n d P h ar m a c o d y n a mi c A n al y s i s
6. 1
P h ar m a c o ki n eti c
T ol va pta n ( O P C -4 1 0 6 1) plas ma c o nce ntrati o ns ma y be use d f or a p o p ulati o n P K a nal y sis 
(t hat w o ul d be re p orte d se paratel y).
T he D M - 4 1 0 3 meta b olite has a half-life of a p pr o xi matel y 1 8 0 h o urs a n d, c o nse q ue ntl y, is 
a g o o d mar ker of l o n g ter m c o m plia nce wit h d osi n g . D M -4 1 0 3 c o nce ntrati o ns will be 
re vie we d f or c o nsiste nc y wit h I M P dis pe nsi n g a n d ret ur n rec or ds i n or der t o deter mi ne 
c o m plia nce. C o nce ntrati o ns will be pl otte d b y  ge n der ( male, fe male, t otal p o p ulati o n)
a n d m o dal d ose wit hi n t he pre vi o us treat me nt peri o d a n d treat me nt da y .
6. 2
P h ar m a c o d y n a mi c
Uri ne os m olalit y  a n d s pecific gra vity will be s u m marize d b y  treat me nt (t ol va pta n or 
place b o) a n d ti me p oi nt usi n g descri pti ve statistics. Baseli ne val ues will be fr o m t he 
sa m ple o btai ne d at t he e n d of t he place b o r u n -i n peri o d.
7
St ati sti c al A n al y s i s
7. 1
S a m pl e Si z e
7. 1. 1
S a m pl e Si z e E sti m ati o n
I n t his sa m ple size esti mati o n, it is ass u me d t hat 3 calc ulati o ns of e G F R will be o btai ne d
at baseli ne d uri n g a 3- wee k i nter val d uri n g scree ni n g ( 1-2 wee ks) a n d place b o r u n-i n
( 1 wee k), a n d a n ot her 3 calc ulati o ns will be o btai ne d p ost -treat me nt d uri n g a 2 - wee k 
i nter val t hat be gi ns 1 wee k after t he e n d of treat me nt (3- wee k p ost -treat me nt f oll o w-u p ).  
T he mea n of t he 3 e G F R val ues o bser ve d d uri n g t he scree ni n g a n d place b o -r u n peri o ds 
will be set as t he baseli ne a n d t he mea n of t he 3 e G F R val ues o bser ve d d uri n g t he 
p ost -treat me nt f oll o w-u p peri o d will be set as t he re nal f u ncti o n meas ure me nt p ost -
treat me nt.  T he ti mi n g of t he baseli ne a n d p ost -treat me nt o bser vati o ns will be set t o t he 
me dia n of t he o bser vati o n ti mes i n t he 2- wee k i nter val, res pecti vel y .  T h us, t he 
pre -treat me nt baseli ne will be set at a p pr o xi matel y 6 wee ks pri or t o ra n d o mizati o n, a n d 
t he p ost-treat me nt re nal f u ncti o n meas ure me nt will be set at a p pr o xi matel y 2 wee ks after 
t he e n d of treat me nt.
Base d o n a Mi xe d M o del Re peate d Meas ure me nts
( M M R M) a nal ys is of t he n o n-Ja pa n 
C K D - 3 su bjects fr o m T rial 
, t he treat me nt differe nce i n re nal f u ncti o n at 
M o nt h 1 2 , base d o n t he p ost -ra n d o mizati o n baseli ne, is 
.   
 
 

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, we ma y ass u me the treat me nt differe nce i n re nal 
f u ncti o n is 1. 0 7 m L / mi n/ 1. 7 3 m2 i n o ur sa m ple size calc ulati o n.
T o i n vesti gate t he re d ucti o n i n i ntra-s u bject variati o n ac hie ve d by t a ki n g t he mea n of a n 
i ncrease d n u m ber of o bser vati o ns at baseli ne a n d p ost -treat me nt f oll ow - u p, a n d its i m pact
o n t he sa m ple size, we ha ve t o esti mate t he i ntra-s u bject err or a n d i nter- s u bject err or.
O ne of t he a p pr oac hes i n sa m ple size calc ulati o n f or t his pr ot oc ol is t o use M M R M t o 
esti mate t he i ntra- a n d i nter-s u bject varia nces.  I n t he A D P K D p has e 3 trial 
, 
t here was a pre -treat me nt baseli ne visit a n d t w o p ost-treat me nt foll o w -u p visits, al o n g 
wit h ot her o n -treat me nt visits.  Ass u me t hese data f oll o w t he f oll o wi n g m o del ( de n ote d 
as j = 0 f or baseli ne a n d j = 3 7 f or f oll o w -u p, a s well as j = 4, 8, 1 2, …, 3 6):
Y i, 0 = α i + ε i, 0
( 1)
Y i,j = α i + δ i,j + ε i,j
(2 )
w here δ i,j, as a ra n d o m effect of c ha n ge fr o m pre-treat me nt baseli ne at visit j f or s u bject i.  
T hese δ i,js j oi ntl y f oll o w a m ulti variate n or mal distri b uti o n wit h mea ns bei n g δ P,j f or 
place b o s u bjects a n d δ T,j f or t ol va pta n s u bjects.  T heir i n di vi d ual varia nce is ass u me d t o 
be  δ,j 2 .  T hese δi,js are s u p p ose d t o be c orrelate d; h o we ver, t heir c orrelati o ns are n ot 
utilize d f or t he p ur p ose of sa m ple size calc ulati o n i n t his pr ot oc ol.  In a d diti o n, α is are 
ass u me d ii d t o ha ve a n or mal distri b uti o n , εi,j are ass u me d ii d N( 0,  2 ), a n d t hese ra n d o m 
varia bles are m ut uall y i n de pe n de nt. T he n , t he c ha n ge fr o m baseli ne data f oll o ws t his 
c o m m o n M M R M m o del
Y i,j - Yi, 0 = δ i,j - ε i, 0 + ε i,j = ζi,j + ε i,j
( 3)
w h er e ζi,j = δ i,j - ε i, 0.  N ote t hat t he varia nce of ζi,j ( de n ote d by  ζ,j2 ) is e q ual t o  δ,j 2 +  2 .  
T his m o del bec o mes a o ne -w a y  ra n d o m effect m o del if we o nly c o nsi der t he p ost -
treat me nt f oll o w-u p visits f or a treat me nt gr o u p.  T h us, a p pl y i n g a o ne -wa y  ra n d o m 
effect m o del t o t he c ha n ge fr o m pre -treat me nt baseli ne t o p ost-treat me nt f oll o w-u p data 
of place b o a n d t ol va pta n res pecti vel y, i n s u bjects w h o ha d b ot h f oll o w -u p visits a n d 
baseli ne i n 
,  2 is esti mate d as 
  Ta ke 
t he a vera ge of t hese t w o esti mates of  2 t o o btai n a n esti mate of  2 as 7. 1 t o be use d i n 
t his sa m ple size calc ulati o n, w hic h is t he .  N ote t hat 
V ar( Y i,j - Yi, 0) =  δ,j 2 + 2  2
( 4)

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2 6 Mar 2 0 1 5 
At M o nt h 1 2, t he S D ( Sta n dar d De viati o n) c o ul d be ass u me d as 
 
.  T he n base d o n ( 4),  δ,j 2 at M o nt h 1 2 is 
esti mate d as 2 8. 0 5 
.
Wit h k re peate d meas ure me nts at pre -treat me nt baseli ne a n d at 1 2 m o nt h p ost-treat me nt 
f oll o w- u p i n t his trial, t he baseli ne i ntra-s u bject varia nce a n d t he f oll o w-u p i ntra -s u bject 
varia nce are re d uce d fr o m  2 t o  2 / k res pecti vel y.  T h us, t he varia nce of a vera ge c ha n ge 
fr o m a vera ge baseli ne at M o nt h 1 2 is ( δ, 1 2 2 +  2 / k) +   2 / k, w hic h is esti mate d as 3 1. 6 
 w he n k = 4 a n d 3 2. 8 
 w he n k = 3.  Here 
we ha ve t he f oll o wi n g ta ble of sa m ple size:
T a ble 7. 1- 1 
T ot al S a m ple Size wit h C h a n ge = 1. 0 7 a n d 1 0 % Dr o p o ut 
R ate ( Al p h a = 0. 0 5 )
# of Bl o o d dr a ws
1
2
3
4
9 0 % p o w er
1 7 2 2
1 4 3 4
1 3 3 6
1 2 8 8
8 5 % p o w er
1 4 7 7
1 2 3 0
1 1 4 6
1 1 0 6
8 0 % p o w er
1 2 8 6
1 0 7 0
9 9 8
9 6 2
Fr o m t he sa m ple size ta ble, t he i ncrease of re peate d meas ure me nt at baseli ne a n d f oll o w -
u p re d uces t he sa m ple size si g nifica ntl y  i nitiall y b ut q uic kl y l oses its effect w he n k is 
grea ter t ha n 3.  It see ms t hat 3 re peate d meas ure me nts ma y be a p pr o priate i n or der t o 
a v oi d s u bjects’ b ur de n.  T h us, wit h a n ass u m pti o n of 1 0 % dr o p o ut rate i n t he trial, t he 
t otal sa m ple size (ra n d o mize d s u bjects) w o ul d be a p pr o xi matel y 1 3 0 0.
I n or der t o a v oi d e xcessi ve bl o o d dra ws, mec ha nis ms were u n der ta ke n t o mi ni mize t he 
i ntra-s u bject varia bilit y b y sta n dar dizi n g, as m uc h as p ossi ble, t he ti mi n g a n d c o n diti o ns 
b y  w hic h ser u m creati ni ne was assesse d (i n partic ular rec o m me n di n g a si milar diet, 
a v oi di n g variati o n i n pr otei n , es pecially c o o ke d meat pr otei n, i nta ke a n d e xercise patter n 
d uri n g t hese peri o ds). I n a d diti o n t o t he eff orts t o re d uce varia bilit y  b y sta n dar dizi n g 
s u bject diet at t he ti me of bl o o d dra ws, t he n u m ber of sc he d ule d bl o o d dra ws will hel p 
esta blis h precisi o n i n t he esti mate d meas ure me nts.
F or t he sa m ple size of t he ke y  sec o n dar y e n d p oi nt, l o n git u di nal a nalys is s pecifie d 
 
 was a p plie d t o t he e G F R data of C K D -3 
 
s u bjects usi n g p ost-ra n d o mizati o n baseli ne, t o o btai n t he esti mates of t he varia nce of 
i nter-s u bject e G F R sl o pe 
 
 a n d t he varia nce of 
i ntra-s u bject e G F R o bser vati o ns 
.  T he p o wer calc ulati o n usi n g 
t he sa m ple size f or m ula pr o vi de d b y Lefa nte 2 1 ass u mes t he f oll o wi n g:
1)
place b o s u bjects w o ul d ha ve a n e G F R decli ne of 4. 5 m L / mi n/ 1.7 3 m 2 per year;

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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2) t ol va pta n s u bjects w o ul d ha ve a n e G F R decli ne re d uce d 2 5 % c o m pare d wit h 
place b o s u bjects;
3)
treat me nt d urati o n is 1 ye ar wit h m o nt hl y o bser vati o ns i n e G F R.
In a d diti o n, t he 1: 1 ra n d o mizati o n a n d t he al p ha ( 0. 0 5, 2-si de d) s pecifie d a b o ve i n t he 
sa m ple size of t he pri mar y e n d p oi nt are als o ass u me d i n t he sa m ple size calc ulati o n.  It is 
t he n esti mate d t hat 7 3 4 s u bjects are re q uire d f or 9 0 % p o wer.  T h us, wit h a t otal sa m ple 
size of a p pr o xi matel y 1 3 0 0 , t he ke y sec o n dar y e n d p oi nt will ha ve m ore t ha n 9 0 % p o wer 
i n detecti n g a sl o pe differe nce i n t his trial.
7. 1. 2
Bli n d e d S a m pl e Si z e R e- e sti m ati o n
Bli n de d sa m ple size re - esti mati o n will be c o n d ucte d w he n at least a t hir d of t he pla n ne d 
ra n d o mize d s u bjects (4 0 0 t o 5 0 0) ha ve bee n ra n d o mize d.  T his is e x pecte d t o be 
c o n d ucte d bef ore t he a vaila bilit y of a n y p ost 1 2-m o nt h off -treat me nt f oll o w-u p e G F R 
data use d f or t he pri mar y a nal ys is.  T he g oal of t his bli n de d sa m ple size re -esti mati o n is 
t o c hec k:  1) t he differe nces bet wee n t he o bser ve d varia nces a n d t he varia nces use d i n t he 
sa m ple size calc ulati o n; 2) w het her t he a p pr oac h of a vera gi n g t he 3 e G F R o bser vati o n s at 
pre -treat me nt baseli ne a n d p ost-treat me nt f oll o w-u p has ac hie v e d t he g oal of re d uci n g t he 
varia nce t o t he le vel pla n ne d.  T his sa m ple size re -esti mati o n is necessar y, es peciall y, as 
rec o m me n de d by o ur ve n d or, a met h o d t o a nal yz e f or ser u m creati ni ne calle d Rate 
Bla n ke d is t o be use d i n t his pr ot oc ol, w hile t he sa m ple size calc ulati o n is base d o n t he 
data fr o m 
, i n w hic h a n ot her met h o d calle d “ E nz ymatic” was use d t o a nal yz e 
f or ser u m creati ni ne.  Base d o n t hese fi n di n gs, t he ser u m creati ni ne sa m ple n u m ber a n d 
s u bject sa m ple size of t his trial ma y nee d t o be adj uste d.  Detaile d pr oce d ure of t he 
bli n de d sa m ple size re- esti mati o n will be pr o vi de d i n t he S A P.
7. 2
D at a s et s f or A n al y si s
T he f oll o wi n g datasets are defi ne d f or t his trial:

Ra n d o mize d P o p ulati o n:  All s u bjects w h o are ra n d o mize d i n t his trial.

Ra n d o mize d Sa fet y P o p ulati o n:  All s u bjects w h o are ra n d o mize d i n t his trial a n d 
ta ke at least 1 d ose of I M P after ra n d o mizati o n.  T his is t he pri mar y  safety 
p o p ulati o n.

Treate d Safet y P o p ulati o n:  All s u bjects w h o ta ke at least 1 d ose of I M P d uri n g t he 
t ol va pta n titrati o n/r u n-i n peri o ds.  T his is a sec o n dar y safet y p o p ulati o n.

Pri mar y  E n d p oi nt Efficac y P o p ulati o n:  All s u bjects w h o are i n t he Ra n d o mize d 
P o p ulati o n , ta ke at least 1 d ose of I M P after ra n d o mizati o n, a n d ha ve a baseli ne a n d 
at least 1 vali d p ost -treat me nt e val uati o n i n e G F R (ie, after at least 1 wee k off 
treat me nt).  T he pri mar y  e n d p oi nt’s baseli ne is defi ne d as t he a vera ge of u p t o 3
e G F R val ues o bser ve d d uri n g t he scree ni n g a n d place b o r u n -i n peri o ds.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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2 6 Mar 2 0 1 5 

K e y  Sec o n dar y E n d p oi nt Efficac y P o p ulati o n:  All s u bjects w h o are i n t he 
Ra n d o mize d P o p ulati o n , ta ke at least 1 d ose of I M P after ra n d o mizati o n, a n d ha ve a 
baseli ne a n d at least 1 p ost -ra n d o mizati o n e val uati o n i n e G F R d uri n g t he d o u ble -
bli n d treat me nt peri o d .  T his is si milar t o t he Pri mar y E n d p oi nt Efficac y P o p ulati o n , 
e xce pt t hat p ost -treat me nt e val uati o n i n e G F R is re place d by a p ost -ra n d o mizati o n 
e val uati o n.
T he c ore s u bject p o p ulati o n f or all efficac y  a nalys es is base d o n t he i nte nt -t o-treat (I T T) 
p o p ulati o n w hic h c o nsists of all ra n d o mize d s u bjects w h o ta ke at least o ne d ose of I M P
p ost ra n d o mizati o n .  As will be descri be d bel o w, i n or der t o ha n dle missi n g a n d 
restricti o ns i m p ose d b y differe nt ty pes of a nal ys es (e g, c ha n ge fr o m baseli ne a nal ys is), 
datasets base d o n m o difie d I T T p o p ulati o n will be use d i n t he efficac y a nal yses.
T he O bser ve d Cases ( O C) dataset of t his pr ot oc ol is defi ne d as t he data o bser ve d at st u d y 
s pecifie d visits.  F or t he pri mar y o utc o me varia ble of t his pr ot oc ol, t he O C dataset 
c o nsists of t he pre-treat me nt baseli ne (a vera ge of e G F R obser ve d i n scree ni n g peri o d a n d 
t he first e G F R o bser ve d i n place b o r u n-i n peri o d) a n d p ost-treat me nt f oll o w-u p (a vera ge 
of e G F R o bser ve d i n a t w o -wee k i nter val w hic h is o ne wee k p ost t he last I M P d ose).  F or 
t he ke y sec o n dar y o utc o me varia ble of t his pr ot oc ol, t he O C dataset wit hi n treat me nt 
peri o d is defi ne d as t he data o bser ve d at st u d y  s pecifie d visits w hile s u bjects are ta ki n g 
I M P or wit hi n 2 4 h o urs of t he last I M P d ose .
7. 3
H a n dli n g of Mi s si n g D at a
T he eG F R esti mate d b y  t he C K D-E PI f or m ula is utilize d as t he pri mar y efficac y 
asses s me nt i n t his trial.
I n t his pr ot oc ol, all data c ollecte d i n t he pre-treat me nt baseli ne a n d p ost-treat me nt 
f oll o w- u p peri o ds (e xce pt t he wee k i m me diatel y after treat me nt wit h dra wal) will be use d 
a n d missi n g data will n ot be i m p ute d i n deri vi n g t he pre -treat me nt a n d p ost-treat me nt 
e G F R o bser vati o ns use d f or t he pri mar y  a nalys is.
F or se nsiti vit y  a nalys es of t he pri mar y a nalys is, i n ge neral, missi n g data will be ha n dle d 
b y  a nalys is usi n g mi xe d m o del met h o d ol o g y u n der t he ass u m pti o n of “ missi n g at 
ra n d o m” ( M A R).  H o we ver, t he p ossi bilit y of “ missi n g n ot at ra n d o m” ( M N A R) data ca n 
ne ver be r ule d o ut.  T h us, e ver y  eff ort will be ma de t o f oll o w t he s u bjects w h o 
disc o nti n ue I MP after ra n d o mizati o n wit h o ut wit h dra wi n g c o nse nt f or f oll o w - u p of t heir 
e G F R assess me nts. W he n c ollecte d wit hi n t he last 2 wee ks of t he 3 wee ks i m me diatel y  
p ost I M P wit h dra wal, t he data will be i ncl u de d i n t he pri mar y  a nalys is. Ot her wise, e G F R 
assess me nts c ollecte d d uri n g or after t his peri o d will be i ncl u de d i n t he se nsiti vit y 
a nal ys is.  A d diti o nal se nsiti vit y a nal ys is will be c o n d ucte d f or t he ke y  sec o n dar y 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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e n d p oi nt f or all s u bjects w h o wit h dra w c o nse nt or w h o are l ost t o f oll o w-u p, usi n g 
m ulti ple i m p utati o n met h o d ol o g y  u n der a p pr o priate ass u m pti o ns.  T hese se nsiti v it y 
a nal ys es are descri be d i n Secti o n 7. 4. 2. 4 a n d m ore detail will be pr o vi de d i n t he S A P.
7. 4
Pri m ar y  a n d S e c o n d ar y O ut c o m e An al y si s
T his trial’s esti ma n d is t he differe nce i n o utc o me i m pr o ve me nt if all s u bjects t olerate d 
a n d a d here d t o t heir treat me nt.  T o e nric h t his p o p ulati o n, o nl y  s u bjects w h o ca n t olerate 
t he t ol va pta n titrati o n a n d r u n-i n peri o ds will be ra n d o mize d.  T his a p pr oac h c o m bi nes 
esti man ds # 2 a n d # 3 as rec o m me n de d b y t he 2 0 1 0 Nati o nal Aca de m y of Scie nces’ N R C
re p ort o n pre ve nti o n a n d treat me nt of missi n g data1 4 w here esti ma n d # 2 is " differe nce i n 
o utc o me i m pr o ve me nt i n t olerat ors" a n d "esti ma n d # 3 is " differe n ce i n o utc o me 
i m pr o ve me nt if all s u bjects t olerate d or a d here d".  T h us, M A R data is ass u me d i n t he 
pri mar y  a nalys is.  Se nsiti vit y a nalys is will be pr o vi de d t o a d dress t he c o ncer n of M N A R 
data.
T his esti ma n d f oc uses o n t he efficac y  of t ol va pta n i n sl o wi n g re nal f u ncti o n decli ne.  T he 
o bjecti ve of t his trial is t o c o nfir m a ca usal effect of t ol va pta n i n sl o wi n g re nal f u ncti o n 
decli ne, c o nsiste nt wit h t he selecti o n of a n efficac y rat her t ha n a n effecti ve ness esti ma n d. 
A n effecti ve ness esti ma n d c o m pares treat m e nt p olicies a n d reas o na bl y c o ul d i ncl u de data 
ac q uire d l o n g after wit h dra wal fr o m t he trial (e g, w he n s u bjects disc o nti n ue t ol va pta n b ut 
are f oll o we d f or ma n y wee ks or m o nt hs) or m o ve t o a n alter nate treat me nt re gi me n 
(e g, place b o s u bjects bei n g prescri be d c o m mercial t ol va pta n u p o n a p pr o val f or A D P K D).  
I n t he a bse nce of a n a p pr o ve d a n d effecti ve alter nate treat me nt f or A D P K D; it is 
pre mat ure t o disc uss treat me nt p olicies.  T h us, w hile e G F R data c ollecte d i n t he sec o n d 
a n d t hir d wee k p ost -wit h dra w al are use d f or t he a nal ysis of t he pri mar y e n d p oi nt, data 
c ollecte d l o n g after wit h dra wal or after a s u bject m o ves t o a n alter nate treat me nt re gi me n 
will be e xcl u de d i n t he pri mar y  a nalys es of b ot h t he pri mar y a n d t he ke y sec o n dar y 
e n d p oi nts.
7. 4. 1
Pri m ar y  Effic a c y  O ut c o m e An al y si s
7. 4. 1. 1
Pri m ar y  E n d p oi nt A n al y si s
T he pri mar y  e n d p oi nt of t his trial is t he c ha n ge i n e G F R (calc ulate d b y  t he C K D -E PI
f or m ula) fr o m pre-treat me nt baseli ne t o p ost-treat me nt f oll o w- u p, a n n ualize d ( di vi de d) 
b y  eac h s u bjects’ I M P treat me nt d urat i o n.  T his n or malizati o n is necessar y, ot her wise t he 
treat me nt gr o u p ha vi n g m ore dr o p o uts or m ore earlier dr o p o uts ma y ass u me a n u nfair 
a d va nta ge.  T o re d uce t he variati o n i n t his pri mar y  e n d p oi nt, 3 o bser vati o ns of e G F R will 
be o btai ne d at baseli ne d uri n g a 3 -wee k i nter val (scree ni n g a n d place b o r u n-i n peri o ds) 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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a n d a n ot her 3 o bser vati o ns will be o btai ne d p ost -treat me nt d uri n g a 2- wee k i nter val t hat 
be gi ns 1 wee k after t he e n d of treat me nt ( 3-wee k p ost -treat me nt f oll o w-u p).  T he a vera ge 
of t he 3 e G F R val ues o bser ve d d uri n g t he baseli ne peri o d is set as t he baseli ne a n d t he 
a vera ge of t he 3 e G F R val ues o bser ve d d uri n g t he p ost -treat me nt f oll o w-u p peri o d is set 
as t he re nal f u ncti o n meas ure me nt p ost -treat me nt.  Ti mi n gs of baseli ne a n d p ost -
treat me nt f oll o w- u p o bser vati o ns are set t o t he me dia n of t he ti me of t hese o bser vati o ns
i n t he res pecti ve 2 t o 3-wee k i nter val s, a n d t he d urati o n is e q ual t o t he ti mi n g of baseli ne 
mi n us t he ti mi n g of p ost -treat me nt f oll o w- u p pl us 1.
Use of t he d urati o n t o a n n ual ize t he c ha n ge is als o reas o na ble si nce it will pr o vi de a n 
“esti mate” of a n n ualize d e G F R c ha n ge i n sl o pe f or eac h s u bject, t h o u g h t here is n o 
esti mate f or i ntra-s u bject variati o n.  T h us, a wei g hte d a nal ys is of c o varia nce (A N C O V A )
wit h effects of treat me nt a n d ra n d o mizati o n stratificati o n fact ors a n d c o variate baseli ne 
will be a p plie d t o t hese “esti mate d sl o pes” as t he pri mar y  a nalys is.  T his wei g hte d 
a nal ys is is base d o n t he reci pr ocal of t he esti mate d varia nce of t he “esti mate d sl o pes,” 
a n d t he detaile d al g orit h m t o deri ve t he esti mate d varia nce is pr o vi de d i n Secti o n 8. 3 of 
t he S A P. 
7. 4. 1. 2
S e n siti vit y A n al y si s of t h e Pri m ar y  E n d p oi nt
Ali g ne d wit h t he desire t o e val uate effects free fr o m ac ute he m o d y na mic treat me nt 
effects, a se nsiti vit y a nal ysis of t he pri mar y en d p oi nt will be perf or me d i ncl u di n g all 
a vaila ble place b o data.  I n t his se nsiti vit y a nalys is, i n a d diti o n t o t he 3 pre -treat me nt 
baseli ne o bser vati o ns a n d t he 3 p ost -treat me nt f oll o w-u p o bser vati o ns, all 
p ost -ra n d o mizati o n o n-treat me nt e G F R o bser vati o ns i n t he pr ot oc ol -s pecifie d visits f or 
place b o s u bjects will als o be i ncl u de d.  T he li near mi xe d effect m o del wit h effects of 
ti me (as a c o nti n u o us varia ble), treat me nt, a n d ti me-treat me nt i nteracti o n, ra n d o mizati o n 
stratificati o n fact ors a n d baseli ne as c o variate will be use d t o fit t he e G F R data , i n w hic h 
t he i nterce pt a n d ti me are b ot h a fi xe d effect a n d a ra n d o m effect.  A n u n- str uct ured
varia nce c o varia nce matri x is ass u me d f or t he ra n d o m i nterce pt a n d ti me.   T he ti me 
varia ble use d i n t he m o del ma y start fr o m t he first o bser vati o n of e G F R baseli ne as 
me nti o ne d i n Secti o n 7. 1. 1 , a n d t his baseli ne will be use d i n t he m o del. Missi n g data will 
be i g n ore d i n t his a nalys is u n der t he M A R ass u m pti o n.  Data ac q uire d w hile ta ki n g 
t ol va pta n ca n n ot be use d i n t his a nal ysis wit h o ut a p pr o priate a dj ust me nt, b ut is e val uate d 
i n t he ke y sec o n dar y efficac y e n d p oi nt of e G F R sl o pe wit h a met h o d ol o g y w hic h ta kes 
the ac ute he m o d y na mic dr u g effects of t ol va pta n i nt o acc o u nt.

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7. 4. 1. 3
S e n siti vit y A n al y si s I n cl u di n g D at a fr o m S u bj e ct s W h o 
Di s c o nti n u e I M P
T his se nsiti vit y  a nalys is de viates fr o m t he M A R ass u m pti o n t o i ncl u de t he p ost-
disc o nti n uati o n f oll o w -u p data i n t he a nal ys is s pecifie d i n t he pri mar y  a nal ysis secti o n.  
S u bjects w h o disc o nti n ue I MP after ra n d o mizati o n wit h o ut wit h dra wi n g c o nse nt will be 
f oll o we d f or a d diti o nal off-treat me nt e G F R val ues u p t o M o nt h 1 2.  T hese p ost “ p ost-
treat me nt f oll o w-u p” e G F R data at M o nt h 1 2 will be i ncl u de d t o re place t he data 
o bser ve d d uri n g p ost -treat me nt f oll o w- u p f or t he s u bjects w h o disc o nti n ue I M P earl y i n a 
se nsiti vit y a nalys is usi n g t he sa me a nalyt ic a p pr oac h s pecifie d i n t he pri mar y a nal ysis
secti o n.
7. 4. 2
S e c o n d ar y  O ut c o m e A n al y s e s
I n a d diti o n t o t he ke y sec o n dar y efficac y e n d p oi nt descri be d bel o w, safet y varia bles will 
als o be a nal yz e d as sec o n dar y o utc o mes i n t his pr ot oc ol (see Secti o n 7. 6 ).
7. 4. 2. 1
K e y  S e c o n d ar y E n d p oi nt A n al y si s
T he ke y  sec o n dar y e n d p oi nt of t he trial is t he a n n ualize d rate of e G F R c ha n ge, w hic h is 
deri ve d fr o m eac h i n di vi d ual s u bject’s e G F R sl o pe usi n g t he C K D -E PI f or m ula.  Sl o pe is 
preferre d as a practical a n d cli nicall y  mea ni n gf ul e n d p oi nt.  In t his a nal y sis, all e G F R 
o bser vati o ns fr o m place b o r u n -i n, t ol va pta n r u n-i n ( n ot i ncl u di n g t ol va pta n titrati o n), 
d o u ble bli n d treat me nt, a n d p ost -treat me nt f oll o w-u p ( n ot i ncl u di n g data c ollecte d i n t he 
first wee k after t he last I M P d ose) peri o ds will be i ncl u de d i n t he a nalys is, wit h t he data 
fr o m t ol va pta n r u n-i n a n d t ol va pta n s u bjects i n t he d o u ble-bli n d treat me nt peri o d fla g ge d 
( yes = 1 a n d n o = 0) f or a t ol va pta n ac ute he m o d y na mic effect.
T he li near mi xe d effect m o del wit h effects of ti me (as a c o nti n u o us varia ble), treat me nt, 
ti me-treat me nt i nteracti o n, ac ute he m o dy n a mic effect, pre-treat me nt baseli ne ( of t he 
pri mar y  e n d p oi nt), a n d ra n d o mizati o n stratificati o n fact ors will be use d t o fit t he G F R 
esti mates, i n w hic h t he i nterce pt a n d ti me are b ot h a fi xe d effect a n d a ra n d o m effect.  A n 
u n-str uct ure d varia nce c o varia nce matri x is ass u me d f or t he ra n d o m i nterce pt a n d ti me.  
T he ti me varia ble use d i n t he m o del ma y  start fr o m t he first o bser vati o n of e G F R 
o btai ne d fr o m place b o r u n -i n peri o d.  T he c o variate “ac ute he m o d y na mic effect” i n t he 
m o del is t he fla g varia ble wit h val ue of 0 a n d 1 s pecifie d earlier i n t his secti o n f or t he 
data o bser ve d d uri n g t ol va pta n r u n -i n a n d t he data o bser ve d f or t ol vapta n s u bjects d uri n g 
t he d o u ble-bli n d treat me nt peri o d.   T he starti n g p oi nt of t his e G F R sl o pe a nal ysis is t he 
e G F R o bser vat io n d uri n g t he place b o r u n -i n peri o d.

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7. 4. 2. 2
S e n siti vit y A n al y si s of t h e K e y  S e c o n d ar y E n d p oi nt
T his se nsiti vit y  a nalys is of t he ke y sec o n dar y e n d p oi nt of t his trial is t o c o m pare t he 
li near tre n d of e G F R bet wee n t ol va pta n a n d place b o gr o u ps.  T he a d va nta ge of t his 
se nsiti vit y a nalys is is t hat it d oes n ot de pe n d o n t he ass u m pti o n of li nearity a n d e q ual 
t ol va pta n he m o d yna mic o nset a n d offset effects use d i n Secti o n 7. 4. 2. 1 .  T he c ha n ge 
fr o m t he pre-treat me nt baseli ne d uri n g t he o n-treat me nt visits i n t he d o u ble-bli n d 
treat me nt peri o d will be i ncl u de d i n t he a nalys is.  Si nce t he he m o d yna mic effects of 
t ol va pta n are belie ve d t o be gi n t o re verse wit hi n 1 -2 da y s, o n- treat me nt will be defi ne d as 
wit hi n 2 4 h o urs of t he last I M P d ose.
A nal y sis of M M R M will be a p plie d t o t he data of c ha n ge fr o m baseli ne i n e G F R i n eac h 
m o nt h fr o m M o nt h 1 t o M o nt h 1 2.  T he m o del will ha ve fi xe d effect of treat me nt, visit, 
treat me nt visit i nteracti o n, ra n d o mizati o n stratificati o n fact ors, a n d c o variate baseli ne a n d 
baseli ne visit i nteracti o n.  A n u nstr uct ure d varia nce -c o varia nce matri x is ass u me d f or t he 
re peate d meas ure me nts.  A li near c o ntrast of t he treat me nt differe nces i n t hese 1 2 m o nt hs 
will be use d as t he se nsiti vit y  a nalys is of t he ke y sec o n dar y e n d p oi nt.
7. 4. 2. 3
S e n siti vit y A n al y si s I n cl u di n g D at a fr o m S u bj e ct s W h o 
Di s c o nti n u e I M P
T his se nsiti vit y  a nalys is de viates fr o m t he M A R ass u m pti o n t o i ncl u de t he 
p ost -disc o nti n uati o n f oll o w -u p data i n t he a nal ys is of t he ke y sec o n dar y e n d p oi nt.  
S u bjects w h o disc o nti n ue treat me nt afte r ra n d o mizati o n wit h o ut wit h dra wi n g c o nse nt 
will be f oll o we d f or a d diti o nal e G F R (n ot i ncl u di n g t he e G F R o bser ve d i n t he 3 - wee k 
f oll o w- u p peri o d i m me diatel y  after E o T x ) u p t o M o nt h 1 2.  T he data c ollecte d d uri n g t his 
ti me will n ot be i ncl u de d i n t he ke y  sec o n dar y e n d p oi nt a nal ysis f or t he reas o ns gi ve n 
a b o ve. H o we ver, a se nsiti vit y  a nalys is i ncl u di n g t hese data f or t he ke y sec o n dar y 
a nal ys is will be perf or me d.  T his a nal ysis uses t he sa me a p pr oac h pr o vi de d i n 
Secti o n 7. 4. 2. 1 f or t he a nal ysis of t he ke y sec o n dar y e n d p oi nt.
7. 4. 2. 4
S e n siti vit y A n al y si s I n cl u di n g I m p ut ati o n of Mi s si n g D at a 
M ulti ple i m p utati o n is c o m m o nl y  use d i n t he a nal ysis of M N A R data.  F or all 
ra n d o mize d s u bjects w h o wit h dra w c o nse nt f or f urt her testi n g or w h o are l ost t o f oll o w 
u p, i m p utati o n of missi n g data will be a p plie d t o pr ojecte d visits u p t o t heir pla n ne d e n d 
of t he trial ( 1 2 m o nt hs p ost -ra n d o mizati o n). T he s u bjects’ reas o ns f or disc o nti n uati o n 
will be ca pt ure d a n d cate g orize d t o hel p deter mi ne t he missi n g data patter n (see 
Secti o n 3. 8. 3. 4 ). I mp utati o n will be base d o n t he M M R M m o del s pecifie d i n 
Secti o n 7. 4. 2. 2 .  F or place b o s u bjects, a n d i n t he a b se nce of e vi de nce s u g gesti n g biase d 
missi n g data patter n, t he i m p utati o n will f oll o w t he place b o tre n d.

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P ost -wit h dra wal data fr o m Trial 1 5 6 - 0 4- 2 5 1 a n d Trial 1 5 6- 0 8- 2 7 1 i nteri m a nal ys es s h o w 
t hat t ol va pta n’s e G F R be nefit s acc u m ulate a n d are s ustai ne d after treat me nt 
disc o nti n uati o n; t heref ore, i m p utati o n f or s u bjects ra n d o mize d t o t ol va pta n s h o ul d 
reas o na bly be gi n at t he val ue of t heir last e G F R . If a s u bject has t he p ost-treat me nt 
f oll o w- u p i n t he t w o-wee k i nter val, i m p utati o n will base d o n t his p os t-treat me nt 
o bser vati o n; if a s u bject d oes n ot ha ve t he p ost -treat me nt f oll o w-u p o bser vati o n, 
i m p utati o n will be base d o n t he last o n-treat me nt o bser vati o n a n d fla g ge d wit h t he 
t ol va pta n ac ute he m o dy n a mic effect me nti o ne d i n S ecti o n 7. 4. 2. 1 .
Trial 
 data als o s u p p ort tr ue disease m o dificati o n a n d preser vati o n of 
f u ncti o ni n g ki d ne y pare nc h ym a t hr o u g h re d ucti o n of c yst gr o wt h. T h us , disc o nti n u ati o n 
of t ol va pta n w o ul d n ot res ult i n a n i m me diate ret ur n t o t he place b o tre n d. T heref ore ,
e G F R decli ne i n s u bjects disc o nti n ui n g t ol va pta n will reas o na bl y fall s o me w here 
bet wee n t he t ol va pta n tre n d a n d place b o tre n d. T his s u p p orts a series of a nal yses f or 
i m p utati o n of missi n g data f or t ol va pta n s u bjects, w hic h will be gi n usi n g t he t ol va pta n 
tre n d, a n d m o ve ste p wise t o war d t he place b o tre n d.  F urt her details will be pr o vi de d i n 
t he S A P.
7. 4. 3
S u b gr o u p Effi c a c y  An al y si s
S u b gr o u p a nal ys es will be pr o vi de d f or t he pri mar y a n d t he ke y sec o n dar y e n d p oi nts b y 
re gi o ns ( U S a n d n o n-U S),
 
 
 
 
 
.
7. 4. 4
E x pl or at or y  A n al y s e s
7. 4. 4. 1
A n al y si s of Effi c a c y  B a s e d o n M o d al D o s e s
 
 
.
7. 4. 4. 2
A D P K D O ut c o m e s
A ssess me nt of A D P K D outc o mes is a n e x pl orat or y e n d p oi nt i n t his pr ot oc ol.  
 
  
.  
 

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7. 4. 4. 3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 4. 5
I nt eri m An al y si s
T his trial is t o be c o n d ucte d o ver a critical ti me peri o d d uri n g w hic h t ol va pta n ma y  be 
a p pr o ve d as t hera p y f or A D P K D i n s o me of t he partici pati n g re gi o ns.  T he E ur o pea n 
Me dici nes A ge nc y ’s ( E M A) decisi o n f or a pe n di n g mar keti n g aut h orizati o n a p plicati o n 
f or t he use of t ol va pta n i n treat me nt of A D P K D is e x pecte d i n 2 0 1 5.  F oll o wi n g 
re g ulat or y a p pr o val, rei m b urse me nt a n d c o m mercial a vaila bilit y ma y ha ve a n i m pact o n 
t he o n g oi n g et hical c o n d uct of t he trial.  T his ma y i m pact s u bjects e nr olle d i n E ur o pe 
w h o are c o nti n ui n g i n t he ra n d o mize d, place b o -c o ntr olle d treat me nt p hase.
T heref ore, t he I D M C f or t his trial will be e m p o were d t o c o n d uct a n i nteri m a nalys is (I A) 
of t he pri mar y  e n d p oi nt o nce a p pr o xi matel y half of e nr olle d s u bjects ( 6 0 0-7 0 0) are 
e x pecte d t o c o m plete t heir pla n ne d o ne -ye ar treat me nt.  T he s p o ns o r ma y deci de t he 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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2 6 Mar 2 0 1 5 
act ual ti mi n g of t he I A t o be c o n d ucte d, base d o n t he a vaila bilit y of c o m mercial t ol va pta n 
i n A D P K D.  T his I A w o ul d use t he O’ Bria n - Fle mi n g s pe n di n g f u ncti o n t o a p p orti o n 
al p ha a n d t h us ma na ge T ype 1 err or. Deter mi nati o n of t he i nf or mati o n ti me of t he I A 
ass u mes t otal sa m ple size i n t his trial t o be set at 1 3 0 0 if t he trial is still ra n d o mizi n g 
s u bjects at t he ti me of t he I A. Alter nati vel y, t he act ual t otal sa m ple size will be use d if 
t he trial has st o p pe d e nr oll me nt. F or e xa m ple, if t he first 6 5 0 s u bjects o ut of 1 3 0 0 t otal 
sa m ple size are i ncl u de d, a p-val ue < 0. 0 0 3 0 5 1 is re q uire d t o reject t he n ull h y p ot hesis, 
satisf y t he o bjecti ve of re plicati n g efficac y, a n d offer a p ossi bilit y f or early trial 
c o m pleti o n. If a rec o m me n dati o n f or early ter mi nati o n is acce pte d, all s u bjects 
re mai ni n g i n t he trial ca n be offere d partici pati o n i n a pla n ne d o pe n-la bel e xte nsi o n trial. 
If t he n ull h yp ot hesis is n ot rejecte d at t his i nteri m e val uati o n, t he trial w o ul d c o nti n ue 
a n d t he al p ha of t he fi nal test of t he pri mar y e n d p oi nt w o ul d be 0. 0 4 9 0 0 2.
7. 5
A n al y si s of D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s
De m o gra p hic c haracteristics, disease se verit y, a n d me dical hist or y at (pre -treat me nt) 
baseli ne will be s u m marize d b y  descri pti ve statistics, e g, pr o p orti o n, mea n, me dia n, 
sta n dar d de viati o n (S D ), mi ni m u m a n d ma xi m u m val ues.  T hese s u m mar y statistics will 
be re vie we d t o i de ntif y  a n y p ote ntial lac k of bala nce bet wee n t he treat me nt gr o u ps.
7. 6 
S af et y  An al y si s
I n ge neral, baseli ne meas ure me nts of safety varia bles are defi ne d as t he last 
meas ure me nts pri or t o ra n d o mizati o n f or t he pri mar y  Ra n d o mize d S afet y P o p ulati o n 
(e xce pt f or ser u m creati ni ne, w hic h is defi ne d si milarl y t o t he baseli ne of e G F R 
assess me nt f or t he pri mar y e n d p oi nt, see Secti o n 7. 4. 1. 1 ) a n d as t heir last meas ure me nts 
pri or t o t he first d ose of I M P f or t he sec o n dar y safet y p o p ulati o n (Treate d Safet y 
P o p ulati o n ).  
 
  Sta n dar d safet y varia bles t o be a nalyz e d i ncl u de A Es, self-
re p orte d t olera bilit y, cli nical la b orat or y data , p h y sical e xa mi nati o ns, a n d vital si g ns.  
Safet y  varia bles will be s u m marize d b y descri pti ve statistics, (e g, pr o p orti o n, mea n, 
me dia n, S D, mi ni m u m , a n d ma xi m u m val ues ). I n ge neral, s u m mary statistics, i ncl u di n g 
c ha n ges fr o m baseli ne, will be pr o vi de d f or safet y varia bles base d o n all a vaila ble data.
7. 6. 1
A d v er s e E v e nt s
All A Es will be c o de d b y s y ste m or ga n class a n d Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A) preferre d ter m.  T he i nci de nce of t he f oll o wi n g e ve nts will b e 
s u m marize d b y treat me nt gr o u p f or t he pri mar y safet y p o p ulati o n; su m mar y of t hese 
e ve nts will als o be pr o vi de d f or t he sec o n dar y safet y p o p ulati o n:

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a)
Treat me nt -e mer ge nt A Es ( T E A Es) b y se verit y
b)
T E A Es p ote ntiall y  ca usall y relate d t o t he I M P
c)
T E A Es wit h a n o utc o me of deat h
d)
Seri o us T E A Es
e)
Disc o nti n uati o ns d ue t o T E A Es
7. 6. 2
Cli ni c al L a b or at or y  D at a
S u m mar y  statistics f or c ha n ges fr o m baseli ne i n t he ce ntral cli nical la b orat or y 
meas ure me nts will be pr o vi de d f or t he pri mar y  a n d sec o n dar y safety p o p ulati o ns.  
P ote ntiall y  cli nicall y si g nifica nt res ults i n la b orat or y tests i de ntifie d usi n g pr os pecti vely 
defi ne d criteria, i ncl u di n g cr iteria f or li ver e nzy m e ele vati o ns, will als o be s u m marize d 
f or t he pri mar y a n d sec o n dar y safet y p o p ulati o ns.  In a d diti o n, b y -s u bject listi n gs will be 
pr o vi de d f or data of l ocal la b orat or y  tests.
I n a d diti o n, la b orat or y meas ure me nts t hat si g nal t he p ote ntial f or H y’s La w will be 
re p orte d. A n i nci de nce ta ble a n d a listi n g will be pr o vi de d f or s u bjects w h o meet o ne or 
c o m bi nati o ns of f oll o wi n g criteria, wit h o ut i nitial fi n di n gs of c h olestas is ( A LP acti vit y 
> 2 × U L N) :

A L T or A S T 3 × U L N 

Bilir u bi n 2 × U L N 
7. 6. 3
P h y si c al E x a mi n ati o n a n d Vit al Si g n s D at a
B y -s u bject listi n gs will be pr o vi de d f or p h ysical e xa mi nati o ns.  S u m mar y statistics f or 
c ha n ges fr o m baseli ne i n vital si g ns a n d p ote ntiall y cli nicall y  si g nifica nt res ults i n vital 
si g ns will be s u m marize d for t he pri mar y  safety p o p ulati o n as well as t he sec o n dar y 
safety p o p ulati o n.
8
M a n a g e m e nt of I n v e sti g ati o n al M e di ci n al Pr o d u ct
8. 1
P a c k a gi n g a n d L a b eli n g
All I M P
will be pr o vi de d t o t he i n vesti gat or(s) b y t he s p o ns or or desi g nate d age nt as 
ta blets of 1 5 or 3 0 m g t ol va pta n ( O P C-4 1 0 6 1) or matc hi n g place b o .  Eac h b ottle use d i n 
t he d osi n g peri o d will be la bele d t o clearly discl ose t he s u bject i de ntificati o n n u m ber 
(I D), c o m p o u n d I D, trial n u m ber, s p o ns or's na me a n d a d dress, i nstr ucti o ns f or use, r o ute 
of a d mi nistrat i o n, a p pr o priate preca uti o nar y state me nts, a n d ot her i nf or mati o n re q uire d 
b y  l ocal re g ulat or y a ut h orities.  A n y  re gi o n-s pecific re q uire me nts will a p pear i n t he 
official la n g ua ge of t he c o u ntr y  i n w hic h t he i n vesti gati o nal pr o d uct is t o be use d.

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O ne or m ore b ottles of t he desi g nate d I M P will be dis pe nse d at t he be gi n ni n g of t he 
place b o r u n -i n peri o d, t he t ol va pta n r u n i n peri o d, a n d m o nt hl y d uri n g t he d o u ble-bli n d, 
ra n d o mize d treat me nt peri o d.
F or t he t ol va pta n titrati o n peri o d, s u bjects will recei ve 2 cart o ns at t he first visit ; o ne wit h 
a yell o w la bel ( Kit A) a n d o ne wit h a bl ue la bel ( Kit B).  S u bjects will be i nstr ucte d t o 
start wit h Kit A a n d t ol d h o w ma n y ta blets t o ta ke per da y.  Kit A ca n acc o m m o date t he 
f oll o wi n g d oses f or titrati o n:

3 0/ 1 5 – 2 ta blet s u p o n wa ki n g a n d 1 ta blet a p pr o xi matel y  8 t o 9 h o urs later

4 5/ 1 5 – 3 ta blets u p o n wa ki n g a n d 1 ta blet a p pr o xi matel y 8 t o 9 h o urs later
O nce t he s u bject is rea dy t o titrate t o t he 6 0/ 3 0 d ose, t he site will i nstr uct t he s u bject t o 
start ta ki n g I M P fr o m Kit B.  Kit B ca n acc o m m o date t he f oll o wi n g d oses f or titrati o n:

6 0/ 3 0 – 2 ta blets u p o n wa ki n g a n d 1 ta blet a p pr o xi matel y 8 t o 9 h o urs later

9 0/ 3 0 – 3 ta blets u p o n wa ki n g a n d 1 ta blet a p pr o xi matel y 8 t o 9 h o urs later
If t he s u bject ca n n ot t olerate t he d oses i n Kit B, h e/ s he will be i nstr ucte d t o ret ur n t o 
Kit A f or d osi n g.
8. 2
St or a g e
All I MPs will be st ore d i n a sec urel y l oc ke d ca bi net or e ncl os ure.  Access will be li mite d 
t o i n vesti gat ors a n d t heir desi g nees.  Neit her i n vesti gat ors n or a n y desi g nees ma y pr o vi de 
I M P t o a ny s u bject n ot partici pati n g i n t his pr ot oc ol.
T he I M P s h o ul d be st ore d acc or di n g t o t he c o n diti o ns s pecifie d i n t he I M P la bel.  T he 
cli nical site staff will mai ntai n a te m perat ure l o g i n t he dr u g st ora ge area rec or di n g t he 
te m perat ure at least o nce eac h w or ki n g da y.
8. 3
A c c o u nt a bilit y
T he i n vesti gat or or desi g nee m ust mai ntai n a n i n ve nt or y rec or d of I M P (i ncl u di n g 
i n vesti gati o nal, acti ve c o ntr ol, or place b o) recei ve d, dis pe nse d, a d mi nistere d, a n d 
ret ur ne d. 
8. 4
R et ur n s a n d D e str u cti o n
U p o n c o m pleti o n or ter mi nati o n of t he trial, all u n use d a n d/ or partiall y  use d IM P m ust be 
ret ur ne d t o t he s p o ns or or a desi g nate d a ge nt.
All I M P ret ur ne d t o t he s p o ns or m ust be acc o m pa nie d b y  a p pr o priate d oc u me ntati o n a n d 
be i de ntifie d b y pr ot oc ol n u m ber wit h trial site n u m ber o n t he o uter m ost s hi p pi n g 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 3
2 6 Mar 2 0 1 5 
c o ntai ner.  Ret ur ne d s u p plies s h o ul d be i n t he ori gi nal c o ntai ners (e g, s u bject kits).  T he 
assi g ne d trial m o nit or will facilitate t he ret ur n of u n use d a n d/ or partiall y  use d I M P.
9
R e c or d s M a n a g e m e nt
9. 1
S o u r c e D o c u m e nt s
S o urce d oc u me nts are defi ne d as t he res ults of ori gi nal o bser vati o ns a n d acti vities of a 
cli nical i n vesti gati o n.  S o urce d oc u me nts will i ncl u de b ut are n ot li mite d t o pr o gress 
n otes, electr o nic data, scree ni n g l o gs, a n d rec or de d data fr o m a uto mate d i nstr u me nts.  All 
s o urce d oc u me nts pertai ni n g t o t his trial will be mai ntai ne d by t he i n vesti gat ors. 
I n vesti gat or(s)/i nstit uti o n(s) will per mit trial-relate d m o nit ori n g, a u dits, IR B/I E C re vie w, 
a n d re g ulat or y i ns pecti o n(s) b y pr o vi di n g direct access t o s o urce data/ d oc u me nts b y
a ut h orize d pers o ns as defi ne d i n t he I C F.
9. 2
D at a C oll e cti o n
D uri n g eac h s u bject’s visit t o t he cli nic, a cli nicia n partici pati n g i n t he trial will rec or d 
pr o gress n otes t o d oc u me nt all si g nifica nt o bser vati o ns.  At a mi ni m u m, t h ese n otes will 
c o ntai n:

D oc u me ntati o n of t he i nf or me d c o nse nt pr ocess, i ncl u di n g a n y re vise d c o nse nts;


Ge neral s u bject stat us re mar ks, i ncl u di n g a n y si g nific a nt me dical fi n di n gs.  T he 
se verity, fre q ue nc y, d urati o n, acti o n ta ke n, a n d o utc o me of a n y A Es a n d t he 
i n vesti gat or's assess me nt of relati o ns hi p t o IM P m ust als o be rec or de d;

A n y  c ha n ges i n c o nc o mita nt me dicati o ns or d osa ges;

A ge neral refere nce t o t he pr oce d ures c o m p lete d; 

T he si g nat ure ( or i nitials) a n d date of eac h cli nicia n ( or desi g nee) w h o ma de a n e ntr y  
i n t he pr o gress n otes.
I n a d diti o n, a n y c o ntact wit h t he s u bject via tele p h o ne or ot her mea ns t hat pr o vi des 
si g nifica nt cli nical i nf or mati o n will als o be d oc u mente d i n t he pr o gress n otes as 
descri be d a b o ve.  A n y c ha n ges t o i nf or mati o n i n t he trial pr o gress n otes a n d ot her s o urce 
d oc u me nts will be i nitiale d a n d date d o n t he da y t he c ha n ge is ma de b y  a site staff 
me m ber a ut h orize d t o ma ke t he c ha n ge.  C ha n ges will be ma de b y stri ki n g a si n gle li ne 
t hr o u g h err o ne o us data (s o as n ot t o o bliterate t he ori gi nal data), a n d clearl y e nteri n g t he 
c orrect data (e g, wr o n g data ri g ht data).  If t he reas o n f or t he c ha n ge is n ot a p pare nt, a 
brief e x pla nati o n f or t he c ha n ge will be writte n i n t he s o urce d oc u me ntati o n b y  t he 
cli nicia n.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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I nf or mati o n fr o m t he trial pr o gress n otes a n d ot her s o urce d oc u me nts will be e ntere d b y 
i n vesti gati ve site pers o n nel directly o nt o eC R Fs i n t he s p o ns or’s electr o nic data ca pt ure
s yste m. C ha n ges t o t he data will be ca pt ure d b y a n a ut o matic a u dit trail.
9. 3
Fil e M a n a g e m e nt at t h e Tri al Sit e
T he i n vesti gat or will e ns ure t hat t he trial site file is mai ntai ne d i n acc or da nce wit h 
Secti o n 8 of t he I C H G C P G ui deli ne a n d as re q uire d b y  a p plica ble l ocal re g ulati ons. T he 
i n vesti gat or/i nstit uti o n will ta ke meas ures t o pre ve nt acci de ntal or pre mat ure destr ucti o n 
of t hese d oc u me nts.
9. 4
R e c or d s R et e nti o n at t h e Tri al Sit e
Re g ulat or y  re q uire me nts f or t he arc hi val of rec or ds f or t his trial necessitate t hat 
partici pati n g i n vesti gat ors mai ntai n detaile d cli nical data f or t he l o n gest of t he f oll o wi n g 
3 peri o ds:

A peri o d of at least 2 y ears f oll o wi n g t he date o n w hic h a p pr o val t o mar ket t he dr u g 
is o btai ne d ( or if I M P de vel o p me nt is disc o nti n ue d, t he date re g ulat or y a ut h orities
were n otifie d of disc o nti n uati o n); O R

A peri o d of at least 3 y ears after t he s p o ns or n otifies t he i n vesti gat or t hat t he fi nal 
re p ort has bee n file d wit h re g ulat or y a ut h orities.

L o n ger, re gi o n -s pecific st ora ge re q uire me nts, if a p plica ble.
T he i n vesti gat or m ust n ot dis p ose of a n y  rec or ds rele va nt t o t his trial wit h o ut eit her 
( 1) writte n per missi o n fr o m t he s p o ns or or ( 2) pr o visi o n of a n o p p ort u nit y  f or s p o ns or t o 
c ollect s uc h rec or ds.  T he i n vesti gat or will be res p o nsi ble t o mai ntai n a de q uate a n d 
acc urate electr o nic or har d c o p y s o urce d oc u me nts of all o bser vati o ns a n d data ge nerate d 
d uri n g t his trial.  S uc h d oc u me ntati o n is s u bject t o i ns pecti o n b y  t he s p o ns or a n d rele va nt 
re g ulat or y a ut h orities.  If t he i n vesti gat or wit h dra ws fr o m t he trial (e g, d ue t o rel ocati o n 
or retire me nt), all trial -relate d rec or ds s h o ul d be tra nsferre d t o a m ut ually a gree d - u p o n 
desi g nee wit hi n a s p o ns or -s pecifie d ti mefra me.  N otice of s uc h tra nsfer will be give n t o 
t he s p o ns or i n writi n g.
1 0
Q u alit y  C o ntr ol a n d Q u alit y As s ur a n c e 
1 0. 1
M o nit ori n g
T he s p o ns or has et hical, le gal, a n d scie ntific o bli gati o ns t o f oll o w t his trial caref ull y i n a 
detaile d a n d or derl y ma n ner i n acc or da nce wit h esta blis he d researc h pri nci ples, t he I C H 
G C P G ui deli ne, a n d a p plica ble re g ulat or y  re q uire me nts a n d l ocal la ws.  As part of a 
c o ncerte d eff ort t o f ulfill t hese o bli gati o ns ( mai ntai n c urre nt pers o nal k n o wle d ge of t he 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 5
2 6 Mar 2 0 1 5 
pr o gress of t he trial), t he s p o ns or's m o nit ors will visit t he site d uri n g t he trial, as well as 
c o m m u nicate fre q ue ntl y via tele p h o ne a n d wr itte n c o m m u nicati o ns.
1 0. 2
A u diti n g
T he s p o ns or's Q ualit y Ma na ge me nt U nit ( or re prese ntati ve) ma y c o n d uct trial site a u dits.  
A u dits will i ncl u de b ut are n ot li mite d t o dr u g s u p pl y , prese nce of re q uire d d oc u me nts, 
t he i nf or me d c o nse nt pr ocess, a n d c o m paris o n of eC R Fs wit h s o urce d oc u me nts.  T he 
i n vesti gat or a grees t o partici pate wit h a u dits.
Re g ulat or y  a ut h orities ma y i ns pect t he i n vesti gat or site d uri n g or after t he trial.  T he 
i n vesti gat or will c o o perate wit h s uc h i ns pecti o ns a n d will c o ntact t he s p o ns or 
i m me diatel y if s uc h a n i ns pecti o n occ urs.
1 1
Et hi c s a n d R e s p o n si bilit y
T his trial m ust be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, t he I C H G C P G ui deli ne, 
a n d a p plica ble l ocal la ws a n d re g ulat or y  re q uire me nts. Eac h trial site will see k a p pr o val 
b y  a n I RB or I E C acc or di n g t o re gi o nal re q uire me nts. T he I R B/I E C will e val uate t he 
et hical, scie ntific a n d me dical a p pr o priate ness of t he trial. F urt her, i n pre pari n g a n d 
ha n dli n g eC R Fs, t he i n vesti gat or, s u b -i n vesti gator a n d t heir staff will ta ke meas ures t o 
e ns ure a de q uate care i n pr otecti n g s u bject pri vac y . T o t his e n d, a s u bject n u m ber a n d 
s u bject i de ntificati o n c o de will be use d t o i de ntif y eac h s u bject. 
Fi na ncial as pects, s u bject i ns ura nce a n d t he p u blicati o n p ol ic y f or t he trial will be 
d oc u me nte d i n t he a gree me nt bet wee n t he s p o ns or a n d t he i n vesti gat or.
1 2
C o nfi d e nti alit y
All i nf or mati o n ge nerate d i n t his trial will be c o nsi dere d c o nfi de ntial a n d will n ot be 
discl ose d t o a n y o ne n ot directl y  c o ncer ne d wit h t he trial wit h o ut t he s p o ns or’s pri or 
writte n per missi o n.  S u bject c o nfi de ntialit y re q uire me nts of t he re gi o n(s) w here t he trial 
is c on d ucte d will be met.  H o we ver, a ut h orize d re g ulat or y  officials a n d s p o ns or pers o n nel 
( or t heir re prese ntati ves) will be all o we d full access t o i ns pect a n d c o p y  t he rec or ds.  All 
I M Ps, s u bject b o dily fl ui ds, a n d/ or ot her materials c ollecte d s hall be use d s olel y i n 
acc or da nce wit h t his pr ot oc ol, u nless ot her wise a gree d t o i n writi n g b y t he s p o ns or.
S u bjects will be i de ntifie d o nl y  b y i nitials a n d u ni q ue s u bject n u m bers i n eC R Fs.  T heir 
f ull na mes ma y, h o we ver, be ma de k n o w n t o a re g ulat or y a ge nc y or ot her a ut h orize d 
officials if necessar y .

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 6
2 6 Mar 2 0 1 5 
1 3
A m e n d m e nt P oli c y
T he i n vesti gat or will n ot ma ke a n y c ha n ges t o t his pr ot oc ol wit h o ut t he s p o ns or ’s pri or 
writte n c o nse nt a n d s u bse q ue nt a p pr o val b y  t he I R B/I E C.  A n y per ma ne nt c ha n ge t o t he 
pr ot oc ol, w het her it is a n o verall c ha n ge or a c ha n ge f or s pecific trial site(s), m ust be 
ha n dle d as a pr ot oc ol a me n d me nt.  A n y a me n d me nt will be writte n b y t he s p o ns or.  Eac h 
a me n d me nt will be s u b mitte d t o t he IR B/ I E C.  E xce pt f or “a d mi nistrati ve” or 
“ n o n-s u bsta ntial” a me n d me nts, i n vesti gat ors will wait f or I R B/I E C a p pr o val of t he 
a me n de d pr ot oc ol bef ore i m ple me nti n g t he c ha n ge(s).  A d mi nistrati ve a me n d me nts are 
d efi ne d as ha vi n g n o effect o n t he safet y of s u bjects, c o n d uct or ma na ge me nt of t he trial, 
trial desi g n, or t he q ualit y  or safety of I M P(s) use d i n t he trial.  A pr ot oc ol c ha n ge 
i nte n de d t o eli mi nate a n a p pare nt i m me diate hazar d t o su bjects s h o ul d be i m ple m e nte d 
i m me diatel y, f oll o we d b y IR B/I E C n otificati o n wit hi n 5 w or ki n g da y s.  T he s p o ns or will 
s u b mit pr ot oc ol a me n d me nts t o t he a p plica ble re g ulat or y a ge ncies.
W he n t he I R B/I E C, i n vesti gat ors, a n d/ or t he s p o ns or c o ncl u de t hat t he pr ot oc ol 
a me n d me nt s u bsta nt iall y alters t he trial desi g n a n d/ or i ncreases t he p ote ntial ris k t o t he 
s u bject, t he c urre ntl y a p pr o ve d writte n I C F will re q uire si milar m o dificati o n.  In s uc h 
cases, re peat i nf or me d c o nse nt will be o btai ne d fr o m s u bjects e nr olle d i n t he trial bef ore 
e x pecti n g c o nti n ue d partici pati o n.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 7
2 6 Mar 2 0 1 5 
1 4
R ef er e n c e s
1
E ur o pea n Me dici nes A ge nc y , P u blic s u m mar y of o pi ni o n o n or p ha n desi g nati o n: 
T ol va pta n f or t he treat me nt of a ut os o mal d o mi na nt p ol y c ystic ki d ne y disease. 
C o m mittee f or Or p ha n Me dici nal Pr o d ucts. 2 0 1 3; E M A/ C O M P/ 4 4 4 6 8 4/ 2 0 1 3.
2
U S Re nal Data S ys te m, U S R D S 2 0 1 2 A n n ual Data Re p ort: Atlas of C hr o nic Ki d ne y 
Disease a n d E n d -Sta ge Re nal Disease i n t he U nite d States, Nati o nal I nstit utes of 
Healt h, Nati o nal I nstit ute of Dia betes a n d Di gesti ve a n d Ki d ne y Diseases, Bet hes da, 
M D, 2 0 1 2
3
Le nti ne K L, Xia o H, Mac h nic ki G, G he or g hia n A, Sc h nitzler M A. Re nal f u ncti o n 
a n d healt hcare c osts i n patie nts wit h p ol y c ystic ki d ne y disease. Cli n J A m S oc 
Ne p hr ol. 2 0 1 0 A u g; 5( 8): 1 4 7 1- 9.
4
O P C -4 1 0 6 1 I n vesti gat or’s Br oc h ure. R oc k ville ( M D): Ots u ka P har mace utical 
De vel o p me nt & C o m mercializati o n, I nc.; E diti o n 1 9 Ots u ka Re p ort, iss ue d 1 1 J ul y  
2 0 1 3.
5
O P C -4 1 0 6 1 C o m m o n Tec h nical D oc u me nt.  R oc k ville ( M D): Ots u ka P har mace utical 
De vel o p me nt & C o m mercializati o n, I nc.; Secti o n 2. 5: Cli nical O ver vie w; 2 0 1 3.
6
Wa n g X, Gatt o ne V 2 n d, Harris P C, T orres V E. Effecti ve ness of vas o pressi n V 2 
rece pt or a nta g o nists O P C-3 1 2 6 0 a n d O P C -4 1 0 6 1 o n p ol y c ystic ki d ne y disease 
de vel o p me nt i n t he P C K rat. J A m S oc Ne p hr ol. 2 0 0 5 A pr; 1 6( 4): 8 4 6 - 5 1. 
7
Reif G A, Ya ma g uc hi T, Ni ve ns E, F uji ki H, Pi nt o C S, Wallace D P. T ol va pta n 
i n hi bits E R K-de pe n de nt cell pr oliferati o n, Cl - secreti o n, a n d i n vitr o c yst gr o wt h of 
h u ma n A D P K D cells sti m ulate d b y  vas o pressi n. A mer J P h ysi ol Re nal P h ysi ol. 2 0 1 1 
N o v; 3 0 1( 5): F 1 0 0 5 - 1 3.
8
T orres V E, C ha p ma n A B, De v u y st O, Ga nse v o ort R T, Gra nt ha m JJ, Hi gas hi hara E, 
et al f or t he T E M P O 3: 4 Trial I n vesti gat ors.  T ol va pta n i n patie nts wit h a ut os o mal 
d o mi na nt p ol y c ystic ki d ne y disease. N E n gl J Me d 2 0 1 2; 3 6 7: 2 4 0 7- 1 8.
9
Hi gas hi hara E, T orres V E, C ha p ma n A B, Gra nt ha m JJ, Bae K, Wat nic k TJ, et al. 
T ol va pta n i n a ut os o mal d o mi na nt p ol y c ystic ki d ne y disease: t hree years' e x perie nce. 
Cli n J A m S oc Ne p hr ol. 2 0 1 1 Oct; 6( 1 0): 2 4 9 9 -5 0 7.
1 0
T orres V E, Ba n kir L, Gra nt ha m JJ. A case f or water i n t he treat me nt of p ol yc ystic 
ki d ne y  disease. Cli n. J A m S oc Ne p hr ol. 2 0 0 9;( 4): 1 1 4 0- 5 0.
1 1
Le ve y  A S, Ste ve ns L A, et al. A ne w e q uati o n t o esti mate gl o mer ular filtrati o n rate.  
A n n I nter n Me d. 2 0 0 9; 1 5 0: 6 0 4- 6 1 2.
1 2
B oertie n W E, Meijer E, de J o n g P E, Ba k ker SJ, Czer wiec F S, Str uc k J, et al. S h ort-
ter m re nal he m o d yna mic effects of t ol va pta n i n s u bjects wit h a ut os o mal d o mi na nt 
p ol y c ystic ki d ne y disease at vari o us sta ges of c hr o nic ki d ne y disease. Ki d ne y Int. 
2 0 1 3 Dec; 8 4( 6): 1 2 7 8 - 8 6.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 8
2 6 Mar 2 0 1 5 
1 3
Iraza bal M V, T orres V E, H o ga n M C, Gl oc k ner J, Ki n g B F, Ofstie T G, et al. S h ort-
ter m effects of t ol va pta n o n re nal f u ncti o n a n d v ol u me i n patie nts wit h a ut os o mal 
d o mi na nt p ol y c ystic ki d ne y disease. Ki d ne y Int. 2 0 1 1 A u g; 8 0( 3): 2 9 5 - 3 0 1.
1 4
Nati o nal Researc h C o u ncil. ( 2 0 1 0). T he Pre ve nti o n a n d Treat me nt of Missi n g Data i n 
Cli nical Trials. Pa nel o n Ha n dli n g Missi n g Data i n Cli nical Trials. C o m mittee o n 
Nati o nal Statistics, Di visi o n of Be ha vi oral a n d S ocial Scie nces a n d E d ucati o n. 
Was hi n gt o n, D C: T he Nati o nal Aca de mies Press.
1 5
 A p hase II, ra n d o mize d, d o uble -bli n d, place b o -c o ntr olle d, asce n di n g 
d ose st u d y  t o deter mi ne t he safety, p har mac o ki netics, a n d p har mac o d y na m ics of 
orall y  a d mi nistere d t ol va pta n ta blets i n male a n d fe male a d ults dia g n ose d wit h 
a ut os o mal d o mi na nt p ol yc ystic ki d ne y disease. Ots u ka Cli nical St u d y Re p ort f or 
Pr ot oc ol 1 5 6 - 0 4-2 4 8, iss ue d 1 9 Ja n 2 0 0 6.
1 6
A p hase 2, m ultice nter, o pe n -la bel, st u d y t o deter mi ne l o n g-ter m safety, 
t olera bilit y, a n d efficac y of s plit-d ose oral re gi me ns of t ol va pta n ta blets i n a ra n ge of 
3 0 t o 1 2 0 m g/ d i n patie nts wit h a ut os o mal d o mi na nt p ol y c ystic ki d ne y disease. 
Ots u ka Cli nical Trial Re p ort f or Pr ot oc ol 1 5 6 - 0 4-2 5 0, iss ue d 2 4 Mar 2 0 1 1, a me n de d 
3 0 N o v 2 0 1 1.
1 7
U. S. F o o d a n d Dr u g A d mi nistrati o n. 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 ng cli nical e val uati o n [re p ort o n t he i nter net]. 2 0 0 9 J ul [cite d 2 0 1 2 
Oct 1 0];[a b o ut 2 3 p.].  A vaila ble fr o m: 
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 1 7 4 0 9 0. p df.
1 8
Pei Y, O baji J, D u p uis A, et al. U nifie d cri teria f or ultras o n o gra p hic dia g n osis of 
A D P K D. J A m S oc Ne p hr ol 2 0 1 0 2 0: 2 0 5- 2 1 2.
1 9
Ra vi ne D, Gi bs o n R N, Wal ker R G, et al. E val uati o n of ultras o n o gra p hic dia g n ostic 
criteria f or a ut os o mal d o mi na nt p ol y c ystic ki d ne y disease 1. La ncet 1 9 9 4; 3 4 3: 8 2 4-
8 2 7.
2 0
I nter nati o nal C o nfere nce o n Har m o nisati o n; G o o d Cli nical Practice: C o ns oli date d 
G ui deli ne; N otice of A vaila bilit y , 6 2 C. F. R. Sect. 9 0 ( 1 9 9 7).
2 1
Lefa nte JJ. T he p o wer t o detect differe nces i n a vera ge rates of c ha n ge i n l o n git u di nal 
st u dies. Stat Me d. 1 9 9 0 A pr; 9( 4): 4 3 7 - 4 6.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
9 9
2 6 Mar 2 0 1 5 
A p pe n di x 1
N a mes of S p o ns or Pers o n nel
Re p ort I m me diatel y Re p orta ble E ve nts ( seri o us a d verse e ve nts, p ote ntial H y’s La w cases, 
pre g na ncies a n d a d verse e ve nts re q uiri n g disc o nti n uati o n of trial dr u g ) t o:
Q ui ntiles
Cli nic al Safet y a n d P har mac o vi gila nce
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C 2 7 5 6 0, U S A
P h o ne: 
Fa x: 
F o r Me dic al E mer ge ncies ( use o nly if s p o ns or pers o n nel liste d a b o ve are u na vaila ble): 
Gl o b al Pr oject Le a ders
 
P h o ne:  
Fa x 
 
P h o ne:  
 Fa x 
Gl o b al Cli nic al M a n a ge me nt
Gl o bal Cli nical Ma na ge me nt
 
P h o ne:  
; Fa x 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 0
2 6 Mar 2 0 1 5 
A p pe n di x 2
I nstit uti o ns C o ncer ne d Wit h t he Tri al
P h o ne: 
 
P h o ne: 
 
P h o ne: 
Fa x: 
Gl o b al Me dic al M o nit ori n g
Q ui ntiles
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne:  
M o bile: 
Fa x: 
St u d y M a n a ge m e nt
Q ui ntiles
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C
2 7 5 6 0 , U S A
Office:
M o bile:
Fa x: 
S afet y Re p orti n g
Q ui ntiles
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne: 
Fa x:
I n vesti g ati o n al M ateri als
Al mac 
2 5 Fretz R d
S o u dert o n, P A 1 8 9 6 4 , U S A 
P h o ne:  
B u d get a n d C o ntr act Ne g oti ati o n
I N C Researc h, L L C
3 2 0 1 Beec hleaf Ct., # 6 0 0
Ralei g h, N C 2 7 6 0 4 , U S A
P h o ne:  
I n vesti g at or P a y me nts
Q ui ntiles
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne:  
M o bile: 
Fa x: 
Electr o nic D at a C a pt ure
Me di Data S ol uti o ns
7 9 Fift h A ve n ue, 8t h Fl o or
Ne w  Y or k, N Y 1 0 0 0 3 , U S A
P h o ne: 
Fa x: 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 1
2 6 Mar 2 0 1 5 
I R T S ystems
Al mac Cli nical Tec h n ol o gies
2 5 Fretz R oa d
S o u dert o n, P A 1 8 9 6 4 , U S A
U S Tel: 
R o W Tel: 
H o m e N ursi n g Ser vices
Tel: 
P atie nt Recr uit m e nt a n d Rete nti o n
Matt he ws M e dia Gr o u p ( M M G)
7 0 0 Ki n g Far m Bl v d, 5t h Fl o or
R oc k ville, M D 2 0 8 5 0 , U S A
P h o ne:  
Fa x:  
Tr a veli n g C o or di n at or Assist a nt
Pri ncet o n Me dical 
3 4 9 R o ute 2 0 6 S o ut h
Hills b or o u g h, NJ 0 8 8 4 4 , U S A
P h o ne:  
Fa x:  
Ce ntr al L a b or at or y Ser vices
C o va nce Ce ntral La b orat or y Ser vices
8 2 1 1 Sci C or Dr.
I n dia na p olis, I N 4 6 2 1 4, U S A
P h o ne:  
T oll -free: 
Fa x: 
 
P K/ P D A n al ysis
I C O N
8 2 8 2 Halse y R d.
W hites b or o, N Y 1 3 4 9 2 , U S A
P h o ne:  

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 2
2 6 Mar 2 0 1 5 
A p pe n di x 3  
H a n dli n g a n d S hi p me nt of Bi o a n al ytic al S a m ples
Ha n dli n g of S peci me ns
All t u bes m ust be la bele d usi n g t he ce ntral la b orat or y 's bar c o de la bels pr o vi de d wit h t he 
sa m ple c ollecti o n kits.  T he ce ntral la borat or y 's re q uisiti o n f or m m ust be c o m pletel y 
fille d o ut i n re gar ds t o t he all sa m ple i nf or mati o n.  In a d diti o n, t h e s u bject I D n u m ber a n d 
date of c ollecti o n m ust be ha n d -writte n o n t he sa m ple t u be.  I t is i m p orta nt t o n ote t he 
e xact ti me of t he bl o o d c ollecti o n o n t he e C R F.
Eac h s peci me n m ust be la bele d usi n g a water pr o of pe n.  A la bel s uita ble f or t he st ora ge 
c o n ditio ns m ust c o ntai n t he S u bject I D n u m ber a n d date of c ollecti o n, m ust c orres p o n d t o 
t he re q uisiti o n f or m, a n d m ust be fir ml y attac he d.  T he re q uisiti o n f or m m ust c o ntai n t he 
na me, a d dress, a n d tele p h o ne n u m ber of t he c o ntact pers o n fr o m t he trial site.
Plas m a P K Sa m ple C ollecti o n
C ollect bl o o d sa m ples t o a nal yz e t ol va pta n a n d meta b olite(s) c o nce ntrati o ns usi n g 4 -m L  
dra w c ollecti o n t u bes c o ntai ni n g s o di u m he pari n.  After o btai ni n g t he bl o o d sa m ple, mi x 
c ollecti o n t u be t h or o u g hl y b y sl o wl y i n verti n g t he c ollect i o n t u be 8-1 0 ti mes. Place t he 
c ollecti o n t u be i n a n ice/ water bat h. Wit hi n 4 5 mi n utes of c ollecti o n, pr ocess c ollecti o n 
t u bes i n a refri gerate d ce ntrif u ge set at a p pr o xi matel y 1 3 0 0 g f or 1 5 mi n utes at 
a p pr o xi matel y 5° C. T he se parate d plas ma fr o m t he bl o o d c ollecti o n t u be s h o ul d t he n be 
di vi de d e q uall y  bet wee n t he 2 bar-c o de la bele d p ol ypr o p yl e ne t u bes. Wit hi n 9 0 mi n utes 
of c ollecti o n, st ore b ot h plas ma ali q u ot sa m ples at −7 0 ° C, e xce pt f or brief peri o ds o n dr y 
ice f or s hi p me nt. If a −7 0 ° C freezer is u na vaila ble, t he n t he sa m ples ca n be st ore d o n dr y  
ice f or u p t o 1 wee k u ntil a s hi p me nt t o t he ce ntral la b orat or y ca n be arra n ge d.
 
 
 
 
 
 
 
 
 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 3
2 6 Mar 2 0 1 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sa m ple S hi p me nt
Plas ma a n d uri ne sa m ples m ust be neatl y pac ke d i n t he kits pr o vi de d b y t he ce ntral la b 
a n d restrai ne d i n a St y r of oa m c o ntai ner t hat is c o m pletel y fille d wit h dr y ice t o a v oi d air 
s paces t hat all o w e va p orati o n of t he dr y ice. T he St y r of oa m c o ntai ner s h o ul d be seale d 
wit h ta pe a n d place d i n a car d b oar d b o x. T he ce ntral la b m ust be alerte d of sa m ple 
s hi p me nt. Pac ka ges m ust n ot be s hi p pe d o n T h urs da ys, Fri da ys, Sat ur da ys, or a n y da y 
pri or t o a h oli da y  wit h o ut t he e x presse d c o nse nt of O P D C or t he ce ntral la b. S hi p me nts 
fr o m cli nical sites will be via a n o ver ni g ht carrier t o t he ce ntral la b orat or y.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 4
2 6 Mar 2 0 1 5 
A p pe n di x 4  
A d mi nistr ati ve C h a n ges / Pr ot oc ol A me n d me nts
A d mi nistr ati ve C h a n ge N u m ber:
1
Iss ue D ate:
2 1 Fe br uar y  2 0 1 4
P U R P O S E:
T his a d mi nistrati ve c ha n ge will n ot affect t he safet y  of s u bjects, t he sc o pe of t he 
i n vesti gati o n, or t he scie ntific q ualit y of t he trial.
T he p ur p ose of t his a d mi nistrati ve c ha n ge was t o c orrect t y p o g ra p hical err ors a n d a d d 
a d diti o nal clarif yi n g i nf or mati o n i nt o Fi g ure 3. 1-1 - Trial Desi g n Sc he matic.
B A C K G R O U N D:
I n Fi g ure 3. 1- 1:  T y p o gra p hical err ors were c orrecte d i n t he b o xes f or trial da y s a n d 
ad diti o nal te xt b o xes were a d de d / m o difie d t o i n dicate s pecific peri o ds of data c ollecti o n 
f or t he pri mar y a n d ke y sec o n dar y e n d p oi nts.
M O DI FI C A TI O N S T O P R O T O C O L:
Ori gi n al Fi g ure 3. 1 -1 - Tri al Desi g n Sc he m atic:

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 5
2 6 Mar 2 0 1 5 
Re vise d Fi g ure 3. 1 - 1 - Tri al Desi g n Sc he m atic:
A D DI TI O N A L RI S K T O T H E S U B J E C T:
T here is n o a d d iti o nal ris k t o t he s u bjects.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 6
2 6 Mar 2 0 1 5 
A me n d me nt N u m ber 
1
Iss ue D ate:
3 1 Marc h 2 0 1 4
P U R P O S E:
T he pri mar y  p ur p ose of t his a me n d me nt was t o i ncrease t he sa m ple size a n d peri o d of 
e nr oll me nt t o i ncrease p o wer f or t he pri mar y  a n d sec o n dar y e n d p oi nts.
I n a d diti o n, i nf or mati o n ass ociate d wit h a p ote ntial i nteri m a nalys is was a d de d, t he 
n u m ber of creati ni ne bl o o d dra ws was re d uce d , a n i ncl usi o n criteri o n was a d de d, a n d a n 
e xcl usi o n criteri o n was m o difie d.  M i n or re visi o ns were als o ma de t o t he pr ot oc ol f or 
clarit y.
B A C K G R O U N D:
I ncre ase i n s a m ple size
I n t he ori gi nal pr ot oc ol, t he sa m ple size was calc ulate d usi n g t he i ntra-a n d i nter-s u bject 
varia nces deri ve d fr o m a sl o pe a nal ys is m o del.  T he n a met h o d base d o n M M R M was 
de vel o pe d a n d use d t o deri ve a ne w set of i ntra a n d i nter-s u bject varia nces f or t he sa m ple 
size calc ulati o n f or t he e n d p oi nt a nal ysis f or t his pr ot oc ol.  T his ne w sa m ple size is m ore 
c o nser vati ve.
A d diti o n of a n i nteri m an al ysis
T his trial is t o be c o n d ucte d o ver a critical ti me peri o d d u ri n g w hic h t ol va pta n ma y be 
a p pr o ve d as t hera p y f or A D P K D i n s o me of t he partici pati n g re gi o ns. T he E ur o pea n 
Me dici nes A ge nc y ’s ( E M A) decisi o n f or a pe n di n g mar keti n g a ut h orizati o n a p plicati o n 
f or use of t ol va pta n i n treat me nt of A D P K D is e x pecte d i n 2 0 1 5. F oll o wi n g re g ulat or y  
a p pr o val, rei m b urse me nt a n d c o m mercial a vaila bilit y  m a y ha ve a n i m pact o n t he o n g oi n g 
et hical c o n d uct of t he trial. T his ma y  i m pact s u bjects e nr olle d i n E ur o pe w h o are 
c o nti n ui n g i n t he ra n d o mize d, place b o -c o ntr olle d treat me nt p has e.  If a n i nteri m a nalys is 
is c o n d ucte d a n d t he res ults satisf y t he n ull h yp ot hesis, t he trial ma y  be ter mi nate d early 
a n d t he e xisti n g e nr olle d s u bjects ma y  be offere d partici pati o n i n a n o pe n-la bel trial.
Decre ase i n bl o o d dr a ws f or e G F R c alc ul ati o n
Wit h t he i ncrease d sa m ple size f or t his pr ot oc ol, t he n u m ber of bl o o d sa m ples c ollecte d 
f or creati ni ne fr o m eac h s u bject was re d uce d f or b ot h t he pre-treat me nt a n d p ost-
treat me nt e G F R calc ulati o ns.
A d diti o n of a n i n cl usi o n criteri o n t o s pecif y t ol v a pt a n n aï ve s u bjects
D ue t o t he relati vely s h ort ( 1 2 m o nt hs ) treat me nt peri o d d uri n g w hic h treat me nt effect 
ca n be o bser ve d , a n d i n or der t o mi ni mize a n y carr y o ver effect fr o m pre vi o us e x p os ure 
t o t he IM P, t his st u d y  will e nr oll o nl y t ol va pta n naï ve s u bjects.  A n i ncl usi o n criteri o n 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 7
2 6 Mar 2 0 1 5 
was t heref ore a d de d t o s pecif y  t hat o nly t ol va pta n naï ve s u bjects will be per mitte d t o 
e nr oll i n t his trial.
Cl arific ati o n of e xcl usi o n c riteri o n # 5
A c ha n ge was ma de t o t he e xcl usi o n criteria t o f urt her defi ne s u bjects wit h “a d va nce d 
dia betes” w h o w o ul d be e xcl u de d fr o m t he pr ot oc ol.
Ot her Re visi o ns
It was deci de d t hat s o me of t he la n g ua ge s h o ul d be c ha n ge d, or e x pa n de d, f or clarity i n 
s pecific secti o ns of t he d oc u me nt.  Als o, la n g ua ge was a d de d t o defi ne t he mi ni m u m 
“ was h-o ut” peri o d f or s u bjects e nr olle d i n t he trial w h o were bei n g treate d wit h t ol va pta n 
fr o m pre vi o us trials.
C ha n ges wer e ma de t o t he f o ot n otes i n t he Sc he d ule of Assess me nts ta ble t o c orres p o n d 
t o c ha n ges i n visit assess me nts, t o clarif y t he a nal ysis of ser u m creati ni ne sa m ples, t o 
s pecif y visits t hat were i n-cli nic, a n d t o defi ne s pecifics li ke “c o o ke d meat pr otei n”, etc.

C ha n ge d i nsta nces of “s ha m” t o “ matc hi n g place b o 0 m g ta blets”.

Clarifie d all i nsta nces of dietar y  “ pr otei n” t o dietar y “c o o ke d meat pr otei n”.

C ha n ge d C hair ma n of t he he patic a dj u dicati o n c o m mittee t o Dr. Da vi d Al pers.

Fi xe d t y p o gra p hical err ors.
Secti o n al Re visi o ns
L oc ati o n
Ol d Te xt
U p d ate d Te xt
S y n o psis, Trial Desi g n, 
Scree ni n g Peri o d
Scree ni n g peri o d ( 2 we e ks):
... T his ma y i ncl u de, f or e xa m ple, 
sta bilizi n g a nti-h y perte nsi ve re gi me ns 
f or s u bjects disc o nti n ui n g di uretics or 
“ was h -o ut” of t ol va pta n or ot her 
i n vesti gati o nal a ge nts f or s u bjects 
w h o partici pate d i n pre vi o us trials.
....Eli gi bilit y will be c o nfir me d b y t he 
mea n of e G F R calc ulate d fr o m t he 
s u bjects’first 2 pre -treat me nt, ce ntral-
la b ser u m creati ni ne assess me nts.
Scree ni n g peri o d ( 1 - 2 we e ks):
... T his ma y i ncl u de, f or e xa m ple, 
sta bilizi n g a nti-h y perte nsi ve 
re gi me ns f or s u bjects disc o nti n ui n g 
di ureti cs or “ was h -o ut” of ot her 
i n vesti gati o nal a ge nts.
....Eli gi bilit y will be c o nfir me d b y 
t he mea n of e G F R calc ulate d fr o m 
t he s u bjects’ 2 p re-treat me nt, 
ce ntral-la b ser u m creati ni ne 
assess me nts (c ollecte d at le ast 2 4 
h o urs a p art).  T he fi n al scree ni n g 
visit o n D a y -4 3 will n ot be 
sc he d ule d u ntil l a b or at or y res ults 
f r o m t he sec o n d scree ni n g visit 
( V2) are recei ve d a n d e v al u ate d.
S y n o psis, Trial Desi g n, 
Place b o R u n -i n peri o d 
( 1 wee k)
Place b o r u n -i n peri o d ( 1 wee k):  
S u bject s will be gi ve n place b o i n a 
dail y s plit d ose of a si n gle 0 m g ta blet 
u p o n a wa ke ni n g a n d a n ot her 0 m g 
ta blet a p pr o xi matel y 8 t o 9 h o urs later 
Place b o r u n -i n peri o d ( 1 wee k):  
S u bjects will be gi ve n place b o ( as a 
si n gle-bli n d “s h a m ” 1 5/ 1 5 m g 
d ose ) i n a dail y s plit d ose of a si n gle 
0 m g ta blet u p o n a wa ke ni n g a n d 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 8
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
(a b bre viate d 0/ 0 m g), i n a f or m 
i de ntical t o t ol va pta n ta blets.
B l o o d will be dra w n 2 ti mes o n 
se parate da ys (at least 2 4 h o urs a part), 
i ncl u di n g t he last da y of t he r u n-i n 
peri o d,
a n ot her 0 m g ta blet a p pr o xi matel y 8 
t o 9 h o urs later (a b bre viate d 0/ 0 m g), 
i n a f or m i de ntical t o t ol va pta n 
ta blets.
B l o o d will be dra w n o nce o n t he last 
da y of t he r u n -i n peri o d ( D a y -3 6) .
S y n o psis, Trial Desi g n, 
T ol v apta n Titrati o n 
Peri o d ( 2 w ee ks)
T ol va pta n titrati o n peri o d ( 2 wee ks):  
S u bjects will be gi ve n a s plit d ose of 
3 0/ 1 5 m g t ol va pta n wit h u p w ar d 
titrati o n e ver y 3 t o 4 da ys t o 4 5/ 1 5 
m g, 6 0/ 3 0 m g, u p t o a ma xi m u m d ose 
of 9 0/ 3 0 m g per da y o ver 2 wee ks.  
T ol va pta n titrati o n peri o d ( 2 wee ks):  
S u bjects will be gi ve n a s plit d ose of 
3 0/ 1 5 m g t ol va pta n (si n gle-bli n d)
wit h u p war d titrati o n e ver y 3 t o 4 
da ys t o 4 5/ 1 5 m g, 6 0/ 3 0 m g, u p t o a 
ma xi m u m d ose of 9 0/ 3 0 m g per da y 
o ver 2 w ee ks.  
S y n o psis, Trial Desi g n, 
T ol va pta n R u n -i n 
Peri o d ( 3 w ee ks)
T ol va pta n r u n -i n peri o d ( 3 wee ks):  
S u bjects w h o t olerate t he t ol va pta n 
6 0/ 3 0 m g or 9 0/ 3 0 m g dail y d ose 
re gi me n will e nter t he t ol va pta n ru n -
i n peri o d at t he t olerate d d ose f or 3 
a d diti o nal wee ks.  
T ol va pta n r u n -i n peri o d ( 3 wee ks):  
S u bjects w h o t olerate t he t ol va pta n 
6 0/ 3 0 m g or 9 0/ 3 0 m g dail y d ose 
re gi me n will e nter t he t ol va pta n r u n-
i n peri o d (si n gle-bli n d) at t he 
t olerate d d ose f or 3 a d diti o nal 
wee ks.  
S y n o psis, Trial Desi g n, 
F oll o w -u p Peri o d ( 3 
wee ks)
....N o assess me nts will be ta ke n f or 
t he first wee k of t his peri o d; h o we ver,
5 visits will be sc he d ule d f or t he last 
2 w ee ks of f oll o w-u p f or p ost -
treat me nt efficac y a n d safet y 
meas ures.
....N o assess me nts will be ta ke n f or 
t he first wee k of t his peri o d; 
h o we ver, 3 visits will be sc he d ule d 
f or t he last 2 wee ks of f oll o w-u p f or 
p ost -treat me nt efficac y a n d safet y 
meas ures .
S y n o psis, S u bject 
P o p ulati o n
T his trial w ill ra n d o mize 
a p pr o xi matel y 8 0 0 s u bjects wit h 
A D P K D, wit h a mi ni m u m of 7 0 0 a n d 
a ma xi m u m of 1 0 0 0 s u bjects pla n ne d 
t o be e nr olle d.
T his trial w ill ra n d o mize 
a p pr o xi m atel y 1 3 0 0 t ol v a pt a n 
n aï ve s u bjects wit h A D P K D.
S y n o psis, I ncl usi o n 
Criteria
N/ A

T ol va pta n naï ve
S y n o psis, E xcl usi o n 
Criteria a n d Secti o n 
3. 4. 3, Ta ble 3. 4. 3 -1, 
E xcl usi o n Criteri o n 5

S u bjects wit h a d va nce d 
dia betes (e g, gl yc os ylate d 
he m o gl o bi n [ H g b A 1c ] > 7. 5 ,
a n d/or gl yc os uria b y 
di pstic k), e vi de nce of 
a d diti o nal si g nifica nt re nal 
disease(s) (ie, c urre ntl y 
acti ve gl o mer ular 
ne p hriti dies), re nal ca ncer, 
si n gle ki d ne y, or rece nt 
( wit hi n last 6 m o nt hs ) re nal 
s ur ger y, or ac ute ki d ne y 
i nj ur y.

S u bjects wit h a d va nce d 
dia betes (e g, gl yc os ylate d 
he m o gl o bi n 
[H g b A 1c ] > 7. 5 , a n d/ or 
gl yc os uria b y di pstic k, 
si g nific a nt pr otei n uri a, 
reti n o p at h y ), e vi de nce of 
a d diti o nal si g nifica nt re nal 
disease(s) (ie, c urre ntl y 
acti ve gl o mer ular 
ne p hriti des ), re nal ca ncer, 
si n gle ki d ne y, or rece nt 
( wit hi n last 6 m o nt hs ) re nal 
s ur ger y, or ac ute ki d ne y 
i nj ur y.
S y n o psis, Trial Site(s)
A p pr o xi matel y 2 0 0 e nr olli n g sites 
i ncl u di n g, b ut n ot li mite d t o, t he 
f oll o wi n g re gi o ns:  N ort h A merica, 
S o ut h A merica, Easter n E ur o pe, 
Wester n E ur o pe, Asia, a n d A ustralia.
A p pr o xi matel y 2 2 0 e nr olli n g sites 
i ncl u di n g, b ut n ot li mite d t o, t he 
f oll o wi n g re gi o ns:  N ort h A merica, 
S o ut h A merica, Easter n E ur o pe, 
Wester n E ur o pe, Asia, a n d A ustralia.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 0 9
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
S y n o psis, 
I n vesti gati o nal 
Pr o d uct(s), etc
D oses will be e x presse d as ea rl y 
d ose/late d ose (e g, 6 0/ 3 0 ).
Place b o w ill be a d mi nistere d t o all 
s u bjects d uri n g t he place b o r u n-i n 
peri o d .
D oses will be e x presse d as earl y 
d ose/late d ose (e g, 6 0/ 3 0 m g ).
Place b o w ill be a d mi nistere d t o all 
s u bjects d uri n g t he place b o r u n-i n 
peri o d as a si n gle -bli n d “s h a m ” 
1 5/ 1 5 m g d ose .
S y n o psis, Trial 
Assess me nts
Scree ni n g: Me dical hist or y, c o m plete 
p h ysical e xa mi nati o n,
uri ne pre g na nc y test ( w o m e n of 
c hil d -beari n g p ote ntial o nl y).
Safet y:   Vital si g ns, directe d p h ysical 
e xa mi na ti o n, A Es, he mat ol o g y, 
uri nal ysis, a n d ser u m c he mistr y tests 
(i ncl u di n g ser u m tra nsa mi nases, 
al kali ne p h os p hatase, bilir u bi n, ser u m 
s o di u m), bi o mar ker plas ma a n d uri ne 
sa m ples, a n d D N A bl o o d sa m ples 
(f or c o nse nti n g s u bjects).
P har m a c o d yna mic ( P D):   Uri ne 
os m olalit y ( U os m), s pecific gra vit y.
Scree ni n g: Me dical hist or y, 
c o m plete p h ysical e xa mi nati o n,
uri ne pre g na nc y test ( w o m e n of 
c hil d-beari n g p ote ntial o nl y), a n d 
l a b or at or y tests t o deter mi ne 
i niti al eli gi bilit y.
Safet y:   Vital si g ns, directe d 
p h ysical e xa mi nati o n, self-assesse d 
t oler a bilit y, A Es, he mat ol o g y, 
uri nal ysis, a n d ser u m c he mistr y tests 
(i ncl u di n g ser u m tra nsa mi nases, 
al kali ne p h os p hatase, bilir u bi n, 
ser u m s o di u m), bi o mar ker plas ma 
a n d uri ne sa m ples, a n d D N A bl o o d 
sa m ples (f or c o nse nti n g s u bjects).
P har m ac o d yna mic ( P D):   Uri ne 
os m olalit y ( U os m), uri ne s pecific 
gra vit y.
S y n o psis, Criteria f or 
E val uati o n
Pri mar y Efficac y E n d p oi nt:
Treat me nt differe nce i n t he c ha n ge of 
e G F R fr o m pre -treat me nt baseli ne t o 
p ost -treat me nt f oll o w-u p, n or malize d
( di vi de d) b y eac h s u bject’s treat me nt 
d urati o n.
P D E n d p oi nts:  U os m a n d s pecific 
gra vit y.
E x pl orat or y E n d p oi nts:
Efficac y:  Assess me nt of A D P K D 
o utc o mes.
Pri mar y Efficac y E n d p oi nt:
Treat me nt differe nce i n t he c ha n ge 
of e G F R fr o m pre -treat me nt baseli ne 
t o p ost-treat me nt f oll o w-u p, 
a n n u alize d ( di vi de d) by eac h 
s u bject’s I M P treat me nt d urati o n.
P D E n d p oi nts:  U os m a n d uri ne
s pecific gra vit y.
E x pl orat or y E n d p oi nts:
Efficac y:  Assess me nt of A D P K D 
o utc o mes a n d a n al ysis of effic ac y 
b ase d o n m o d al d oses.
S y n o psis, Statistical 
Met h o ds , Sa m ple Size
Base d o n a Mi xe d M o del Re peate d 
Meas ure me nts a nal ysis of t he n o n -
Ja pa nese C K D-3 S u bjects fr o m trial 
1 5 6 -0 4 -2 5 1, t he treat me nt differe nce 
i n re nal f u ncti o n at M o nt h 1 2 is 1. 0 7 
i n o ur sa m ple size calc ulati o n.  It is 
e x pecte d t hat t he resi d ual varia nce 
a n d slo pe varia nce w o ul d be 2 2. 1 3 
a n d 5. 2 7, res pecti vel y, ass u mi n g 4 t o 
5 pre -treat me nt a n d p ost-treat me nt 
o bser vati o ns ta ke n i n 2 -wee k 
Base d o n a Mi xe d M o del Re peate d 
Meas ure me nts a nal ysis of t he n o n -
Ja pa nese C K D-3 S u bjects fr o m trial 
1 5 6 -0 4 -2 5 1, t he treat me nt differe nce 
i n re nal f u ncti o n at M o nt h 1 2 is 1. 0 7 
in o ur sa m ple size calc ulati o n.   It is 
e x pecte d t h at t he i ntr a -s u bject 
v ari a nce is 1 4. 2 a n d i nter -s u bject 
v ari a nce is 2 8. 0 5 at M o nt h 1 2.  
Wit h 3 re pe ate d m e as ures at pre -
tre at me nt b aseli ne a n d p ost -

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 0
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
i nter vals.  T he p o wer calc ulati o n 
esti mates t hat, f or a 2 -si de d al p ha set 
at 0. 0 5 f or a p o wer of 8 5 % t o 9 0 %, 
a n d wit h a n ass u mpti o n of 1 5 % 
dr o p o ut rate i n t he trial, a t otal s a mple 
size of a p pr o xi matel y 6 6 0 t o 7 7 0 
s u bjects (r o u n de d u p t o 7 0 0 t o 8 0 0 
s u bjects) is nee de d.
tre at me nt f oll o w -u p, res pecti vel y
the p o w er calc ulati o n esti mates t hat, 
f or a 2-si de d al p ha set at 0. 0 5 f or a 
p o w er of 9 0 %, a n d wit h a n 
ass u m pti o n of 1 0 % dr o p o ut rate i n 
t he trial, a t otal sam p le size of
a p pr o xi m atel y 1 3 0 0 s u bjects is
nee de d.
S y n o psi s, Trial 
D urati o n
T he d urati o n of t he d o u ble -bli n d, 
ra n d o mize d treat me nt peri o d will be 
1 2 m o nt hs.  T he t otal d urati o n of t he 
trial (i ncl u di n g pre-ra n d o mizati o n
a n d f oll o w-u p peri o ds) w ill be 
a p pr o xi matel y 1 5 m o nt hs.
T he d urati o n of t he d o u ble -bli n d, 
ra n d omize d treat me nt peri o d will be 
1 2 m o nt hs.  T he t otal d urati o n f or 
e ac h s u bject e ntere d i nt o of t he 
tri al is a p pr o xi m atel y 1 5-1 7 
m o nt hs (i ncl u di n g t he pre -
r a n d o miz ati o n a n d f oll o w -u p 
peri o ds , a n d a n a d diti o n al 8 wee ks 
f or e xte nsi o n of t he scree ni n g 
peri o d i n s u bjects f or w h o m  t his is 
necess ar y) .
Secti o n 1. 4, K n o w n a n d 
P ote ntial Ris ks a n d 
Be nefits
T y picall y, t his w o ul d re prese nt 2 t o 3 
liters of water per da y i n s u bjects 
wit h relati vel y i ntact re nal f u ncti o n, 
a n d lesser a m o u nts i n t h ose wit h 
m o re i m paire d f uncti o n.
A n i m bala nce i n t he pr o p orti o n of 
s u bjects wit h ele vate d tra nsa mi nases 
(t ol va pta n > place b o) le d t o 
i de ntificati o n of 3 s u bjects (t otal fr o m 
b ot h Trial 1 5 6 -0 4 -2 5 1 a n d its o pe n -
la bel e xte nsi o n trial, 1 5 6-0 8 -2 7 1) 
wit h la b orat or y a n d cli nical e vi de nc e 
of p ote ntiall y seri o us dr u g -i n d uce d 
li ver i nj ur y ( DI LI).
T hese a d verse reac ti o ns s h o ul d be 
c o nsi dere d i n li g ht of t he be nefits of a 
re d uce d ris k of A D P K D ki d ne y 
c o m plicati o ns, i ncl u di n g re nal pai n, 
uri nar y tract i nfecti o n, he mat uri a, 
a ne mia, a n d ne p hr ol it hiasis.
T y picall y, t his w o ul d re prese nt a 
mi ni m u m of 2 t o 3 liters of water 
per da y i n s u bjects wit h relati vel y 
i ntact re nal f u ncti o n, a n d lesser 
a mo u nts i n t h os e wit h m ore i m paire d 
f u ncti o n.
....Wit h a o nce e ver y 4 -m o nt h 
m o nit ori n g sc he me , a n i m bala nce
i n t he pr o p orti o n of s u bjects wit h 
ele vate d tra nsa mi nases (t ol va pta n > 
place b o) le d t o i de ntificati o n of 3 
s u bjects (t otal fr o m b ot h Trial 1 5 6-
0 4 -2 5 1 a n d its o pe n -la bel e xte nsi o n 
trial, 1 5 6-0 8 -2 7 1) w it h la b orat or y 
a n d cli nical e vi de nce of p ote ntiall y 
serio us dr u g -i n d uce d li ver i nj ur y 
( DI LI).
....T hese a d verse e ve nts a n d t he 
a b o ve attri b ut a ble a d verse 
reacti o ns s h o ul d be c o nsi dere d i n 
li g ht of t he be nefits of a re d uce d ris k 
of A D P K D ki d ne y c o m plicati o ns, 
i ncl u di n g re nal pai n, uri nar y tract 
i nfecti o n, he maturia, a ne mia, a n d 
ne p hr olit hiasis.
Secti o n 2. 1, Trial 
Rati o nale
....H o me n ursi n g visits or l ocal 
la b orat or y visits will als o be a vaila ble
f or c ollecti o n of f oll o w-u p bl o o d 
sa m ples a n d t o c o nti n ue healt h-stat us 
f oll o w u p e ve n if I M P is per ma ne ntl y 
disc o nti n ue d.
T heref ore, t he i nf or mati o n gat here d 
....H o me n ursi n g visits or l ocal 
la b orat or y visits will als o be 
a vaila ble at m ost sites f or c ollecti o n 
of f oll o w -u p bl o o d sa m ples a n d t o 
c o nti n ue healt h -stat us f oll o w u p 
e ve n if I M P is per ma ne ntl y 
disc o nti n ue d.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 1
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
t hr o u g h ge netic/ bi o mar ker a nal ysis 
s h o ul d i m pr o ve t he s p o ns or’s 
u n dersta n di n g of t he disease, its 
dia g n osis, pr o g n osis, a n d p ossi bl y 
treat me nt o utc o me b y  i de ntif yi n g 
w hic h patie nts are m ore li kel y t o 
res p o n d t o t ol va pta n, a n d/ or 
pre dicti n g w hic h s u bjects are li kel y t o 
pr o gress t o m ore se vere disease 
states, a n d/ or pre dicti n g w hic h 
s u bjects ma y ha ve a n a d verse e ve nt 
s uc h as DI LI, a n d/ or lea d t o ne w 
o p p ort u nities f or t hera pies .
T heref ore, t he i nf or mati o n gat here d 
t hr o u g h ge netic/ bi o mar ker a nal ysis 
s h o ul d i m pr ove t he s p o ns or’s 
u n dersta n di n g of t he disease, its 
dia g n osis, pr o g n osis, a n d p ossi bl y 
treat me nt o utc o me. T his c a n be 
acc o m plis he d b y  ide ntif yi n g w hic h 
s u bjects are more li kel y t o res p o n d 
t o t ol va pta n, a n d/ or pre dicti n g w hic h 
s u bjects are li kel y t o pr o gress t o 
m o re se vere disease states, a n d/ or 
pre dicti n g w hic h s u bjects ma y ha ve 
a n a d verse e ve nt s uc h as DI LI, 
a n d/ or lea d t o ne w o p p ort u nities f or 
t hera pies.
Secti o n 2. 2, D osi n g 
Rati o nale
All s u bjects will be e nc o ura ge d t o 
pr o gress t o 9 0/ 3 0 m g per da y, as t his 
is li kel y t o be m ost effecti ve.
All s u bjects will be e nc o ura ge d t o 
pr o gress t o 9 0/ 3 0 m g
per da y, as a hi g her d ose is li kel y t o 
be m ost effecti ve.
D uri n g t he d o u ble -bli n d ra n d o mize d 
treat me nt peri o d, s u bjects will eit her 
be mai ntai ne d o n t heir ma x i mall y 
t olerate d s plit d ose of t ol va pta n at 
6 0/ 3 0 m g or 9 0/ 3 0 m g or 
ra n d o mize d t o place b o.  T o ma na ge 
a d diti o nal t olera bilit y iss ues d uri n g 
t his peri o d, s u bjects ma y d o w n-
titrate bli n de d treat me nt t o 4 5/ 1 5 m g 
or e ve n 3 0/ 1 5 m g wit h me dical 
m o nit or a p pr o val.   S u bjects will be 
e nc o ura ge d t o mai ntai n ma xi mall y 
t olerate d d ose t o o pti mize a n d 
mai ntai n desire d s u p pressi o n.  If 
d o w n- titrati o n occ urs, s u bjects will 
be e nc o ura ge d t o ret ur n t o pre vi o us 
ma xi mal t olerate d d ose, if p ossi ble.
Secti o n 3. 1. 1, Fi g ure 
3. 1 - 1
See pre vi o us Fi g ure bel o w
See re vise d Fi g ure bel o w
Secti o n 3. 2. 1, Pre -
ra n d o mizati o n
S u bjects w h o pr o vi de i nf or me d 
c o nse nt, w h o meet t he 
i ncl usi o n/e xcl usi o n criteria, a n d f or 
w h o m preli mi nar y eli gi bilit y is 
esta blis he d, will enter a n 8 -we e k r u n-
i n peri o d.
...T his pre -ra n d o mizati o n peri o d 
c o nsists of a scree ni n g peri o d 
(t ypicall y 2 wee ks f or t ol va pta n -nai ve 
s u bjects; h o we ver, l o n ger peri o ds u p 
t o 8 a d diti o nal wee ks are acce pta ble 
f or s u bjects wit h dra wi n g fr o m 
t ol va pta n, or nee di n g sta bilizati o n 
after c ha n gi n g ot her treat me nts, 
S u bjects w h o pr o vi de i nf or me d 
c o nse nt, a n d f or w h o m preli mi nar y 
eli gi bilit y is esta blis he d, will e nter 
a n 8 -wee k r u n -i n peri o d.
...T his pre -ra n d o mizati o n peri o d 
c o nsists of a scree ni n g peri o d 
(t ypicall y 1- 2 we e ks; h o we ver, 
l o n ger peri o ds u p t o 8 a d diti o nal 
wee ks are acce pta ble f or s u bjects 
nee di n g sta bilizati o n after c ha n gi n g 
ot her treat me nts, es peciall y a nti -
h y perte nsi ves a n d di uretics , or w h o 
re q uire a d diti o n al assess me nts f or 
q u alific ati o n ); a place b o r u n i n 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 2
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
es peciall y a nti -h y perte nsi ves a n d 
di uretics), a place b o r u n i n peri o d ( 1 
wee k), a t ol va pta n titrati o n peri o d ( 2 
wee ks), a n d a t ol va pta n r u n -i n peri o d 
( 3 wee ks), descri be d i n m ore detail 
bel o w .
peri o d ( 1 w ee k), a t ol va pta n titrati o n 
peri o d ( 2 w ee ks), a n d a t ol va pta n 
r u n-i n peri o d ( 3 wee ks).
N/ A
D uri n g t his peri o d, s u bjects s h o ul d 
be t ol d “ Y o u will recei ve place b o or 
acti ve treat me nt (t ol va pta n) d uri n g 
t he treat me nt p hase, b ut y o u will n ot 
k n o w w hic h.”  T he s u bjects s h o ul d 
n ot be t ol d t hat t here is a se parate 
r u n-i n p hase a n d ra nd o m izati o n 
p hase, a n d t he y s h o ul d n ot be t ol d 
w he n f or mal ra n d o mizati o n will 
occ ur.  T he y s h o ul d als o be t ol d 
“ Y o ur eli gi bilit y f or c o nti n ue d 
partici pati o n w ill be assesse d 
i nter mitte ntl y d uri n g t he treat me nt 
peri o d.”
Secti o n 3. 2. 1. 1, 
Scree ni n g Peri o d
S u b jects will be t ol d t hat t hey will 
recei ve b ot h t ol va pta n a n d place b o 
d uri n g vari o us s u bse q ue nt peri o ds of 
t he trial a n d t hat t he ne xt peri o d 
i n v ol ves a d ose escalati o n wit h 
m ulti ple efficac y, safet y, a n d 
t olera bilit y assess me nts.
S u bjects will be t ol d t hat t he y will 
recei ve t ol va pta n or place b o d uri n g 
vari o us s u bse q ue nt peri o ds of t he 
trial a n d t hat t he ne xt peri o d 
i n v ol ves a d ose escalati o n wit h 
m ulti ple efficac y, safet y, a n d 
t olera bilit y assess me nts.
Trial me dicati o n will be dis pe nse d 
o n Da y - 4 3 after s u bject eli gi bilit y is 
c o nfir me d.  I n e xce pti o nal 
circ u msta nces, trial me dicati o n ma y 
be pr o vi de d at t he sec o n d scree ni n g 
visit wit h i nstr ucti o n n ot t o ta ke a n y 
me dicati o n u ntil c o nfir mati o n o n 
Da y  -4 3 b y t he i n vesti gat or.  If trial 
me dicati o n is dis pe nse d at t he 
sec o n d scree ni n g visit, c o nfir mati o n 
of eli gi bilit y a n d i nstr ucti o ns t o ta ke 
me dicati o n will be pr o vi de d b y 
tele p h o ne o n Da y -4 3.
Secti o n 3. 2. 1. 2, Place b o 
R u n -i n Peri o d
I n t he first wee k after t he scree ni n g 
peri o d, all s u bjects w ill be gi n t he 
si n gle- bli n d, place b o r u n-i n peri o d 
w here t he y will be gi ve n place b o i n a 
dail y s plit d ose of 0 m g (a b bre viate d 
0/ 0 m g), i n a f or m i de ntical t o 
t ol va pta n ta blets.  T he s u bject will 
remai n bli n de d t o treat me nt a n d 
recei ve a b ottle of dr u g w hic h t he y 
u n dersta n d c o ul d be eit her t ol va pta n 
or place b o.
I n t he first wee k after t he scree ni n g 
peri o d, all s u bjects will be gi n t he 
si n gle-bli n d, p lace b o r u n-i n peri o d 
wit h place b o i n a dail y s plit d ose of 
0 m g (a b bre viate d 0/ 0 m g), i n a f or m 
i de ntical t o t ol va pta n ta blets at t he 
1 5/ 1 5 m g d ose .  T he s u bject will 
r e mai n bli n de d t o treat me nt , h a vi n g 
recei ve d a b ottle of tri al dr u g 
d uri n g t he scree ni n g peri o d w hic h 
t he y u n derst o o d c o ul d be eit her 
t ol va pta n or place b o.
Secti o n 3. 2. 1. 4, 
S u bjects t olerati n g at least 6 0/ 3 0 m g  
S u bjects t olerati n g at least 6 0/ 3 0 m g 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 3
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
T ol va pta n R u n -i n 
Peri o d ( Da y -2 1 t o Da y 
-1)
t ol va pta n ma y e nter t he t ol va pta n 
r u n-i n peri o d ( 3 wee k d urati o n).
t ol va pta n ma y e nter t he si n gle-bli n d,
t ol va pta n r u n-i n peri o d ( 3 wee k 
d urati o n).
Secti o n 3. 2. 2, D o u ble -
bli n d Ra n d o mize d 
Treat me nt Peri o d ( Da y 
0 t o M o nt h 1 2)
N/ A
S u bjects n ot c o nti n ui n g i n t his trial 
will c o m plete E o T x visit 
assess me nts a n d be f oll o we d f or 2 1 
da ys t o assess a n y o n g oi n g A Es.
Secti o n 3. 2. 2, Ta ble 
3. 2. 2 - 1 D osi n g 
Sc he d ule
Trial Da y
D a y  -5 6 t o -4 3
Trial Da y
1 t o 2 wee ks (t o D a y -4 3 )
Secti o n 3. 3, Trial 
P o p ulati o n
T his trial w ill c o nse nt a n d scree n 
s u bjects i n or der t o ra n d o mize 
a p pr o xi matel y 8 0 0 s u bjects wit h 
A D P K D....
   I n or der t o ma xi mize p o w er a n d 
mi ni mize t he p ossi bilit y of T y pe 2 
err or, trial e nr oll me nt will c o nti n ue 
u ntil a mi ni m u m of 7 0 0 s u bjects are 
ra n d o mize d.  Ti me all o wi n g, t he 
s p o ns or ma y, at its discreti o n, e xte n d 
e nr oll me nt i n or der t o ra n d o mize u p 
t o 1 0 0 0 s u bjects t o f urt her i mpr o ve 
t he trial’s p o wer.
T his trial w ill c o nse nt a n d scree n 
t olva pta n naï ve s u bjects wit h 
A D P K D... .
....In or der t o ma xi mize p o w er a n d 
mi ni mize t he p ossi bilit y of T y pe 2 
err or, trial e nr oll me nt will c o nti n ue 
u ntil a p pr o xi m atel y 1 3 0 0 s u bjects 
are ra n d o miz e d.
Secti o n 3. 4. 1, I nf or me d 
C o nse nt
Eac h i n vesti gat or has b ot h et hical a n d 
le gal res p o nsi bilit y t o e ns ure t hat 
s u bjects bei n g c o nsi dere d f or 
i ncl usi o n i n t his trial are gi ve n a f ull 
e x pla nati o n of t he pr ot oc ol a n d of
t heir r ole a n d res p o nsi bilities i n t he 
pr o p ose d researc h.
Eac h i n vesti gat or has b ot h et hical 
a n d le gal res p o nsi bilit y t o e ns ure 
t hat s u bjects bei n g c o nsi dere d f or 
i ncl usi o n i n t his trial are gi ve n a f ull 
e x pla nati o n of t he pr ot oc ol ( wit h o ut 
re ve ali n g det ails of its i niti al 
si n gle-bli n d n at u re) a n d of
t heir r ole a n d res p o nsi bilities i n t he 
pr o p ose d researc h.
Secti o n 3. 4. 2, I ncl usi o n 
Criteria, Ta ble 3. 4. 2 - 1
3 .....

Wit h o ut fa mil y hist or y: 1 0 c ysts 
per ki d ne y ( b y a n y ra di ol o gic 
met h o d, a b o ve) a n d e xcl usi o n of 
ot her c ystic ki d ne y diseases.  
C o n diti o ns t o be e xcl u de d 
i ncl u de: m ulti ple si m ple re nal 
c ysts, re nal t u b ular aci d osis, 
c ystic d ys plasia of t he ki d ne y, 
m ultic ystic ki d ne y, m ultil oc ular 
c ysts of t he ki d ne y, me d ullar y 
c ystic ki d ne y a n d ac q uire d c ystic 
disease of t he ki d ne y.
4.  Distri b uti o n a n d n u m ber of c ysts 
c o nsiste nt wit h t he o bser ve d le vel of 
re nal f u ncti o n deficit.
3.   M ale a n d f e male s u bjects w h o 
are t ol v a pt a n n aï ve .
4 .....

Wit h o ut fa mil y hist or y: 1 0 c ysts 
per ki d ne y ( b y a n y ra di ol o gic 
met h o d, a b o ve) a n d e xcl usi o n of 
ot he r c ystic ki d ne y diseases.  
C o n diti o ns t o be e xcl u de d 
i ncl u de: m ulti ple si m ple re nal 
c ysts, re nal t u b ular aci d osis, 
c ystic d ys plasia of t he ki d ne y, 
m ultic ystic ki d ne y, m ultil oc ular 
c ysts of t he ki d ne y, me d ullar y 
c ystic ki d ne y a n d ac q uire d 
c ystic disease of t he ki d ne y.

Distri b uti o n a n d n u m ber of 
c ysts c o nsiste nt wit h t he 
o bser ve d l e vel of re nal f u ncti o n 
deficit.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 4
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Secti o n 3. 5. 1. 1, 
Pri mar y Efficac y 
E n d p oi nt
Treat me nt differe nce i n t he c ha n ge of 
e G F R fr o m pre -treat me nt baseli ne t o 
p ost -treat me nt f oll o w-u p, n or ma lize d 
( di vi de d) b y eac h s u bject’s treat me nt 
d urati o n.
Treat me nt differe nce i n t he c ha n ge 
of e G F R fr o m pre -treat me nt baseli ne 
t o p ost-treat me nt f oll o w-u p, 
a n n u alize d ( di vi de d) b y eac h 
s u bject’s I M P treat me nt d urati o n.
Secti o n 3. 5. 2. 3, 
P har m ac o ki netic/ P har m
ac o d y na mic E n d p oi nts
P D E n d p oi nts:  U os m a n d s pecific 
gra vit y
P D E n d p oi nts:  U os m a n d uri ne
s pecific gra vit y
Ta ble 3. 7 -1, Sc he d ule 
of Assess me nts
Pre vi o us Ta ble is at t he e n d of 
A p pe n di x 4
U p date d Ta ble wit h trac ke d c ha n ges
is at t he e n d of A p pe n di x 4
Secti o n 3. 7. 1. 1, Pr e -
ra n d o mizati o n Peri o d

scree ni n g peri o d ( 2 wee ks; 
l o n ger d urati o ns of u p t o 8 
a d diti o nal wee ks ma y be re q uire d 
acc or di n g t o t he i n vesti gat or’s 
j u d g me nt, as descri be d bel o w)
T o esta blis h t he pre -ra n d o mizati o n
e G F R, m ulti ple ser u m creati ni ne 
val ues (is ot o pe dil uti o n mass 
s pectr osc o p y [I D M S]-tracea ble) will 
be o btai ne d u n der sta n dar dize d 
c o n diti o ns.....
scree ni n g peri o d (1- 2 we e ks; l o n ger 
d urati o ns of u p t o 8 a d diti o nal w ee ks 
ma y be re q uire d acc or di n g t o t he 
i n vesti gat or’s j u d g me nt, as descri be d 
bel o w )
T o esta blis h t he pre -ra n d o mizati o n 
e G F R, m ulti ple ser u m creati ni ne 
val ues will be o btai ne d u n der 
sta n dar dize d c o n diti o ns.......
Secti o n 3. 7. 1. 1. 1, 
Scree ni n g Peri o d
T he scree ni n g peri o d will be f or 2 
wee ks ( 1 da y) f or t ol va pta n-nai ve 
s u bjects.  T he scree ni n g peri o d ma y 
be e xte n de d u p t o a n a d diti o nal 8 
wee ks f or s u bjects w h o re q uire 
m o dificati o n of me dical care 
s pecificall y f or t his trial.
T he scree ni n g peri o d will be f or 1- 2
wee ks , b ut ma y be e xte n de d u p t o a n 
a d diti o nal 8 wee ks f or s u bjects w h o 
re q uire m o dificati o n of me dical care 
or f urt her m e dic al e v al u ati o n
s pecificall y f or t his trial.
T his ma y i ncl u de, f or e xa m ple, 
sta bilizi n g a nti h y perte nsi ve re gi me ns 
f or s u bjects disc o nti n ui n g di uretics or 
“ was h -o ut” of t ol va pta n or ot her 
i n vesti gati o nal a ge nts f or ca n di dates 
w h o partici pate d i n pre vi o us trials.  
S u bjects w h o were pre vi o usl y ta ki n g 
tol va pta n are re q uire d t o si g n a n I C F 
a n d ha ve at least a 2 wee k was h-o ut 
peri o d pri or t o be gi n ni n g t he 1 - 2-
wee k scree ni n g assess me nts.   
T his ma y i ncl u de, f or e xa m ple, 
sta bilizi n g a nti h y perte nsi ve 
re gi me ns f or s u bjects disc o nti n ui n g 
di uretics or “ was h -o u t” of ot her 
i n vesti gati o nal a ge nts.
T he scree ni n g peri o d will c o nsist of 
t hree visits, eac h at least 2 4 h o urs 
a part.  T he first a n d last visits will be 
cli nic visits, b ut a visiti n g n urse 
h o use call or l ocal la b orat or y visit 
ma y be s u bstit ute d f or t he ot her visit 
w here o nl y bl o o d sa m ples will be 
c ollecte d.
T he scree ni n g peri o d s h o ul d be 
c o m p lete d wit hi n 1- 2 wee ks of t he 
place b o r u n -i n peri o d ( u nless 
e xte n de d as descri be d a b o ve) .  
Bl o o d will be d r a w n 2 ti mes o n 
se p ar ate d a ys ( visit 1 a n d visit 2) ,
at le a st 2 4 h o urs a p art. T he D a y -
4 3 visit will n ot be sc he d ule d u ntil 
l a b or at or y res ults fr o m t he sec o n d 
visit are recei ve d a n d e v al u ate d s o 
t h at t he c alc ul ate d me a n e G F R 
res ult is a v ail a ble f or eli gi bilit y 
assess me nt o n D a y -4 3.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 5
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
6)
Assess vital si g ns (i ncl u de 
sitti n g heart rate a n d bl o o d press ure 
[first a n d last visits])
9)
C ollect uri nal ysis sa m ples 
(first a n d last visits)
1 0)
C ollect bl o o d f or ser u m 
creati ni ne f or e G F R calc ulati o n ( 3 
c ollecti o ns, eac h at least 2 4 h o urs 
a part)
1 1)
C ollect bl o o d f or ce ntral 
cli nical la b orat or y a nal yses (s o di u m 
[first a n d last visits]
1 2)
C ollect P D uri ne sa m ple 
(last visit)
1 3)
C ollect bi o mar ker plas ma 
a n d uri ne sa m ples (last visit, see 
Secti o n 3. 7. 3. 5
1 6)
C ollect bl o o d f or D N A 
sa m ple (first visit, f or c o nse nti n g 
s u bjects o nl y)
6)
Assess vital si g ns (i ncl u de 
sitti n g heart rate a n d bl o o d press ure 
[first a nd sec o n d visits])
9)
C ollect uri nal ys is sa m ples 
(first a n d sec o n d visits)
1 0)
C ollect bl o o d f or ser u m 
creati ni ne f or e G F R calc ulati o n ( 2
c ollecti o ns, first a n d sec o n d visits , 
at least 2 4 h o urs a part)
1 1)
C ollect bl o o d f or ce ntral 
cli nical la b orat or y a nal yses (s o di u m 
[first a n d sec o n d visits] )
1 2)
C ollect P D uri ne sa m ple 
(sec o n d visit)
1 3)
C ollect bi o mar ker plas ma 
a n d uri ne sa m ples ( sec o n d visit, see 
Secti o n 3. 7. 3. 5
1 6)
C ollect b l o o d f or D N A 
sa m ple (sec o n d visit, f or c o nse nti n g 
s u bjects o nl y)
N/ A
Trial me dicati o n will be dis pe nse d at 
Da y  -4 3 after s u bject eli gi bilit y is 
c o nfir me d.  I n e xce pti o nal 
circ u msta nces, trial me dicati o n ma y 
be dis pe nse d at t he sec o n d visit, wit h 
t he i nstr ucti o n n ot t o ta ke a n y trial 
me dicati o n u ntil eli gi bilit y is 
c o nfir me d b y t he i n vesti gat or.  I n 
t hese cases, c o nfir mati o n of 
eli gi bilit y a n d i nstr ucti o ns f or ta ki n g 
trial me dicati o n will be pr o vi de d b y 
tele p h o ne o n Da y -4 3.
Secti o n 3. 7. 1. 1. 2, 
Place b o R u n -i n Peri o d 
( Da ys -4 2 t o -3 6)
S u bjects will be gi ve n place b o i n a 
dail y s plit d ose of a si n gle 0 m g ta blet 
u p o n a wa ke ni n g a n d a n ot her 0 m g 
ta blet a p pr o xi matel y 8 t o 9 h o urs later 
(a b bre viate d 0/ 0 m g), i n a f or m 
i de ntical t o t ol va pta n ta blets.
5)
C ollect bl o o d f or ser u m 
creati ni ne f or e G F R calc ulati o n ( x 2) 
a n d f or assess me nt of s o di u m ( x 2) 
a n d li ver f u ncti o n pa nel ( x 1) o n 
se parate da ys bet wee n Da ys - 3 9 t o -
3 6 wit h t he last sa m ple bei n g 
o btai ne d o n Da y - 3 6. If s o di u m a n d 
li ver f u ncti o n pa nel are c ollecte d at 
t he sa me visit, a si n gle t u be of bl o o d 
s h o ul d be dra w n f or all assess me nts.
S u bjects will be gi ve n place b o i n a 
dail y s plit d ose of a si n gle 0 m g 
ta blet u p o n a wa ke ni n g a n d a n ot her 0 
m g ta blet a p pr o xi matel y 8 t o 9 h o urs 
later (a b bre viate d 0/ 0 m g), i n a f or m 
i de ntical t o 1 5/ 1 5 m g t ol va pta n 
ta blets.
5)
C ollect bl o o d f or ser u m 
creati ni ne f or e G F R calc ul ati o n a n d 
f or assess me nt of so di u m a n d li ver 
f u ncti o n pa nel o n Da y -3 6 .
1 2)
S u bjects f o u n d t o be 
i neli gi ble t o c o nti n ue i n t his trial 
after recei vi n g I M P m ust ha ve a 7 -
da y f oll o w -u p visit (see Secti o n 
3. 8. 3. 1).
Secti o n 3. 7. 1. 1. 3, 
T ol va pta n Titrati o n 
Peri o d ( Da ys -3 5 t o -
N/ A
1 0)
S u bjects n ot t olerati n g at 
least 6 0/ 3 0 m g d ose s h o ul d be 
i nf or me d t he y di d n ot meet 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 6
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
2 2)
eli gi bilit y criteria f or c o nti n uati o n
1 2)
S u bjects f o u n d t o be 
i neli gi ble t o c o nti n ue i n t his trial 
m ust ha ve a 7 -d a y  f oll o w-u p visit 
(see Secti o n 3. 8. 3. 1).
Secti o n 3. 7. 1. 1. 4, 
T ol va pta n R u n -I n 
Peri o d ( Da ys -2 1 t o -1)
Ra n d o mizati o n ( Da y 1) will be 
stratifie d b y mea n e G F R deter mi ne d 
b y a vaila ble ce ntral is ot o pe dil uti o n 
mass s pectr osc o p y (I D M S) tracea ble 
ser u m creati ni ne meas ure me nts ta ke n 
d uri n g t he scree ni n g peri o d a n d 
place b o r u n -i n peri o d.
Ra n d o mizati o n ( Da y 1) will be
stratifie d b y mea n e G F R ser u m 
creati ni ne meas ure me nts ta ke n 
d uri n g t he scree ni n g peri o d a n d 
place b o r u n -i n peri o d.
1 5)
S u bjects f o u n d i neli gi ble t o 
be ra n d o mize d a n d c o nti n ue i n t his 
trial m ust ha ve a 7-da y f oll o w - u p 
visit (see Secti o n 3. 8. 3. 1).
Secti o n 3. 7. 1. 2, 
D o u ble -bli n d, 
Ra n d o mize d Treat me nt 
Peri o d
1 4)
Dis pe nse I M P at m o nt hl y 
visits u p t o a n d i ncl u di n g M o nt h 1 1
S u bjects disc o nti n ui n g I M P i n t he 
place b o r u n -i n peri o d, t ol va pta n 
titrati o n peri o d, or t he
t ol va pta n r u n-i n peri o d s h o ul d als o 
ha ve E o T x assess me nts perf or me d 
(see Secti o n 3. 8. 3. 3).
1 4)
Dis pe nse I M P at m o nt hl y 
visits u p t o a n d i ncl u di n g M o nt h 1 1.  
I n cert ai n circ u mst a nces, wit h 
me dic al m o nit or a p pr o v al, a 3 -
m o nt h dr u g s u p pl y m a y be 
pr o vi de d; h o we ver, i niti ati o n of 
t he ne xt m o nt h’s s u p pl y m ust be 
directe d b y t he site.
1 6)
S u bjects n ot c o nti n uin g i n 
t his trial m ust ha ve a 2 1-d a y  f oll o w-
u p peri o d (see Secti o n 3. 8. 3. 3).
Re gar dless of disc o nti n uati o n of 
I M P, t he s u bjects are e x pecte d t o 
c o m plete all m o nt hl y visits a n d 
assess me nts i ncl u di n g t he M o nt h 1 2 
visit.
Secti o n 3. 7. 1. 3, F oll o w -
u p Peri o d ( M o nt h 
1 2/ E n d of Treat me nt t o 
D a y  2 1 P ost treat me nt)
T here w ill be n o sc he d ule d 
visits/assess me nts d uri n g t he first 
wee k of t he f oll o w - u p peri o d.  After 
t he first wee k, 5 visits s h o ul d be 
sc he d ule d d uri n g t he re mai ni n g 2 
wee ks of t he f oll o w-u p peri o d 
( bet wee n Da y + 7 a n d Da y + 2 1 ), wit h 
eac h visit at least 2 4 h o urs a part.  
T here w ill be n o sc he d ule d 
visits/assess me nts d uri n g t he first 
wee k of t he f oll o w -u p peri o d. After 
t he first wee k, 3 visits s h o ul d be 
sc he d ule d d uri n g t he re mai ni n g 2 
wee ks of t he f oll o w -u p peri o d 
( bet wee n Da y + 7 a n d Da y + 2 1) .  
T he first visit s h o ul d be sc he d ule d 
o n a p pr o xi matel y Da y + 7, t he 
sec o n d visit o n a p pr o xi matel y Da y 
+ 1 4 a n d t he t hir d visit o n 
a p pr o xi matel y Da y + 2 1 ( -2 da ys).
Secti o n 3. 7. 2. 1, Ser u m 
Creati ni n e f or 
Esti mate d Gl o mer ular 
Filtrati o n Rate
T he e G F R val ues will be calc ulate d 
fr o m t he ce ntral-la b orat or y I D M S-
tracea ble  ser u m creati ni ne 
c o nce ntrati o ns ta ke n at scree ni n g a n d 
d uri n g e ver y trial visit .
T he e G F R val ues will be calc ulate d 
fr o m t he ce ntral-la b orat or y ser u m 
creati ni ne c o nce ntrati o ns ta ke n at 
scree ni n g a n d d uri n g e ver y trial visit.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 7
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Secti o n 3. 7. 3. 2, Cli nical 
La b orat or y 
Assess me nts
Cli nical la b orat or y sa m ples f or 
a nal ysis b y t he ce ntral la b orat or y will 
be c ollecte d at t he f oll o w i n g visits:

d uri n g scree ni n g ( 3 visits at 
least 2 4 h o urs a part t hat 
occ ur d uri n g t he 2 wee ks 
pri or t o place b o r u n -i n) -
creati ni ne (all 3 visits ), 
s o di u m a n d uri nal ysis (first 
a n d last visits), he mat ol o g y 
a n d c oa g ulati o n pa nel, 
ser u m c he mistr y pa nel, a n d 
li ver f u ncti on pa nel (first 
visit)

d uri n g place b o r u n -i n -
uri nal ysis ( Da y - 3 6), li ver 
f u ncti o n pa nel, creati ni ne, 
a n d s o di u m (t wice o n 
se parate da ys bet wee n Da ys  
3 9 t o - 3 6 w it h t he last 
sa m ple bei n g o btai ne d o n 
Da y  - 3 6)

d uri n g t he f oll o w -u p peri o d 
( 5 visits at least 2 4 h o urs 
a part t hat be gi n 1 wee k after 
t he M o nt h 1 2/ E o T x visit) -
creati ni ne (all 5 visits), 
s o di u m (first visit), li ver 
f u ncti o n pa nel a n d ser u m 
c he mistr y pa nel (last visit)
Cli nical la b orat or y sa m ples f or 
a nal ysis b y t he ce ntral la b orat or y 
will be c o llecte d at t he f oll o wi n g 
visits:

d uri n g scree ni n g ( 2 visits at 
least 2 4 h o urs a part t hat occ ur 
d uri n g t he 1- 2 we e ks pri or t o 
place b o r u n -i n) - creati ni ne 
(first a n d sec o n d visits), 
s o di u m a n d uri nal ysis (first 
a n d sec o n d visits), he mat ol o g y 
a n d c oa g ulati o n pa nel, ser u m 
c he mistr y pa nel, a n d li ver 
f u ncti o n pa nel (first visit)

d uri n g place b o r u n -i n -
uri nal ysis, li ver f u ncti o n pa nel, 
creati ni ne, a n d s o di u m o n 
Da y  -3 6)

d uri n g t he f oll o w -u p peri o d ( 3
visits t hat be gi n 1 w ee k a fter t he 
M o nt h 1 2/ E o T x visit) -
creati ni ne ( 3 visits), s o di u m 
(first visit), li ver f u ncti o n pa nel 
a n d ser u m c he mistr y pa nel (last 
visit)
Secti o n 3. 7. 3. 2, Ta ble 
3. 7. 3. 2 - 1
N/ A
Uri nal ysis pa nel:

os m olalit y

s pecific gra vit y

uri ne creati ni ne
Secti o n 3. 7. 3. 4. 2, Li ver 
Test A b n or malities a n d 
I nterr u pti o n/ Disc o nti n u
ati o n of I n vesti gati o nal 
Me dici nal Pr o d uct
N/ A
All ele vati o ns will be assesse d b y 
t he me dical m o nit ori n g tea m.
Secti o n 3. 7. 3. 4. 3, 
Re q uire me nts f or 
S pecial Re p orti n g 
Usi n g t he Li ver Dis ease 
Electr o nic Case Re p ort 
F or m  a n d I m me diatel y 
Re p orta ble E ve nt F or m
N/ A
T he H A C will i n de pe n de ntl y deci de 
attri b uti o n a n d will c o m m u nicate 
wit h t he I n de pe n de nt Data 
M o nit ori n g C o m mittee (I D M C ) t hat 
o versees t he trial.
Secti o n 3. 7. 3. 5. 1, 
Bi o mar ker Plas ma 
Sa m ples
Bl o o d sa m ples ( 1 0 m L) f or p ote ntial 
bi o mar ker a nal ysis will be c ollecte d 
at t he f oll o wi n g ti mes:
•
e n d of t he scree ni n g peri o d 
( Da y - 4 3)
Bl o o d sa m ples ( 1 0 m L) f or p ote ntial 
bi o mar ker a nal ysis will be c ollecte d 
at t he f oll o wi n g ti mes:
•
sec o n d visit of t he 
scree ni n g peri o d
Secti o n 3. 7. 3. 5. 2, 
Bi o mar ker Uri ne 
A s p ot uri ne sa m ple ( 2 0 m L) will be 
A s p ot uri ne sa m ple will be o btai ne d 
at t he f oll o wi n g ti mes:

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 8
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Sa m ples
o btai ne d at t he f oll o wi n g ti mes:

e n d of t he scree ni n g peri o d ( Da y 
-4 3)

sec o n d visit of t he scree ni n g 
peri o d
T o e ns ure a fasti n g uri ne sa m ple is 
c ollecte d, s u bjects will be pr o vi de d 
wit h a sterile uri ne c u p o n t he visit 
prece di n g t he date of uri ne sa m ple 
c ollecti o n.  S u bjects will be 
i nstr ucte d t o c ollect a uri ne sa m ple 
pri or t o eat i n g brea kfast, a n d t o st ore 
t he sa m ple i n t he refri gerat or u ntil 
t heir cli nic visit.
Secti o n 3. 7. 3. 5. 3, D N A 
Bl o o d Sa m ples
A bl o o d sa m ple f or D N A c ollecti o n 
will be o btai ne d f or e ver y c o nse nti n g 
s u bject at t he be gi n ni n g of t he 
scree ni n g peri o d.
A bl o o d sa m ple f or D N A c ollecti o n 
will be o btai ne d f or e ver y c o nse nti n g 
s u bject at t he sec o n d visit of t he 
scree ni n g peri o d.
Secti o n 3. 7. 4. 2, 
P har m a c o d yna mic 
Uri ne Sa m ples
A s p ot uri ne sa m ple f or deter mi nati o n 
of U os m a n d s pecific gra vit y will be 
o btai ne d at t he f oll o wi n g ti mes:

e n d of t he scree ni n g peri o d ( Da y 
- 4 3)
A s p ot uri ne sa m ple f or 
deter mi nati o n of U os m a n d s pecific 
gra vit y will be o btai ne d at t he 
f oll o wi n g ti mes:

sec o n d visit of t he scree ni n g 
peri o d
T o e ns ure a fasti n g uri ne sa m ple is 
c ollecte d, s u bjects will be pr o vi de d 
wit h a sterile uri ne c u p o n t he visit 
prece di n g t he date of uri ne sa m ple 
c ollecti o n.  S u bjects will be 
i nstr ucte d t o c ollect a uri ne sa m ple 
pri or t o eati n g brea kfast , a n d t o st ore 
t he sa m ple i n t he refri gerat or u ntil 
t heir cli nic visit.
Secti o n 3. 7. 6, 
I n de pe n de nt Data 
M o nit ori n g C o m mittee
N/ A
.... A dj u dicati o n res ults as deter mi ne d 
b y t he H A C will be re p orte d t o t he 
I D M C o n a q uarterl y basis or m ore 
fre q ue ntl y as necessar y....
Secti o n 3. 8. 3. 2, 
Treat me nt I nterr u pti o n
.....It is ass u me d t hat a n i nterr u pti o n 
of t his d urati o n ma y bec o m e 
per ma ne nt, t heref ore t he s u bject will 
ha ve a t otal of 5 sa m ples c ollecte d f or 
ser u m creati ni ne meas ure me nts....
.....It is ass u me d t hat a n i nterr u pti o n 
of t his d urati o n ma y bec o m e 
per ma ne nt, t heref ore t he s u bject will 
ha ve a t otal of 3 sa m ples c ollecte d 
f or ser u m creati ni ne 
meas ure me nts ....
Treat me nt ma y still be restarte d 
d uri n g or after t hese assess me nts are 
c o m plete d.
Treat me nt ma y still be restarte d 
d uri n g or after t hese assess me nts are 
c o m plete d ; a n y r e mai ni n g ser u m 
cre ati ni ne assess me nts will n ot 
nee d t o be c o m plete d if tre at me nt 
is rest arte d d uri n g t his peri o d.
Secti o n 3. 8. 3. 3, 
Treat me nt 
Disc o nti n uati o n
    D uri n g t he last t w o wee ks of t he 
f oll o w-u p peri o d, t h e s u bject will 
ha ve a t otal of 5 sa m ples c ollecte d f or 
ser u m creati ni ne meas ure me nts.
    D uri n g t he last t w o wee ks of t he 
f oll o w-u p peri o d, t he s u bject will 
ha ve a t otal of 3 sa m ples c ollecte d 
f or ser u m creati ni ne meas ure me nts.
Secti o n 3. 8. 3. 4
D oc u me nti n g Reas o ns 

S u bject deci des t o disc o nti n ue 
d ue a n n o ya nce or disc o mf ort d ue 

S u bjec t c o ul d n ot t oler ate 
I M P d ue t o a n A E w hic h is 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 1 9
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
f or Treat me nt 
I nterr u pti o n/ Disc o nti n u
ati o n
t o a n o n-seri o us A E w hic h is n ot 
ot her wise deter mi ne d t o be a n 
u n d ue hazar d

C o nti n ui n g I M P places t he 
s u bject at u n d ue hazar d as 
deter mi ne d b y t he i n vesti gat or 
(e g, a safet y c o ncer n t hat is 
p ossi bl y, pr o ba bl y, or li kel y 
relate d t o I M P)

e G F R decrease d t o a le vel 
re q uiri n g dial ysis or ki d ne y 
tra ns pla ntati o n (c o nfir me d b y 
re peat testi n g p ost I M P 
disc o nti n uati o n)

Cli nical ja u n dice (re q uires a n 
i m me diate i nterr u pti o n of IM P 
a n d pr o m pt re peat testi n g t o 
c o nfir m a b n or malit y)

Reas o ns u nrelate d t o me dical 
c o n diti o n ( pr o vi de detail a n d 
re vie w A E hist or y wit h s u bject)

Wit h dra w al of i nf or me d c o nse nt 
(c o m plete writte n wit h dra wal of 
c o nse nt f or m)

Pre g na nc y (see Secti o n 5. 4)
a n n o yi n g or u nc o m f ort a ble 
b ut n ot seri o us or h az ar d o us

P h ysici a n deter mi ne d t h at 
t here are p ote nti al I M P 
rel ate d s afet y c o ncer n or S A E 
pl aci n g s u bject at u n d ue 
h az ar d

Pr o gressi o n of dise ase le a di n g 
t o di al ysis, tr a ns pl a nt ati o n or 
e G F R decli ne as deter mi ne d 
b y t he i n vesti g at or

Cli nic al si g ns of DI LI (e g, 
j a u n dice, ri g ht u p per 
q u a dr a nt p ai n)

Reas o ns u nrelate d t o me dical 
c o n diti o n ( e g, pre g n a nc y, tri al 
t o o b ur de ns o me)

Wit h dr a w al of i nf or me d c o nse nt 
(p arti al rel ate d t o I M P or 
c o mplete fr o m  t he tri al)

Ta ki n g mar kete d pr o d uct f or 
t ol va pta n ( disc o nti n ue d s u bjects 
o nl y)
Secti o n 3. 8. 3. 5, 
Wit h dra w al of C o nse nt
N/ A
•
Partici pati o n i n all re g ularl y 
sc he d ule d, st u d y-relate d f oll o w- up 
visits a n d e n d of treat me nt visits
Secti o n 3. 1 0, Defi niti o n 
of C o m plete d S u bjects
S u bjects w h o are ra n d o mize d, ta ke 
I M P ( or ne ver be gi n treat me nt), b ut 
D O N O T c o m plete t he M o nt h 1 2 visit 
A N D at least 1 f oll o w -u p ser u m 
creati ni ne assess me nt will
be defi ne d as “ N o n -c o mpleters”.
S u bjects w h o are ra n d o mize d, ta ke 
I M P ( or ne ver be gi n treat me nt), b ut 
D O N O T c o m plete t he M o nt h 1 2 
visit A N D at least 1 E o T x f oll o w- u p 
ser u m creati ni ne assess me nt will
be defi ne d as “ N o n -c o mpleters”.
Secti o n 5. 6, F oll o w - u p 
of A d verse E ve nts
F or t his t rial, A Es will be f oll o we d u p
f or 2 1 da ys after t he last d ose of I M P 
has bee n a d mi nistere d (f oll o w- u p 
peri o d)
F or t his trial, A Es will be f oll o w e d 
u p f or 7 d a ys i n s u bjects w h o 
disc o nti n ue d pri or t o 
r a n d o miz ati o n a n d f or 2 1 da ys after 
t he last d ose of I M P has bee n 
a d mi nistere d (f oll o w-u p peri o d) i n 
s u bjects w h o were r a n d o mize d.
Secti o n 7. 1. 1, Sa m ple 
Size Esti mati o n
I n t his sa m ple size esti mati o n, it is 
ass u me d t hat 4 t o 5 calc ulati o ns of 
e G F R will be o btai ne d at baseli ne 
d uri n g a 3 -wee k i nter val d uri n g 
scree ni n g ( 2 wee ks) a n d place bo r u n -
i n ( 1 wee k), a n d a n ot her 4 t o 5
calc ulati o ns will be o btai ne d p ost -
treat me nt d uri n g a 2-wee k i nter val 
t hat be gi ns 1 wee k after t he e n d of
treat me nt ( 3-wee k p ost -treat me nt 
I n t his sa m ple size esti mati o n, it is 
ass u me d t hat 3 calc ulati o ns of e G F R 
will be o btai ne d at baseli ne d uri n g a 
3- wee k i nter val d uri n g scree ni n g ( 1-
2 wee ks ) a n d place bo r u n -i n ( 1 
wee k), a n d a n ot h er 3 calc ulati o ns 
will be o btai ne d p ost -treat me nt 
d uri n g a 2 -wee k i nter val t hat be gi ns 
1 w ee k after t he e n d of treat me nt ( 3 -
wee k p ost -treat me nt f oll o w-u p).  

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 0
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
f oll o w-u p).  T he mea n of t he 4 t o 5
e G F R val ues o bser ve d d uri n g t he 
scree ni n g a n d place b o-r u n peri o ds 
will be set as t h e baseli ne a n d t he 
mea n of t he 4 t o 5 e G F R val ues 
o bser ve d d uri n g t he p ost -treat me nt 
f oll o w-u p peri o d w ill be set as t he 
re nal f u ncti o n meas ure me nt p ost-
treat me nt.
T he mea n of t he 3 e G F R val ues 
o bser ve d d uri n g t he scree ni n g a n d 
place b o -r u n peri o ds will be set as t he 
baseli ne a n d t he mea n of t he 3 e G F R 
val ues o bser ve d d uri n g t he p ost -
treat me nt f oll o w-u p peri o d w ill be 
set as t he re nal f u ncti o n 
meas ure me nt p ost -treat me nt.
T o deri ve t he i ntra -s u bject varia nce 
a n d i nter-s u bject varia nce, t he 
a p pr oac h pr o vi de d b y 
, 
 
 
as 
f oll o we d.  F or s u bject i ra n d o mize d 
t o t he place b o gr o u p (i = 1, ..., n), t he 
e G F R at ti me tj is ass u me d t o be 
Yi,j = αi + βi tj + εi,j 
( 1)
F or s u b ject i ra n d o mize d t o t he 
t ol va pta n gr o u p (i = n + 1, ..., 2 n), t he 
e G F R at ti me tj is ass u me d t o be 
Yi,j = αi + βi tj + εi,j if j is o bser ve d 
at baseli ne
( 2)
Yi,j = αi + Δ + βi tj + εi,j if j is 
o bser ve d at p ost -treat me nt f oll o w- u p 
( 3)
Yi,j = αi + γ + ( Δ + βi) tj + εi,j if j is 
o bser ve d d uri n g t he treat me nt peri o d 
( 4)
w here εi,j are ass u me d ii d N( 0,  2),  
βi are ass u me d ii d N(  ,  β 2), εi,j a n d 
βi are m ut uall y i n de pe n de nt, a n d Δ is 
treat me nt effect, γ is t he 
he m o d y na mic o nset effect.  Base d o n 
t his m o del, wit h baseli ne ti me is set 
t o 0, t he varia nce of c ha n ge fr o m 
baseli ne at a p ost -baseli ne visit is 
Var ( Yi,j - Yi, 0) = Var( βi tj + εi,j -
εi, 0) =  tj 2  β 2 + 2  2
( 5)
 deri vati o n is base d o n 
t he ass u m pti o n t hat a n o bser vati o n of 
e G F R is ma de at t he e n d of a 2 -wee k 
i nter val f or k ti mes (t h us, t otall y 2 k 
wee ks) at baseli ne a n d p ost -treat me nt 
f oll o w-u p visit res pecti vel y.  T h us, 
varia nce of c ha n ge 
fr o m baseli ne t o p ost-treat me nt 
f oll o w-u p is 
( 2/ k)  2 + ( 1 + 1/ 1 2 + k/ 2 6) 2  β 2 ( 6)
If we c ha n ge t he ass u m pti o n t o t his 
o ne t hat all t hese k o bser vati o ns are 
o bser ve d i n t he 2 -wee k i nter vals 
me nti o ne d i n t he first para gra p h i n 
O ne of t he a p pr oac hes i n sa m ple size 
calc ulati o n f or t his pr ot oc ol is t o use 
M M R M t o esti mate t he i ntra - a n d 
i nter-s u bject varia nces.  I n t he 
A D P K D p hase 3 trial 
, 
t here was a pre-treat me nt baseli ne 
visit a n d t w o p ost -treat me nt 
foll o w -u p visits, al o n g wit h ot her 
o n -treat me nt visits.  Ass u me t hese 
data f oll o w  t he f oll o wi n g m o del 
( de n ote d as j = 0 f or baseli ne a n d j = 
3 7 f or f oll o w -u p, as well as j = 4, 8, 
1 2, …, 3 6):
Yi, 0 = αi + εi, 0 
( 1)
Yi,j = αi + δi,j + εi,j 
( 2)
w here δi,j, as a ra n d o m effect of 
c ha n ge fr o m pre -treat me nt baseli ne 
at visit j f or s u bject i.  T hese δi,js
j oi ntl y f oll o w a m ulti variate n or mal 
distri b uti o n wit h mea ns bei n g δ P,j 
f or place b o s u bjects a n d δ T,j f or 
t ol va pta n s u bjects.  T heir i n di vi d ual 
varia nce is ass u me d t o be  δ,j 2.  
T hese δi,js are s u p p ose d t o be 
c orrelate d; h o we ver, t heir 
c orrelati o ns are n ot utilize d f or t he 
p ur p ose of sa m ple size calc ulati o n i n 
t his pr ot oc ol.  I n a d diti o n, αis are 
ass u me d ii d t o ha ve a n or mal 
distri b uti o n, εi,j are ass u me d ii d N( 0, 
 2), a n d t hese ra n d o m varia bles are 
m ut uall y i n de pe n de nt.  T he n, t he 
c ha n ge fr o m baseli ne data f oll o ws 
t his c o m m o n M M R M m o del
Yi,j - Yi, 0 = δi,j - εi, 0 + εi,j =  ζi,j + 
εi,j
( 3)
w here ζi,j = δ i,j - εi, 0.  N ote t hat t he 
varia nce of ζi,j ( de n ote d b y  ζ,j 2) is 
e q ual t o  δ,j 2 +  2.  T his m o del 
bec o mes a o ne -wa y ra n d o m effect 
m o del if we o nl y c o nsi der t he p ost -
treat me nt f oll o w-u p visits f or a 
treat me nt gr o u p.  T h us, a p pl yi n g a 
o ne- wa y ra n d o m effe ct mo del t o t he 
c ha n ge fr o m pre -treat me nt baseli ne 
t o p ost-treat me nt f oll o w-u p data of 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 1
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
t his secti o n, t he variance w o ul d ( 2/ k) 
 2 + ( 1 + 1/ 1 2 + 3/ 5 2) 2  β 2 ( 7)
T his varia nce f or m ula was use d i n 
o ur sa m ple size calc ulati o n, si nce it 
matc hes o ur pr ot oc ol desi g n m ore 
cl osel y.
If t he m o del gi ve n b y ( 1) t o ( 4) is 
a p plie d t o t he data of C K D -3 n o n -
Ja pa n s u bjects i n Trial
, 
wit h e G F R data fr o m pre -
ra n d o mizati o n baseli ne t o F oll o w- u p 
Visit # 2, t he resi d ual varia nce (  2) 
a n d sl o pe varia nce (  β 2) are 
esti mate d as 2 2. 1 3 a n d 5. 2 7, 
res pecti vel y, w hic h ma y be 
i nter prete d as i ntra- a n d i nter-s u bject 
varia nces.  
Wit h a
2- si de d al p ha of 0. 0 5 a n d 1: 1 
ra n d o mizati o n t o t ol va pta n a n d 
place b o, usi n g t he para meters gi ve n 
a b o ve a n d sa m ple size f or m ula of 2 -
sa m ple t-test, we ha ve t he f oll o wi n g 
ta ble: 
( T A B L E 7. 1. 1. 1 delete d).
T he ass u m pti o n of dr o p o ut rate of 
1 5 % is reas o na ble si nce t he dr o p o ut 
rate was 2 0 % i n Trial 
, 
a n d it is e x pecte d t hat t he i ncl usi o n of 
t he t ol va pta n r u n-i n peri o d i n t his trial 
will re d uce t he dr o p o ut rate i n t he 
d o u ble bli n d treat me nt peri o d.  Fr o m 
t his ta ble, it see ms t hat k = 4 w o ul d 
pr o d uce a n acce pta ble sa m ple size 
a n d n ot a n e xcessi ve b ur de n f or 
e nr olle d s u bjects.
place b o a n d t ol va pta n res pecti vel y, 
i n s u bjects w h o ha d b ot h f oll o w- u p 
visits a n d baseli ne i n 
,  2 
is esti mate d as 
 
.  Ta ke t he a vera ge 
of t hese t w o esti mates of  2 t o 
o btai n a n esti mate of  2 as  
 t o be 
use d i n t his sa m ple size calc ulati o n, 
w hic h is t he  
.  N ote t hat 
Var( Yi,j - Yi, 0) =  δ,j 2 + 2  2 ( 4)
At M o nt h 1 2, t he S D ( Sta n dar d 
De viati o n) c o ul d be ass u me d as  
 
 
 T he n base d 
o n ( 4),  δ,j 2 at M o nt h 1 2 is 
esti mate d as 2 8. 0 5 
. 
Wit h k re peate d meas ure me nts at 
pre -treat me nt baseli ne a n d at 1 2 
m o nt h p ost -treat ment f oll o w -u p i n 
t his trial, t he baseli ne i ntra-s u bject 
varia nce a n d t he f oll o w -u p i ntra -
s u bject varia nce are re d uce d fr o m  2 
t o  2/ k res pecti vel y.  T h us, t he 
varia nce of a vera ge c ha n ge fr o m 
a vera ge baseli ne at M o nt h 1 2 is 
( δ, 1 2 2 +  2/ k) +   2/ k, w hic h is 
esti mate d as 3 1. 6 
 
 whe n k = 4 a n d 3 2. 8  
 
w he n k = 3.  Here 
we ha ve t he f oll o wi n g ta ble of 
sa m ple size: 
( Ne w T A B L E 7. 1. 1. 1 i nserte d)
Secti o n 7. 1. 1, Sa m ple 
Size Esti mati o n
T h us, wit h a n ass u m pti o n of 1 5 %
dr o p o ut rate i n t he trial, t he t otal 
sa m ple size (ra n d o mized s u bjects) 
w o ul d be fr o m 6 6 0 t o 7 7 0, a n d will 
be set as a ra n ge of bet wee n 7 0 0 a n d 
1 0 0 0 ra n d o mize d s u bjects, w it h a 
g oal of 8 0 0 s u bjects, de pe n di n g als o 
o n t he trial's a bilit y t o e nr oll a n d t h e 
acc u m ulate d n u m ber of s u bjects 
ra n d o mize d u p t o t he e n d of 2 0 1 4.  
Beca use t his i nf or mati o n will be 
hel pf ul i n g ui di n g t he treat me nt of 
A D P K D patie nts wit h m ore a d va nce d 
sta ges of C K D, a n d beca use 
mar keti n g a p pr o val i n ma n y 
partici pati n g c o u ntries ma y be 
reac he d b y 2 0 1 5, it is critical t o 
c o ncl u de e nr oll me nt near t he e n d of 
F r o m  t he s a m ple size t a ble, t he 
i ncre ase of re pe ate d me as ure me nt 
at b aseli ne a n d f oll o w -u p re d uces 
t he s a m ple size si g nific a ntl y 
i niti all y b ut q uic kl y l oses its effect 
w he n k is gre a ter t h a n 3.  It see ms 
t h at 3 re pe ate d me as ure me nts 
m a y be a p pr o pri ate i n or der t o 
a v oi d s u bjects’ b ur de n.  T h us, w it h 
a n ass u m pti o n of 1 0 % dr o p o ut rate 
i n t he trial, t he t otal sa m ple size 
(ra n d o mize d s u bjects) wo ul d be 
a p pr o xi m atel y 1 3 0 0 . 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 2
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
2 0 1 4 or be gi n ni n g of 2 0 1 5.  T his will 
hel p a v oi d missi n g data d ue t o 
s u bjects lea vi n g t he trial t o see k 
c o m merciall y a vaila ble treat me nt i n 
t h ose c o u ntries.    
Secti o n 7. 1. 1, Sa m ple 
Size Esti mati o n
T he desire f or a s mall n u m ber of 
bl o o d dra ws d uri n g t hese peri o ds w as 
e mp hasize d b y t he trial’s Steeri n g 
C o m mittee, w hic h f urt her s u g geste d 
t hat meas ures be ta ke n t o mi ni mize 
t he i ntra-s u bject varia bilit y b y 
sta n dar dizi n g, as m uc h as p ossi ble, 
t he ti mi n g a n d c o n diti o ns b y w hic h 
ser u m creati ni ne was assesse d (i n 
partic ular re c o m me n di n g a si milar 
diet, a v oi di n g variati o n i n pr otei n, 
es peciall y c o o ke d pr otei n, i nta ke a n d 
e xercise patter n d uri n g t hese peri o ds).  
T he Steeri n g C o m mittee als o 
s u g geste d t hat t he i ntra s u bject 
varia nce d uri n g t he pre -treat me nt a n d 
p ost -treat me nt peri ods be m o nit ore d 
t hr o u g h o ut t he trial wit h a ma n dat or y 
i ncrease i n ser u m creati ni ne sa m ple 
n u m bers (ie, fr o m a mi ni m u m of 4 t o 
a mi ni m u m of 5) or s u bject n u m bers 
if o bser ve d varia nce was greater t ha n 
t hat use d i n t he p o wer ass u m pti o n 
(assesse d usi n g o nl y baseli ne e G F R 
data i n a p o w er re -esti mati o n 
pr oce d ure).
T he y als o fa v ore d t he p ossi bilit y t hat 
sa m ple n u m bers, b ut n ot t he 
mi ni m u m e nr oll me nt, be l o w ere d (ie, 
t o a ma xi m u m of 4 sa m ples) if 
varia nce was si g nifica ntl y less d ue t o 
t hese meas ures (see Secti o n 7.1. 2. 
“ Bli n de d Sa m ple - Size Re-
esti mati o n”).
I n or der t o a v oi d e xcessi ve bl o o d 
dr a ws, m ec h a nis ms were 
u n dert a ke n t o mi ni mize t he i ntra-
s u bject varia bilit y b y sta n dar dizi n g, 
as m uc h as p ossi ble, t he ti mi n g a n d 
c o n diti o ns b y w hic h ser u m 
creati ni ne was assesse d (i n partic ular 
rec o m me n di n g a si milar diet, 
a v oi di n g variati o n i n pr otei n, 
es peciall y c o o ke d meat pr otei n, 
i nta ke a n d e xercise patter n d uri n g 
t hese peri o ds).  I n a d diti o n t o t he 
eff orts t o re d uce v ari a bilit y b y 
st a n d ar dizi n g s u bject diet at t he 
ti me of blo o d dr a ws, t he n u m ber 
of sc he d ule d bl o o d dr a ws will hel p 
est a blis h precisi o n i n t he esti m ate d 
me as ure me nts.
Secti o n 7. 1. 1, Sa m ple 
Size Esti mati o n
I n a d diti o n, t he 1: 1 ra n d o mizati o n 
a n d t he al p ha ( 0. 0 5, 2- si de d) 
s pecifie d a b o ve i n t he sa m ple size of 
t he pri mar y e n d p oi nt are als o 
ass u me d i n t he sa m ple size 
calc ulati o n.  It is t he n esti mate d t hat 
3 1 5 s u bjects per gr o u p are re q uire d 
f or 8 5 % p o wer a n d 3 6 7 s u bjects per 
gr o u p are re q uire d f or 9 0 % p o wer.  
T hese sa m ple sizes are ver y cl ose t o 
t he sa m ple size calc ulate d usi n g  
 
 
  
 
f or e xa m ple, sa m ple size of 3 6 8 per 
gr o u p wit h 9 0 % p o w er, w he n t he 
varia nces pr o vi de d a b o ve w ere use d.   
T h us, wit h a t otal sa m ple size of fr o m 
I n a d diti o n, t he 1: 1 ra n d o mizati o n 
a n d t he al p ha ( 0. 0 5, 2 -si de d) 
s pecifie d a b o ve i n t he sa m ple size of 
t he pri mar y e n d p oi nt are als o 
ass u me d i n t he sa m ple size 
calc ulati o n.  It is t he n esti mate d t hat
7 3 4 s u bjects are re q uire d f or 9 0 % 
p o wer.  T h us, w it h a t ot al s a m ple 
size of a p pr o xi m atel y 1 3 0 0, t he ke y 
sec o n dar y e n d p oi nt will ha ve m ore 
t ha n 9 0 % p o wer i n detecti n g a sl o pe 
differe nce i n t his trial.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 3
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
6 6 0 t o 7 7 0 (r o u n de d t o 7 0 0 t o 8 0 0),
t he ke y sec o n dar y e n d p oi nt will ha ve 
at least 8 5 % t o m ore t ha n 9 0 % p o wer 
i n detecti n g a sl o pe differe nce i n t his 
trial.
Secti o n 7. 1. 2, Bli n de d 
Sa m ple Size Re -
esti mati o n
Bli n de d sa m ple size re -esti mati o n 
will be c o n d ucte d w he n a b o ut half of 
t he pla n ne d ra n d o mize d s u bjects ( 3 5 0 
t o 4 0 0) ha ve bee n ra n d o mize d.  T his 
is e x pecte d t o be c o n d ucte d bef ore 
t he e n d of 2 0 1 4 a n d t h us bef ore t he 
a vaila b ilit y of a n y p ost 1 2 m o nt h off-
treat me nt f oll o w-u p e G F R data use d 
f or t he pri mar y a nal ysis.  T he g oal of 
t his bli n de d sa m ple size re-esti mati o n 
is t o c hec k:  1) t he differe nces 
bet w ee n t he o bser ve d varia nces a n d 
t he varia nces use d i n t he sa m ple size 
calc ulati o n; 2) w het her t he a p pr oac h 
of a vera gi n g t he 4 t o 5 baseli ne pre -
treat me nt e G F R o bser vati o ns has 
ac hie ve d t he g oal of re d uci n g t he 
varia nce t o t he le vel pla n ne d.  
Bli n de d sa m ple size re -esti mati o n 
will be c o n d ucte d w he n at le ast a 
t hir d of t he p la n ne d ra n d o mize d 
s u bjects (4 0 0 t o 5 0 0 ) ha ve bee n 
ra n d o mize d.  T his is e x pecte d t o be 
c o n d ucte d bef ore t he a vaila bilit y of 
a n y p ost 1 2 m o nt h off -treat me nt 
f oll o w-u p e G F R data use d f or t he 
pri mar y a nal ysis.  T he g oal of t his 
bli n de d sa m ple size re -esti mati o n is 
t o c hec k:  1) t he differe nces bet wee n 
t he o bser ve d varia nces a n d t he 
varia nces use d i n t he sa m ple size 
calc ulati o n; 2) w het her t he a p pr o ac h 
of a vera gi n g t he 3 e G F R 
o bser vati o ns at pre -tre at me nt 
b aseli ne a n d p ost -tre at me nt 
f oll o w-u p has ac hie ve d t he g oal of 
re d uci n g t he varia nce t o t he le vel 
pla n ne d.  
Secti o n 7. 2, Datasets 
f or A nal ysis, Pri mar y 
E n d p oi nt Efficac y 
P o p ulati o n:
....T he pri mar y e n d p oi nt’s baseli ne is 
defi ne d as t he a vera ge of u p t o 5
e G F R val ues o bser ve d d uri n g t he 
scree ni n g a n d place b o r u n-i n peri o ds.
T he c ore s u bject p o p ulati o n f or all 
efficac y a nal yses is base d o n t he 
i nte nt-t o-treat (I T T) p o p ulati o n w hic h 
c o nsists of all ra n d o mize d s u bjects 
w h o ta ke at least o ne d ose of I M P.
   T he pri mar y e n d p oi nt’s baseli ne is 
defi ne d as t he a vera ge of u p t o 3
e G F R val ues o bser ve d d uri n g t he 
scree ni n g a n d place b o r u n-i n 
peri o ds.
T he c ore s u bject p o p ulati o n f or all 
efficac y a nal yses is base d o n t he 
i nte nt-t o-treat (I T T) p o p ulati o n 
w hic h c o nsists of  all ra n d o mize d 
s u bjects w h o ta ke at least o ne d ose 
of I M P p ost r a n d o miz ati o n.
Secti o n 7. 4. 1. 1, 
Pri mar y E n d p oi nt 
A nal ysis
T o re d uce t he varia ti o n i n t his 
pri mar y e n d p oi nt, 4 t o 5 o bser vati o ns 
of e G F R will be o btai ne d at baseli ne 
d uri n g a 3 w ee k i nter val (scree ni n g 
a n d placeb o r u n -i n peri o ds) a n d 
a n ot her 4 t o 5 o bser vati o ns will be 
o btai ne d p ost -treat me nt d uri n g a 2-
wee k i nter val t hat be gi ns 1 wee k after 
t he e n d of treat me nt ( 3-wee k p ost -
treat me nt foll o w -u p).  T he a vera ge of 
t he 4 t o 5 e G F R val ues o bser ve d 
d uri n g t he baseli ne peri o d is set as t he 
b aseli ne a n d t he a vera ge of t he 4 t o 5
e G F R val ues o bser ve d d uri n g t he 
p ost -treat me nt f oll o w-u p peri o d is set 
as t he re nal f u ncti o n meas ure me nt 
p ost -treat me nt
T o re d uce t he varia ti o n i n t his 
pri mar y e n d p oi nt, 3 o bser vati o ns of 
e G F R will be o btai ne d at baseli ne 
d uri n g a 3 w ee k i nter val (scree ni n g 
a n d placeb o r u n -i n peri o ds) a n d 
a n ot her 3 o bser vati o ns will be 
o btai ne d p ost -treat me nt d uri n g a 
2- wee k i nter val t hat be gi ns 1 wee k 
after t he e n d of treat me nt ( 3 -wee k 
p ost -treat me nt foll o w -u p).  T he 
a vera ge of t he 3 e G F R val ues 
o bser ve d d uri n g t he baseli ne peri o d 
is set as t he baseli ne a n d t he a vera ge 
of t he 3 e G F R val ues o bser ve d 
d uri n g t he p ost -treat me nt f oll o w- u p 
peri o d is set as t he re nal f u ncti o n 
meas ure me nt p ost -treat me nt

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 4
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Secti o n 7. 4. 1. 2, 
Se nsiti vit y A nal ysis of 
t he Pri mar y E n d p oi nt
Ali g ne d wit h t he desire t o e val uate 
effects free fr o m ac ute he m o d y na mic 
treat me nt effects, a se nsiti vit y 
a nal ysis of t he pri mar y e n d p oi nt will 
be perf or me d i ncl u di n g all a vaila ble 
place b o data.  I n t his se nsiti vit y 
a nal ysis, i n a d diti o n t o t he 4 t o 5 pre -
treat me nt baseli ne o bser vati o ns a n d 
t he 4 t o 5 p ost -treat me nt f oll o w- u p 
o bser vati o ns, all p ost ra n d o mizati o n 
o n -treat me nt e G F R o bser vati o ns i n 
t he pr ot oc ol-s pecifie d visits f or 
place b o s u bjects will als o be i ncl u de d
Ali g ne d wit h t he desire t o e val uate 
effects free fr o m ac ute he m o d y na mic 
treat me nt effects, a se nsiti vit y 
a nal ysis of  t he pri mar y e n d p oi nt will 
be perf or me d i ncl u di n g all a vaila ble 
place b o data.  I n t his se nsiti vit y
a nal ysis, i n a d diti o n t o t he 3 pre -
treat me nt baseli ne o bser vati o ns a n d 
the 3 p ost -treat me nt f oll o w-u p 
o bser vati o ns, all p ost ra n d o mizati o n 
o n -treat me nt e GF R o bser vati o ns i n 
t he pr ot oc ol-s pecifie d visits f or 
place b o s u bjects will als o be 
i ncl u de d
Secti o n 7. 4. 3, S u b gr o u p 
Efficac y A nal ysis
N/ A
S u b gr o u p a nal yses will be pr o vi de d 
f or t he pri mar y a n d t he ke y 
sec o n dar y e n d p oi nts b y re gi o ns ( U S 
a n d n o n -U S), ge n der ( male a n d 
fe male), race ( Ca ucasia n a n d Ot her), 
a ge ( 5 5 years, > 5 5 years), baseli ne 
G F R le vel 
 
 a n d 
baseli ne T K V
 
.
Secti o n 7. 4. 4. 1, 
E x pl orat or y A nal ysis of 
Efficac y Base d o n 
M o dal D oses
N/ A
E x pl orat or y a nal yses will be a p plie d 
t o t he pri mar y a n d ke y sec o n dar y 
e n d p oi nts will t ol va pta n s u bjects 
c o de d b y t heir m o dal d oses i n t he 
trial, usi n g t he sa me a nal ytic 
a p pr oac he d s pecifie d f or t hese 
e n d p oi nts.
Secti o n 7. 4 . 5, I nteri m 
A n al ysis
N/ A
T his trial is t o be c o n d ucte d o ver a 
critical ti me peri o d d uri n g w hic h 
t ol va pta n ma y be a p pr o ve d as 
t hera p y f or A D P K D i n s o me of t he 
partici pati n g re gi o ns.  T he E ur o pea n 
Me dici nes A ge nc y’s ( E M A) 
decisi o n f or a pe n di n g mar keti n g 
a ut h orizati o n a p p licati o n f or t he use 
of t ol va pta n i n treat me nt of A D P K D 
is e x pecte d i n 2 0 1 5.  F oll o wi n g 
re g ulat or y a p pr o val, rei m b urse me nt 
a n d c o m mercial a vaila bilit y ma y 
ha ve a n i m pact o n t he o n g oi n g 
et hical c o n d uct of t he trial.  T his 
ma y i m pact s u bjects e nr olle d i n 
E ur o pe w h o are c o nti n ui n g i n t he 
ra n d o mize d, place b o-c o ntr olle d 
treat me nt p hase.
T heref ore, t he I D M C f or t his trial 
will be e m p o w ere d t o c o n d uct a n 
i nteri m a nal ysis (I A) of t he pri mar y 
e n d p oi nt o nce a p pr o xi matel y half of 
e nr olle d s u bjects ( 6 0 0 -7 0 0) are 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 5
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
e x pecte d t o c o m plete t heir pla n ne d 
o ne- year treat me nt.  T he s p o ns or 
ma y deci de t he act ual ti m i n g of t he 
I A t o be c o n d ucte d, base d o n t he 
a vaila bilit y of c o m mercial t ol va pta n 
i n A D P K D.  T his I A w o ul d use t he 
O’ Bria n -Fle mi n g s pe n di n g f u ncti o n 
t o a p p orti o n al p ha a nd t h us ma na ge 
T y pe 1 err or. Deter mi nati o n of t he 
i nf or mati o n ti me of t he I A ass u mes 
t otal sa m ple size i n t his trial t o be set 
at 1 3 0 0, if t he trial is still 
ra n d o mizi n g s u bjects at t he ti me of 
t he I A.  F or e xa m ple, if t he first 6 5 0 
s u bjects o ut of 1 3 0 0 t otal sa m ple 
size are i ncl u de d, a p-val ue < 
0. 0 0 3 0 5 1 is re q uire d t o reject t he 
n ull h y p ot hesis, satisf y t he o bjecti ve 
of re plicati n g efficac y, a n d offer a 
p ossi bilit y f or earl y trial c o m pleti o n.  
If a rec o m me n dati o n f or earl y 
ter mi nati o n is acce pte d, all s u bjects 
r e mai ni n g i n t he trial ca n be offere d 
partici pati o n i n a pla n ne d o pe n -la bel 
e xte nsi o n trial.  If t he n ull h y p ot hesis 
is n ot rejecte d at t his i nteri m 
e val uati o n, t he trial wo ul d c o nti n ue 
a n d t he al p ha of t he fi nal test of t he 
pri mar y e n d p oi nt w o ul d be
0. 0 4 9 0 0 2.
Secti o n 7. 6, Safet y 
A nal ysis
Sta n dar d safet y varia bles t o be 
a nal yze d i ncl u de A Es, cli nical
la b orat or y data, p h ysical 
e xa mi nati o ns, a n d vital si g ns.
Sta n dar d safet y varia bles t o be 
a nal yze d i ncl u de A Es, self-re p orte d 
t oler a bilit y, cli nical la b orat or y data, 
p h ysical e xa mi nati o ns, a n d vital 
si g ns.
A p pe n di x 3, Ha n dli n g 
a n d S hi p me nt of 
Bi oa nal ytical Sa m ples
T he 2 0 m L bi o mar ker sa m ple will be 
c ollecte d b y t he s u bject at h o me a n d 
tra ns p orte d t o t he site at r o o m 
t e mperat ure. At t he site, t he sa m ple 
s h o ul d be i m me diatel y e q uall y 
di vi de d i nt o t he bar -c o de la bele d 
p ol y pr o p yle ne t u bes ( n u m ber of 
ali q u ots will be defi ne d i n t he 
o perati o ns ma n ual) a n d fr oze n.  
T he P D/ b i o mar ker uri ne sa m ple 
will be c ollecte d b y t he s u bject at 
h o m e a n d tra ns p orte d t o t he site at 
r o o m te mperat ure.  At t he site, 
2 0 m L of t he sa m ple s h o ul d be 
i m me diatel y e q uall y di vi de d i nt o t he 
bar -c o de la bele d p ol y pr o p yle ne 
t u bes ( n u m ber of ali q u ots will be 
defi ne d i n t he o perati o ns ma n ual) 
a n d fr oze n.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 6
2 6 Mar 2 0 1 5 
Pre vi o us Fi g ure 3. 1 - 1 - Tri al Desi g n Sc he m atic:

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 7
2 6 Mar 2 0 1 5 
Re vise d Fi g ure 3. 3 - 1 Tri al Desi g n Sc he m atic

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 8
2 6 Mar 2 0 1 5 
Pre vi o us Sc he d ule of Assess me nts
T a ble 1 0. 2 -1:  Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g
( 2 wee ks
1 d a y)
Pl ace b o
r u n- i n
( 1 wee k 1 d a y)
( D a ys -4 2 t o -3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n
r u n- i n
( 3 wee ks 1 d a y)
( D a ys -2 1 t o -1)
( D a y 0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h 1 2/ 
E o T x
visit
3 wee ks
p ost -tre at me nt
D a ys -5 6 t o 
-4 3 a
D a y 
-4 2
D a y
-3 9 
1 d a y
D a y 
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1
p ost -fi n al visita
-3 5 -3 2 -2 8 -2 4 -2 2 -2 1 -1 5
- 8 
- 1
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n
X
D e m o gr a p hic/ Me dic al hist or y
X
Vit al si g ns b
X  
X
X
X
X
( X)b
X
X
P h ysic al e x a mi n ati o n c
X
X
Uri ne pre g n a nc y test ( W O C B P 
o nl y) d
X
( X)c
X
X
Cli nic al l a b or at or y s a m ples e:
   H e m at ol o g y a n d c o a g ul ati o n
X
   Uri n al ysis
X  
X
X
X
X
   Ser u m  C he mistr y P a nel
X
X
X
   Li ver F u ncti o n P a nel
X
X
X  
X  
X
X  
X
X
   Cre ati ni ne
X
X 
X  
X  
X
X  
X  
X
X  
X  
X  
X  
X  
X
X
   S o di u m
X  
X  
X  
X
X  
X  
X
X  
X  
X
P K pl as m a s a m ple f
X
( X)f
X
X
P D uri ne s a m ple f
X
X
X
X
( X)f
X
X
Bi o m ar ker uri ne a n d pl as m a 
X
X
X
X
( X)f
X
X

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 2 9
2 6 Mar 2 0 1 5 
T a ble 1 0. 2 -1:  Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g
( 2 wee ks
1 d a y)
Pl ace b o
r u n- i n
( 1 wee k 1 d a y)
( D a ys -4 2 t o -3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n
r u n- i n
( 3 wee ks 1 d a y)
( D a ys -2 1 t o -1)
( D a y 0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h 1 2/ 
E o T x
visit
3 wee ks
p ost -tre at me nt
D a ys -5 6 t o 
-4 3 a
D a y 
-4 2
D a y
-3 9 
1 d a y
D a y 
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1
p ost -fi n al visita
-3 5 -3 2 -2 8 -2 4 -2 2 -2 1 -1 5
- 8 
- 1
s a m plef
D N A bl o o d s a m ple g
X
St art ne wl y dis pe nse d I M P
X
X
X
X
T oler a bilit y/ D osi n g re vie w
X  
X  
X  
X  
X
X
X  
X
R a n d o miz ati o n
X
Dr u g dis pe ns ati o n h
X
X
X
X
X
Dr u g rec o ncili ati o n h
X
X
X
X  
X
I V R S e ntr yi
X  
X
X  
X  
X  
X  
X
X
X  
X
X
E x pl or at or y P K D o utc o m es j
X 
-
X
X  
X
A d verse e ve nts
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------->
C o nc o m it a nt me dic ati o ns
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------->
aT he scree ni n g peri o d ma y be e xte n de d u p t o a n a d diti o nal 8 w ee ks f or s u bjects w h o re q uire m o dificati o n of me dical care s pecificall y f or t his trial.  Visits 
d uri n g t he scree ni n g a n d f oll o w -u p peri o ds m ust be sc he d ule d at least 2 4 h o urs ( 1 da y) a part.  At eac h visit, bl o o d w ill be c ollecte d a n d a nal yze d ce ntrall y 
f or ser u m creati ni ne c o nce ntrati o ns, i n a d diti o n t o a n y ot her assess me nts liste d.  A visiti n g n urse h o use call or l ocal la b orat or y visit ma y be s u bstit ute d f or 
visits w here o nl y bl o o d/ uri ne will be c ollecte d.  Visits d uri n g t he scree ni n g peri o d m ust be sc he d ule d wit hi n a 2 -wee k peri o d bef ore t he start of t he place b o 
r u n-i n peri o d.  Visits d uri n g t he f oll o w-u p peri o d m ust be sc he d ule d d uri n g a 2 -we e k peri o d t hat be gi ns 1 wee k after t he e n d of treat me nt visit.
b T he f oll o wi n g visits (a n d all assess me nts re q uire d d uri n g t h ose visits) s h o ul d be perf or me d i n -cli nic: scree ni n g, e n d of place b o r u n -i n, e n d of t ol va pta n 
titrati o n, e n d of t ol va pta n r u n-i n, q uarterl y visits d uri n g t he ra n d o mize d, d o u ble-bli n d treat me nt peri o d (e g, M o nt hs 3, 6, 9), M o nt h 1 2/e n d of treat me nt 
( E o T x) visit, a n d t he last f oll o w-u p visit.  Vital si g ns at eac h of t he a b o ve visits i ncl u de sitti n g heart rate a n d bl o o d press ure.  P ost -v oi d b o d y wei g ht s h o ul d 

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be meas ure d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit o nl y.  Hei g ht s h o ul d be assesse d at t he first scree ni n g visit o nl y.  Eit her hei g ht or 
wei g ht ma y be c ollecte d as a n u nsc he d ule d meas ure me nt if its assess me nt was misse d.
cA f ull p h ysical e xa mi nati o n is re q uire d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit.  A “ directe d p h ysica l e xa mi nati o n” ma y be perf or me d at t he 
q uarterl y visits (e g, M o nt hs 3, 6, 9) f or assess me nt of si g ns or s y m pt o ms re p orte d b y t he s u bject t hat mi g ht re q uire f urt her e val uati o n.
d D uri n g t he trial, a pre g na nc y test s h o ul d be c o m plete d at scree ni n g a n d at t he q uarterl y visits.  O n s us pici o n of pre g na nc y, u nsc he d ule d uri ne or ser u m 
pre g na nc y testi n g will be perf or me d.  P ositi ve uri ne pre g na nc y tests s h o ul d be c o nfir me d wit h a ser u m pre g na nc y test.
eT he s pecifics a n d ti mi n g f or cli nical la b orat or y sa m ples f or ce ntral a n d l ocal la b orat or y a nal yses are as f oll o ws:
Scree ni n g peri o d:   S u bjects will ha ve 3 bl o o d dra ws o n se parate da ys bet wee n Da y -5 6 a n d Da y -4 3.  T he s u bject’s eli gi bilit y will be c o nfir me d b y t he 
mea n of e G F R calc ulate d fr o m t he s u bjects’ first 2 pre -treat me nt, ce ntral la b orat or y ser u m creati ni ne assess me nts.
Pl ace b o r u n -i n peri o d:  S u bjects will ha ve 2 bl o o d dra ws o n se parate da ys (at least 2 4 h o urs a part) bet wee n Da ys -4 2 t o -3 6 w it h t he last sa m ple o n 
D a y  -3 6.
T ol v a pt a n titr ati o n peri o d:   S u bjects will ha ve 1 bl o o d dra w at t he e n d of 2 wee ks wit h t he sa m ple bei n g o btai ne d o n Da y -2 2.
T ol v a pt a n r u n -i n peri o d:  D uri n g t he last 2 wee ks of t his peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys (at least 2 4 h o urs a part) wit h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt peri o d:   Sa m ples will be c ollecte d f or ce ntral la b a nal ysis m o nt hl y a n d at t he M o nt h 1 2/ E o T x visit.  L ocal sta n dar d of care 
la b orat or y tests will be perf or me d m o nt hl y per t he s u bject’s i n di vi d ual cli nical ma na ge me nt needs.  L ocal li ver f u ncti o n pa nel a nal yses will als o be 
perf or me d m ore fre q ue ntl y, if necessar y.
fD uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d, P K plas ma sa m ples, P D uri ne sa m ples, a n d bi o mar ker uri ne/ plas ma sa m ples will be c ollecte d
q uarterl y (e g, M o nt hs 3, 6, 9, 1 2/ E o T x).  
g Sa m ples are o pti o nal.
h Dr u g dis pe nsi n g a n d rec o nciliati o n will be d o ne m o nt hl y a n d s u bjects w ill be re mi n de d of t he i m p orta nce of t heir c o m mit me nt to c o nti n ue partici pati o n i n 
t he trial..
iIf, d uri n g t he titrati o n c o ntact, t he d eter mi nati o n is ma de t o a dj ust t he d ose -r e gim e n, the investigator will e nter t he s u bject’s stat us i n t he I V R S a n d arra n ge f or
dis pe nsati o n of a ne w I M P kit a n d rec o nciliati o n of ret ur ne d I M P.
jE x pl orat or y P K D o utc o mes will be c o m plete d eit her m o nt hl y o ver t he p h o ne or i n pers o n d uri n g q uarterl y cli nic visits.

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Re vise d Sc he d ule of Assess me nts
T a ble 1 0. 2 -1  Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys -4 2 t o -
3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n
r u n- i n
( 3 wee ks 1 d a y)
( D a ys -2 1 t o -1)
( D a y 
0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt
V 1
V 2
D a y 
-4 3
D a y -
4 2
D a y -
3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1 ( - 2 
d a ys)
p ost -fi n al visita
-3 5 -3 2 -2 8
-2 4
-2 2
-2 1 -1 5
- 8 
- 1
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n
X
D e m o gr a p hic/ Me dic al hist or y
X
Vit al si g ns c
X
X 
X
X
X
( X)c
X
X
P h ysic al e x a mi n ati o n d
X
( X)d
X
Uri ne pre g n a nc y test ( W O C B P 
o nl y) e
X
X
( X)e
X
X
C he mistr y Bl o o d S a m ple c,f:
   Ser u m C he mistr y Pa nel
X
X
X
   Li ver F u ncti o n Pa nel
X  
X
X
X
X
X  
X
X
   Creati ni ne
X
X 
X
X  
X  
X
X  
X  
X  
X  
X
   S o di u m
X  
X
X
X
X
X  
X
X
H e m at ol o g y a n d c o a g ul ati o n
X
P K pl as m a s a m ple
X
( X)g
X
X
Bi o m ar ker pl as m a s a m ple
X
X
X
X
( X)g
X
X
D N A bl o o d s a m ple h
X

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T a ble 1 0. 2 -1  Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys -4 2 t o -
3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n
r u n- i n
( 3 wee ks 1 d a y)
( D a ys -2 1 t o -1)
( D a y 
0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt
V 1
V 2
D a y 
-4 3
D a y -
4 2
D a y -
3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1 ( - 2 
d a ys)
p ost -fi n al visita
-3 5 -3 2 -2 8
-2 4
-2 2
-2 1 -1 5
- 8 
- 1
Uri n al ysis
X
X 
X
X
X
P D a n d Bi o m ar ker uri ne 
s a m ple
X
X
X
X
( X)g
X
X
St art ne wl y dis pe nse d I M P
X  
X
X
X
T oler a bilit y/ D osi n g re vie w
X  
X  
X  
X  
X
X
X  
X
R a n d o miz ati o n
X
Dr u g dis pe ns ati o n i
X
X
X
X
X
Dr u g rec o ncili ati o n i
X
X
X
X  
X
I V R S e ntr yj
X  
X  
X
X  
X  
X  
X  
X
X
X  
X
X
E x pl or at or y P K D o utc o m es k
X
X
X  
X
A d verse e ve nts
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------->
C o nc o m it a nt me dic ati o ns
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------->
aT he scree ni n g peri o d s h o ul d be c o m plete d wit hi n 1 -2 w ee ks bef ore t he start of t he place b o r u n -i n peri o d.  T he scree ni n g peri o d ma y be e xte n de d u p t o a n 
a d diti o nal 8 wee ks f or s u bjects w h o re q uire m o dificati o n of me dical care s pecificall y f or t his trial.  Visits d uri n g t he scre e ni n g a n d f oll o w-u p peri o ds m ust 
be sc he d ule d at least 2 4 h o urs ( 1 da y) a part.   T he Da y -4 3 visit ca n n ot occ ur u ntil la b orat or y val ues fr o m V 2 are recei ve d.  F or t w o visits ( V 1, V 2) d uri n g 
t he scree ni n g peri o d, bl o o d will be c ollecte d a n d a nal yze d ce ntrall y f or ser u m creati ni ne c o nce ntrati o ns, i n a d diti o n t o a n y ot her assess me nts li ste d.  A 
visiti n g n urse h o use call or l ocal la b orat or y visit ma y be s u bstit ute d f or visits w here o nl y bl o o d/ uri ne will be c ollecte d d u ri n g t he f oll o w-u p peri o d.  Visits 
d uri n g t he f oll o w -u p peri o d m ust be sc he d ule d d uri n g a 2 -wee k peri o d t hat be gi ns 1 w e e k after t he e n d of treat me nt visit.
b If I M P treat me nt is i nterr u pte d f or 7 da ys d uri n g t his peri o d, pr oce d ures s h o ul d be f oll o we d as detaile d i n Secti o n 3. 8. 3. 2 .

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cT he f oll o w i n g visits (a n d all assess me nts re q uire d d uri n g t h ose visits) s h o ul d be perf or me d i n-cli nic: scree ni n g ( V 1, V 2, Da y -4 3), e n d of place b o r u n -i n, e n d 
of t ol va pta n titrati o n, e n d of t ol va pta n r u n-i n, q uarterl y visits d uri n g t he ra n d o mize d, d o u ble-bli n d treat me nt peri o d (e g, M o nt hs 3, 6, 9), M o nt h 1 2/e n d of 
treat me nt ( E o T x) visit, a n d t he last f oll o w-u p visit.  Vital si g ns at eac h of t he a b o ve visits i ncl u de sitti n g heart rate a n d bl o o d press ure.  P ost -v oi d b o d y 
wei g ht s h o ul d be meas ure d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit o nl y.  Hei g ht s h o ul d be assesse d at t he fi rst scree ni n g visit o nl y.  Eit her 
hei g ht or wei g ht ma y be c ollecte d as a n u nsc he d ule d meas ure me nt if i ts assess me nt was misse d.
d A f ull p h ysical e xa mi nati o n is re q uire d at  scree ni n g ( V 1)  a n d t he M o nt h 1 2/ E o T x visit.  A “ directe d p h ysical e xa mi nati o n” is perf or me d at t he q uarterl y visits 
(e g, M o nt hs 3, 6, 9) f or assess me nt of si g ns or s y m pt o ms re p orte d b y t he s u bject t hat mi g ht re q uire f urt her e val uati o n.
eD uri n g t he trial, a pre g na nc y test s h o ul d be c o m plete d at scree ni n g, e n d of place b o r u n -i n a n d at t he q uarterl y visits.  O n s us pici o n of pre g na nc y, 
u nsc he d ule d uri ne or ser u m pre g na nc y testi n g will be pe rf or me d.  P ositi ve uri ne pre g na nc y tests s h o ul d be c o nfir me d wit h a ser u m pre g na nc y test.
fAll ser u m creati ni ne sa m ples will be a nal yze d b y t he ce ntral la b orat or y.  T he s pecifics a n d ti mi n g f or all cli nical la b orat or y sa m ples f or ce ntral a n d l ocal 
la b orat or y a nal yses are as f oll o ws:
All visits: O ne or m ore t u bes of bl o o d ma y be c ollecte d t o acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 1 -2 w ee ks of t he scree ni n g peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys ( V 1, V 2) at least 2 4 h o urs a part.  T he 
s u bject’s eli gi bilit y will be c o nfir me d b y t he mea n of e G F R calc ulate d fr o m t he s u bjects’ 2 pre-treat me nt ( V 1, V 2), ce ntral la b orat or y ser u m creati ni ne 
assess me nts a n d e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  S u bjects will ha ve 1 bl o o d dra w  at t he e n d of 1 wee k wit h t he sa m ple bei n g o btai ne d o n Da y -3 6.
T ol v a pt a n titr ati o n peri o d:   S u bjects will ha ve 1 bl o o d dra w at t he e n d of 2 wee ks wit h t he sa m ple bei n g o btai ne d o n Da y -2 2.
T ol v a pt a n r u n -i n peri o d:  D uri n g t he last 2 wee ks of t h is peri o d, bl o o d will be dra w n 2 ti mes o n se parate da ys (at least 2 4 h o urs a part) wit h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt peri o d:   Sa m ples will be c ollecte d f or ce ntral la b a nal ysis m o nt hl y a n d at t he M o nt h 1 2/ E o T x visit.  L ocal sta n dar d of care 
la b orat or y tests will be perf or me d m o nt hl y per t he s u bject’s i n di vi d ual cli nical ma na ge me nt nee ds.  L ocal li ver f u ncti o n pa nel a nal yses will als o be 
perf or me d m ore fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects will ha ve bl o o d dra w n o n 3 visi ts o ver Da ys + 7 t o + 2 1 p ost-treat me nt.
    F ull C he mistr y pa nel will be o btai ne d d uri n g f oll o wi n g visit: Scree ni n g ( V 1), q uarterl y visit ( M 3, M 6, M 9, M 1 2/ E o T x, F/ U peri o d Da y 2 1
    Ser u m creati ni ne, ser u m s o di u m,: Scree ni n g ( V 2), e n d of place b o peri o d, e n d of  t ol va pta n titrati o n,  2 ti mes d uri n g t ol va pta n r u n -i n,  m o nt hl y d uri n g 
d o u ble bli n d treat me nt peri o d, 2 ti mes d uri n g F/ U peri o d
    Li ver f u ncti o n pa nel: Scree ni n g ( V 2), e n d of place b o peri o d, e n d of  t ol va pta n titrati o n, 2 ti mes d uri n g t ol va pta n r u n -i n,  m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d Da y 2 1
g D uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d, P K plas ma sa m ples, P D uri ne sa m ples, a n d bi o mar ker uri ne/ plas ma sa m ples will be c ollecte d
q uarterl y (e g, M o nt hs 3, 6, 9, 1 2/ E o T x).
h D N A sa m ples are o pti o nal.
iDr u g dis pe nsi n g a n d rec o nciliati o n will be d o ne m o nt hl y (e xce pti o ns t o all o w dis pe nsi n g/rec o nciliati o n at eac h 3 -m o nt h cli nic visit ma y be ma de b y t he 
me dical m o nit or i n e xce pti o nal circ u msta nces, wit h i nstr ucti o ns t o ta ke o nl y o ne m o nt h’s s u p pl y a n d start t he ne xt m o nt h o nl y after acce pta ble safet y la b 
res ults are c o nfir me d b y t he i n vesti gat or).  I nstr ucti o ns t o be gi n ta ki n g t he ne xt m o nt h’s trial me dicati o n will be gi ve n b y tele p h o ne c o ntact.  S u bjects will 

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be re mi n de d of t he i m p orta nce of t heir c o m mit me nt t o c o nti n ue partici pati o n i n t he trial.  At t he c o m pleti o n of t he scree ni n g peri o d, trial me dic ati o n will be 
dis pe nse d at Da y -4 3 after s u bject eli gi bilit y is c o nfir me d.  I n e xce pti o nal circ u msta nces, trial me dicati o n ma y be d is pe nse d at V 2, wit h t he i nstr ucti o n n ot 
t o ta ke a n y trial me dicati o n u ntil eli gi bilit y is c o nfir me d b y t he i n vesti gat or.  I n t hese cases, c o nfir mati o n of eli gi bilit y a n d i nstr ucti o ns f or ta ki n g trial 
me dicati o n will be pr o vi de d b y tele p h o ne o n Da y -4 3.
jIf, d uri n g t he titrati o n c o ntact, t he deter mi nati o n is ma de t o a dj ust t he d ose -r e gim e n, the investigator will e nter t he s u bject’s stat us i n t he I V R S a n d arra n ge f or
dis pe nsati o n of a ne w I M P kit a n d rec o nciliati o n of ret ur ne d I M P.  At t he e n d of t he titrati o n peri o d, t he s u bject’s hi g hest t olerate d d ose will be utilize d f or 
t he 3-wee k t ol va pta n r u n -i n peri o d.
k E x pl orat or y P K D o utc o mes will be c o m plete d eit her m o nt hl y o ver t he p h o ne or i n pers o n d uri n g q uarterl y cli nic visits.

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A d mi nistr ati ve C h a n ge N u m ber:
2
Iss ue D ate:
2 5 J u ne 2 0 1 4
P U R P O S E:
T his a d mi nistrati ve c ha n ge will n ot affect t he safet y  of s u bjects, t he sc o pe of t he 
i n vesti gati o n, or t he scie ntific q ualit y of t he trial.
T he mai n p ur p ose of t his a d mi nist rati ve c ha n ge was t o ali g n t he Statistical A nal ysis Pla n 
wit h t he pr ot oc ol.  I n a d diti o n, an a d mi nistrati ve c ha n ge t o H o me N ursi n g Ser vices was 
ma de , a n d se veral clarificati o ns t o t he pr ot oc ol were a d de d.
B A C K G R O U N D:
T he U S -F D A’s S pecial Pr ot oc ol A gree me nt ( S P A) re q ueste d se veral m o dificati o ns t o t he 
pr ot oc ol t o m ore cl osel y ali g n a nal ys es wit h t he Statistical A nal ysis Pla n.  T he dele gate d 
H o me N ursi n g Ser vices ve n d or was als o c ha n ge d a n d is n o w u p date d . 
Secti o n al Re visi o ns
L oc ati o n
Ol d Te xt
U p d ate d Te xt
S y n o psis, Trial Desi g n, 
D o u ble -bli n d, 
ra n d o mize d treat me nt 
peri o d ( 1 2 m o nt hs):  
...S u bjects w ill als o be stratifie d b y 
t otal ki d ne y v ol u me 
 
 if k n o w n.  
...S u bjects w ill als o be stratifie d b y 
t hree t otal ki d ne y v ol u me ( T K V)
criteri a
 
S y n o psis, Pri mar y 
Efficac y A nal ysis
Pri mar y efficac y a nal ysis: T he 
c ha n ge i n e G F R fr o m pre -treat me nt 
baseli ne t o p ost -treat me nt f oll o w-u p, 
a n n ualize d ( di vi de d) b y eac h 
s u bject’s I M P treat me nt d urati o n, will 
be calc ulate d.  T he a n n ualize d c ha n ge 
i n e G F R will be a nal yze d b y a nal ysis 
of c o varia nce ( A N C O V A ) wit h 
treat me nt a n d ra n d o mizati o n 
stratificati o n fact ors as fact or a n d 
c o variate baseli ne s.
Pri mar y efficac y a nal ysis: T he 
c ha n ge i n e G F R fr o m pre -treat me nt 
baseli ne t o p ost -treat me nt f oll o w-u p, 
a n n ualize d ( di vi de d) b y eac h 
s u bject’s I M P treat me nt d urati o n, 
will be calc ulate d.  T he a n n ualize d
c ha n ge i n e G F R will be a nal yze d b y 
a wei g hte d a nal ysis of c o varia nce 
(A N C O V A ) wit h treat me nt a n d 
ra n d o mizati o n stratificati o n fact ors 
as fact or a n d c o variate baseli ne s.  
T his wei g hte d a n al ysis is b ase d o n 
t he reci pr oc al of t he esti mate d 
v ari a nce of t he “esti m ate d sl o pes. ”
A b bre viati o ns List
I D M S - Is ot o pe dil uti o n mass 
s pectr o metr y
Secti o n 2. 1, Trial 
Rati o nale
T o decrease varia bilit y, m ulti ple 
ser u m creati ni ne meas ure me nts will 
be ta ke n b ot h pre - a n d p ost -treat me nt 
f or eac h s u bject, a n d t he eG F R val u es
will t he n be a vera ge d.
T o decrease varia bilit y, m ulti ple 
ser u m creati ni ne meas ure me nts 
(is ot o pe dil uti o n mass 
s pectr o metr y [I D M S]-tr ace a ble)
will be ta ke n b ot h pre - a n d p ost-
treat me nt f or eac h s u bject, a n d t he 
e G F R val ues will t he n be a vera ge d.
Secti o n 3. 2. 2 , D o u ble -
Afte r stratifie d ra n d o mizati o n, 
After stratifie d ra n d o mizati o n , b y 

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1 3 6
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L oc ati o n
Ol d Te xt
U p d ate d Te xt
bli n d Ra n d o mize d 
Treat me nt Peri o d ( Da y 
0 t o M o nt h 1 2)
s u bjects will e nter t he d o u ble-bli n d, 
ra n d o mize d treat me nt peri o d 
recei vi n g eit her t ol va pta n or place b o 
i n a 1: 1 rati o.
b aseli ne e G F R ( at a t hres h ol d of 
, b y 
a ge ( 5 5 or > 5 5 ye ars ol d), a n d 
b y t hree T K V criteri a 
 
 s u bjects 
will e nter t he d o u ble -bli n d, 
ra n d o mize d treat me nt peri o d 
recei vi n g eit her t ol va pta n or place b o 
i n a 1: 1 rati o.
Secti o n 3. 4. 1 , I nf or me d 
C o nse nt
O nce t he a p pr o priate esse ntial 
i nf or mati o n has bee n pr o vi de d t o t he 
s u bject a n d f ull y e x plai ne d i n 
la y ma n’s la n g ua ge b y t he i n vesti gat or 
( or a q ualifie d desi g nee) a n d it is felt 
t hat t he s u bject u n dersta n ds t he 
i mplicati o ns of partici pati n g, t he 
I R B/I E C-a p pr o ve d writte n I C F s hall 
be pers o nall y si g ne d a n d date d b y 
b ot h t he s u bject a n d t he pers o n 
o btai ni n g c o nse nt (i n vesti gat or or 
desi g nee), ...
O nce t he a p pr o priate esse ntial 
i nf or mati o n has bee n pr o vi ded t o t he 
s u bject a n d f ull y e x plai ne d i n 
la y ma n’s la n g ua ge b y t he 
i n vesti gat or ( or a q ualifie d desi g nee) 
a n d it is felt t hat t he s u bject 
u n dersta n ds t he i m plicati o ns of 
partici pati n g, t he I R B/I E C -a p pr o ve d
writte n I C F s hall be si g ne d a n d 
date d b y all s u bjects ( or t heir 
g u ar di a n or le g al re prese nt ati ve, 
as a p plic a ble f or l oc al l a ws), a n d 
t he pers o n o btai ni n g c o nse nt 
(i n vesti gat or or desi g nee),..
Secti o n 3. 5. 2. 1 , Ke y 
Sec o n dar y Efficac y 
E n d p oi nt
Treat me nt differe nce i n a n n ualize d 
sl o pe of e G F R calc ulate d f or 
i ndi vi d ual s u bjects usi n g a n 
a p pr o priate baseli ne a n d a vaila ble, 
p ost -ra n d o mizatio n, o n treat me nt 
assess me nts.
Treat me nt differe nce i n a n n ualize d 
sl o pe of e G F R calc ulate d f or 
i n di vi d ual s u bjects usi n g e G F R d at a 
o bser ve d i n t he pl ace b o r u n -i n, 
t ol v a pt a n r u n-in ( n ot i ncl u di n g 
t ol v a pt a n titr ati o n), d o u ble-bli n d 
tre at me nt, a n d p ost -tre at me nt 
f oll o w-u p ( n ot i ncl u di n g d at a 
c ollecte d i n t he first wee k a fter t he 
l ast I M P d ose) peri o ds.
Secti o n 3. 6 , Meas ures 
t o Mi ni mize/ A v oi d 
Bias
S u bjects will als o be stratifie d b y 
t otal ki d ne y v ol u me ( T K V; 2 0 0 0 
m L or > 2 0 0 0 m L ), if k n o w n.
S u bjects will als o be stratifie d b y 
t hree T K V criteri a (2 0 0 0 m L, > 
2 0 0 0 m L, or u n k n o w n ).
Secti o n 3. 7, Trial 
Pr oce d ures , Sc he d ule of 
Assess me nts
c...Eit her hei g ht or wei g ht ma y be 
c ollecte d as a n u nsc he d ule d 
meas ure me nt if its assess me nt w as 
misse d .
c...Eit her hei g ht or wei g ht ma y be 
c ollecte d as a n u nsc he d ule d 
meas ure me nt if t he pl a n ne d
assess me nt was misse d .  Wei g ht 
m a y be assesse d as necess ar y t o 
assess c h a n ges i n b o d y wei g ht.
i...I nstr ucti o ns t o be gi n ta ki n g t he ne xt 
m o nt h’s trial me dicati o n will be 
gi ve n b y tele p h o ne c o ntact....
i...I nstr ucti o ns t o be gi n ta ki n g t he 
ne xt m o nt h’s trial me dicati o n will be 
gi ve n d uri n g t he ti me of I M P 
dis pe ns ati o n at e ac h m o nt hl y visit 
or b y tele p h o ne c o ntact after t he 
m o nt hl y L F T s a m ple s are
c ollecte d.  If L F T res ults are 
a b n or m al, t he site will c o n d uct a
tele p h o ne c o nt act wit h t he tri al 
s u bject t o i nf or m t he m t h at 
pr o m pt i m me di ate retesti n g (ie, 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
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L oc ati o n
Ol d Te xt
U p d ate d Te xt
w it hi n 7 2 h o urs) ma y be necess ar y 
(see Secti o n 3. 7. 3. 4 f or g ui d a nce) 
a n d t o arr a n ge f or f oll o w -u p a n d 
a dj us t me nt of me dic ati o n ( as 
nee de d); if a d o w n titr ati o n is 
re q uire d, t he s u bject ma y nee d t o 
ret ur n t o t he site or h a ve ne w dr u g 
deli vere d .
T ol va pta n R u n -i n ( 3 wee ks 1 da y)
Da y  - 1 5 c ol u m n was delete d
Secti o n 3. 7. 1. 1, Pr e -
ra n d o mizati o n Peri o d
Pr e -ra n d o mizati o n e G F R val ue(s) 
will be c ollecte d f or eac h p ote ntial 
treat me nt assi g n me nt f or all s u bjects.
Pre -ra n d o mizati o n e G F R val ue(s) 
will be c alc ul ate d b y C K D -E PI f or 
eac h p ote ntial treat me nt assi g n me nt 
f or all s u bjects.
T o esta blis h t he pre -ra n d o mizati o n 
e G F R, m ulti ple ser u m creati ni ne 
val ues will be o btai ne d u n der 
sta n dar dize d c o n diti o ns
T o esta blis h t he pre -ra n d o mizati o n 
e G F R, m ulti ple ser u m creati ni ne 
val ues (I D M S-tr ace a ble) wi ll be 
o btai ne d u n der sta n dar dize d 
c o n diti o ns
Secti o n 3. 7. 1. 1. 4, 
T ol va pta n R u n -I n 
Peri o d ( Da ys -2 1 t o -1)
S u bjects will al s o be stratifie d b y a ge 
(5 5 or > 5 5 years ol d) a n d b y t otal 
ki d ne y v ol u me ( T K V; 2 0 0 0 m L, or 
> 2 0 0 0 m L), if k n o w n.
S u bjects w ill als o be st ratifie d b y 
a ge ( 5 5 or > 5 5 years ol d) a n d b y  
t hree T K V criteri a (2 0 0 0 m L, > 
2 0 0 0 m L, or u n k n o w n ).
Secti o n 3. 7. 2. 1, Ser u m 
Creati ni ne f or 
Esti mate d Gl o mer ular 
Filtrati o n Rate
T he e G F R val ues will be calc ulate d 
fr o m t he ce ntral-la b orat or y ser u m 
creati ni ne c o nce ntrati o ns ta ke n at 
scree ni n g a n d d uri n g e ver y trial visit.
T he e G F R val ues will be calc ulate d 
b y C K D -E PI fr o m t he ce ntral-
la b orat or y ser u m creati ni ne 
c o nce ntrati o ns ta ke n at scree ni n g 
a n d d uri n g e ver y trial visit.
Secti o n 7. 4. 1. 1, 
Pr i mar y E n d p oi nt 
A nal ysis
T he pri mar y e n d p oi nt of t his trial is 
t he c han ge i n e G F R fr o m pre -
treat me nt baseli ne t o p ost-treat me nt 
f oll o w-u p, a n n ualize d ( di vi de d) b y 
eac h s u bjects’ I M P treat me nt 
d urati o n .
T he pri mar y e n d p oi nt of t his trial is 
t he c ha n ge i n e G FR ( c alc ul ate d b y 
t he C K D-E PI f or m ul a) fr o m pre-
treat me nt baseli ne t o p ost-treat me nt 
f oll o w-u p, a n n ualize d ( di vi de d) b y 
eac h s u bjects’ I M P treat me nt 
d urati o n .
...T h us, a nal ysis of c o varia nce 
( A N C O V A) wit h effects of treat me nt 
a n d ra n d o mizati o n stratificati o n 
fact ors a n d c o variate baseli ne will be 
a p plie d t o t hese “esti mate d sl o pes” as 
t he pri mar y a nal ysis.  
...T h us, a wei g hte d a nal ysis of 
c o varia nce ( A N C O V A) wit h effects 
of treat me nt a n d ra n d o mizati o n 
stratificati o n fact ors a n d c o variate 
baseli ne will be a p plie d t o t hese 
“esti mate d sl o pes” as t he pri mar y 
a nal ysis.  T his wei g hte d a n al ysis is 
b ase d o n t he reci pr oc al of t he 
esti mate d v ari a nce of t he 
“esti m ate d sl o pes, ” a n d t he 
det aile d al g orit h m  t o deri ve t he 
esti mate d v ari a nce is pr o vi de d i n 
Secti o n 8. 3 of t he S A P.
Secti o n 7. 4. 1. 3, 
Se nsiti vit y A nal ysis 
I ncl u di n g Data fr o m 
S u bjects W h o 
Disc o nti n ue I M P
T his se nsiti vit y a nal ysis de viates 
fr o m t he M A R ass u m pti o n t o i ncl u de 
t he p ost-disc o nti n uati o n f oll o w - u p 
data i n t he a nal ysis s pecifie d i n t he 
pre vi o us secti o n.  S u bjects w h o 
disc o nti n ue I M P after ra n d o mizati o n 
T his se nsiti vit y a nal ysis de viates 
fr o m t he M A R ass u m pti o n t o 
i ncl u de t he p ost-disc o nti n uati o n 
f oll o w-u p data i n t he a nal ysis 
s pecifie d i n t he pri m ar y a n al ysis
secti o n.  S u bjects w h o disc o nti n ue 

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Ol d Te xt
U p d ate d Te xt
wit h o ut wit h dra w i n g c o nse nt will be 
f oll o we d f or a d diti o nal off-treat me nt 
e G F R t hr o u g h t o M o nt h 1 2.  T hese 
p ost “ p ost -treat me nt f oll o w-u p” 
e G F R data will be i ncl u de d wit h t he 
data s pecifie d i n t he pre vi o us secti o n, 
i n a se nsiti vit y a nal ysis usi n g t he 
sa me a nal ytic a p pr oac h s pecifie d i n 
t he pre vi o us secti o n.
I M P after ra n d o mizati o n wit h o ut 
wit h dra wi n g c o nse nt w ill be 
f oll o we d f or a d diti o nal off-treat me nt 
eG F R v al ues u p t o M o nt h 1 2.  
T hese “ p ost -treat me nt f oll o w-u p” 
e G F R data at M o nt h 1 2 will be 
i ncl u de d t o re pl ace t he data 
o bser ve d d uri n g p ost -tre at me nt 
f oll o w-u p f or t he s u bjects w h o 
disc o nti n ue I M P e arl y , i n a 
se nsiti vit y a nal ysis usi n g t he sa me 
a nal ytic a p pr oac h s pecifie d i n t he 
pri m ar y a n al ysis secti o n. 
Secti o n 7. 4. 2. 1, Ke y 
Sec o n dar y E n d p oi nt 
A nal ysis
T he ti me varia ble use d i n t he m o del 
ma y start fr o m t he first o bser vati o n of 
e G F R o btai ne d fr o m place b o r u n-i n 
peri o d.
T he ti me varia ble use d i n t he m o del 
ma y start fr o m t he first o bser vati o n 
of e G F R o btai ne d fr o m place b o r u n -
i n peri o d.  T he c o v ari ate “ ac ute 
he m o d y n a mic effect ” i n t he m o del 
is t he fl a g v ari a ble wit h v al ue of 0 
a n d 1 s pecifie d e arlier i n t his
secti o n f or t he d at a o bser ve d 
d uri n g t ol v a pt a n r u n -i n a n d t he 
d at a o bser ve d f or t ol v a pt a n 
s u bjects d uri n g t he d o u ble bli n d 
tre at me nt peri o d.   T he st arti n g 
p oi nt of t his e G F R sl o pe a n al ysis is 
t he e G F R o bser v atio n d uri n g t he 
pl ace b o r u n -i n peri o d.
Secti o n 7. 4. 3, S u b gr o u p 
Efficac y A nal ysis
S u b gr o u p a nal yses will be pr o vi de d 
f or t he pri mar y a n d t he ke y sec o n dar y 
e n d p oi nts b y re gi o ns ( U S a n d n o n -
U S), ge n der ( male a n d fe male), rac e, 
( Ca ucasia n a n d Ot her), a ge (5 5 
years, > 5 5 ye ars), baseli ne G F R le vel 
 
a n d baseli ne 
T K V
 
S u b gr o u p a nal yses will be pr o vi de d 
f or t he pri mar y a n d t he ke y 
sec o n dar y e n d p oi nts b y re gi o ns ( U S 
a n d n o n -U S), ge n der ( male a n d 
fe male), race ( Ca ucasia n a n d Ot her), 
a ge ( 5 5 years, > 5 5 ye ars), baseli ne 
G F R le vel 
 
 a n d 
t hree baseli ne T K V criteri a
 
A p pe n di x 2, I nstit uti o ns 
C o ncer ne d Wit h t he 
Trial , H o me N ursi n g 
Ser vices
P h o ne: 
Fa x: 
Tel: 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 3 9
2 6 Mar 2 0 1 5 
A me n d me nt N u m ber 
2
Iss ue D ate:
2 6 N o ve m ber 2 0 1 4
P U R P O S E:
T he pri mar y  p ur p ose of t his a me n d me nt was t o a d d a n a d diti o nal e xcl usi o n criteri o n f or 
Fra nce.
B A C K G R O U N D:
A letter fr o m t he Fre nc h healt h a ge nc y  A ge nce nati o nale de séc urité d u me dica me nt 
(A N S M ) re q ueste d ver bia ge be a d de d t o t he e xcl usi o n criteria e x plai ni n g 
c o ntrai n dicati o ns of t ol va pta n. 
Secti o n al Re visi o ns
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Secti o n 3. 4. 3, 
E xcl usi o n Criteria, 
Ta ble 3. 4. 3 - 1
8. T ol va pta n is c o ntrai n dicate d i n 
patie nts w h o:  are k n o w n t o ha ve 
h y perse nsiti vit y t o t ol va pta n or o ne 
of t he e xci pie nts, are h y p o v ole mic 
( v ol u me de pleti o n), ca n n ot percei ve 
t hirst.  A d diti o nall y, s u bjects wit h 
baseli ne scree ni n g a b n or malities of 
ser u m s o di u m c o nce ntrati o ns 
( h y p o natre mia or h y per natre mia) 
ma y n ot be e nr olle d i n t he trial u ntil 
t hese a b n or malities res ol ve a n d t he n 
m ust be m o nit ore d acc or di n gl y.  
A D DI TI O N A L RI S K T O T H E S U B J E C T :
T here is n o a d diti o nal ris k t o t he s u bjects.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 0
2 6 Mar 2 0 1 5 
A me n d me nt N u m ber 
3
Iss ue D ate:
2 6 Marc h
2 0 1 5
P U R P O S E:
T he pri mar y  p ur p ose of t his a me n d me nt is t o clarif y t he i ncl usi o n criteri o n f or ol der 
s u bjects, a n d t o c orrect a misstate me nt re gar di n g S U S A R re p orti n g f or pr oce d ures. Ot her 
clarificati o ns were a d de d f or c o nsiste nc y  bet ween t he Sc he d ule of Assess me nts ta ble a n d 
te xt or t o clarif y sa m ple c ollecti o n pr ocess or ti mi n g.  T he D N A sa m ple c ollecti o n ti me 
was c ha n ge d fr o m t he sec o n d scree ni n g visit o nl y t o a n y  visit fr o m t he seco n d scree ni n g 
visit o n war ds. 
B A C K G R O U N D:
Cl arific ati o n of I ncl usi o n Criteri o n # 2 (ot her t h a n s y n o psis, first a p pe ars i n 
Secti o n 3. 4 )
A c ha n ge is ma de t o t he i ncl usi o n criteri o n t o clarif y t hat s u bjects li kel y t o ha ve sl o wly 
pr o gressi ve A D P K D d ue t o t heir a d va nce d a ge at e ntr y  be e xcl u de d if a vaila ble re nal 
f u ncti o n hist or y c o nfir ms a pr o gressi o n rate i nc o nsiste nt wit h t he scie ntific g oals of t he 
trial. As t his trial is o nl y 1 year i n d urati o n, it is t heref ore i m p orta nt t hat e nr olle d 
s u bjects ha ve a decrease of at least 2 m L/ mi n/ 1. 7 3 m2 per y ear s o t hat t he e x pecte d 
meas u ra ble effect of t ol va pta n (a 3 3 % re d ucti o n i n t he rate of decli ne) ma y be 
deter mi ne d .
Cl arific ati o n of S a m ple C ollecti o n ( ot her t h a n s y n o psis, first a p pe ars i n Secti o n 3. 7 )
I n or der t o e ns ure t hat uri ne sa m ples are c ollecte d i n t he sa me ma n ner at e ver y site, 
w or di n g is a d de d t o t he Sc he d ule of Assess me nts ta ble t o s pecif y  t hat uri ne sa m ples will 
be c ollecte d d uri n g t he sec o n d m or ni n g v oi d as a mid- strea m, clea n-catc h sa m ple, a n d 
o btai ne d pri or t o t he s u bject’s eati n g brea kfast.  T his i nstr ucti o n was a d de d t o e ver y  visit 
w here a uri ne sa m ple is c ollecte d.  W here necessar y, all s u p plies f or t he c ollecti o n s h o ul d 
be pr o vi de d t o t he s u bject pri or t o t he ne xt visit s o t he sa m ple ca n be c ollecte d eit her 
i n-cli nic or at h o me o n t he da y of t he sc he d ule d visit.
In t he pre vi o us versi o n of t he pr ot oc ol, ser u m creati ni ne sa m ples are t o be c ollecte d t hree 
ti mes o ver t he f oll o w-u p peri o d.  T he la n g ua ge is clarifie d t o e m p hasize t hat t he first of 
3 sa m ples i n t he 3- wee k f oll o w-u p peri o d occ urs at least 7 d a y s after t he last dose of I M P 
t o e ns ure t he ac ute, re versi ble effects of t ol va pta n o n ser u m creati ni ne ha ve a mi ni mall y 
reas o na ble ti me peri o d t o a bate.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 1
2 6 Mar 2 0 1 5 
Cl arific ati o n of D N A Bl o o d S a m ples (first a p pe ars i n t he Sc he d u le of Assess me nts 
t a ble, Secti o n 3. 7 )
La n g ua ge was a d de d t o all o w fle xi bilit y  i n t he ti mi n g of D N A bl o o d sa m ple c ollecti o n i n 
case s u bjects d o n ot pr o vi de c o nse nt at t he sec o n d scree ni n g visit, b ut c o nse nt t o d o s o at 
a later visit. T his eli mi nates p ote ntial pr ot oc ol de viati o ns t hat ha ve n o i m pact o n t he 
a bilit y t o i nter pret t he data f or t he pri mar y e n d p oi nt of t his trial.
Secti o n al Re visi o ns
L oc ati o n
Ol d Te xt
U p d ate d Te xt
S y n o psis, Trial Desi g n
D o u ble -bli n d, r a n d o mize d treat me nt
peri o d ( 1 2 m o nt hs) :  O nl y s u bjects 
w h o reac h t he e n d of t he t ol va pta n 
r u n-i n peri o d a n d are a ble t o t olerate 
t ol va pta n 6 0/ 3 0 m g or 9 0/ 3 0 m g 
dail y “f or t he rest of t heir li ves” are 
eli gi ble t o e nter t h is peri o d.   
Ra n d o mizati o n will be 1: 1, t ol va pt a n 
t o place b o.  S u bjects w ill be stratifie d 
b y t heir baseli ne eG F R , at a 
t hres h ol d of 
 
, a n d b y a ge 
(5 5 or > 5 5 years ol d).  S u bjects 
will als o be stratifie d b y t hree t otal 
ki d ne y v ol u me ( T K V) criteria 
 
.  P ost-ra n d o mizati o n, t he 
ma xi mall y -t olerate d d ose of 
t ol va pta n esta blis he d d uri n g t he r u n-
i n peri o d, or t he e q ui vale nt as 
matc hi n g place b o ta blets, w ill be 
dis pe nse d acc or di n g t o t he s u bject’s 
ra n d o mizati o n o utc o me.  If c o nti n ue d 
t olera bilit y bec omes a n iss ue, 
s u bjects ma y titrate d o w n war d t o 
4 5/ 1 5 m g (or 3 0/ 1 5 m g , wit h me dical 
m o nit or a p pr o val) or te m p oraril y 
i nterr u pt treat me nt as nee de d.  Ret ur n 
t o hi g her d oses is als o all o we d.
F oll o w -u p peri o d ( 3 w ee ks):  F or 
ra n d o mize d s u bjects, after M o nt h 1 2 
( or t he E o T x visit, if a s u bject 
D o u ble -bli n d, r a n d o mize d treat me nt
peri o d ( 1 2 m o nt hs) :  O nl y s u bjects 
w h o reac h t he e n d of t he t ol va pta n 
r u n-i n peri o d a n d are a ble t o t olerate 
t ol va pta n 6 0/ 3 0 m g or 9 0/ 3 0 m g
dail y “f or t he rest of t heir li ves” are 
eli gi ble t o e nter t h is peri o d.   
Ra n d o mizati o n will be 1: 1, t ol va pta n 
t o place b o.  S u bjects w ill be stratifie d 
b y t heir baseli ne eG F R , at a 
t hres h ol d of 
 
, a n d b y a ge 
(5 5 or > 5 5 years ol d).  S u bjects 
will als o be stratifie d b y t hree t otal 
ki d ne y v ol u me ( T K V) criteria 
 
 P ost-ra n d o mizati o n, t he 
ma xi mall y -t olerate d d ose of 
t ol va pta n esta blis he d d uri n g t he r u n-
i n peri o d, or t he e q ui vale nt as 
matc hi n g place b o ta blets, w ill be 
dis pe nse d acc or di n g t o t he s u bject’s 
ra n d o mizati o n o utc o me.  If c o nti n ue d 
t olera bilit y bec o mes a n iss ue, 
s u bjects ma y titrate d o w n war d t o 
4 5/ 1 5 m g (or 3 0/ 1 5 m g , wit h me dical 
m o nit or a p pr o val) or te m p oraril y 
i nterr u pt treat me nt as nee de d.  Ret ur n 
t o hi g her d oses is als o all o we d.  
S u bjects w h o disc o nti n ue I M P bef ore 
t he M o nt h 1 2 visit will c o m plete a n 
E o T x visit, w hic h s h o ul d be 
sc he d ule d as s o o n as p ossi ble after 
t he s u bject’s last d ose of 
i n vesti gati o nal me dici nal pr o d uct 
(I M P) a n d c o m plete t he f oll o w- u p 
peri o d .  
F oll o w -u p peri o d ( 3 w ee ks):  F or all 
ra n d o mize d s u bjects, t he f oll o w- u p 
peri o d starts i m me diatel y after t he 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 2
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
disc o nti n ues i n vesti gati o nal 
me dici nal pr o d uct pre mat urel y) eac h 
s u bject will e nter a 3 wee k f oll o w- u p 
peri o d.  N o assess me nts will be ta ke n 
f or t he first wee k of t his peri o d; 
h o we ver, 3 visits will be sc he d ule d 
for t he last 2 wee ks of f oll o w -u p f or 
p ost -treat me nt efficac y a n d safet y 
meas ures.
last d ose of I M P.  N o f oll o w -u p 
assess me nts will be ta ke n d uri n g t he 
first wee k of t his peri o d.  D uri n g t he 
last 2 we e ks, Da ys 8 t hr o u g h 2 1, 
i ncl usi ve, 3 f oll o w-u p visits will be 
sc he d ule d.  T he last f oll o w-u p visit 
will i ncl u de meas ure me nts of 
efficac y a n d safet y.  S u bjects will 
ha ve bl o o d dra w n at eac h visit.
S y n o psis, S u bject 
P o p ulati o n
T his trial w ill ra n d o mize 
a p pr o xi matel y 1 3 0 0 t ol va pta n naï ve 
s u bjects wit h A D P K D.  Male a n d 
fe male a d ults will be e nr olle d, fr o m 
1 8 -5 5 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 6 5 m L/ mi n/ 1. 7 3 m 2 
or 5 6 t o < 6 6 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 4 4 m L/ mi n/ 1. 7 3 m 2 
( wit h me dical m o nit or a p pr o val),
T his trial w ill ra n d o mize 
a p pr o xi matel y 1 3 0 0 t ol va pta n naï ve 
s u bjects wit h A D P K D.  Male a n d 
fe male a d ults will be e nr olle d, fr o m 
1 8 -5 5 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 6 5 m L/ mi n/ 1. 7 3 m 2 
or 5 6 t o < 6 6 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 4 4 m L/ mi n/ 1. 7 3 m 2 
( wit h e vi de nce of A D P K D 
pr o gressi o n a n d me dical m o nit or 
a p pr o val) .
S y n o psis, 
I ncl usi o n/ E xcl usi o n 
Criteria
Mai n i ncl usi o n criteria:

e G F R bet wee n 2 5 a n d 
6 5 m L/ mi n/ 1. 7 3 m 2 ( 1 8 t o 
5 5 years) or e G F R b et wee n 
2 5 a n d 4 4 m L/ mi n/ 1. 7 3 m 2
( 5 6 t o < 6 6 years, b y 
me dical m o nit or discreti o n 
o nl y).
Mai n i ncl usi o n criteria:

e G F R bet wee n 2 5 a n d 
6 5 m L/ mi n/ 1. 7 3 m 2 ( 1 8 t o 
5 5 years of a ge) or e G F R 
bet w ee n 2 5 a n d 4 4 
m L/ mi n/ 1. 7 3 m 2 ( 5 6 t o < 6 6 
years of a ge, wit h e vi de nce 
of A D P K D pr o gressi o n , ie, 
e G F R decli ne of
> 2. 0 m L/ mi n/ 1. 7 3 m 2 per 
ye ar , b ase d o n hist oric al 
e G F R d at a a n d me dical 
m o nit or discreti o n.
Secti o n 3. 2. 1. 1, 
Scree ni n g Peri o d ( u p t o 
D a y -4 3)
N o i n vesti gati o nal treat me nts will be 
a d mi nistere d d uri n g t he scree ni n g 
p eri o d.  D uri n g t his peri o d , t he 
s u bject’s eli gi bilit y f or t he trial will 
be c o nfir me d usi n g hist orical 
i ma gi n g data of t otal ki d ne y v ol u me 
( T K V; if a vaila ble) t o s u p p ort a 
dia g n osis of A D P K D a n d t o verif y 
t he le vel of C K D pri maril y d ue t o 
A D P K D a n d n ot t o ot her re nal 
( h y p o plasia) or meta b olic ( dia betic or 
h y perte nsi ve ne p hr o pat h y) dis or ders .
N o i n vesti gati o nal treat me nts will be 
a d mi nistere d d uri n g t he scree ni n g 
peri o d.  D uri n g t his peri o d , t he 
s u bject’s eli gi bilit y f or t he trial will 
be c o nfir me d usi n g hist orical 
i ma gi n g data t o s u p p ort a dia g n osis 
of A D P K D a n d t o verif y t he le vel of 
C K D pri maril y d ue t o A D P K D a n d 
n ot t o ot her re nal ( h y p o plasia) or 
meta b olic ( dia betic or h y perte nsi ve 
ne p hr o pat h y) dis or ders .
Secti o n 3. 4. 2, I ncl usi o n 
Criteria, Ta ble 3. 4. 2 -1, 
I ncl usi o n Criteria
2. Male a n d fe male s u bjects a ge 5 6 t o 
< 6 6 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 4 4 m L/ mi n/ 1. 7 3 m 2
( b y me dical m o nit or discreti o n, 
o nl y).
2. Male a n d fe male s u bjects a ge 5 6 t o 
< 6 6 years of a ge wit h e G F R 
bet w ee n 2 5 a n d 4 4 m L/ mi n/ 1. 7 3 m 2
wit h e vi de nce of A D P K D
pr o gressi o n , ie, e G F R decli ne of 
> 2. 0 m L/ mi n/ 1. 7 3
m 2 per ye ar , 
b ase d o n hist oric al e G F R d at a a n d 
me dic al m o nit or discreti o n.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 3
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
Secti o n 3. 7, 
Ta ble 3. 7 -1, Sc he d ule 
of Assess me nts 
F oll o w  u p c ol u m n has t he t w o 
s u b hea ders bel o w:
3 w ee k s p ost-treat me nt
D a y s + 7 t o + 2 1 (-2 da ys) p ost fi nal 
visit a
I n t he assess me nt r o w calle d Li ver 
F u ncti o n Pa nel, a n X is mar ke d f or 
D a y -1 d uri n g t he t ol va pta n r u n -i n. 
I n t he assess me nt r o w calle d P D a n d 
Bi o mar ker uri ne sa m ple a n X wit h 
f o ot n ote g occ urs o nl y o nce.  All 
ot her Xs i n t his r o w  d o n ot ha ve a 
f o ot n ote. 
I n t he I V R S e ntr y r o w i n t he c ol u m ns 
u n der T ol va pta n titrati o n, Xs occ ur 
f or Da ys -3 2, -2 8, -2 4, a n d -2 2. 
F o ot n ote a
T he scree ni n g peri o d s h o ul d be 
c o m plete d wit hi n 1-2 wee ks bef ore 
t he start of t he place b o r u n-i n peri o d.  
T he scree ni n g peri o d ma y be 
e xte n de d u p t o a n a d diti o nal 8 wee ks 
f or s u bjects w h o re q uire m o dificati o n 
of me dical care s pecificall y f or t his 
trial.  Visits d uri n g t he scree ni n g a n d 
f oll o w-u p peri o ds m ust be sc he d ule d 
at least 2 4 h o urs ( 1 da y) a part.  T he 
D a y  -4 3 visit ca n n ot occ ur u ntil 
la b orat or y val ues fr o m V 2 are 
recei ve d.  F or t wo visits ( V 1, V 2) 
d uri n g t he scree ni n g peri o d, bl o o d 
will be c ollecte d a n d a nal yze d 
ce ntrall y f or ser u m creati ni ne 
co nce ntrati o ns, i n a d diti o n t o a n y 
ot her assess me nts liste d.  A visiti n g 
n urse h o use call or l ocal la b orat or y 
visit ma y be s u bstit ute d f or visits 
w here o nl y bl o o d/ uri ne will be 
c ollecte d d uri n g t he f oll o w -u p 
peri o d.  Visits d uri n g t he f oll o w - u p 
peri o d m ust be sc he d ule d d uri n g a 2 -
wee k peri o d t hat be gi ns 1 w ee k after 
t he e n d of treat me nt visit.
F oll o w  u p c ol u m n has t he t w o 
s u b hea ders bel o w:
3 w ee ks p ost -treat me nta
Da y s + 8 t o + 2 1 
T he r o w  be neat h has V 1, V 2, a n d V 3 
a d de d t o s h o w t he t hree visit dates 
m o re clearl y.
I n t he assess me nt r o w calle d Li ver 
F u ncti o n Pa nel, a n X is mar ke d f or 
Da y -8 d uri n g t he t ol va pta n r u n -i n, 
a n d t he X mar ke d f or Da y -1 has 
bee n delete d.
E ver y X is t he assess me nt r o w calle d 
P D a n d Bi o mar ker uri ne sa m ple ha s
f o ot n ote g.
I n t he I V R S e ntr y r o w, t he X f or 
Scree ni n g V 2 has bee n delete d, a n d
i n t he c ol u m ns u n der T ol va pta n 
titrati o n, a n X occ urs f or Da y -2 2 
o nl y.
F o ot n ote a
T he scree ni n g peri o d s h o ul d be 
c o m plete d wit hi n 1 -2 wee ks bef ore 
t he start of t he place b o r u n-i n peri o d.  
T he scree ni n g peri o d ma y be 
e xte n de d u p t o a n a d diti o nal 8 wee ks 
f or s u bjects w h o re q uire m o dificati o n 
of me dical care s pecificall y f or t his 
trial.  Visits d uri n g t he scree ni n g a n d 
f oll o w-u p peri o ds m ust be sc he d ule d 
at least 2 4 h o urs ( 1 da y) a part.  T he 
Da y  -4 3 visit ca n n ot occ ur u ntil 
la b orat or y val ues fr o m V 2 are 
recei ve d.  F or t wo visits ( V 1, V 2) 
d uri n g t he scree ni n g peri o d, bl o o d 
will be c ollecte d a n d a nal yze d 
ce ntrall y f or ser u m creati ni ne 
c o nce ntrati o ns, i n a d diti o n t o a n y 
ot her assess me nts liste d.  A visiti n g 
n urse h o use call or l ocal la b orat or y 
visit ma y be s u bstit ute d f or visits 
w here o nl y bl o o d/ uri ne will be 
c ollecte d d uri n g t he f oll o w -u p ( F/ U) 
peri o d.  T hree visits i n t he F/ U peri o d 
s h o ul d be sc he d ule d bet wee n Da y 8 
a n d Da y 2 1 (i ncl usi ve) after t he last 
d ose of I M P .  N o F/ U assess me nts 
will be ta ke n d uri n g t he first wee k of 
t his peri o d.  Bl o o d sa m ples will be 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 4
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
F o ot n ote f
fAll ser u m creati ni ne sa m ples will 
be a nal yze d b y t he ce ntral 
la b orat or y.  T he s pecifics a n d 
ti mi n g f or all cli nical 
la b orat or y sa m ples f or ce ntral 
a n d l ocal la b orat or y a nal yses 
are as f oll o ws:
All visits: O ne or m ore t u bes of 
bl o o d ma y be c ollecte d t o 
acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 
1 -2 w ee ks of t he scree ni n g 
peri o d, bl o o d will be dra w n 2 
ti mes o n se parate da ys ( V 1, 
V 2) at least 2 4 h o urs a part.  
T he s u bject’s eli gi bilit y will be 
c o nfir me d b y t he mea n of 
e G F R calc ulate d fr o m t he 
s u bjects’ 2 pre-treat me nt ( V 1, 
V 2), ce ntral la b orat or y ser u m 
creati ni ne assess me nts a n d 
e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  
S u bje cts will ha ve 1 bl o o d 
dr a w  at t he e n d of 1 wee k wit h 
t he sa m ple bei n g o btai ne d o n 
D a y  -3 6.
T ol v a pt a n titr ati o n peri o d:   
S u bjects will ha ve 1 bl o o d 
dr a w  at t he e n d of 2 wee ks wit h 
t he sa m ple bei n g o btai ne d o n 
D a y  -2 2.
T ol v a pt a n r u n -i n peri o d:  
D uri n g t he last 2 wee ks of t his 
peri o d, bl o o d will be dra w n 2 
ti mes o n se parate da ys (at least 
2 4 h o urs a part) w it h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt 
peri o d:   Sa m ples will be 
c ollecte d f or ce ntral la b 
a nal ysis m o nt hl y a n d at t he 
M o nt h 1 2 / E o T x visit.  L ocal 
sta n dar d of care la b orat or y tests 
will be perf or me d m o nt hl y per 
t he s u bject’s i n di vi d ual cli nical 
ma na ge me nt nee ds.  L ocal li ver 
f u ncti o n pa nel a nal yses will 
dr a w n at eac h visit f or ser u m 
creati ni ne ( V 1, V 2) a n d ser u m 
creati ni ne a n d ot her safet y, efficac y, 
P K a n d P D meas ure me nts ( V 3). 
F o ot n ote f
fAll ser u m creati ni ne sa m ples will 
be a nal yze d b y t he ce ntral 
lab orat or y.  T he s pecifics a n d 
ti mi n g f or all cli nical 
la b orat or y sa m ples f or ce ntral 
a n d l ocal la b orat or y a nal yses 
are as f oll o ws:
All visits:
O ne or m ore t u bes 
of bl o o d ma y be c ollecte d t o 
acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 
1 -2 we e ks of t he scree ni n g 
peri o d, bl o o d will be dra w n 2 
ti mes o n se parate da ys ( V 1, 
V 2) at least 2 4 h o urs a part.  
T he s u bject’s eli gi bilit y will be 
c o nfir me d b y t he mea n of 
e G F R calc ulate d fr o m t he 
s u bjects’ 2 pre-treat me nt ( V 1, 
V 2), ce ntral la b orat or y ser u m 
creati ni ne assess me nts a n d 
e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  
S u bjects will ha ve 1 bl o o d 
dr a w  at t he e n d of 1 wee k wit h 
t he sa m ple bei n g o btai ne d o n 
Da y  -3 6.
T ol v a pt a n titr ati o n peri o d:   
S u bjects will ha ve 1 bl o o d 
dr a w  at t he e n d of 2 wee ks wit h 
t he sa m ple bei n g o btai ne d o n 
Da y  -2 2.
T ol v a pt a n r u n -i n peri o d:  
D uri n g t he last 2 wee ks of t his 
peri o d, bl o o d will be dra w n 
2 ti mes o n se parate da ys (at 
least 2 4 h o urs a part) wit h t he 
last sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt 
peri o d:   Sa m ples will be 
c ollecte d f or ce ntral la b 
a nal ysis m o nt hl y a n d at t he 
M o nt h 1 2/ E o T x visit.  L ocal 
sta n dar d of care la b orat or y tests 
will be perf or me d m o nt hl y per 
t he s u bject’s i n di vi d ual cli nical 
ma na ge me nt nee ds.  L ocal li ver 
f u ncti o n pa nel a nal yses will 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 5
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
als o be perf or me d m ore 
fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects 
will ha ve bl o o d dra w n o n 3 
visits o ver Da ys + 7 t o + 2 1 
p ost -treat me nt.
    F ull C he mistr y pa nel will be 
o btai ne d d uri n g f oll o wi n g visit: 
Scree ni n g ( V 1), q uarterl y visit 
( M 3, M 6, M 9, M 1 2/ E o T x, F/ U 
peri o d Da y 2 1
    Ser u m creati ni ne, ser u m 
s o di u m,: Scree ni n g ( V 2), e n d 
of place b o peri o d, e n d of
t ol va ptan titrati o n, 2 ti mes 
d uri n g t ol va pta n r u n -i n, 
m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, 2 ti mes 
d uri n g F/ U peri o d
    Li ver f u ncti o n pa nel: Scree ni n g 
( V 2), e n d of place b o peri o d, 
e n d of t ol va pta n titrati o n, 2
ti mes d uri n g t ol va pta n r u n-i n, 
m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d 
D a y  2 1
F o ot n ote g:
gD uri n g t he d o u ble -bli n d, 
ra n d o mize d treat me nt peri o d, P K 
plas ma sa m ples, P D uri ne sa m ples, 
a n d bi o mar ker uri ne/ plas ma sa m ples 
will be c ol lecte d q uarterl y (e g, 
M o nt hs 3, 6, 9, 1 2/ E o T x).   
F o ot n ote h:
hD N A sa m ples are o pti o nal.
als o be perf or me d m ore 
fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects 
will ha ve bl o o d dra w n o n 
3 visits at least 2 4 h o urs a part 
d uri n g t he 3 -wee k peri o d ,
w hic h starts after t he last d ose 
of I M P .  Visits s h o ul d be 
sc he d ule d bet wee n Da ys 8 a n d 
2 1 , i ncl usi ve.
    F ull C he mistr y pa nel will be 
o btai ne d d uri n g t he f oll o wi n g 
visit s: Scree ni n g ( V 1), 
q uarterl y visit ( M 3, M 6, M 9, 
M 1 2/ E o T x, F/ U peri o d ( V 3)
    Ser u m creati ni ne, ser u m 
s o di u m: Scree ni n g ( V 2), e n d of 
place b o peri o d, e n d of
t ol va ptan titrati o n, 2 ti mes 
d uri n g t ol va pta n r u n -i n, 
m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, 3 ti mes f or 
ser u m creati ni ne a n d 1 ti me f or 
ser u m s o di u m ( V 3) d uri n g t he 
F/ U peri o d .  N ote t hat t he first 
F/ U visit will occ ur at least
7 da ys ( Da y 8) after t he last 
d ose of I M P.
    Li ver f u ncti o n pa nel: Scree ni n g 
( V 2), e n d of place b o peri o d, 
e n d of t ol va pta n titrati o n, 
1 ti me d uri n g t ol va pta n r u n-i n, 
m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d 
( V 3).
F o ot n ote g:
gD uri n g t he d o u ble -bli n d, 
ra n d o mize d treat me nt peri od, P K 
plas ma sa m ples, P D uri ne sa m ples, 
a n d bi o mar ker uri ne/ plas ma sa m ples 
will be c ollecte d q uarterl y (e g, 
M o nt hs 3, 6, 9, 1 2/ E o T x).  Uri ne 
bi o mar ker s s h o ul d be c ollecte d as a 
mi d -strea m, clea n-catc h sa m ple
d uri n g t he sec o n d m or ni n g v oi d pri or 
t o t he s u bject eati n g brea kfast. 
W here necessar y, s u p plies f or 
c ollecti o n s h o ul d be dis pe nse d pri or 
t o t he visit wit h i nstr ucti o ns t o c ollect 
t he uri ne sa m ple o n t he da y of t he
visit.
F o ot n ote h:
hD N A sa m ples are o pti o nal a n d ma y 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 6
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
F o ot n ote j:
jIf, d uri n g t he titrati o n c o ntact, t he 
deter mi nati o n is ma de t o a dj ust t he 
d ose -re gi me n, t he i n vesti gat or will 
e nter t he s u bject’s stat us i n t he I V R S 
a n d arra n ge f or dis pe nsati o n of a ne w 
I M P kit a n d rec o nciliati o n of 
ret ur ne d I MP.  At t he e n d of t he 
titrati o n peri o d, t he s u bject’s hi g hest 
t olerate d d ose will be utilize d f or t he 
3- wee k t ol va pta n r u n -i n peri o d.
be c ollecte d at s u bse q ue nt visits wit h 
s u bject’s c o nse nt.
F o ot n ote j:
jAt t he e n d of t he titrati o n peri o d, t he 
s u bject’s hi g hest t olerate d d ose will 
be utilize d f or t he 3 -wee k t ol va pta n 
r u n-i n peri o d.
Secti o n 3. 7. 1. 1 . 1, 
Scree ni n g Peri o d ( u p t o 
D a y -4 3)
1 6) C ollect bl o o d f or D N A sa m ple 
(sec o n d visit, f or c o nse nti n g s u bjects 
o nl y)
1 6) C ollect bl o o d f or D N A sa m ple 
(sec o n d visit, f or c o nse nti n g s u bjects 
o nl y).  D N A sa m ples ma y be 
c ollecte d at a s u bse q ue nt visit if 
s u bjects c o nse nt at a later date.
Secti o n 3. 7. 1. 1. 3, 
T ol va pta n Titrati o n 
Peri o d ( Da ys -3 5 
t o -2 2)
8) U p date s u bject stat us i n I V R S at 
eac h u p war d titrati o n visit
8) U p date s u bject stat us i n I V R S o n 
Da y -2 2
Secti o n 3. 7. 1. 1. 4, 
T ol va pta n R u n -I n 
Peri o d ( Da ys -2 1 t o -1)
Assess me nts d uri n g t he t ol va pta n 
ru n -i n peri o d will i ncl u de ( See 
Ta ble 3. 7 -1):
…
5)   C ollect bl o o d ( 2 ti mes o n se parate 
da ys d uri n g t he last 2 wee ks of t he 
peri o d, w ith t he last sa m ple dra w n o n 
D a y  -1) f or ser u m creati ni ne f or 
e G F R calc ulati o n a n d f or assess me nt 
of s o di u m a n d li ver f u ncti o n pa nel 
(see Secti o n 3. 7. 3. 2).  If s o di u m a n d 
li ver f u ncti o n pa nel are c ollecte d at 
t he sa me visit, a si n gle t u be of bl o o d 
s h o ul d be dra w n f or all assess me nts.
Assess me nts d uri n g t he t ol va pta n 
r u n-i n peri o d will i ncl u de ( See 
Ta ble 3. 7 -1):
…
5)  C ollect bl o o d ( 2 ti mes o n se parate 
da ys d uri n g t he last 2 wee ks of t he 
peri o d, w it h t he last sa m ple dra w n o n 
Da y  -1) f or ser u m creati ni ne f or 
e G F R calc ulati o n a n d f or 1
assess me nt of s o di u m a n d li ver 
f u ncti o n pa nel (see Secti o n 3. 7. 3. 2).  
If s o di u m a n d li ver f u ncti o n pa nel are 
c ollecte d at t he sa me visit, a si n gle 
t u be of bl o o d s h o ul d be dra w n f or all 
assess me nts.
Secti o n 3. 7. 1. 2, 
D o u ble -bli n d, 
Ra n d o mize d Treat me nt 
Peri o d ( Da y 0 t o 
M o nt h
1 2)
Re gar dless of disc o nti n uati o n of 
I M P, t he s u bjects are e x pecte d t o 
c o m plete all m o nt hl y visits a n d 
assess me nts i ncl u di n g t he M o nt h 1 2 
visit . 
… (e n u merate d list of assess me nts)
1 3) U p date s u bject stat us i n I V R S 
( mo nt hl y a n d at t h e M o nt h 1 2/ E o T x 
visit)
1 4) Dis pe nse I M P at m o nt hl y visits 
u p t o a n d i ncl u di n g M o nt h 1 1.  I n 
certai n circ u msta nces, wit h me dical 
m o nit or a p pr o val, a 3 -m o nt h dr u g 
s u p pl y ma y be pr o vi de d; h o we ver, 
i nitiati o n of t he ne xt m o nt h’s s u p pl y 
m ust be directe d b y t he site.
Re gar dless of disc o nti n uati o n of 
I M P, t he s u bjects are e x pecte d t o 
c o m plete all m o nt hl y visits a n d 
assess me nts i ncl u di n g t he M o nt h 1 2 
visit (see Secti o n 3. 8. 3. 3).
… (e n u merate d list of assess me nts)
1 3) As k s u bject “ C a n y o u t oler ate 
t his d ose of tri al me dic ati o n f or t he 
rest of y o ur life ? ” at e ac h visit
1 4) U p date s u bject stat us i n I V R S 
( mo nt hl y a n d at t he M o nt h 1 2/ E o T x 
visit)
1 5) Dis pe nse I M P at m o nt hl y visits 
u p t o a n d i ncl u di n g M o nt h 1 1.  I n 
certai n circ u msta nces, wit h me dical 
m o nit or a p pr o val, a 3 -m o nt h dr u g 
s u p pl y ma y be pr o vi de d; h o we ver, 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 7
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
i nitiati o n of t he ne xt m o nt h’s s u p pl y 
m ust be directe d b y t he site.
Secti o n 3. 7. 1. 3, F oll o w -
u p Peri o d 
( M o nt h 1 2/ E n d of 
Treat me nt t o Da y 2 1 
P ost -treat me nt)
Ra n d o mize d s u bjects will e nter t he 
f oll o w-u p peri o d after t he y c o m plete 
t he d o u ble-bli n d, ra n d o mize d 
treat me nt peri o d, or after t heir E o T x 
visit, if t he y disc o nti n ue d I M P.  T he 
f oll o w-u p peri o d will be f or 2 1 da ys 
i n d urati o n.
T here w ill be n o sc he d ule d 
visits/assess me nts d uri n g t he first 
wee k of t he f oll o w -u p peri o d.  After 
t he first wee k, 3 visits s h o ul d be 
sc he d ule d d uri n g t he re mai ni n g 
2 we e ks of t he f oll o w-u p peri o d 
( bet wee n Da y + 7 a n d Da y + 2 1).  T he 
first visit s h o ul d be sc he d ule d o n 
a p pr o xi matel y Da y + 7, t he sec o n d 
visit o n a p pr o xi matel y Da y + 1 4 a n d 
the t hir d visit o n a p pr o xi matel y 
D a y + 2 1 ( -2 da ys).  T hese visits ma y 
be visiti n g n urse h o use calls or l ocal 
la b orat or y visits w he n o nl y bl o o d 
sa m ples will be c ollecte d, w it h t he 
e xce pti o n of t he last visit, w hic h will 
be a cli nic visit .
Assess me nts d uri n g t he last 2 wee ks 
of t he f oll o w -u p peri o d will i ncl u de 
( See Ta ble 3. 7 -1):
…
6)   C ollect bl o o d f or assess me nt of 
s o di u m le vels at t he first visit (see 
Secti o n 3. 7. 3. 2)
F or all ra n d o mize d s u bjects, t he 
3 -wee k f oll o w -u p peri o d starts 
i m me diatel y after t he last d ose of 
I M P.  N o f oll o w-u p assess me nts will 
be ta ke n d uri n g t he first wee k of t his 
peri o d.  D uri n g t he last 2 we e ks, 
Da y s 8 t hr o u g h 2 1, i ncl usi ve, 
3 f oll o w-u p visits will be sc he d ule d.  
T he visits m ust occ ur at least 
2 4 h o urs a part.  Bl o o d sa m ples will 
be c ollecte d at eac h visit f or ser u m 
creati ni ne meas ure me nts.  T he bl o o d 
sa m ple c ollecte d at t he last f oll o w- u p 
visit will als o i ncl u de meas ure me nt s 
of p ost -treat me nt efficac y a n d safet y. 
T hese visits ma y be visiti n g n urse 
h o use calls or l ocal la b orat or y v isits 
w he n o nl y bl o o d sa m ples will be 
c ollecte d, wit h t he e xce pti o n of t he 
last visit, w hic h will be a cli nic visit.  
Assess me nts d uri n g t he last 2 wee ks 
of t he f oll o w -u p peri o d will i ncl u de 
( See Ta ble 3. 7 -1):
…
6)   C ollect bl o o d f or assess me nt of 
s o di u m le vels at t he l ast visit (see 
Secti o n 3. 7. 3. 2)
Secti o n 3. 7. 3. 2, Cli nical 
La b orat or y 
Assess me nts
• d uri n g t ol va pta n r u n -i n - uri nal ysis 
( Da y -1), li ver f u ncti o n pa nel, 
creati ni ne, a n d s o di u m ( 2 ti mes o n 
se parate da ys d uri n g t he last 2 wee ks 
of t he peri o d, w it h t he last sa m ple 
dr a w n o n Da y - 1
• d uri n g t he f oll o w -u p peri o d ( 3 
visits t hat be gi n 1 w ee k after t he 
M o nt h
1 2/ E o T x visit) - creati ni ne 
( 3 visits), s o di u m (first visit), li ver 
f u ncti o n pa nel a n d ser u m c he mistr y 
pa nel (last visit)

d uri n g t ol va pta n r u n -i n - li ver 
f u ncti o n pa nel ( Da y-8), 
uri nal ysis ( Da y -1), creati ni ne, 
( 2 ti mes o n se parate da ys d uri n g 
t he last 2 wee ks of t he peri o d, 
wit h t he last sa m ple dra w n o n 
Da y  -1), a n d s o di u m ( Da y -1)
•d uri n g t he 3- wee k f oll o w-u p peri o d 
( 3 visits t hat occ ur bet wee n Da y s 8 
a n d 2 1, i ncl usi ve, after t he last d ose 
of I M P, a n d at least 2 4 h o urs a part) -
creati ni ne ( 3 visits), s o di u m (first 
visit), li ver f u ncti o n pa nel a n d ser u m 
c he mistr y pa nel (last visit)
S ecti o n 3. 7. 3. 5. 3, D N A 
Bl o o d Sa m ples
A bl o o d sa m ple f or D N A c ollecti o n 
will be o btai ne d f or e ver y c o nse nti n g 
s u bject at t he sec o n d visit of t he 
scree ni n g peri o d.
A bl o o d sa m ple f or D N A c ollecti o n 
will be o btai ne d fr o m e ver y 
c o nse nti n g s u bject at t he sec o n d visit 
of t he scree ni n g peri o d .  Sa m ples 
ma y be c ollecte d at a s u bse q ue nt visit 
if s u bjects pr o vi de c o nse nt after t he 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 8
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
sec o n d visit of t he scree ni n g peri o d.  
Secti o n 3. 8. 3. 3, 
Treat me nt 
Disc o nti n uati o n
A s u bject w h o per ma ne ntl y 
disc o nti n ues treat me nt will be 
rec or de d as a n I M P disc o nti n uati o n 
o n t he e C R F.  T he y will ha ve a n 
E o T x visit t o c ollect vital si g ns, 
p h ysical e xa m, ser u m creati ni ne 
assess me nt, cli nical la b orat or y 
assess me nts, P K/ P D sa m ples, a n d 
bi o mar ker uri ne/ plas ma sa m ples.  
T he s u bject will t he n e nter t he 
f oll o w-u p peri o d as t h o u g h t he y ha d 
reac he d t he M o nt h 1 2 visit.  D uri n g 
t he first wee k of t he f oll o w-u p 
peri o d, n o pr oce d ures will be d o ne.  
D uri n g t he last t w o wee ks of t he 
f oll o w-u p peri o d, t he s u bject will 
ha ve a t otal of 3 sa m ples c ollecte d 
f or ser u m creati ni ne meas ure me nts.  
A s u bject w h o per ma ne ntl y 
disc o nti n ues treat me nt will be 
rec or de d as a n I M P disc o nti n uati o n 
o n t he e C R F.  T he y will ha ve a n 
E o T x visit , w hic h s h o ul d be 
sc he d ule d as s o o n as p ossi ble after 
t he s u bject’s last d ose of I M P, t o
c ollect vital si g ns, p h ysical e xa m, 
ser u m creati ni ne assess me nt, cli nical 
la b orat or y assess me nts, P K/ P D 
sa m ples, a n d bi o mar ker uri ne/ plas ma 
sa m ples.  T he s u bject’s f oll o w- u p 
peri o d will be 3 we e ks as t h o u g h 
t he y ha d reac he d t he M o nt h 1 2 visit, 
a n d t he f oll o w-u p peri o d will start 
after t he last da y of treat me nt, w hic h 
ma y be a differe nt da y fr o m t he 
E o T x visit .  N o f oll o w-u p 
assess me nts will be ta ke n d uri n g t he 
first wee k of t his peri o d.  T here w ill 
be t hree visits i n t he f oll o w  u p peri o d 
bet w ee n Da y 8 a n d Da y 2 1.  T he first 
t wo will be f or t he c ollecti o n of 
ser u m creati ni ne meas ure me nt a n d 
t he t hir d will ha ve a d diti o nal safet y, 
efficac y, P K, a n d P D meas ure me nts.
Secti o n 3. 1 3, Pr ot oc ol 
De viati o ns
I n t he e ve nt of a si g nifica nt de viati o n 
fr o m t he pr ot oc ol d ue t o a n 
e mer ge nc y, acci de nt, or mista ke (e g, 
vi olati o n of i nf or me d c o nse nt 
pr ocess, I M P dis pe nsi n g or s u bject 
d osi n g err or, treat me nt assi g n me nt 
err or, s u bject e nr olle d i n vi olati o n of 
eli gi bilit y criteria or c o nc o mita nt 
me dicati o n criteria), t he i n vesti gat or 
or desi g nee will c o ntact t he s p o ns or 
at t he earliest p ossi ble ti me b y 
tele p h o ne.
I n t he e ve nt of a si g nifica nt de viati o n 
fr o m t he pr ot oc ol d ue t o a n 
e mer ge nc y, acci de nt, or mista ke (e g, 
vi olati o n of i nf or me d c o nse nt 
pr ocess, I M P dis pe nsi n g or s u bject
d osi n g err or, treat me nt assi g n me nt 
err or, s u bject e nr olle d i n vi olati o n of 
eli gi bilit y criteria or c o nc o mita nt 
me dicati o n criteria), t he i n vesti gat or 
or desi g nee will c o ntact t he me dic al 
m o nit or at t he earliest p ossi ble ti me 
b y tele p h o ne .
Secti o n 5. 1, De fi niti o ns
A s us pecte d a d verse reacti o n mea ns 
a n y A E f or w hic h t here is a 
reas o na ble p ossi bilit y t hat t he dr u g 
ca use d t he A E.  F or t he p ur p ose of 
I N D safet y re p orti n g, “reas o na ble 
p ossi bilit y” mea ns t here is e vi de nce 
t o s u g gest a ca usal relati o ns hi p 
bet w e e n t he dr u g a n d t he A E.  
S us pecte d a d verse reacti o n i m plies a 
lesser de gree of certai nt y a b o ut 
ca usalit y.  A d diti o nall y, i n t he 
E ur o pea n U ni o n ( E U), a n a d verse 
pr oce d ure -relate d reacti o n is a n y 
n o xi o us or u ni nte n de d res p o nse t o a 
trial-relate d pr oce d ure a n d re q uires a 
A s us pecte d a d verse reacti o n mea ns 
a n y A E f or w hic h t here is a 
reas o na ble p ossi bilit y t hat t he dr u g 
ca use d t he A E.  F or t he p ur p ose of 
I N D safet y re p orti n g, “reas o na ble 
p ossi bilit y” mea ns t here is e vi de nce 
t o s u g gest a ca usal relati o ns hi p 
bet w ee n t he dr u g a n d t he A E.  
S us pecte d a d verse reacti o n i m plies a 
lesser de gree of certai nt y a b o ut 
ca usalit y.   

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 4 9
2 6 Mar 2 0 1 5 
L oc ati o n
Ol d Te xt
U p d ate d Te xt
S U S A R re p ort. 
Secti o n 5. 3, 
I m me diatel y Re p orta ble 
E ve nts
T he i n vesti gat or m ust i m me diatel y 
re p ort wit hi n 2 4 h o urs after eit her t he 
i n vesti gat or or site pers o n nel bec o me 
a ware of a n y S A E, ne w li ver la b 
a b n or malit y re q uiri n g s pecial li ver 
e C R F c o m pleti o n, or c o nfir me d 
pre g na nc y, b y tele p h o ne or b y fa x t o 
t he s p o ns or as o utli ne d i n 
A p pe n di x 1.  A n I R E f or m m ust be 
c o m plete d a n d se nt b y fa x or 
o ver ni g ht c o urier t o t he s p o ns or.  
( Please n ote t hat t he I R E f or m is 
N O T t he A E e C R F.)
T he i n vesti gat or m ust i m me diatel y 
re p ort wit hi n 2 4 h o urs after eit her t he 
i n vesti gat or or site pers o n nel bec o me 
a ware of a n y S A E, ne w li ver la b 
a b n or malit y re q uiri n g s pecial li ver
e C R F c o m pleti o n, or c o nfir me d 
pre g na nc y, b y tele p h o ne or b y fa x t o 
Q ui ntiles dr u g s afet y ser vices as 
o utli ne d i n A p pe n di x 1.  A n I R E 
f or m m ust be c o m plete d a n d se nt b y 
fa x or o ver ni g ht c o urier t o t he 
s p o ns or.  ( Please n ote t hat t he I R E 
f or m is N O T t he A E e C R F.)
A p pe n di x 1
Gl o bal Cli nical Ma na ge me nt
La urie De b u q ue
Sr. Ma na ger, Gl o bal Cli nical 
De vel o p me nt
Ots u ka P har mace utical De vel o p me nt 
& C o m mercializati o n, I nc.
1 U ni versit y S q uare Dri ve
S uite 5 0 0
Pri ncet o n, NJ 0 8 5 4 0, U S A
P h o ne:  + 1 -6 0 9 -5 2 4 -6 8 9 4; Fa x + 1 -
2 4 0 -5 1 4 -3 9 9 4
Gl o bal Cli nical Ma na ge me nt
La urie De b u q ue
Sr. Ma na ger, Gl o bal Cli nical 
De vel o p me nt
Ots u ka P har mace utical De vel o p me nt 
& C o m mercializati o n, I nc.
5 0 6 Car ne gie Ce nter
Pri ncet o n, NJ 0 8 5 4 0, U S A
P h o ne:  + 1 -6 0 9 -5 2 4 -6 8 9 4; Fa x + 1 -
2 4 0 -5 1 4 -3 9 9 4
A p pe n d i x 2
…
I n vesti gat or Pa y me nts
C F S Cli nical
1 0 0 0 Ma dis o n A ve, 1st Fl o or
A u d u b o n, P A 1 9 4 0 3 , U S A
P h o ne: 
 
Fa x: 
…
D N A Sa m ple St ora ge
Ge ntris C or p orati o n
1 3 3 S o ut hce nter C o urt, S uite 4 0 0
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne: 
…
I n vesti gat or Pa y me nts
Q ui ntiles
5 9 2 7 S o ut h Mia mi Bl v d
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne:  
M o bile: 
Fa x: 
…
D N A Sa m ple St ora ge
Ca ncer Ge n etics, I nc.
1 3 3 S o ut hce nter C o urt, S uite 4 0 0
M orris ville, N C 2 7 5 6 0 , U S A
P h o ne: 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 0
2 6 Mar 2 0 1 5 
Pre vi o us Sc he d ule of Assess me nts
T a ble 3. 7 - 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1)
( D a y 
0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1 
(- 2 d a ys)
p ost -fi n al visita
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n
X
D e m o gr a p hic/ Me dic al hist or y
X
Vit al si g ns c
X
X 
X
X
X
( X)c
X
X
P h ysic al e x a mi n ati o n d
X
( X)d
X
Uri ne pre g n a nc y test ( W O C B P 
o nl y) e
X
X
( X)e
X
X
C he mistr y Bl o o d S a m ple c,f:
   Ser u m C he mistr y Pa nel
X
X
X
   Li ver F u ncti o n Pa nel
X  
X
X
X
X
X  
X
X
   Creati ni ne
X
X 
X
X  
X  
X
X  
X  
X  
X  
X
   S o di u m
X  
X
X
X
X
X  
X
X
H e m at ol o g y a n d c o a g ul ati o n
X
P K pl as m a s a m ple
X
( X)g
X
X
Bi o m ar ker pl as m a s a m ple
X
X
X
X
( X)g
X
X

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 1
2 6 Mar 2 0 1 5 
T a ble 3. 7 - 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1)
( D a y 
0)
Visits:
m o nt hl y
( ± 2 d a ys)
M o nt h
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 7 t o + 2 1 
(- 2 d a ys)
p ost -fi n al visita
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
D N A bl o o d s a m ple h
X
Uri n al ysis
X
X 
X
X
X
P D a n d Bi o m ar ker uri ne 
s a m ple
X
X
X
X
( X)g
X
X
St art ne wl y dis pe nse d I M P
X  
X
X
X
T oler a bilit y/ D osi n g re vie w
X  
X  
X  
X  
X
X
X  
X
R a n d o miz ati o n
X
Dr u g dis pe ns ati o n i
X  
X
X
X
X
Dr u g rec o ncili ati o n i
X
X
X
X  
X
I V R S e ntr yj
X  
X  
X  
X  
X  
X  
X  
X
X
X  
X
X
E x pl or at or y P K D o utc o m es k
X
X
X  
X
A d verse e ve nts
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>
C o nc o m it a nt me dic ati o ns
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>
aT he scree ni n g peri o d s h o ul d be c o m plete d wit hi n 1 -2 w ee ks bef ore t he start of t he place b o r u n -i n peri o d.  T he scree ni n g peri o d ma y be e xte n de d u p t o a n 
a d diti o nal 8 wee ks f or s u bjects w h o re q uire m o dificati o n of me dical care s pecificall y f or t his trial. V isits d uri n g t he scree ni n g a n d f oll o w-u p peri o ds m ust 
be sc he d ule d at least 2 4 h o urs ( 1 da y) a part.  T he Da y -4 3 visit ca n n ot occ ur u ntil la b orat or y val ues fr o m V 2 are recei ve d.  F or t w o visits ( V 1, V 2) d uri n g 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 2
2 6 Mar 2 0 1 5 
t he scree ni n g peri o d, bl o o d will be c ollecte d a n d a nal yze d ce ntrall y f or ser u m creati ni ne c o nce ntrati o ns, i n a d diti o n t o a n y ot her assess me nts liste d.  A 
visiti n g n urse h o use call or l ocal la b orat or y visit ma y be s u bstit ute d f or visits w here o nl y bl o o d/ uri ne will be c ollecte d d u ri n g t he f oll o w-u p peri o d.  Visits 
d uri n g t he f oll o w -u p peri o d m ust be sc he d ule d d uri n g a 2 -wee k peri o d t hat be gi ns 1 w ee k after t he e n d of treat me nt visit.
b If I M P treat me nt is i nterr u pte d f or 7 da ys d uri n g t his peri o d, pr oce d ures s h o ul d be f oll o we d as detaile d i n Secti o n 3. 8. 3. 2 .
cT he f oll o w i n g visits (a n d all assess me nts re q uire d d uri n g t h ose visits) s h o ul d be perf or me d i n-cli nic: scree ni n g ( V 1, V 2, Da y -4 3), e n d of place b o r u n -i n, e n d 
of t ol va pta n titrati o n, e n d of t ol va pta n r u n-i n, q uarterl y visits d uri n g t he ra n d o mize d, d o u ble-bli n d treat me nt peri o d (e g, M o nt hs 3, 6, 9), M o nt h 1 2/e n d of 
treat me nt ( E o T x) visit, a n d t he last f oll o w-u p visit.  Vital si g ns at eac h of t he a b o ve visits i ncl u de sitti n g heart rate a n d bl o o d press ure.  P ost -v oi d b o d y 
wei g ht s h o ul d be meas ure d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit o nl y.  Hei g ht s h o ul d be assesse d at t he fi rst scree ni n g visit o nl y.  Eit her 
hei g ht or wei g ht ma y be c ollecte d as a n u nsc he d ule d meas ure me nt if the pla n ne d assess me nt was misse d .  Wei g ht ma y be assesse d as necessar y t o assess 
c ha n ges i n b o d y wei g ht.
d A f ull p h ysical e xa mi nati o n is re q uire d at scree ni n g ( V 1) a n d t he M o nt h 1 2/ E o T x visit.  A “ directe d p h ysical e xa mi nati o n” is perf or me d at t he q uarterl y visits 
(e g, M o nt hs 3, 6, 9) f or assess me nt of si g ns or s y m pt o ms re p orte d b y t he s u bject t hat mi g ht re q uire f urt her e val uati o n.
eD uri n g t he trial, a pre g na nc y test s h o ul d be c o m plete d at scree ni n g, e n d of place b o r u n -i n a n d at t he q uarterl y visits.  O n s us pici o n of pre g na nc y, 
u nsc he d ule d uri ne or ser u m pre g na nc y testi n g will be perf or me d.  P ositi ve uri ne pre g na nc y tests s h o ul d be c o nfir me d wit h a se r u m pre g na nc y test.
fAll ser u m creati ni ne sa m ples will be a nal yze d b y t he ce ntral la b orat or y.  T he s pecifics a n d ti mi n g f or all cli nical la b orat or y sa m ples f or ce ntral a n d l ocal 
la b orat or y a nal yses are as f oll o ws:
All visits: O ne or m ore t u bes of bl o o d ma y be c ollecte d t o acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 1 -2 w ee ks of t he scree ni n g per i o d, bl o o d will be dra w n 2 ti mes o n se parate da ys ( V 1, V 2) at least 2 4 h o urs a part.  T he 
s u bject’s eli gi bilit y will be c o nfir me d b y t he mea n of e G F R calc ulate d fr o m t he s u bjects’ 2 pre-treat me nt ( V 1, V 2), ce ntral la b orat or y ser u m creati ni ne 
assess me nts a n d e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  S u bjects will ha ve 1 bl o o d dra w  at t he e n d of 1 wee k wit h t he sa m ple bei n g o btai ne d o n Da y -3 6.
T ol v a pt a n titr ati o n peri o d:   S u bjects will ha ve 1 bl o o d dra w at t he e n d of 2 wee ks wit h t he sa m ple bei n g o btai ne d o n Da y -2 2.
T ol v a pt a n r u n -i n peri o d:  D uri n g t he last 2 wee ks of t his peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys (at least 2 4 h o urs a part) wit h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt peri o d:   Sa m ples will be c ollecte d f or ce ntral la b a nal ysis m o nt hl y a n d at t he M o nt h 1 2/ E o T x visit.  L ocal sta n dar d of care 
la b orat or y tests will be perf or me d m o nt hl y per t he s u bject’s i n di vi d ual cli nical ma na ge me nt nee ds.  L ocal li ver f u ncti o n pa nel a nal yses will als o be 
perf or me d m ore fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects will ha ve bl o o d dra w n o n 3 visits o ver Da ys + 7 t o + 2 1 p ost -treat me nt.
    F ull C he mistr y pa nel will be o btai ne d d uri n g f oll o wi n g visit: Scree ni n g ( V 1), q uarterl y visit ( M 3, M 6, M 9, M 1 2/ E o T x, F/ U peri o d Da y 2 1
    Ser u m creati ni ne, ser u m s o di u m,: Scree ni n g ( V 2) , e n d of place b o peri o d, e n d of t ol va ptan titrati o n, 2 ti mes d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g d o u ble 
bli n d treat me nt peri o d, 2 ti mes d uri n g F/ U peri o d
    Li ver f u ncti o n pa nel: Scree ni n g ( V 2), e n d of place b o peri o d , e n d of t ol va pta n titrati o n, 2 ti mes d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d Da y 2 1
g D uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d, P K plas ma s a m ples, P D uri ne sa m ples, a n d bi o mar ker uri ne/ plas ma sa m ples will be c ollecte d 
q uarterl y (e g, M o nt hs 3, 6, 9, 1 2/ E o T x).

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 3
2 6 Mar 2 0 1 5 
h D N A sa m ples are o pti o nal.
iDr u g dis pe nsi n g a n d rec o nciliati o n will be d o ne m o nt hl y (e xce pti o ns t o all o w dis pe nsi n g/rec o nciliati o n at ea c h 3 -m o nt h cli nic visit ma y be ma de b y t he 
me dical m o nit or i n e xce pti o nal circ u msta nces, wit h i nstr ucti o ns t o ta ke o nl y o ne m o nt h’s s u p pl y a n d start t he ne xt m o nt h o nl y after acce pta ble safet y la b 
res ults are c o nfir me d b y t he i n vesti gat or).  I nstr ucti o ns to be gi n ta ki n g t he ne xt m o nt h’s trial me dicati o n will be gi ve n d uri n g t he ti me of I M P dis pe nsati o n 
at eac h m o nt hl y visit or b y tele p h o ne c o ntact after t he m o nt hl y L F T sa m ples are c ollecte d.  If L F T res ults are a b n or mal, t he site will c o n d uct a tele p h o ne 
c o ntact wit h t he trial s u bject t o i nf or m t he m t hat pr o m pt i m me diate retesti n g (ie, w it hi n 7 2 h o urs) ma y be necessar y (see Secti o n 3. 7. 3. 4 f or g ui da nce) a n d 
t o arra n ge f or f oll o w-u p a n d a dj ust me nt of me dicati o n (as nee de d); if a d o w n titrati o n is re q uire d, t he s u bject ma y nee d t o ret ur n t o t he site or h a ve ne w 
dr u g deli vere d.   S u bjects will be re mi n de d of t he i m p orta nce o f t heir c o m mit me nt t o c o nti n ue partici pati o n i n t he trial.  At t he c o m pleti o n of t he scree ni n g 
peri o d, trial me dicati o n will be dis pe nse d at Da y -4 3 after s u bject eli gi bilit y is c o nfir me d.  I n e xce pti o nal circ u msta nces, trial me dicati o n ma y be dis pe nse d 
at V 2, w it h t he i nstr ucti o n n ot t o ta ke a n y trial me dicati o n u ntil eli gi bilit y is c o nfir me d b y t he i n vesti gat or.  I n t hese cases, c o nfir mati o n of eli gi bilit y a n d 
i nstr ucti o ns f or ta ki n g trial me dicati o n will be pr o vi de d b y tele p h o ne o n Da y -4 3.
jIf, d uri n g the titrati o n c o ntact, t he deter mi nati o n is ma de t o a dj ust t he d ose -r e gim e n, the investigator will e nter t he s u bject’s stat us i n t he I V R S a n d arra n ge f or
dis pe nsati o n of a ne w I M P kit a n d rec o nciliati o n of ret ur ne d I M P.  At t he e n d of t he titrati o n peri o d, t he s u bject’s hi g hest t olerate d d ose will be utilize d f or 
t he 3-wee k t ol va pta n r u n -i n peri o d.
k E x pl orat or y P K D o utc o mes will be c o m plete d eit her m o nt hl y o ver t he p h o ne or i n pers o n d uri n g q uarterl y cli nic visits.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 4
2 6 Mar 2 0 1 5 
Re vise d Sc he d ule of Assess me nts
T a ble 3. 7- 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1) ( D a y 0)
Visits:
m o nt hl y
( ± 2 
d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt a
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 8 t o + 2 1 
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
V 1  
V 2  
V 3
I nf or me d c o nse nt
X
I ncl usi o n/ E xcl usi o n
X
D e m o gr a p hic/ Me dic al hist or y
X
Vit al si g ns c
X
X 
X
X
X
( X)c
X
X
P h ysic al e x a mi n ati o n d
X
( X)d
X
Uri ne pre g n a nc y test ( W O C B P 
o nl y) e
X
X
( X)e
X
X
C he mistr y Bl o o d S a m ple c,f:
   Ser u m C he mistr y Pa nel
X
X
X
   Li ver F u ncti o n Pa nel
X  
X
X
X  
X
X  
X
X
   Creati ni ne
X
X 
X
X  
X  
X
X  
X  
X  
X  
X
   S o di u m
X  
X
X
X
X
X  
X
X
H e m at ol o g y a n d c o a g ul ati o n
X
P K pl as m a s a m ple
X
( X)g
X
X
Bi o m ar ker pl as m a s a m ple
X
X
X
X
( X)g
X
X

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 5
2 6 Mar 2 0 1 5 
T a ble 3. 7- 1
Sc he d ule of Assess me nts
Assess me nt
Pre -r a n d o miz ati o n
D o u ble -bli n d R a n d o mize d 
Tre at m e nt
F oll o w -u p
Scree ni n g a
( 1-2 wee ks)
Pl ace b o
r u n- i n
( 1 wee k 1 
d a y) 
( D a ys - 4 2 
t o - 3 6)
T ol v a pt a n titr ati o n
( 2 wee ks 1 d a y)
( D a ys -3 5 t o -2 2)
T ol v a pt a n r u n -
i n ( 3 wee ks 1 
d a y)
( D a ys -2 1 t o -1) ( D a y 0)
Visits:
m o nt hl y
( ± 2 
d a ys)
M o nt h 
1 2/ E o T x
visit
3 wee ks
p ost -tre at me nt a
V 1  
V 2
D a y
-4 3
D a y
-4 2
D a y
-3 6
D a ys
D a ys
D a y 0
M o nt hs
1 t o 1 1 b
M o nt h 1 2 
/ E o T x
D a ys + 8 t o + 2 1 
-3 5
-3 2 -2 8 -2 4 -2 2
-2 1
- 8 
- 1
V 1  
V 2  
V 3
D N A bl o o d s a m ple h
X
Uri n al ysis
X
X 
X
X
X
P D a n d Bi o m ar ker uri ne 
s a m ple
X g
X g
X g
X g
( X)g
X g
X g
St art ne wl y dis pe nse d I M P
X  
X
X
X
T oler a bilit y/ D osi n g re vie w
X  
X  
X  
X  
X
X
X  
X
R a n d o miz ati o n
X
Dr u g dis pe ns ati o n i
X  
X
X
X
X
Dr u g rec o ncili ati o n i
X
X
X
X  
X
I V R S e ntr yj
X  
X  
X
X
X
X  
X
X
E x pl or at or y P K D o utc o m es k
X
X
X  
X
A d verse e ve nts
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>
C o nc o m it ant me dic ati o ns
X 
< ----------------------------------------------------------------------------------------------------------------------------- ------------>
aT he scree ni n g peri o d s h o ul d be c o m plete d wit hi n 1 -2 w ee ks bef ore t he start of t he place b o r u n -i n peri o d.  T he scree ni n g peri o d ma y be e xte n de d u p t o a n 
a d diti o nal 8 wee ks f or s u bjects w h o re q uire m o dificati o n of me dical care s pecificall y f or t his trial. V isits d uri n g t he scree ni n g a n d f oll o w-u p peri o ds m ust 
be sc he d ule d at least 2 4 h o urs ( 1 da y) a part.  T he Da y -4 3 visit ca n n ot occ ur u ntil la b orat or y val ues fr o m V 2 are recei ve d.  F or t w o visits ( V 1, V 2) d uri n g 

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 6
2 6 Mar 2 0 1 5 
t he scree ni n g peri o d, bl o o d will be c ollecte d a n d a nal yze d ce ntrall y f or ser u m creati ni ne c o nce ntrati o ns, i n a d diti o n t o a n y ot her assess me nts liste d.  A 
visiti n g n urse h o use call or l ocal la b orat or y visit ma y be s u bstit ute d f or visits w here o nl y bl o o d/ uri ne will be c ollecte d d u ri n g t he f oll o w- u p ( F/ U) peri o d.  
T hree visits i n t he F/ U peri o d s h o ul d be sc he d ule d bet wee n Da y 8 a n d Da y 2 1 (i ncl usi ve) after t he last d ose of I M P .  N o F/ U assess me nts will be ta ke n 
d uri n g t he first wee k of t his peri o d.  Bl o o d sa m ples will be dra w n at eac h visit f or ser u m creati ni ne ( V 1, V 2) a n d ser u m creat i ni ne a n d ot her safet y, 
efficac y, P K a n d P D meas ure me nt s ( V 3).  
b If I M P treat me nt is i nterr u pte d f or 7 da ys d uri n g t his peri o d, pr oce d ures s h o ul d be f oll o we d as detaile d i n Secti o n 3. 8. 3. 2 .
cT he f oll o w i n g visits (a n d all assess me nts re q uire d d uri n g t h ose visits) s h o ul d be perf or me d i n-cli nic: scree ni n g ( V 1, V 2, Da y -4 3), e n d of place b o r u n -i n, e n d 
of t ol va pta n tit rati o n, e n d of t ol va pta n r u n-i n, q uarterl y visits d uri n g t he ra n d o mize d, d o u ble-bli n d treat me nt peri o d (e g, M o nt hs 3, 6, 9), M o nt h 1 2/e n d of 
treat me nt ( E o T x) visit, a n d t he last f oll o w-u p visit.  Vital si g ns at eac h of t he a b o ve visits i ncl u de sitti n g hear t rate a n d bl o o d press ure.  P ost-v oi d b o d y 
wei g ht s h o ul d be meas ure d at t he first scree ni n g visit a n d t he M o nt h 1 2/ E o T x visit o nl y.  Hei g ht s h o ul d be assesse d at t he fi rst scree ni n g visit o nl y.  Eit her 
hei g ht or wei g ht ma y be c ollecte d as a n u nsc he d ule d me as ure me nt if t he pla n ne d assess me nt was misse d .  Wei g ht ma y be assesse d as necessar y t o assess 
c ha n ges i n b o d y wei g ht.
d A f ull p h ysical e xa mi nati o n is re q uire d at scree ni n g ( V 1) a n d t he M o nt h 1 2/ E o T x visit.  A “ directe d p h ysical e xa mi nati o n” is perf or me d at t he q uarterl y visits 
(e g, M o nt hs 3, 6, 9) f or assess me nt of si g ns or s y m pt o ms re p orte d b y t he s u bject t hat mi g ht re q uire f urt her e val uati o n.
eD uri n g t he trial, a pre g na nc y test s h o ul d be c o m plete d at scree ni n g, e n d of place b o r u n -i n a n d at t he q uarterl y visits.  O n s us pici o n of pre g na nc y, 
u nsc he d ule d uri ne or ser u m pre g na nc y testi n g will be perf or me d.  P ositi ve uri ne pre g na nc y tests s h o ul d be c o nfir me d wit h a se r u m pre g na nc y test.
fAll ser u m creati ni ne sa m ples will be a nal yze d b y t he ce ntral la b orat or y. T he s pecifics a n d ti mi n g f or all cli nical la b orat or y sa m ples f or ce ntral a n d l ocal 
la b orat or y a nal yses are as f oll o ws:
All visits:
O ne or m ore t u bes of bl o o d ma y be c ollecte d t o acc o m m o date t he nee de d tests.
Scree ni n g peri o d:   D uri n g t he 1 -2 w ee ks of t he scree ni n g peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys ( V 1, V 2) at least 2 4 h o urs a part.  T he 
s u bject’s eli gi bilit y will be c o nfir me d b y t he mea n of e G F R calc ulate d fr o m t he s u bjects’ 2 pre-treat me nt ( V 1, V 2), ce ntral la b orat or y ser u m creati ni ne
assess me nts a n d e ntere d i n I V R S o n Da y -4 3.
Pl ace b o r u n -i n peri o d:  S u bjects will ha ve 1 bl o o d dra w  at t he e n d of 1 wee k wit h t he sa m ple bei n g o btai ne d o n Da y -3 6.
T ol v a pt a n titr ati o n peri o d:   S u bjects will ha ve 1 bl o o d dra w at t he e n d of 2 wee ks wit h t he sa m ple bei n g o btai ne d o n Da y -2 2.
T ol v a pt a n r u n -i n peri o d:  D uri n g t he last 2 wee ks of t his peri o d, bl o o d w ill be dra w n 2 ti mes o n se parate da ys (at least 2 4 h o urs a part) wit h t he last 
sa m ple o n Da y -1.
D o u ble -bli n d tre at m e nt peri o d:   Sa m ples will be c ollecte d f or ce ntral la b a nal ysis m o nt hl y a n d at t he M o nt h 1 2/ E o T x visit.  L ocal sta n dar d of care 
la b orat or y tests will be perf or me d m o nt hl y per t he s u bject’s i n di vi d ual cli nical ma na ge me nt nee ds.  L ocal li ver f u ncti o n pa nel a nal yses will als o be 
perf or me d m ore fre q ue ntl y, if necessar y.
F oll o w -u p peri o d:   S u bjects will ha ve bl o o d dra w n o n 3 visits at least 2 4 h o urs a part d uri n g t he 3 -wee k F/ U peri o d, w hic h starts after t he last d ose of I M P .  
Visits s h o ul d be sc he d ule d bet wee n Da ys 8 a n d 2 1 , i ncl usi ve.
    F ull C he mistr y pa nel will be o btai ne d d uri n g t he f oll o wi n g visits: Scree ni n g ( V 1), q uarterl y visit ( M 3, M 6, M 9, M 1 2/ E o T x, F/ U peri o d ( V 3). 
    Ser u m creati ni ne, ser u m s o di u m: Scree ni n g ( V 2) , e n d of place b o peri o d, e n d of t ol va ptan tit rati o n, 2 ti mes d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g 
d o u ble - bli n d treat me nt peri o d, 3 ti mes f or ser u m creati ni ne a n d 1 ti me f or ser u m s o di u m ( V 3) d uri n g t he F/ U peri o d .  N ote t hat t he first F/ U visit will 
occ ur at least 7 da ys ( Da y 8) after t he last d ose of I M P.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 7
2 6 Mar 2 0 1 5 
    Li ver f u ncti o n pa nel:
Scree ni n g ( V 2), e n d of place b o peri o d , e n d of t ol va pta n titrati o n, 1 ti me d uri n g t ol va pta n r u n-i n, m o nt hl y d uri n g d o u ble bli n d 
treat me nt peri o d, F/ U peri o d ( V 3).
g D uri n g t he d o u ble -bli n d, ra n d o mize d treat me nt peri o d, P K plas ma sa m ples, P D uri ne sa m ples, a n d bi o mar ker uri ne/ plas ma sa m ples will be c ollecte d 
q uarterl y (e g, M o nt hs 3, 6, 9, 1 2/ E o T x).   Uri ne bi o mar ker sa m ples s h o ul d be c ollecte d as a mi d -strea m, clea n-catc h sa m ple d uri n g t he sec o n d m or ni n g v oi d 
pri or t o t h e s u bject eati n g brea kf ast.  W here necessar y, s u p plies f or c ollecti o n s h o ul d be dis pe nse d pri or t o t he visit wit h i nstr ucti o ns t o c ollect t he uri ne 
sa m ple o n t he da y of t he visit.
h D N A sa m ples are o pti o nal a n d ma y be c ollecte d at s u bse q ue nt visits wit h s u b ject’s c o nse nt.
iDr u g dis pe nsi n g a n d rec o nciliati o n will be d o ne m o nt hl y (e xce pti o ns t o all o w dis pe nsi n g/rec o nciliati o n at eac h 3 -m o nt h cli nic visit ma y be ma de b y t he 
me dical m o nit or i n e xce pti o nal circ u msta nces, wit h i nstr ucti o ns t o ta ke o nl y o ne m o nt h’s
s u p pl y a n d start t he ne xt m o nt h o nl y after acce pta ble safet y la b 
res ults are c o nfir me d b y t he i n vesti gat or).  I nstr ucti o ns t o be gi n ta ki n g t he ne xt m o nt h’s trial me dicati o n will be gi ve n d uri n g t he ti me of I M P dis pe nsati o n 
at eac h m o nt hl y visit or b y tele p h o ne c o ntact after t he m o nt hl y L F T sa m ples are c ollecte d.  If L F T res ults are a b n or mal, t he site will c o n d uct a tele p h o ne 
c o ntact wit h t he trial s u bject t o i nf or m t he m t hat pr o m pt i m me diate retesti n g (ie, wit hi n 7 2 h o urs) ma y be necessar y (see Secti o n 3. 7. 3. 4 f or g ui da nce) a n d 
t o arra n ge f or f oll o w-u p a n d a dj ust me nt of me dicati o n (as nee de d); if a d o w n titrati o n is r e q uire d, t he s u bject ma y nee d t o ret ur n t o t he site or ha ve ne w 
dr u g deli vere d.   S u bjects will be re mi n de d of t he i m p orta nce of t heir c o m mit me nt t o c o nti n ue partici pati o n i n t he trial.  At t he c o m pleti o n of t he scree ni n g 
peri o d, trial me dicati o n will be di s pe nse d at Da y -4 3 after s u bject eli gi bilit y is c o nfir me d.  I n e xce pti o nal circ u msta nces, trial me dicati o n ma y be dis pe nse d 
at V 2, wit h t he i nstr ucti o n n ot t o ta ke a n y trial me dicati o n u ntil eli gi bilit y is c o nfir me d b y t he i n vesti gat or.  I n t hese cases, c onfir mati o n of eli gi bilit y a n d 
i nstr ucti o ns f or ta ki n g trial me dicati o n will be pr o vi de d b y tele p h o ne o n Da y -4 3.
jAt t he e n d of t he titrati o n peri o d, t he s u bject’s hi g hest t olerate d d ose will be utilize d f or t he 3 -we e k t ol va pta n r u n -i n peri o d.
k E x pl orat or y P K D o utc o mes will be c o m plete d eit her m o nt hl y o ver t he p h o ne or i n pers o n d uri n g q uarterl y cli nic visits.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 8
2 6 Mar 2 0 1 5 
A D DI TI O N A L RI S K T O T H E S U B J E C T :
T here is n o a d diti o nal ris k t o t he s u bjects.

Pr ot oc ol 1 5 6 -1 3 -2 1 0
C o nfi de ntial - Ots u ka Pr o prietar y I nf or mati o n
1 5 9
2 6 Mar 2 0 1 5 
A gr e e m e nt
I, t h e u n d er si g n e d pri n ci p al i n v e sti g at or, h a v e r e a d a n d u n d er st a n d t h e pr ot o c ol (i n cl u di n g t h e 
I n v e sti g at or' s Br o c h ur e) a n d a gr e e t h at it c o nt ai n s all t h e et hi c al, l e g al a n d s ci e ntifi c i nf or m ati o n 
n e c e s s ar y t o c o n d u ct t hi s tri al i n a c c or d a n c e wit h t h e pri n ci pl e s of G o o d Cli ni c al Pr a cti c e s a n d a s 
d e s cri b e d h er ei n a n d i n t h e s p o n s or' s ( or d e si g n e e' s) Cli ni c al R e s e ar c h A gr e e m e nt.
I will pr o vi d e c o pi e s of t h e pr ot o c ol t o all p h y si ci a n s, n ur s e s a n d ot h er pr of e s si o n al p er s o n n el t o 
w h o m I d el e g at e tri al r e s p o n si biliti e s. I will di s c u s s t h e pr ot o c ol wit h t h e m t o e n s ur e t h at t h e y ar e 
s uffi ci e ntl y i nf or m e d r e g ar di n g t h e i n v e sti g ati o n al n e w dr u g, [i n s ert c o m p o u n d n u m b er], t h e 
c o n c urr e nt m e di c ati o n s, t h e effi c a c y  a n d s af et y p ar a m et er s a n d t h e c o n d u ct of t h e tri al i n g e n er al. 
I a m a w ar e t h at t hi s pr ot o c ol m u st b e a p pr o v e d b y t h e I n stit uti o n al R e vi e w B o ar d (I R B) or 
I n d e p e n d e nt Et hi c s C o m mitt e e (I EC) r e s p o n si bl e f or s u c h m att er s i n t h e cli ni c al tri al f a cilit y w h er e 
[i n s ert c o m p o u n d n u m b er] will b e t e st e d pri or t o c o m m e n c e m e nt of t hi s tri al. I a gr e e t o a d h er e 
stri ctl y t o t h e att a c h e d pr ot o c ol ( u nl e s s a m e n d e d i n t h e m a n n er s et f ort h i n P ar a gr a p h I of t h e 
s p o n s or' s Cli ni c al R e s e ar c h A gr e e m e nt, at w hi c h ti m e I a gr e e t o a d h er e stri ctl y t o t h e pr ot o c ol a s 
a m e n d e d).
I u n d er st a n d t h at t hi s I R B- or I EC- a p pr o v e d pr ot o c ol will b e s u b mitt e d t o t h e a p pr o pri at e 
r e g ul at ory a ut h orit y/i e s b y t h e s p o n s or. I a gr e e t h at cli ni c al d at a e nt er e d o n c a s e r e p ort f or m s b y 
m e  a n d m y st aff will b e utili z e d b y t h e s p o n s or i n v ari o u s w a y s s u c h a s f or s u b mi s si o n t o 
g o v er n m e nt al r e g ul at or y a ut h oriti e s a n d/ or i n c o m bi n ati o n wit h cli ni c al d at a g at h er e d fr o m ot h er 
r e s e ar c h sit e s, w h e n e v er a p pli c a bl e. I a gr e e t o all o w s p o n s or m o nit or s a n d a u dit or s f ull a c c e s s t o 
all m e di c al r e c or d s at t h e r e s e ar c h f a cilit y f or s u bj e ct s s cr e e n e d or e nr oll e d i n t h e tri al.
I a gr e e t o a w ait I R B/I E C a p pr o v al b ef or e i m pl e m e nt ati o n of a n y pr ot o c ol a m e n d m e nt s t o t hi s 
pr ot o c ol. If, h o w e v er, t h er e i s a n i m m e di at e h a z ar d t o s u bj e ct s, I will i m pl e m e nt t h e a m e n d m e nt 
i m m e di at el y, a n d pr o vi d e t h e i nf or m ati o n to t h e I R B/I E C wit hi n 5 w or ki n g d a y s. A d mi ni str ati v e 
c h a n g e s t o t h e pr ot o c ol will b e tr a n s mitt e d t o t h e I R B/I E C f or i nf or m ati o n al p ur p o s e s o nl y.
I a gr e e t o pr o vi d e all s u bj e ct s wit h i nf or m e d c o n s e nt f or m s, a s r e q uir e d b y t h e a p pli c a bl e 
r e g ul ati o n s a n d b y IC H g ui d eli n e s. I a gr e e t o r e p ort t o t h e s p o n s or a n y a d v er s e e x p eri e n c e s i n 
a c c or d a n c e wit h t h e t er m s of t h e s p o n s or' s Cli ni c al R e s e ar c h A gr e e m e nt a n d t h e r el e v a nt 
r e gi o n al r e g ul ati o n( s) a n d g ui d eli n e( s). I f urt h er a gr e e t o pr o vi d e all r e q uir e d i nf or m ati o n 
r e g ar di n g fi n a n ci al c ertifi c ati o n or di s cl o s ur e t o t h e s p o n s or f or all i n v e sti g at or s a n d s u b-
i n v e sti g at or s i n a c c or d a n c e wit h t h e t er m s of t h e r el e v a nt r e gi o n al r e g ul ati o n( s). I u n d er st a n d t h at 
p arti ci p ati o n i n t h e pr ot o c ol i n v ol v e s a c o m mit m e nt t o p u bli s h t h e d at a fr o m t hi s tr ail i n a 
c o o p er ati v e p u bli c ati o n pri or t o p u bli c ati o n of effi c a c y a n d s af et y r e s ult s o n a n i n di vi d u al b a si s.
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
Pri n ci p al or C o or di n ati n g I n v e sti g at or Si g n at ur e a n d D at e

Ot s u k a P h ar m a c e uti c al D e v el o p m e nt & C o m m er ci ali z ati o n, I n c.
T hi s p a g e i s a m a nif e st ati o n of a n el e ctr o ni c all y c a pt ur e d si g n at ur e
                                                                                                                                
S I G N A T U R E P A G E
D oc u me nt N a me :
D oc u me nt N u m ber :
D oc u me nt Versi o n :
Si g n e d b y
Me a ni n g of Si g n at ure
Ser ver D ate
(d d -M M M -y y y y H H : m m ‘ G M T’ Z)
O P C- 4 1 0 6 1
1 5 6- 1 3- 2 1 0 Pr ot oc ol A M 3, Fr a nce
0 0 0 1 1 5 4 9 7 0
2. 0
Bi ostatistics A p pr o val
3 0- Mar- 2 0 1 5 1 4: 2 5 G M T + 0 0
Cli nical P har mac ol o g y
3 1- Mar- 2 0 1 5 1 6: 1 6 G M T + 0 0
Cli nical A p pr o val
0 2- A pr- 2 0 1 5 1 3: 0 3 G M T + 0 0
Cli nical A p pr o val
0 2- A pr- 2 0 1 5 2 0: 5 3 G M T + 0