A Randomized, Double -Blind, Placebo-Controlled, Phase 1, Ascending Oral Single and Multiple Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TAK-041 in Healthy Subjects and Subjects With Stable Schizophrenia and a Randomized Open-Label, Single Dose, Parallel Design to Evaluate the Relative Bioavailability and Effect of Food on the Pharmacokinetics of TAK-041 Tablet Formulation in Healthy Subjects
Phase: PHASE1
Conditions: Healthy Volunteers, Schizophrenia
Sponsor: Neurocrine Biosciences

TI T L E P A G E
P R O T O C O L A M E N D M E N T
A R a n d o mize d, D o u ble -Bli n d, Pl ace b o - C o ntr olle d, P h ase 1, Asce n di n g Or al Si n gle a n d 
M ulti ple D ose St u d y t o E v al u ate t he S afet y, T oler a bilit y, a n d P h ar m ac o ki netics of
T A K -0 4 1 
i n He alt h y S u bjects a n d S u bjects wit h St a ble Sc hiz o p hre ni a a n d a R a n d o mize d O pe n-L a bel, 
Si n gle D ose, P ar allel Desi g n t o E v al u ate t he Rel ati ve Bi o a v ail a bilit y a n d Effect of F o o d o n 
t he P h ar m ac o ki netics of T A K-0 4 1 T a blet F or m ul ati o n i n He alt h y S u bje cts
P h ase 1 T A K -0 4 1 First -i n-H u m a n S afet y, T oler a bilit y, a n d P h ar m ac o ki netics St u d y
S p o ns or:
Ta ke da De vel o p me nt Ce nter A mericas, I nc.
O ne Ta ke da Par k wa y
Deerfiel d, I L 6 0 0 1 5
St u d y N u m ber:
T A K - 0 4 1- 1 0 0 1
I N D N u m ber:
1 3 0 0 7 4
E u dr a C T N u m ber:
N ot A p plica ble
C o m p o u n d:
T A K - 0 4 1 
D ate:
0 3 J ul y 2 0 1 8
A me n d me nt N u m ber: 
0 5
A me n d me nt Hist or y:
D ate
A me n d me nt N u m ber
A m e n d me nt T y pe
Re gi o n
2 4 Marc h 2 0 1 6
I nitial versi o n
N ot a p plica ble
U S A
0 2 J u ne 2 0 1 6
0 1
S u bsta ntial
U S A
2 4 J u ne 2 0 1 6
0 2
S u bsta ntial
U S A
2 0 Se pte m ber 2 0 1 6
0 3
S u bsta ntial
U S A
0 6 Dece m ber 2 0 1 7
0 4
S u bsta ntial
U S A
0 3 J ul y 2 0 1 8
0 5
S u bsta ntial
U S A
Pr o p er 
k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1. 0
A D MI NI S T R A TI V E I N F O R M A TI O N
1. 1
C o nt acts
Tri al c o ntact n u m bers ca n be f o u n d i n t he St u d y  Ma n ual, t he c o m m u nicati on pla n, or ot her si milar 
d oc u m e nts pr o vide d t o t he si t e.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1. 2
A p pr o v al
R E P R E S E N T A TI V E S O F T A K E D A
T his st u d y  will be c o n d ucte d wit h t he hi g hest res pect f or t he i n di vi d ual partici pa nts i n acc or da nce 
wi t h t he re q uire me nts of t his clini c al st u d y  pr ot oc ol a n d als o i n acc or da nce with t he f o ll owi n g:

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.

I nter nati o nal C o nfere nce o n Har m o nisati o n E 6 G o o d Cli nical Practice C o ns oli date d 
G ui deli ne.

All a p plica ble la ws a nd re g ul at i ons, i ncl u di n g, wit h o ut li mitat i on, data pri vac y la ws, cli nical 
trial dis clos ur e l a ws, a n d re g ulat i ons.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
I N V E S TI G A T O R A G R E E M E N T
I c o nfir m t hat I ha ve rea d a n d t hat I u n dersta n d t his pr ot oc ol, t he I n vesti gat or’s Br oc h ure, a n d a n y 
ot her pr o d uct i nf o r matio n pr o vi de d b y t he s p o ns or. I a gree t o c o n d uct t his st u d y  in acc or da nce 
wi t h the re q uire me nts of t his pr ot oc ol a n d als o t o pr otect t he ri g hts, safet y,  pri vac y, a n d well-bei n g 
of  st u d y s u bjects i n acc or da nce wit h t he f oll o wi n g:

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.

I nter nati o nal C o nfere nce o n Har m o nisati o n, E 6 G o o d Cli nical Practice: C o ns oli date d 
G ui deli ne.

All a p plica ble la ws a n d re g ulat i ons, i ncl u di n g, wit h o ut li mitat i on, data pri vac y la ws a n d 
re g ulat i ons.

Re g ul at or y r e q uire me nts f or re p orti n g seri o us a d verse e ve nts defi ne d i n Secti on 1 0. 2 of  t his 
pr ot oc ol .

Ter ms o utli ne d i n t he Cli nical St u d y  Site A gree me nt.

A p pe n di x F – Res p o nsi bilit ies of t he I n vest i gat or.
I furt her a ut h orize t hat m y  pers o nal i nf or mati on ma y be pr ocesse d a n d tra nsferre d i n acc or da nce 
wi t h t he uses c o nte m plate d i n  A p pe n di x H of  t his pr ot oc ol.
Si g nat ure of I n vesti gat or
Date
I n vesti gat or Na me ( pri nt or t ype)
I n vesti gat or’s Title
L ocati o n of  Facility ( Ci t y, State/ Pr o ve nce)
L ocati o n of  Facility ( C o u ntr y )
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1. 3 
Pr ot oc ol A me n d me nt 0 5 S u m m ar y of C h a n ges
R ati o n ale f or A me n d me nt 0 5
T his d oc u me nt descri bes t he c ha n ges i n refere nce t o t he pr ot oc ol i nc or p orati n g A me n d me nt 
N o. 0 5. T he pri mar y reas o ns f or t his a me n d me nt are t o m o dif y t he st u d y desi g n t o i ncl u de:
!
Part 3 t o assess t he bi oa vaila bilit y a n d f o o d effect o n t he p har mac o ki netics ( P K) of t he 
T A K- 0 4 1 i m me diate release ta blet f or m ulati o n i n h ealt h y s u bjects
!
Mi n or gra m matical, e dit orial, f or matti n g, a n d a d mi nistrati ve c ha n ges n ot affecti n g t he c o n d uct of 
t he st u d y are i ncl u de d f or clarificati o n a n d a d mi nistrati ve p ur p oses o nl y. F or s pecific descri pti o ns 
of te xt c ha n ges a n d w here t he c ha n ges are l ocate d, see  A p pe n di x I.
C h a n ges i n A me n d me nt:
1.  A d de d Part 3 st u d y desi g n, wit h p o p ulati o n, f or m ulati o n, d osi n g, f o o d effect re gi me n, a n d 
c o nfi ne me nt
2.  A d de d Part 4 st u d y desi g n wit h sta ble sc hiz o p hre nic p o p ulati o n, d ose le vels, d osi n g da ys a n d 
c o nfi ne me nt da ys. 
3.  A d de d o bjecti ves a n d e n d p oi nts f or Parts 3 a n d 4.
4.  A d de d t he j ustificati o n f or t he pr o p ose d st u d y desi g n d ose a n d e n d p oi nts f or Part 3.
5.  A d de d t he j ustificati o n f or t he pr o p ose d st u d y desi g n d ose a n d e n d p oi nts f or Part 4.
6.  A d de d i ncl usi o n a n d e xcl usi o n  crit eria f or Part 3 a n d 4.
7.  A d de d e xcl u de d me dicati o ns, dietar y pr o d ucts a n d st u d y c o ntr ol of diet, fl ui d a n d acti vit y 
c o ntr ol f or Parts 3 a n d 4.
8.  A d de d T A K- 0 4 1 ta blet f or m ulati o n t o st u d y  me dicati o n f or Part 3 a n d ma n ufact uri n g, 
pac ka gi n g, la beli n g, dis pe nsi n g a n d ra n d o mizati o n t o i ncl u de Part 3 a n d 4.
9.  A d de d hei g ht wei g ht a n d B MI t o Part 3 a n d 4, wit h Part 4 s u bjects ha ve a n i ncrease d u p per 
li mit f or B MI of 4 0. 5 k g/ m2.
1 0.
1 1.  A d de d statistical a nal ysis f or Part 3 a n d Part 4.
1 2.  A d de d p har mac o ge n o mic sa m ple c ollecti o ns f or Part 3 a n d 4.
1 3.  A d de d P K para meters a n d P K bl o o d c ollecti o ns f or Part 3 a n d 4 a n d P K uri ne c ollecti o ns f or 
Part 4.
1 4. Re vise d t he st u d y-s pecific d ose escalati o n a n d st o p pi n g r ule f or Part 1 a n d Part 2.
1 5.  A d de d e xcl usi o n crit eria f or rece nt maj or s ur ger y or d o nati o n or l oss of bl o o d.
Pr o p ert y of T 
a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h 
a bl e T er m s of U s e
de:
P K) of t h
K) of t
n ot affec
ot aff
o nl y.
nl y. F o
x I .
ti oi n, d os
n, d o
p hre nic p
p hre nic
rts 3 a n d
3 a n
p ose d st u
ose d s
pr o p ose
pr o p os
si oi on cri
n c i
catat i oi ons, 
ns
a n d 4.4.
1 ta blet
 ta ble
a beli n g,
beli n g
hei g ht w
ei g ht w
for B MI
r B M
f
1.1. A d de
A
1 2.
1 2. A
1
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 6. Re vise d e xcl usi o n f or cli nicall y si g nifica nt hi st or y or hea d i nj ur y or tra u ma t o i ncl u de l oss of 
c o nsci o us ness f or greater t ha n 1 5 mi n utes.
1 7.  U p date d e xcl usi o n la n g ua ge o n ris k of s uici de c o nsi dere d b y t he i n vesti gat or, i ncl u di n g 
s pecific C- S S R S res ults.
1 8.  A d de d u ns uita ble f or i ncl usi o n i n t he o pi ni o n of t he i n vesti gat or or s p o ns or as a n e xcl usi o n 
crit eri o n.
1 9.  Detaile d s pecific ne ur ol o gical e xa mi nati o ns, a n d c o m bi ne d as part of p h ysical e xa mi nati o n, 
wit h re q uire d assess me nt as n ot cli nicall y si g nifica nt ( N C S) or cli nicall y si g nifica nt ( C S).
2 0.  U p date d wear a ble de vice ti mi n g of place me nt a n d re m o val f or Part 2 a n d a d de d t o Part 4.
2 1.  A d de d la b orat or y sa m ple c ollecti o ns a n d bl o o d sa m pli n g v ol u mes f or Part 3 a n d 4
2 2.  A d de d c o ntrace pti o n, a v oi da nce pr oce d ures a n d pre g na nc y state me nts t o Part 3 a n d 4.
2 3.  A d de d E C G assess me nts t o Part 3 a n d 4 a n d re m o ve d tri plicate para meter assess me nts fr o m 
H olter E C G i n part 2.
2 4. 
.
2 5.  U p date d t he n o ncli nical i nf or mati o n o n T A K- 0 4 1
2 6.  U p date d P K a nal ysis f or all sa m ple parts.
2 7.  A d de d P D a nal ysis set f or Part 4 o nl y
2 8.  U p date d safet y a nal ysis.
2 9.  U p date d sa m ple size deter mi nati o n f or t he st u d y.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a 
u bj e ct t o t h e a p pli c a bl e T er m s of U s e
xcl usi o
cl usi o n
al e xa mi
l e xa m
ig nifica
g nific
a n d a d d
n d a d
s f or Par
f or Pa
tate me nt
te me n
plicate p
plicate
0 4 14
natti oi on n f o
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T A B L E O F C O N T E N T S
1. 0
A D MI NI S T R A TI V E I N F O R M A TI O N ...........................................................................2
1. 1
C o ntacts .....................................................................................................................2
1. 2
A p pr o val ....................................................................................................................3
1. 3
Pr ot oc ol  A men d me nt 0 5 S u m mar y  of C ha n ges..........................................................5
2. 0
S T U D Y S U M M A R Y ....................................................................................................1 4
3. 0
S T U D Y R E F E R E N C E I N F O R M A TI O N ......................................................................2 4
3. 1
St u d y -Relate d Res p o nsi bilit ies.................................................................................2 4
3. 2
Pri nci pal I n vest i gat or...............................................................................................2 4
3. 3
List of A b bre viat i ons ...............................................................................................2 5
3. 4
C or p orate I de ntificat i on ...........................................................................................2 7
4. 0
I N T R O D U C TI O N.........................................................................................................2 8
4. 1
Bac k gr o u n d .............................................................................................................2 8
4. 2
Rati o nale f or t he Pr o p ose d St u d y .............................................................................3 1
5. 0
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S ..................................................................3 4
5. 1
St u d y  O bjecti ves......................................................................................................3 4
5. 1. 1
Pr i mary O bject i ves.............................................................................................3 4
5. 1. 2
Sec o n dar y  O bjecti ve ..........................................................................................3 4
5. 1. 3
E x pl or at or y  O bjecti ves.......................................................................................3 4
5. 1. 3. 1 F or Parts 1 a n d 2 ( Healt h y S u bjects) .............................................................3 4
5. 1. 3. 2 F or Part 4 ( S u bjects wit h Sc hiz o p hre nia) ......................................................3 4
5. 2
E n d p oi nts f or Part 1 a n d Part 2 a n d Part 3 ( Healt h y S u bjec ts) a n d Part 4 ( S u bjects 
wi t h Sc hiz o p hre nia)................................................................................................. 3 5
5. 2. 1
Pri mar y E n d p o i nts .............................................................................................3 5
5. 2. 2
Sec o n dar y  E n d p oi nts..........................................................................................3 5
5. 2. 3
E x pl or at or y  E n d p oi nts .......................................................................................3 6
5. 2. 3. 1 F or Parts 1, 2 ( Healt h y  S u bjects)..................................................................3 6
5. 2. 3. 2 F or Part 4 ( S u bjects wit h Sc hiz o p hre nia) ......................................................3 6
6. 0
S T U D Y D E SI G N A N D D E S C RI P TI O N .......................................................................3 7
6. 1
St u d y  Desi g n ...........................................................................................................3 7
6. 1. 1
Part 1 Si n gle -Risi n g D ose: Heal t h y S u bjects......................................................3 7
6. 1. 2
Part 2 M ult i ple-Risi n g D ose: Healt h y  S u bjects...................................................4 0
6. 1. 3
Part 3: Si n gle D ose: Healt h y S u bjects Relat i ve Bi oa vaila blit y a n d F o o d Effect 
St u d y .................................................................................................................4 2
6. 1. 4
Part 4 : Si n gle D ose: S u bjects wit h Sc hiz o p hre nia...............................................4 3
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
6. 1. 5
E n d of Trial ........................................................................................................4 5
6. 1. 6
D ose Escal atio n ..................................................................................................4 5
6. 2
J ustificati o n f or St u d y Desi g n, D ose, a n d E n d p oi nts ................................................4 7
6. 2. 1
St u d y  Desi g n......................................................................................................4 7
6. 2. 2
D ose Selecti o n ...................................................................................................4 8
6. 2. 3
E n d p oi nts ...........................................................................................................5 0
6. 3
Pr e m at ur e Ter mi nat i on or S us pe nsi o n o f St u d y  or I n vesti gati onal Si t e.....................5 2
6. 3. 1
Cri teria f or Pre mat ure Ter mi nati on or S us pe nsi o n of t he St u d y ..........................5 2
6. 3. 2
St u d y -S pecific D ose Escalat i on a n d St o p pi n g R ules ...........................................5 3
6. 3. 3
Cri teria f or Pre mat ure Ter mi nati on or S us pe nsi o n of I n vest i gati onal Si t es .........5 4
6. 3. 4
Pr oce d ures f or Pre mat ure Ter mi nati o n or S us pe nsi o n of t he St u d y  or t he 
P arti cip ati o n of  I n vesti gati onal Si te(s)................................................................5 4
7. 0
S E L E C TI O N A N D DI S C O N TI N U A TI O N/ WI T H D R A W A L O F S U BJ E C T S ..............5 5
7. 1
I ncl usi on Cri t eria .....................................................................................................5 5
7. 1. 1
Heal t h y s u bjects a n d s u bjects wit h sc hiz o p hre nia...............................................5 5
7. 1. 2
S u bjects wit h sc hiz o p hre nia o nl y .......................................................................5 5
7. 2
E xcl usi o n Cri t eria ....................................................................................................5 6
7. 2. 1
Heal t h y s u bjects................................................................................................. 5 6
7. 2. 2
S u bjects wit h sc hiz o p hre nia o nl y .......................................................................5 8
7. 3
E xcl u de d Me dicat i ons a n d Dietar y  Pr o d ucts............................................................5 9
7. 4
Di et, Flui d, a n d Acti vit y C o ntr ol ..............................................................................6 1
7. 4. 1
Part 3 Di et a n d Flui d C o ntr ol .............................................................................6 2
7. 5
Cri teria f or Disc o nti n uatio n or Wi t hdra wal  of a S u bject...........................................6 3
7. 6
Pr oce d ures f or Disc o nt i n uati on or Wit h dra wal o f a S u bject ......................................6 4
8. 0
C LI NI C A L T RI A L M A T E R I A L M A N A G E M E N T ......................................................6 5
8. 1
St u d y  Me dicati on a n d Materials ...............................................................................6 5
8. 1. 1
D osa ge F or m, Ma n ufact uri n g, Pac ka gi n g, a n d La beli n g .....................................6 5
8. 1. 1. 1 S p o ns or -S u p plie d Dr u g ................................................................................6 6
8. 1. 2
St ora ge ...............................................................................................................6 6
8. 1. 3
D ose a n d Re gi me n .............................................................................................6 6
8. 1. 4
O ver d ose ............................................................................................................6 7
8. 2
I n vesti gati onal Dr u g Assi g n me nt a n d Dis pe nsi n g Pr oce d ures ..................................6 7
8. 3
Ra n d o mizati o n C o de Creati o n a n d St ora ge ..............................................................6 8
8. 4
I n vesti gati onal Dr u g Bli n d Mai nte na nce ..................................................................6 8
8. 4. 1
U n bli n di n g Pr oce d ure ........................................................................................6 8
8. 5
Acc o u nta bilit y a n d Destr ucti o n of S p o ns or - S u p plie d Dr u gs.....................................6 9
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 0 
S T U D Y P L A N .............................................................................................................. 7 1
9. 1 
St u d y Pr oce d ures ..................................................................................................... 7 1
9. 1. 1 I nf or me d C o nse nt Pr oce d ure .............................................................................. 7 1
9. 1. 1. 1 P har mac o ge n o mic I nf or me d C o nse nt Pr oce d ure ........................................... 7 1
9. 1. 2  
De m o gra p hics, Me dical Hist or y, a n d Me dicati o n Hist or y  Pr oced ur e.................. 7 1
9. 1. 3 
P h ys ical E xa mi nati o n Pr oce d ure a n d Ne ur ol o gical E xa mi nati o n ........................ 7 1
9. 1. 4  
Wei g ht, Hei g ht, a n d B MI ................................................................................... 7 2
9. 1. 5  
Vit al Si g n P r oce d ure .......................................................................................... 7 2
9. 1. 6  
Weara ble De vice Pr oce d ure ............................................................................... 7 3
9. 1. 7  
D oc u me ntati o n of C o nc o mit a nt Me di c ati o ns...................................................... 7 3
9. 1. 8  
D oc u me ntati o n of C o nc urre nt Me dical C o n diti o ns ............................................. 7 3
9. 1. 9 
Pr oce d ures f or Cli nical La b orat or y Sa m ples ....................................................... 7 3
9. 1. 9. 1 Re nal F u nc ti o n ............................................................................................. 7 5
9. 1. 1 0 C o ntrace pti o n a n d Pre g na nc y A v oi da nce Pr oce d ure ........................................... 7 5
9. 1. 1 1 Pre g na nc y .......................................................................................................... 7 6
9. 1. 1 2 E C G Pr oce d ur e .................................................................................................. 7 7
9. 1. 1 2. 1  
H olter E C G M o nit ori n g ( P art 2, Healt h y S u bject C o h ort s)...................... 7 8
9. 1. 1 3 B o n d- La der Vis u al A nal o g ue Scale .................................................................... 7 9
9. 1. 1 4 C- S S R S .............................................................................................................. 7 9
9. 1. 1 5 P A N S S .............................................................................................................. 7 9
9. 1. 1 6 C o g niti ve Assess me nts ....................................................................................... 8 0
9. 1. 1 7  Ot her Ps yc hiatric/ Ne ur ol o gical Ra ti n g Scales .................................................... 8 1
9. 1. 1 7. 1  
MI NI I nter nati o nal Ne ur o ps yc hiatric I n ter vie w ...................................... 8 1
9. 1. 1 7. 2
9. 1. 1 7. 3
9. 1. 1 7. 4
9. 1. 1 8 P har mac o ge n o mic Sa m ple C o llecti o n ................................................................ 8 2
9. 1. 1 8. 1  
D N A Sa m ple C ollecti o n ......................................................................... 8 2
9. 1. 1 8. 2 
R N A Sa m ple C ollecti o n – Part 1 ............................................................. 8 3
9. 1. 1 8. 3 
R N A Sa m ple C ollecti o n – Part 2, Part 3 a n d Part 4.................................. 8 3
9. 1. 1 9 P har mac o ki netic Sa m ple C o llecti o n................................................................... 8 3
9. 1. 1 9. 1 
C ollecti o n of Plas ma f or P h ar mac o ki netic S a m pli n g ............................... 8 3
9. 1. 1 9. 2 
C ollecti o n of Uri ne f or P har mac o ki netic Sa m pli n g ................................. 8 5
9. 1. 1 9. 3 
Bi oa nal ytic al  M et h o ds............................................................................ 8 6
9. 1. 2 0 P har mac o ki netic Para meters .............................................................................. 8 6
7 17 1
......
......7 17 1
.........
......
.........
......
..........
......
.........
......
..........
...
...........
......
.........
.......
..........
........
.........
......
Pr oce d u
Pr oce d
..........
....
....
.........
..
g ( Part 2
( Part 2
g ue Scale
ue Sc
........
...... .
..........
.....
s me nts
me nt
atritric/ Ne
c/ N
MI NI I nte
NI I n
. 3
. 1 7. 4
. 1 7. 4
. 1 8
1 8 P ha
P
9. 1.
9.
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 2 1 P har mac o d y na mic Para meters ............................................................................ 8 7
9. 1. 2 1. 1
9. 1. 2 2 E x pl or at or y Bi o m ar ker Sa m ple C ollecti o n ......................................................... 8 7
9. 1. 2 3  D oc u me ntati o n of Sc ree n Failure ....................................................................... 8 8
9. 1. 2 4  D oc u me ntati o n of Ra n d o mizati o n ...................................................................... 8 8
9. 2  
M o nit ori n g S u bject Treat me nt C o m p lia nce.............................................................. 8 8
9. 3 
Sc he d ule of O bser vati o n s a n d Pr oced ures ................................................................ 8 8
9. 3. 1  
Disc har g e........................................................................................................... 8 9
9. 3. 2 
Earl y Ter mi n ati o n .............................................................................................. 9 0
9. 4 
Bi ol o gical Sa m ple Rete nti o n a n d Destr ucti o n .......................................................... 9 0
9. 5 
Bl o o d V ol u me ......................................................................................................... 9 1
1 0. 0 
P R E T R E A T M E N T E V E N T S A N D A D V E R S E E V E N T S ............................................ 9 7
1 0. 1  
Defi niti o n s............................................................................................................... 97
1 0. 1. 1 P T Es .................................................................................................................. 9 7
1 0. 1. 2  A Es .................................................................................................................... 9 7
1 0. 1. 3  A d diti o nal P oi nts t o C o ns i der f or P T Es a n d A Es................................................ 9 7
1 0. 1. 4 S A Es .................................................................................................................. 9 9
1 0. 1. 5 Se verit y of P T Es a n d A Es ................................................................................ 1 0 0
1 0. 1. 6 Ca usalit y of A Es .............................................................................................. 1 0 0
1 0. 1. 7 Relati o ns hi p t o St u d y  Pr oce d ures ..................................................................... 1 0 0
1 0. 1. 8 Start D ate ......................................................................................................... 1 0 1
1 0. 1. 9 St o p Date ......................................................................................................... 1 0 1
1 0. 1. 1 0 
Fre q ue nc y .................................................................................................. 1 0 1
1 0. 1. 1 1  
Acti o n C o ncer ni n g St u d y Me dicati o n ......................................................... 1 0 1
1 0. 1. 1 2  
O utc o me ..................................................................................................... 1 0 1
1 0. 2 
Pr oce d ure s ............................................................................................................. 1 0 2
1 0. 2. 1 C ollecti o n a n d Re p ort i n g of A Es...................................................................... 1 0 2
1 0. 2. 1. 1 
P T E a n d A E C oll ecti o n Peri o d ............................................................. 1 0 2
1 0. 2. 1. 2 
P T E a n d A E Re p orti n g ......................................................................... 1 0 2
1 0. 2. 2 C ollecti o n a n d Re p ort i n g of S A Es.................................................................... 1 0 3
1 0. 2. 3 Re p orti n g of A b n or mal Li v er F u ncti o n Tests ...................................................1 0 3
1 0. 3 
F oll o w- u p of S A Es ................................................................................................ 1 0 4
1 0. 3. 1 S afet y Re p orti n g t o I n vesti gat ors, I R Bs or I E Cs, a n d Re g ulat or y A ut h orities ... 1 0 4
1 1. 0 
S T U D Y- S P E CI FI C C O M MI T T E E S ........................................................................... 1 0 5
1 2. 0  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G .......................................................... 1 0 6
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m of U s e
8 78 7
......
......8 88 8
.........
......
.........
......
..........
......
.........
......
..........
...
.........
....
... .......
..
T S
T S .....
...
.......
......
.........
......
..........
....
P T Es a n
P T Es a
..........
.....
.........
......
.........
......
d y Pr oce
Pr oc
y
.........
....
..........
......
ue nc y
nc y .
ctio n C o
o n C
O utc o m
O utc o
oce d ures
oce d ur
2. 1. 1 C ol
C
1 0. 2
1 0
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 2. 1
C R Fs ( El ectr o nic) ..................................................................................................1 0 6
1 2. 2
Rec or d Rete nti o n ...................................................................................................1 0 6
1 3. 0
S T A TI S TI C A L M E T H O D S ........................................................................................1 0 8
1 3. 1
Stati stical a n d A nal ytical Pla ns..............................................................................1 0 8
1 3. 1. 1 A nal ysis Sets ....................................................................................................1 0 8
1 3. 1. 2 A nal ysis of De m o gra p hics a n d Ot her Baseli ne C haracterist ics .........................1 0 8
1 3. 1. 3 P har mac o ki net ic A nal ysis ................................................................................1 0 8
1 3. 1. 4 E x pl or at or y  A nal yses.......................................................................................1 0 9
1 3. 1. 5 S af et y A nal ysis ................................................................................................1 1 0
1 3. 2
I nteri m A nal ysis a n d Criteria f or Earl y Ter mi nati on ..............................................1 1 1
1 3. 3
Deter mi nat i on of Sa m ple Size ................................................................................1 1 1
1 4. 0
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E .............................................1 1 3
1 4. 1
St u d y -Si te M o nit ori n g Visits .................................................................................1 1 3
1 4. 2
Pr ot oc ol  De viati ons ................................................................................................1 1 3
1 4. 3
Q ualit y Ass ura nce A u dits a n d Re g ulat or y  A ge nc y I ns pecti ons ..............................1 1 3
1 5. 0
E T HI C A L A S P E C T S O F T H E S T U D Y ......................................................................1 1 5
1 5. 1
I R B a n d/ or I E C A p pr o val ......................................................................................1 1 5
1 5. 2
S u bject I nf or mati on, I nf or m e d C o nse nt, a n d S u bject A ut h orizat i on .......................1 1 6
1 5. 3
S u bject C o nfi de ntialit y ..........................................................................................1 1 7
1 5. 4
P u blicat i on, Di sclos ure, a n d Cli nical Trial Re gistrati o n P olic y ...............................1 1 7
1 5. 4. 1 P u blicat i on a n d Discl os ure ...............................................................................1 1 7
1 5. 4. 2 Cli nical Trial Re gistrati o n ................................................................................1 1 8
1 5. 4. 3 Cli nical Trial Res ult s Discl os ure ......................................................................1 1 8
1 5. 5
I ns ura nce a n d C om pe nsati o n f or I nj ur y ..................................................................1 1 8
1 6. 0
R E F E R E N C E S ............................................................................................................1 1 9
LI S T O F I N -T E X T T A B L E S
Ta ble 6.a
Part 1: St u d y  Desi g n ..........................................................................................3 9
Ta ble 6. b
Part 1 C o h orts 1 t o 2: St u d y  Sc he d ule f or Eac h Peri o d ( Healt h y S u bjects)..........4 0
Ta ble 6.c
Part 1 C o h orts 3 t o 5: St u d y  Sc he d ule ( Healt h y S u bjects)...................................4 0
Ta ble 6. d
Part 2: St u d y  Desi g n ( Health y S u bjects, C o h orts 1 t o 4) .....................................4 1
Ta ble 6.e
Part 2: St u d y  Sc he d ule ( Healt h y S u bjects, C o h orts 1 t o 4) ..................................4 2
Ta ble 6.f
Part 3: St u d y  Desi g n ( Health y S u bjects ..............................................................4 2
Ta ble 6. g
Part 3 Ta blet F or m ulat i on / F o o d Effect St u d y  Sc he d ule ( Healt hy S u bjects) .......4 3
Ta ble 6. h
Part 4: St u d y  Sc he d ule ( S u bjects wit h Sc hiz o p hre nia)........................................4 5
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Ta ble 6.i
Fi n di n gs a b o ve t he N O A E L ...............................................................................4 9
Ta ble 6.j
Defi nit i on o f D L Ts ............................................................................................5 4
Ta ble 7.a
E xcl u de d Me dicat i ons a n d Dietar y Pr o d ucts f or healt h y s u bjects ( Parts 1, 2 a n d 
3) .......................................................................................................................5 9
T a ble 7. b
E xcl u de d Me dicat i ons a n d Dietar y  Pr o d ucts f or S u bjects wit h Sc hiz o p hre nia 
( Part 4)...............................................................................................................6 0
Ta ble 8.a
C o m p osi tio n of  0. 5 % T wee n 8 0 i n 0. 5 % ( w/ v) Met h ylcell ul ose Ve hicle ............6 5
Ta ble 8. b
C o m p osi tio n of  Cr ystalli ne T A K-0 4 1 Oral  S us pe nsio n ......................................6 5
Ta ble 8.c
C o m p osi tio n of  Place b o t o T A K-0 4 1 Oral  S us pe nsi on .......................................6 6
Ta ble 9.a
Cli nical La b orat or y  Tests...................................................................................7 4
Ta ble 9. b
D o m ai ns f or C o g nitive Assess me nts ..................................................................8 0
Ta ble 9.c
C ollect i on of Bl o o d Sa m ples f or P har mac o ki net ic A nal ysis i n Part 1, C o h orts 1 
a n d 2 ..................................................................................................................8 4
Ta ble 9. d
C ollect i on of Bl o o d Sa m ples f or P har mac o ki net ic A nal ysis i n Part 1, C o h orts 3 
t o 5.....................................................................................................................8 4
Ta ble 9.e
C ollect i on of Bl o o d Sa m ples f or P K A nal ysis i n Part 2 a n d Part 4 ......................8 4
Ta ble 9.f
C ollect i on of Bl o o d Sa m ples f or P har m ac o ki net ic A nal ysis i n Part 3 .................8 4
Ta ble 9. g
C ollect i on of Uri ne Sa m ples f or P har mac o ki net ic A nal ysis f or Part 1 ................8 5
Ta ble 9. h
C ollect i on of Uri ne Sa m ples f or P har mac o ki net ic A nal ysis f or Part 2 ................8 5
Ta ble 9.i
P har mac o ki net ic Para meters ..............................................................................8 6
Ta ble 9.j
Uri ne Para meters Part 1, Part 2 a n d Part 4 ..........................................................8 7
Ta ble 9. k
A p pr o xi mate Bl o o d V ol u me f or Part 1 C o h ort 1 ................................................9 1
Ta ble 9.l
A p pr o xi mate Bl o o d V ol u me f or Part 1 C o h ort 2 ................................................9 2
Ta ble 9. m
A p pr o xi mate Bl o o d V ol u me f or Part 1 C o h orts 3 t o 5 ........................................9 3
Ta ble 9. n
A p pr o xi mate Bl o o d V ol u me f or Part 2 C o h orts 1 t o 4 ........................................9 4
Ta ble 9. o
A p pr o xi mate Bl o o d V ol u me f or Part 3 ...............................................................9 5
Ta ble 9. p
A p pr o xi mate Bl o o d V ol u me f or Part 4 ...............................................................9 6
Ta ble 1 0.a
Ta ke da Me dicall y Si g nifica nt A E List ..............................................................1 0 0
LI S T O F A P P E N DI C E S
A p pe n di x A
Sc he d ule of St u d y  Pr oce d ures Part 1................................................................1 2 1
A p pe n di x B 
Sc he d ule of St u d y  Pr oce d ures Part 2 C o h orts 1 t o 4 ( healt h y s u bjects o nl y) .....1 2 5
A p pe n di x C
Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati on – Rel at i ve 
Bi oa vaila bilit y a n d F o o d Effect) .......................................................................1 3 0
A p pe n di x D
Sc he d ule of St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T................1 3 5
A p pe n di x E
Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit .....................1 4 0
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x F
Res p o nsi bilit ies of t he I n vest i gat or...................................................................1 4 2
A p pe n di x G
Ele me nts of t he S u bje ct I nfor m e d C o nse nt .......................................................1 4 4
A p pe n di x H
I n vesti gat or C o nse nt t o Use of Pers o nal I nf or mati on ........................................1 4 7
A p pe n di x I
Detaile d Descri pt i on of A me n d me nts t o Te xt ...................................................1 4 8
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
2. 0 
S T U D Y S U M M A R Y
N a me of S p o ns or(s):
Ta ke da De vel o p me nt Ce nter A mericas, I nc.
C o m p o u n d:
T A K- 0 4 1
Title of Pr ot oc ol: A Ra n d o mize d, D o u ble- Bli n d, 
Place b o- C o ntr olle d, P hase 1, Asce n di n g Oral Si n gle a n d 
M ulti ple D ose St u d y t o E val uate t he Safet y, T olera bilit y, 
a n d P har mac o ki netics of T A K- 0 4 1 i n Healt h y S u bjects a n d 
S u bjects wit h Sta ble Sc hiz o p hre nia a n d a Ra n d o mize d 
O pe n- La bel, Si n gle D ose, Parallel Desi g n t o E val uate t he 
Relati ve Bi oa vaila bilit y a n d Effect of F o o d o n t he 
P har mac o ki netics of T A K- 0 4 1 Ta blet F or m ulati o n i n 
Healt h y S u bjects
I N D N o.: 1 3 0 0 7 4
E u dr a C T N o.: N ot 
a p plica ble
St u d y N u m ber: T A K- 0 4 1- 1 0 0 1
P h ase: 1
St u d y  Desi g n
T his is a p hase 1, first-i n- h u ma n ( FI H), ra n d o mize d, place b o-c o ntr olle d, d o u ble- bli n d, st u d y t o e val uate t he safet y, 
t olera bilit y, a n d P K of T A K- 0 4 1. T his st u d y desi g n i n t his a me n d me nt reflects a m o dificati o n of t he ori gi nal desi g n, 
d ue t o t he l o n ger t ha n e x pecte d half- life of T A K- 0 4 1 o bser ve d after t he si n gle- d ose a d mi nistrati o n of t he c o m p o u n d 
t o healt h y s u bjects i n t he first 2 c o h orts. T he st u d y is c o m p ose d of 4 parts: Part 1 is a si n gle-risi n g d ose [ S R D] st u d y i n 
healt h y s u bjects, wit h a n alter natin g pa nel desi g n ( C o h orts 1 a n d 2) a n d a se q ue ntial pa nel desi g n ( C o h orts 3 t o 5); Part 
2 is a m ulti ple-risi n g d ose [ M R D], se q ue ntial pa nel desi g n i n healt h y s u bjects ( C o h orts 1 t o 4); Part 3 is a r a n d o mize d,
o pe n-la bel, si n gle d ose parallel desi g n i n healt h y s u bjects, t o e val uate t he relati ve bi oa vaila bilit y a n d effect of f o o d o n 
t he P K of t he T A K- 0 4 1 ta blet f or m ulati o n. Part 4 is a si n gle d ose c o h ort desi g n i n s u bjects wit h sta ble sc hiz o p hre nia.
F or Part 1, C o h orts 1 a n d 2, d ose escalati o n a n d s u bse q ue nt d ose le vels will be deter mi ne d f oll o wi n g a f ull bli n de d 
re vie w of all a vaila ble safet y, t olera bilit y, a n d P K data fr o m t he pre vi o us d ose le vel. F or Part 1, C o h orts 3 t o 5, a n d all 
c o h orts i n Part 2, d ose escalati o n a n d s u bse q ue nt d ose le vels will be base d o n a s p o ns or re vie w of at least 2 1 da ys of 
safet y, t olera bilit y, a n d a vaila ble P K data fr o m t he pre vi o us d ose le vels. F or Part 3 s u bjects will recei ve a si n gle 4 0 m g 
d ose of t he ta blet f or m ulati o n of T A K- 0 4 1 ( 1 x 4 0 m g ta blet) base d o n safet y/t olera bilit y of t he sa me d ose i n healt h y 
s u bjects i n Part 1 a n d Part 2. F or Part 4, t he d ose selecte d will be base d o n e mer gi n g safet y/t olera bilit y a n d a vaila ble 
P K data of t he sa me d ose i n healt h y s u bjects fr o m Part 2. A p pr o xi matel y e q ual n u m bers of male a n d fe male s u bjects 
will be e nr olle d at eac h d ose le vel. T A K- 0 4 1 a n d matc hi n g place b o will be a d mi nistere d as a n oral s us pe nsi o n f or Part 
1, 2 a n d 4, a n d as t he i m me diate release ta blet f or m ulati o n f or Part 3.
 
 
 
 
P art 1 will c o nsist of 5 c o h orts wit h 8 s u bjects per c o h ort ( 6 acti ve: 2 place b o). C o h orts 1 a n d 2 will partici pate i n a 
2- peri o d, alter nati n g- pa nel, d o u ble- bli n d st u d y desi g n t o e val uate si n gle-risi n g d oses of T A K- 0 4 1( 5, 1 0, 2 0, a n d 4 0 
m g) or matc he d place b o wit h a was h o ut peri o d of at leas t 7 da ys bet wee n treat me nt peri o ds (see sc he matic of st u d y 
desi g n bel o w). As of A me n d me nt 0 4, after re vie w of t he data fr o m t hese i nitial c o h orts, C o h orts 3, 4, a n d 5 will 
partici pate i n a se q ue ntial- pa nel, d o u ble- bli n d st u d y desi g n t o e val uate si n gle-risi n g d oses of T A K- 0 4 1 or matc he d 
place b o. T his is a d o u ble- bli n d st u d y; t heref ore, t he s u bject, t he trial site pers o n nel, a n d t he s p o ns or staff w h o are 
i n v ol ve d i n t he treat me nt or cli nical e val uati o n are bli n de d t o treat me nt or i nter ve nti o n. Certai n s p o ns or staff n ot 
directl y i n v ol ve d wit h t he treat me nt or e val uati o n ma y be u n bli n de d t o t he treat me nt or i nter ve nti o n. T he pla n ne d d ose 
le vels of T A K- 0 4 1 t o be e val uate d i n C o h orts 3, 4, 5 are 8 0, 1 2 0, a n d 1 6 0 m g, res pecti vel y (see sc he matic of st u d y 
desi g n bel o w). Alt h o u g h pla n ne d, all s u bse q ue nt d oses after t he d ose of 8 0 m g f or C o h ort 3 will be deter mi ne d base d 
Pr o p ert y of T
rt 1
rt 
2--peri o d
peri o
m g) o
m g)
des
yt y
o m m er ci al u s e o nl y a n d s u bj e ct t o
u ble
u ble -bli n
bl
eflects a m
flects a
t he si n gle
he si n g
4 parts: Pa
parts: 
2) ) a n d a 
a n d a
healt h y s u
ealt h y
t o e val ua
o e va
i n gle d ose
n gle d ose
se q
e que nt d
ue nt
q
data fr o m
data fr o
e nt d ose le
nt d ose 
o m 
m t he pre
t he 
4 1 ( 1 x 4 0
1 ( 1 x 4
4 , t he d os
, t he d
y s u bjects
s u bjec
el. T A K
T A K -0
e releas
rele
t o t h e a p pli c a bl e T er m s of U s e
m sm s
N ot 
N ot 
r mm
e
m
t h
t o
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
o n t he e mer gi n g safet y, t olera bilit y, a n d P K data fr o m t he prece di n g c o h orts.
As t his is a n FI H st u d y, a se nti nel gr o u p will be use d f or Part 1 C o h ort 1 ( wit h t he i nitial 2 s u bjects recei vi n g eit her 
acti ve dr u g or place b o [ 1: 1]) t o e ns ure a de q uate safet y a n d t olera bilit y pri or t o d osi n g T A K- 0 4 1 t o t he re mai ni n g 
s u bjects i n t his c o h ort. I n Part 1 C o h ort 1 Peri o d 1, t he re mai ni n g 6 s u bjects will be d ose d f oll o wi n g a re vie w of 
2 4- h o ur p ost d ose safet y a n d t olera bilit y data a n d will o nl y occ ur f oll o wi n g a gree me nt bet wee n t he i n vesti gat or a n d 
Ta ke da. T he hi g hest pla n ne d d ose is pre dicte d t o ha ve ma xi m u m o bser ve d plas ma c o nce ntrati o n ( C ma x ) a n d area u n der 
t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs ( A U C2 4) val ues bel o w t he c orres p o n di n g e x p os ure 
o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ da y i n t he male a n d fe male d o gs fr o m t he 1 3- wee k t o xic ol o g y st u d y. 
Se nti nel d osi n g ma y be use d f or a d diti o nal c o h orts if deter mi ne d t o be necessar y base d o n t he e mer gi n g safet y, 
t olera bilit y, a n d a vaila ble P K data fr o m t he prece di n g c o h orts.
B o n d- La der vis ual a nal o g scales will be perf or me d i n Part 1, Da y - 1, Da y 1 at 1, 3, 8, a n d 2 4 h o urs p ost d ose, Da y 5, 
a n d (if a p plica ble) at Earl y Ter mi nati o n.
P art 1: Sc he m atic of St u d y Desi g n
P art 1 ( S R D)  
N u m ber of S u bjects 
Peri o d 1 ( a)
W as h o ut Peri o d
( at least 7 da ys)
Peri o d 2 ( b)
C o h ort 1 ( n = 8), faste d
6
T A K- 0 4 1 5 m g
T A K- 0 4 1 2 0 m g
2
Place b o
Place b o
C o h ort 2 ( n = 8), faste d
6
T A K- 0 4 1 1 0 m g
T A K- 0 4 1 4 0 m g
2
Place b o
Place b o
C o h ort 3 ( n = 8), faste d
6
T A K- 0 4 1 8 0 m g
2
Place b o
C o h ort 4 ( n = 8), faste d
6
T A K- 0 4 1 1 2 0 m g
2
Place b o
C o h ort 5 ( n = 8), faste d
6
T A K- 0 4 1 1 6 0 m g
2
Place b o
(a) D oses pla n ne d t o be a d mi nistere d ra n ge fr o m 5 t o u p t o 1 6 0 m g. T he act ual d oses a d mi nistere d after 8 0 m g will be base d o n 
e mer gi n g safet y, t olera bilit y, a n d P K data fr o m t he pre vi o us c o h orts a n d ma y var y fr o m t he act ual d oses s h o w n i n t he ta ble a b o v e.
( b) S u bjects i n C o h orts 1- 5 will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1.
O verall, Part 1 of t he st u d y will c o nsist of a Scree ni n g Visit ( Da ys - 2 1 t o - 2), a pre d ose C hec k-i n Da y f or all s u bjects 
( Da y - 1) d uri n g w hic h baseli ne assess me nts will be c o n d ucte d, a n d a si n gle oral d ose a d mi nistrati o n ( Da y 1) w he n all 
s u bjects will u n der g o st u d y-s pecific assess me nts. T he t otal c o nfi ne me nt peri o d f or eac h s u bject will be 5 da ys.
S u bjects fr o m Part 1 C o h orts 1 a n d 2 i n eac h peri o d will be re q uire d t o re mai n i n t he st u d y u nit f or at least 9 6 h o urs 
after d osi n g f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge. F or s u bjects fr o m Part 1 C o h orts 1 a n d 2 
Peri o d 2, t he wee kl y F oll o w- u p safet y  a n d P K o n-site Visits will occ ur starti n g fr o m 7 da ys after last d ose 
a d mi nistrati o n u ntil T A K- 0 4 1 is n ot q ua ntif ia ble i n plas ma. All s u bjects i n t he c o h orts will be br o u g ht bac k i n or der t o 
mai ntai n t he bli n d. S u bjects fr o m Part 1 C o h orts 3 t o 5 will be re q uire d t o re mai n i n t he st u d y u nit f or 9 6 h o urs after 
d osi n g. F or s u bjects fr o m Part 1 C o h orts 3 t o 5, t he wee kl y f oll o w- u p safet y a n d P K o n-site visits will occ ur starti n g 
fr o m Da y 8 u ntil 6 wee ks after t he d ose. F or s u bjects fr o m Part 1 C o h orts 1 t o 5, a Fi nal visit t hat c o m pletes t he st u d y 
will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K F oll o w- u p visit. 
 
 
 
Pr o p ert y of T a k e d a: F or n o n- c o m
stere d ra n g
re d ra
a n d P K d
n d P K 
5 will fast
will fa
f t he st u d
f t he st u
n g w hic h 
g w hi
ill u n der g
l u n de
ts fr o m Pa
ts fr o m 
r d osi n g f
r d osi n g
eri o d 2, t h
eri o d 2,
a d mi nis
a d m
o m m er ci al u s e o nl y a n d s u bj e ct t 
li c a bl e T er m s of U s e
or a n d 
or a n d 
area u n de
ea u n d
e x p os ure 
x p os u
l o g y st u d
o g y st u
er gi n g saf
er gi n g s
1, 3, 8, a n
3, 8, 
m sm s
j e
W aW
u b
m gg
n d
b o
0 4 1 1 0 m g
4 1 1 0 m
Place b o
lace b
T A K
T A K -0 40
P
T A
2
mai n
ma
d o
o m
yt y
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
 
 
P art 1 C o h orts 1 t o 2: St u d y Sc he d ule f or E ac h Peri o d ( He alt h y S u bjects)
Scree ni n g  
C hec k-i n
D osi n g ( a)
S afet y a n d P K 
Assess me nts
S afet y a n d P K 
Assess me nts  
Disc h ar ge
Wee kl y 
F oll o w- u p
Visits ( b) 
Fi n al Visit (c)
Da ys - 2 1 t o - 2  
Da y - 1  
Da y 1  
Da ys 2- 5  
Da y 5 
T B D ( b)
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1.
( b) S u bjects will ret ur n t o t he site f or wee kl y safet y a n d P K F oll o w- u p Visits, starti n g fr o m 7 da ys after eac h C o h ort’s last treat me nt 
peri o d u ntil t he plas ma c o nce ntrati o n of T A K- 0 4 1 is bel o w t he l o wer li mit of q ua ntitati o n.
(c) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K F oll o w- u p Visit.
P art 1 C o h orts 3 t o 5: St u d y Sc he d ule ( He alt h y S u bjects)
Scree ni n g  
C hec k-i n
D osi n g ( a)
S afet y a n d P K 
Assess me nts
S afet y a n d P K 
Assess me nts  
Disc h ar ge
Wee kl y 
F oll o w- u p
Visits ( b) 
Fi n al Visit (c)
Da ys - 2 1 t o - 2  
Da y - 1  
Da y 1  
Da ys 2- 5  
Da y 5
Da ys 8, 1 5, 
2 2, 2 9, 3 6, 
a n d 4 3
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1. S u bjects will be all o we d t o eat 4 h o urs p ost d ose.
( b) T he F oll o w- u p P K a n d safet y assess me nts will occ ur wee kl y fr o m 7 da ys u ntil 6 wee ks after t he d ose. All s u bjects i n t he c o h orts 
will be br o u g ht bac k i n or der t o mai ntai n t he bli n d. If a b n or mal, cli nicall y si g nifica nt fi n di n gs are o bser ve d after disc har ge,  s u bjects 
m a y be br o u g ht bac k t o t he st u d y u nit f or re-e val uati o n per i n vesti gat or’s discreti o n.
(c) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K F oll o w- u p Visit.
P art 2 will c o nsist of a 4-c o h ort se q ue ntial- pa nel, d o u ble- bli n d, wee kl y d osi n g, m ulti ple-risi n g d ose ( M R D) desi g n. 
T o assess T A K- 0 4 1 plas ma e x p os ure a n d p ote ntial acc u m ulati o n i n Part 2, s u bjects will recei ve a n i nitial l oa di n g d ose 
of T A K- 0 4 1 o n  Da y 1 f oll o we d b y a mai nte na nce d ose t hat is half t he i nitial d ose o n Da ys 8, 1 5, a n d 2 2 or will recei ve 
place b o o n all st u d y d osi n g da ys (see sc he matic of st u d y desi g n bel o w). F o ur d ose c o h orts are c o nsi dere d a de q uate t o 
e x pl ore t he p har mac ol o gicall y acti ve e x p os ure ra n ge i n healt h y s u bjects. H o we ver, a d diti o nal c o h orts ma y be st u die d, 
if dee me d necessar y, t o f ull y c haracterize t he p har mac ol o gical e x p os ure ra n ge. Eac h c o h ort will be c o m p ose d of 8 
s u bjects w here 6 s u bjects will be ra n d o mize d t o recei ve T A K- 0 4 1 a n d 2 s u bjects will be ra n d o ml y assi g ne d t o recei ve 
matc he d place b o. T he st u d y p o p ulati o n f or Part 2 will be c o m p ose d of a t otal of u p t o a p pr o xi matel y  3 2 healt h y 
s u bjects. Part 2 ma y c o m me nce o nl y after 2 1 da ys of safet y, t olera bilit y, a n d a vaila ble P K data ha ve bee n c ollecte d 
fr o m Part 1 C o h ort 3.
T he d ose le vels f or Part 2 C o h orts 2 o n war ds will be base d o n e mer gi n g safet y/t olera bilit y a n d P K data fr o m Part 1 a n d 
fr o m prece di n g c o h orts i n Part 2. D ose escalati o n a n d s u bse q ue nt d ose le vels will be base d o n a s p o ns or re vie w of at 
least 2 1 da ys of safet y, t olera bilit y, a n d a vaila ble P K data fr o m t he pre vi o us d ose re gi me n. T he hi g hest pla n ne d 
l oa di n g d ose i n Part 2 will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, a n d well t olerate d i n Part 1. T he hi g hest 
pr o p ose d wee kl y mai nte na nce d ose will ha ve a pre dicte d mea n a vera ge c o nce ntrati o n d uri n g a d osi n g i nter val, at 
stea d y state ( Ca v,ss) t hat is bel o w t he Ca v,ss o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ da y i n t he male a n d fe male d o gs 
fr o m t he 1 3- wee k t o xic ol o g y st u d y.
P art 2: Sc he m atic of St u d y Desi g n: He alt h y S u bjects ( C o h orts 1 t o 4)
4 0 m g o n D a y 1 a n d 2 0 m g 
o n D a ys 8, 1 5, a n d 2 2
8 0 m g o n D a y 1 a n d 4 0 m g 
o n D a ys 8, 1 5, a n d 2 2
1 2 0 m g o n D a y 1 a n d 6 0 m g 
o n D a ys 8, 1 5, a n d 2 2
1 6 0 m g o n D a y 1 a n d 8 0 m g 
o n D a ys 8, 1 5, a n d 2 2
C o h ort 1
( n = 8; 6 acti ve: 2 place b o)
C o h ort 2
( n = 8; 6 acti ve: 2 place b o)
C o h ort 3
( n = 8; 6 acti ve: 2 place b o)
C o h ort 4
( n = 8; 6 acti ve: 2 place b o)
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y 
S u bjects 
S u bjec
kl y fr o m 7 
y fr o m 7 
r mal, cli nic
mal, cli n
per i n vest
er i n v
o 1 6 da ys 
o 1 6 da y
pa nel, d o
pa nel, 
d p ote ntia
p ote nt
mai nte na n
ai nte n
see sc he m
e sc he
acti ve e x p
i ve e x
y c haracte
harac
will be ra
ill be r
st u d y p o p
u d y p
y c o m me n
c o m m
rtrt 3.3.
ls f or Par
f or P
e di n g c o h o
di n g c o
da ys of s
a ys o
n g d ose i n
g d ose
r o p ose d w
o p ose d 
stea d y st
tea d y 
y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
m sm s
Fi n al V
Fi n al 
T e
c a
pli c
fter eac h C
er eac h C
d P K F oll o
K F ol
p p
Disc h ar g
isc h ar g
ct
Da y
D
s u
a n d
fr o m 
fr o m
y a
yt y
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
O verall, f or healt h y s u bjects ( C o h orts 1 t o 4), Part 2 of t he st u d y will c o nsist of a Scree ni n g Visit ( Da ys - 2 1 t o - 3), a 
pre d ose C hec k-i n Da y f or all s u bjects ( Da ys - 2) d uri n g w hic h  baseli ne assess me nts will be c o n d ucte d, a n d m ulti ple 
or al d ose a d mi nistrati o ns ( Da ys 1, 8, 1 5, a n d 2 2) w he n all s u bjects will u n der g o st u d y-s pecific assess me nts.
S u bjects fr o m Part 2 C o h orts 1 t o 4 will be re q uire d t o re ma i n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3 ( 4 8 h o urs after t he 
first d ose) f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge. S u bjects will be re q uire d t o ret ur n o n Da y 5 f or 
a safet y a n d P K assess me nt. S u bjects will ret ur n o n Da y 7 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he sec o n d 
d ose o n da y 8. S u bjects will re mai n i n t he st u d y u nit fr o m Da y 7 t o Da y 1 0 ( 4 8 h o urs after t he sec o n d d ose). S u bjects 
will ret ur n o n Da y 1 4 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he t hir d d ose o n Da y 1 5. S u bjects will re mai n 
i n t he st u d y u nit fr o m Da y 1 4 t o Da y 1 7 ( 4 8 h o urs after t he t hir d d ose). S u bjects will ret ur n o n Da y 2 1 t o o btai n safet y 
la b orat or y tests bef ore recei vi n g t he t hir d d ose o n Da y 2 2. S u bjects will re mai n i n t he st u d y u nit fr o m Da y 2 1 t o Da y 
2 4 ( 4 8 h o urs after t he f o urt h d ose). After disc har ge o n Da y 2 4, s u bjects will ret ur n t o t he cli nic o n Da ys 2 6, 2 9, 3 6, 4 3, 
5 0, 5 7, a n d 6 4 f or safet y a n d P K f oll o w u p visits. F or s u bjects fr o m Part 2 C o h orts 1 t o 4, a Fi nal visit t hat c o m pletes 
t he st u d y will occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K F oll o w- u p visit. T he sc he d ule f or Part 2 is s h o w n bel o w.
B o n d- La der vis u al a nal o g scales will be perf or me d o n Da y - 1; Da ys 1, 8, 1 5, a n d 2 2 at 1, 3, 8, a n d 2 4 h o urs p ost d ose, 
Da y 2 4, a n d (if a p plica ble) at Earl y Ter mi nati o n.
P art 2: St u d y Sc he d ule: He alt h y S u bjects, C o h orts 1 t o 4
Scree ni n g  
C hec k-i n
D ose
A d mi nistr ati o n ( a, c)
Fi n al
Disc h ar ge
F oll o w- u p
Visits ( d)
Fi n al
Visit (e)
Da y - 2 1 t o - 3  
Da y - 2  
Da ys 1, 8, 1 5, a n d 2 2
Da y 2 4
Da ys 2 6, 2 9, 3 6, 
4 3, 5 0, 5 7, a n d 6 4
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da ys 1, 8 1 5, a n d 2 2. O n all d osi n g da ys, s u bjects will be all o we d t o eat 4 
h o urs p ost d ose.
( b) D osi n g o n Da ys 8, 1 5, a n d 2 2 will be pre dicate d o n t he re vie w of safet y la b orat or y res ults fr o m sa m ples o btai ne d t he da y be f ore 
(i.e., o n Da ys 7, 1 4, a n d 2 1)
(c) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3, Da y 7 t o Da y 1 0, Da y 1 4 t o Da y 1 7, a n d Da y 2 1 t o 
Da y 2 4.
( d) T he F oll o w- u p P K a n d safet y assess me nts will occ ur wee kl y u ntil 6 wee ks after t he last d ose. If a b n or mal, cli nicall y si g nifica nt 
fi n di n gs are o bser ve d u p o n disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or re-e val uati o n per i n vesti gat or’s discr eti o n.
(e) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K F oll o w- u p Visit.
P art 3 will c o nsist of a n o pe n la bel, si n gle- d ose parallel desi g n. A p pr o xi matel y 1 8 h ealt h y s u bjects will be e nr olle d t o 
e val uate t he or al bi oa vaila bilit y of t he T A K- 0 4 1 ta blet f or m ulati o n relati ve t o t he oral s us pe nsi o n a n d t he effect of 
f o o d o n t he P K of t he ta blet f or m ulati o n. T he s u bjects will be ran d o ml y assi g ne d ( 1: 1 rati o) t o be a d mi nistere d orall y 
T A K- 0 4 1 o n Da y 1 as o ne 4 0 m g i m me diate release ta blet after eit her at least 1 0 h o urs of o ver ni g ht fast or 3 0 mi n utes 
after starti n g i n gesti o n of a hi g h-fat, hi g h-cal orie br ea kfast.
O verall, Part 3 of t he st u d y will c o nsist of a Scree ni n g Visit ( Da ys - 2 8 t o - 2), a pre d ose C hec k-i n Da y f or eac h s u bject 
( Da y - 1) d uri n g w hic h baseli ne assess me nts will be c o n d ucte d. S u bjects  w h o satisf y t he Scree ni n g e val uati o n a n d 
selecti o n criteria will be e nr olle d. O n Da y 1, eli gi ble s u bjects will be ra n d o mize d t o recei ve a si n gle d ose of T A K- 0 4 1 
as o ne 4 0 m g ta blet a d mi nistere d orall y after eit her at least 1 0- h o urs of o ver ni g ht fast or 3 0 mi n utes after starti n g 
i n gesti o n of a hi g h-fat, hi g h-cal orie brea kfast. Bl o o d sa m ples will be c ollecte d o ver 9 6 h o urs p ost- d ose t o meas ure
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al
C o ho h
D ose
D os
d mi nistr a
mi nist
al
Da ys 1
Da ys
er
h o urs bef o
urs be
n d 2 2 will 
2 2 w
2 1))
q uire d 
uire d t o r
t o
u p P K a n d 
P K a n
bs er ve d u p
er ve d 
nal/ St u d y C
/ St u d y
rt 3
rt 3 will 
wil
e val uate 
val ua
f o o d o
f o o d
T A
m
yt y
o t h e a p pli c a bl e T er m s of U s e
er t he 
t he 
a y 5 f or 
a y 5 f or
t he sec o n
e sec o
ose). S u bj
se). S
jects will 
cts wi
y 2 1 t o o bt
y 2 1 t o o
it fr o m D
fr o m D
ic o n Da y
o n Da
 a Fi nal v
a Fi nal v
d ule f or P
d ule f o
2 at 1, 3, 
at 1, 3
m sm s
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T A K- 0 4 1 plas ma c o nce ntrati o ns, a n d s u bjects will ret ur n f or a fi nal f oll o w - u p visit a p pr o xi matel y 2  wee ks after Da y 
5.
P art 3: St u d y Sc he d ule: He alt h y S u bjects,
Pretre at me nt
Tre at me nt Peri o d 
F oll o w u p
( a)
Scree ni n g  
C hec k-i n
D osi n g a n d
St u d y Assess me nts
S afet y a n d P K 
Assess me nts
Da y - 2 8 t o - 2  
Da y - 1
Da y 1
Da ys 1- 3  
Da ys 4- 5 
St u d y Da y 
1 9 ( ± 2)
C o nfi ne me nt ( b)
(a) T he F oll o w- u p Visit will occ ur 1 9 ( ± 2) da ys p ost d ose.
( b) S u bjects will be release d fr o m c o nfi ne me nt after Da y 3 st u d y assess me nts are c o m plete.
P art 4 will c o nsist of a 1-c o h ort, d o u ble- bli n d, wee kl y d osi n g desi g n. S u bjects wit h sta ble sc hiz o p hre nia will be 
e nr olle d. O n e d ose c o h ort is c o nsi dere d a de q uate t o e x pl ore t he p har mac ol o gicall y acti ve e x p os ure ra n ge i n s u bjects 
wit h sta ble sc hiz o p hre nia. T he c o h ort will be c o m p ose d of 2 4 s u bjects w here s u bjects will be ra n d o ml y assi g ne d t o 
recei ve T A K- 0 4 1 or place b o i n a rati o of 2: 1. S u bjects will recei ve a n i nitial l oa di n g d ose of T A K- 0 4 1 o n Da y 1 
f oll o we d b y a mai nte na nce d ose t hat will be half t he i nitial d ose o n Da ys 8, 1 5, a n d 2 2 or will recei ve place b o o n all 
st u d y d osi n g da ys. Part 4  m a y c o m me nce o nl y after at least 2 1 da ys of safet y, t olera bilit y, a n d a vaila ble P K data ha ve 
bee n c ollecte d at t he e q ui vale nt d ose c o h ort i n healt h y s u bjects i n Part 2.
T he d ose le vel f or Part 4  will be base d o n e mer gi n g safet y/t olera bilit y a n d a vaila ble P K data of t he sa me d ose i n 
healt h y s u bjects fr o m Part 2. T he d ose selecte d i n Part 4  will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, a n d 
well t olerate d i n Part 2. T he pr o p ose d wee kl y mai nte na nce d ose will ha ve a pre dicte d mea n a vera ge c o nce ntrati o n 
d uri n g a d osi n g i nter val, at stea d y state ( C a v,ss) bel o w t he Ca v,ss o bser ve d at t he N O A E L d ose of 3 0  m g/ k g/ da y i n t he 
male a n d fe male d o gs fr o m t he 1 3 - wee k t o xic ol o g y st u d y.
S u bjects i n Part 4 will be a d mi nistere d a si n gle T A K- 0 4 1 l oa di n g d ose or place b o o n Da y 1 a n d wee kl y mai nte na nce 
d oses o n Da ys 8, 1 5 a n d 2 2. T he si n gle c o h ort of 2 4 s u bjects will be ra n d o mize d wit h 1 6 acti ve : 8 place b o. 
O verall, Part 4 of t he st u d y will c o nsist of a Scree ni n g Visit ( Da ys - 3 5 t o - 3), a pre d ose C hec k-i n Da y f or all s u bjects 
( Da ys - 2) d uri n g w hic h baseli ne assess me nts will be c o n d ucted, Da y - 1 d uri n g w hic h ot her baseli ne assess me nts will 
be c o n d ucte d, a n d 2 2 da ys of treat me nt peri o d w he n all s u bjects will be d ose d o n Da ys 1, 8, 1 5, a n d 2 2 as well as 
u n der g oi n g st u d y-s pecific assess me nts. After 4 wee ks of d osi n g, s u bjects will ret ur n f or wee kl y f oll o w- u p 
st u d y-s pecific assess me nts u ntil  Da y 6 4 a n d st u d y c o m pleti o n o n Da y 7 0.
I n Part 4, s u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3 ( 4 8 h o urs after t he first d ose) f or 
safet y, P K, a n d all st u d y assess me nts bef ore disc har ge. S u bjects will be re q uire d t o ret ur n o n Da y 5 f or a safet y a n d P K 
assess me nt. S u bjects will ret ur n o n Da y 7 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he sec o n d d ose o n Da y 8. 
S u bjects will re mai n i n t he st u d y u nit fr o m Da y 7 t o Da y 1 0 ( 4 8 h o urs after t he sec o n d d ose). S u bjects will ret ur n o n 
Da y 1 4 t o o btai n safet y la b orat or y tes ts bef ore recei vi n g t he t hir d d ose o n Da y 1 5. S u bjects will re mai n i n t he st u d y 
u nit fr o m Da y 1 4 t o Da y 1 7 ( 4 8 h o urs after t he t hir d d ose). S u bjects will ret ur n o n Da y 2 1 t o o btai n safet y la b orat or y 
tests bef ore recei vi n g t he t hir d d ose o n Da y 2 2. S u bjects will re mai n i n t he st u d y u nit fr o m Da y 2 1 t o Da y 2 4 ( 4 8 h o urs 
after t he f o urt h d ose). After disc har ge o n Da y 2 4, s u bjects will ret ur n t o t he cli nic f or safet y a n d P K wee kl y f oll o w u p 
visits. T he fi nal visit t hat c o m pletes t he st u d y will occ ur 1 2 t o  1 6 da ys after t he last safet y a n d P K f oll o w- u p visit. T he 
sc he d ule f or Part 4 is s h o w n bel o w.
t 
pr e-selecte d ti mes a n d (if a p plica ble) at Earl y Ter mi nati o n.
Pr o p ert 
a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s
)
c a b
i c a
c a
p c
te.
sta ble sc h
a ble sc
y acti ve e
y acti ve 
u bjects w
bjects w
l oa di n g d
oa di n g
8, 1 5, a n d
8, 1 5, a
safet y, t o
afet y, t o
art 2.
art 2.
a bilit y a n
bilit y a
n ot e xcee
ot e xc
e d ose wi
d ose
he CC a v,ss
a v,s o b
st u d y.
u d y.
T A K
A K -0 4 1 
0 4 1
t of 2 4 s u b
of 2 4 s
a Scree ni
Scree n
me nts wil
e nts w
e nt peri o d
nt peri o
me nts. Aft
e nts. A
l Da y 
Da y 6 46
e q uire d t o
uire d 
assess me
ssess m
will ret ur
ill ret u
i n i n t he s
n i n t h
n safet y
n safet y la
y
a y 1 4 t o D
1 4 t o
re recei vi n
recei v
e f o urt h d
e f o urt h
ts. T he fi n
T he f
c he d ule f o
ule
t
m s of U s e
m sm s
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
P art 4: St u d y Sc he d ule: S u bjects wit h Sc hiz o p hre ni a,
Scree ni n g  
C hec k-i n
D ose
A d mi nistr ati o n ( a, b, c)
Fi n al
Disc h ar ge
F oll o w- u p
Visits ( d)
Fi n al
Visit
(e)
Da y - 3 5 t o - 3  
Da y - 2  
Da ys 1, 8, 1 5, a n d 2 2  
Da y 2 4
Da ys 2 6, 2 9, 3 6, 4 3, 
5 0, 5 7, 6 4
St u d y
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da ys 1, 8, 1 5, a n d 2 2. O n all d osi n g da ys, s u bjects will be 
all o we d t o eat 4 h o urs p ost d ose.
( b) D osi n g o n Da ys 8, 1 5, a n d 2 2 will be pre dicate d o n t he re vie w of safet y la b orat or y res ults fr o m sa m ples o btai ne d 
t he da y bef ore (i.e., o n Da ys 7, 1 4, a n d 2 1) a n d o verall cli nical stat us of t he s u bjects.
(c) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3, Da y 7 t o Da y 1 0, Da y 1 4 t o Da y 1 7, a n d 
Da y 2 1 t o Da y 2 4.
( d) T he F oll o w- u p P K a n d safet y assess me nts will occ ur u ntil 6 wee ks after t he last d ose. If a b n or mal, cli nicall y 
si g nifica nt fi n di n gs are o bser ve d u p o n disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or re-e val uati o n per 
i n vesti gat or’s discreti o n.
(e) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K F oll o w- u p 
St u d y O bjecti ves 
Pri m ar y O bjecti ve:
T o e val uate t he safet y a n d t olera bilit y of T A K- 0 4 1
!
F oll o wi n g oral si n gle a n d m ulti ple d oses i n healt h y s u bjects ( Parts 1, 2 a n d 3).
!
As a d d- o n t hera p y t o a nti ps yc h otics i n s u bjects wit h sta ble sc hiz o p hre nia ( Part 4).
T o assess t he oral bi oa vaila bilit y of T A K – 0 4 1 i n healt h y s u bjects a d mi nistere d as a 4 0 m g i m me diate release ta blet 
f or m ulati o n i n t he faste d state c o m pare d t o 4 0 m g oral s us pe nsi o n f or m ulati o n i n t he faste d state. ( Part 3)
T o assess t he effect of f o o d o n t he p har mac o ki netics  of 4 0 m g i m me diate release ta blet f or m ulati o n of T A K – 0 4 1 i n 
h ealt h y s u bjects ( Part 3).
Sec o n d ar y  O bjecti ve:
T o e val uate t he P K of T A K- 0 4 1
!
A d mi nistere d u n der fasti n g c o n diti o ns f oll o wi n g si n gle a n d m ulti ple oral d oses i n healt h y s u bjects ( Part 1 a n d 2).
!
As a d d- o n t hera p y t o a nti ps yc h otics i n s u bjects wit h sta ble sc hiz o p hre nia ( Part 4)
E x pl or at or y O bjecti ves:
Pr o p ertt
n o n- c o m m er ci al u s e o nl y a n d s u bj e
ects ( Parts
s ( Pa
h sta ble sc
ta ble s
alt h y s u bj
t h y s u
g oral s us p
oral s u
ki netics o
i netics 
n g c o n diti o
c o n di
a nti ps yc h
nti ps y
ves:
es:
bj e ct t o t h e a p pli c a bl e T er m s of U s e
u d y
u d y
o m pleti o n
pleti
er m
e
bjects wil
bjects w
m sa m ple
m sa m p
1 0, Da y 1
0, Da y 
ose. If a b
se. If a
t he st u d y 
he st u d
afet y a n d
fet y a
m sm s
bj e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
S u bject P o p ul ati o n: Male a n d fe male healt h y s u bjects ( Parts 1- 3) a n d s u bjects wit h sta ble sc hiz o p hre nia ( Part 4)
a ge d 1 8 t o 5 5 years, i ncl usi ve.
N u m ber of S u bjects:
Esti mate d t otal: 1 1 4 s u bjects
P art 1: 4 0 healt h y s u bjects i n C o h orts 1 t o 5 ( 8 s u bjects per 
c o h ort: 6 acti ve, 2 place b o)
P art 2: 3 2 healt h y s u bjects ( 8 s u bjects per c o h ort: 6 acti ve: 
2 place b o)
P art 3: 1 8 healt h y s u bjects ( 9 faste d : 9 fe d wit h a hi g h-fat
a n d hi g h-cal orie  meal)
P art 4: 2 4 s u bjects wit h sta ble sc hiz o p hre nia ( 1 6 acti ve: 8 
place b o )
N u m ber of Sites:
Esti mate d t otal: 1 site i n t he U nite d States
D ose Le vel(s):
P art 1 : C o h orts 1 t o 5, si n gle d ose of 5 t o u p t o 1 6 0 m g 
T A K- 0 4 1 or matc hi n g place b o
P art 2: Si n gle l oa di n g d oses of T A K- 0 4 1 fr o m 4 0 t o 1 6 0 
m g, a n d wee kl y mai nte na nce d oses of T A K- 0 4 1 fr o m 2 0 t o 
8 0 m g or matc hi n g place b o t hr o u g h o ut.
P art 3 : Si n gle d ose of 4 0 m g T A K- 0 4 1 
P art 4 : Si n gle l oa di n g d oses of T A K- 0 4 1, a n d wee kl y 
mai nte na nce d oses of T A K- 0 4 1 or matc he d place b o 
t hr o u g h o ut. T he d ose re gi me ns of T A K- 0 4 1 will be 
deter mi ne d base d o n e mer gi n g safet y/t olera bilit y data a n d 
a vaila ble P K data fr o m Part 2.
R o ute of A d mi nistr ati o n:
Oral
D ur ati o n of Tre at me nt:
P art 1 : 1 da y
P art 2: o nce per wee k f or 4 wee ks.
P art 3: 1 da y
P art 4 : o nce per wee k f or 4 wee ks
Peri o d of E v al u ati o n:
Part 1 C o h ort 1: ~ 5 m o nt hs
Part 1 C o h ort 2: ~ 4 m o nt hs
Part 1 C o h orts 3 t o 5: 3 m o nt hs
Part 2 All C o h orts: 4 m o nt hs
Part 3: ~ 3  m o nt hs
Part 4: 4 m o nt hs
M ai n Criteri a f or I ncl usi o n:
F or healt h y s u bjects a n d s u bjects wit h sc hiz o p hre nia: A d ult me n a n d w o me n of n o n-c hil d beari n g p ote ntial w h o wei g h 
at least 4 5 k g ( 9 9 l b) wit h a b o d y mass i n de x fr o m 1 8 t o 3 2 k g/ m 2 f or h ealt h y s u bjects or 1 8 t o 4 0. 5 k g/ m2 f or s u bjects 
wit h sc hiz o p hre nia, w h o are willi n g t o c o m pl y wit h st u d y restricti o ns descri be d i n t he pr ot oc ol.
F or s u bjects wit h sc hiz o p hre nia o nl y: Male a n d fe male s u bjects wit h sta ble sc hiz o p hre nia w h o are o n a sta ble d ose of 
a n a nti ps yc h otic f or at least 2 m o nt hs as d oc u me nte d b y me dical hist or y a n d assesse d b y site staff.
M ai n Criteri a f or E xcl usi o n:
!
S u bject has k n o w n h y perse nsiti vit y t o a n y c o m p o ne nt of t he f or m ulati o n of T A K- 0 4 1.
!
F or healt h y s u bjects o nl y: s u bject has e vi de nce of c urre nt acti ve car di o vasc ular, ce ntral ner v o us s yste m, 
he pat o biliar y disease i ncl u di n g hist or y of biliar y tree dis or ders, gallst o nes, hist or y of e n d osc o pic retr o gra de 
c h ola n gi o pa ncreat o gra p h y ( E R C P), a n d/ or c h olec ystect o m y, he mat o p oietic disease, re nal d ysf u ncti o n, 
meta b olic or e n d ocri ne d ysf u ncti o n, seri o us aller g y, ast h ma, h y p o xe mia, h y perte nsi o n, seiz ures, or aller gic s ki n 
ras h. T here is a n y fi n di n g i n t he s u bject’s me dical hist or y, p h ysical e xa mi nati o n, or safet y la b orat or y test res ults 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
m sm sm
be 
it y y data
data a n
nistr ati o
istr ati
t t o
nl
ks.s.
r 4 wee ks
4 wee k
ci a
f or I ncl u
or I nc
y s u bjects 
s u bjec
4 5 k g ( 9 9 
5 k g ( 9
sc hiz o p hr
c hiz o p
or s u bject
r s u bje
a n a nti p
a n a nti
F o
M ai
M a
of
yt y
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 2 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
(i ncl u di n g ele vate d al kali ne p h os p hatase ( A L P), ele vate d bilir u bi n, ele vate d γ-gl uta m yl tra nsferase ( G G T), 
ele vate d 5’-n ucle oti dase, or a b n or mal uri ne os m olalit y) t hat i n t he j u d g me nt of t he pri nci pal i n vesti ga t or 
re prese nts a reas o na ble s us pici o n of a disease t hat w o ul d c o ntrai n dicate ta ki n g T A K-0 4 1, or t hat mi g ht i nterfere 
wit h t he c o n d uct of t he st u d y. T his i ncl u des, b ut is n ot li mite d t o, pe ptic ulcer disease, c h olestasis seiz ure 
dis or ders, a n d car diac arr h y t h mias.

S u bject has a b n or mal Scree ni n g or C hec k -i n la b orat or y val ues ( > U L N f or t he res pecti ve ser u m c he mistries) of 
ala ni ne a mi n otra nsferase ( A L T), as partate a mi n otra nsferase ( A S T), t otal bilir u bi n ( T BI LI), A L P, G G T, 
5’ n ucle oti dase a n d/ or a b n or mal uri ne o s m olalit y, c o nfir me d u p o n re peat testi n g.

S u bject h as  a s ustai ne d resti n g heart rate o utsi de t he ra n ge 4 0 t o 1 0 0 beats per mi n ute ( b p m), c o nfir me d o n re peat 
testi n g wit hi n a ma xi m u m of 3 0 mi n utes at Scree ni n g or C hec k-i n.

If fe male, t he s u bject is of c hil dbeari n g p ote ntial (e g, pre me n o pa usal, n ot sterilize d).

If male, t he s u bject i nte n ds t o d o nate s per m d uri n g t he c o urse of t his st u d y or wit hi n 1 4 5 da ys (ie, 9 0 da ys after 5 
half -li ves) of t he last d ose of st u d y dr u g.

T he s u bject is c o nsi dere d b y t he i n vesti gat or t o be at i m mi ne nt ris k of s uici de or i nj ur y t o self, ot hers, or pr o pert y, 
or  s u bjects w h o wit hi n t he past year pri or t o Scree ni n g ha ve atte m pte d s uici de. S u bjects w h o ha ve p ositi ve 
a ns wers o n ite m 4 or 5 o n t he C -S S R S ( base d o n t he past year) pri or t o ra n d o mizati o n are e xcl u de d.

T he s u bject has a cli nicall y si g nifica nt hist o r y of hea d i nj ur y or tra u ma ass ociate d wit h l oss of c o nsci o us ness f or > 
1 5 mi n utes.
M ai n Criteri a f or E v al u ati o n a n d A n al yses:
A pr i mar y e n d p oi nt f or all parts of t his st u d y is t he c o m p osite of safet y varia bles t o deter mi ne t he safet y a n d 
t olera bilit y of si n gle a n d m ulti ple oral d oses of T A K-0 4 1 as well as d ose li miti n g effects of T A K -0 4 1. T he f oll o wi n g 
safet y para meters will be a nal yze d f or eac h of t he st u d y parts as t he n um ber a n d perce nta ge of s u bjects w h o:

E x perie nce at least 1 treat me nt -e mer ge nt a d verse e ve nt ( T E A E).

D isc o nti n ue d ue t o a n a d verse e ve nt ( A E).

M eet t he mar ke dl y a b n or mal criteria f or safet y la b orat or y tests at least o nce p ost d ose.

M eet t he mar ke dl y a b n or mal cr iteria f or vital si g n meas ure me nts at least o nce p ost d ose.

M eet t he mar ke dl y a b n or mal criteria f or 1 2 -lea d electr ocar di o gra m ( E C G) para meters at least o nce p ost d ose.

E x perie nce cli nicall y si g nifica nt a b n or mal c ha n ges i n c o nti n u o us 1 2 -lea d E C G meas ure me nts at least o nce 
p ost d ose ( Part 1, 2 a n d 4 o nl y).
T he pri mar y e n d p oi nts als o i ncl u de t he T A K -0 4 1 plas ma P K para meters f or Part 3, ma xi m u m o bser ve d c o nce ntrati o n 
( Cma x ) a n d area u n der t he plas ma c o nce ntrati o n -ti me c ur ve ( A U C) fr o m ti me 0 t o 9 6 h o urs.
T he sec o n dar y e n d p oi nts f or t his st u d y c o nsist of sta n dar d P K varia bles t o deter mi ne dr u g e x p os ure at eac h d ose i n 
eac h of t he Parts 1, 2, 3 a n d 4:

C ma x : ma xi m u m o bser ve d plas ma c o nce ntrati o n (Part s 1, 2, a n d 4 o nl y ).

tma x : ti me t o Cma x.

A U C 2 4: area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 2 4 h o urs.

A U C 9 6: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 9 6 h o urs. ( Part 1, 2 a n d 4 o nl y )

A U C last: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last q ua ntifia ble 
c o nce ntrati o n.

A U C ∞: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 e xtra p olate d t o i nfi nit y ( Part 1 onl y ).

A U C τ: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve d uri n g a d osi n g i nter val, w here ta u (τ) is t he le n gt h of t he 
d osi n g i nter va l ( Part 2 a n d Part 4 o nl y).

t1/ 2z: ter mi nal dis p ositi o n p hase half-life.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
E x p l orat ory  e n dp oi nts:
St atistic al C o nsi der ati o ns:
P har mac o ki netics: C o nce ntrati o ns of T A K- 0 4 1 i n plas ma will be s u m marize d b y d ose o ver eac h sc he d ule d sa m pli n g 
ti me usi n g descri pti ve statistics f or eac h st u d y part. A m o u nt of T A K- 0 4 1 e xcrete d i n uri ne will be s u m marize d b y d ose 
o ver eac h sc he d ule d sa m pli n g i nter val usi n g descri pti ve statistics f or eac h st u d y part. I n di vi d ual P K data will be 
prese nte d i n a data listi n g. P K para meters of T A K- 0 4 1 will be s u m marize d b y d ose usi n g descri pti ve statistics f or eac h 
st u d y part. D ose pr o p orti o nalit y will be assesse d gra p hicall y ( d ose- n or malize d C ma x a n d A U C vers us d ose) i n Part 1 
a n d Part 2. T o assess d ose pr o p orti o nalit y of si n gle d osi n g ( Part 1), a p o wer m o del will be use d. T he m o del will 
i ncl u de t he nat ural l o g-tra nsf or me d A U C a n d Cma x as res p o nse varia bles a n d t he nat ural l o g-tra nsf or me d d ose 
[l n( d ose)] as a c o nti n u o us c o variate. D ose pr o p orti o nalit y will be assesse d usi n g t he p oi nt esti mates a n d t he 9 0 % 
c o nfi de nce i nter val of t he sl o pes. F or Part 2, d ose pr o p orti o nalit y will be assesse d usi n g a n a nal ysis of varia n ce 
( A N O V A) m o del se paratel y f or d ose- n or malize d A U C a n d Cma x o n Da y 2 2. Treat me nt, as a cate g orical varia ble, will 
be a fi xe d effect. T he d ose- n or malize d para meters will be nat ural l o g-tra nsf or me d pri or t o t he a nal ysis. All treat me nt 
differe nces a n d c orres p o n di n g t w o-si de d 9 0 % CIs will be e xtracte d fr o m t he m o del a n d bac k-tra nsf or me d as t he rati os 
o n t he ori gi nal scale. 
T he effect of f o o d o n T A K- 0 4 1 e x p os ure will be e val uate d i n Part 3 usi n g a n A N O V A o n t he nat ural l o g-tra nsf or me d 
T A K- 0 4 1 C ma x a n d A U C 9 6 wit h re gi me n ( hi g h-fat vs. faste d) as a fi xe d effect. T he L S mea n differe nce bet wee n 
re gi me ns a n d t he c orres p o n di n g t w o-si de d 9 0 % CI will be e xtracte d fr o m t he m o del, bac k-tra nsf or me d, a n d e x presse d 
as ce ntral val ue rati os of T A K- 0 4 1 e x p os ure after t he hi g h-fat meal vers us t he faste d state. T he relati ve bi oa vaila bilit y 
of T A K- 0 4 1 a d mi nistere d as a 4 0 m g i m me diate release ta blet f or m ulati o n c o m pare d t o t he 4 0 m g oral s us pe nsi o n 
f or m ulati o n i n t he faste d state will als o be assesse d usi n g a n A N O V A m o del. S u bjects a d mi nistere d t he 4 0 m g oral 
s us pe nsi o n i n Part 1 a n d Part 2 ( Da y 1 data o nl y) will be p o ole d t o get her a n d treate d as t he refere nce re gi me n f or t his 
a nal ysis; s u bjects treate d wit h t he T A K- 0 4 1 4 0 m g ta blet f or m u lati o n u n der t he faste d c o n diti o n i n Part 3 will be t he 
Pr o p ert y of T a k e d a: F or n o n- c o m m er
of T A K
T A K -0
or eac h st u
eac h 
g i nter val 
i nter v
P K para m
K para
ti o nalit y w
o nalit y
d ose pr o
ose pr
l l o g
l l o g-tra n
c o nti n u o u
o nti n u
nter val of
ter val 
A) m o del s
m o de
xe d effect
d effe
ere nces a n
ere nces 
o n t he ori g
n t he or
T he eff
T he
T A K
T A
re
yt y
 of U s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
test re gi me n. T he A N O V A will be perf or me d o n t he nat ural l o g-tra nsf or me d Da y 1 T A K- 0 4 1 C ma x a n d A U C 9 6 wit h 
re gi me n as a fi xe d effect. T he L S mea n differe nce bet wee n re gi me ns a n d t he c orres p o n di n g t w o-si de d 9 0 % CI will be 
e xtracte d fr o m t he m o del, bac k-tra nsf or me d, a n d e x presse d as ce ntral val ue rati os.
Safet y: Safet y data will be prese nte d b y T A K- 0 4 1 d ose a n d place b o f or Part 1, Part 2, a n d Part 4 a n d b y re gi me n 
(faste d or fe d) f or Part 3. I n eac h part, all place b o s u bjects will be p o ole d i nt o o ne gr o u p i n t he s u m maries. T E A Es will 
be s u m marize d b y place b o, eac h T A K- 0 4 1 d ose le vel, a n d T A K- 0 4 1 o verall f or eac h st u d y part. Cli nical la b orat or y 
varia bles, vital si g ns, a n d E C G para meters will be s u m marize d wit h descri pti ve statistics f or baseli ne, p ost d ose, a n d 
c ha n ge fr o m baseli ne t o p ost d ose val ues b y d ose. T he n u m ber a n d perce nta ge of s u bjects wit h p ost d ose val ues 
meeti n g Ta ke da’s criteria f or mar ke dl y a b n or mal val ues f or cli nical la b orat or y varia bles, vital si g ns, a n d E C G 
para meters will be prese nte d b y treat me nt.
1 2-lea d E C G para meters will be e xtracte d i n tri plicates. T he a vera ge of t he 3 val ues at eac h ti me p oi nt will be 
calc ulate d a n d use d f or all statistical a nal yses a n d s u m maries. U nc orrecte d a n d c orrecte d Q T i nter vals, P R, a n d Q R S 
i nter vals a n d heart rate, as well as t heir c ha n ges fr o m baseli ne will be s u m marize d at eac h sc he d ule d ti me p oi nt. 
Statistical a nal yses will be perf or me d t o e val uate t he relati o ns hi p bet wee n c ha n ge fr o m baseli ne i n certai n E C G 
para meters a n d t he e x p os ure t o T A K- 0 4 1.
Ne ur ol o gical assess me nts will be j u d ge d n or mal, a b n or mal, cli nicall y si g nifica nt or n ot cli nicall y si g nifica nt. P h ysical 
e xa mi nati o n fi n di n gs will be prese nte d i n data listi n gs.
 
S a m ple Size J ustific ati o n: T he sa m ple size of 8 s u bjects per c o h ort ( 6 acti ve: 2 place b o) i n Part 1 C o h orts 1- 5 a n d 
Part 2 C o h orts 1- 4 is c h ose n base d u p o n prece de nts of ot her first-i n- h u ma n trials rat her t ha n a f or mal assess me nt of 
statistical p o wer. 
T he sa m ple size of 1 8 s u bjects ( 9 per re gi me n) i n Part 3 was c h ose n t o pr o vi de a de q uate precisi o n of t he esti mate d 
f o o d effect o n T A K- 0 4 1 e x p os ure, ass u mi n g at least 1 6 s u bjects c o m plete t he st u d y. Ass u mi n g a c oefficie nt of 
variati o n ( %) f or t he C ma x of T A K- 0 4 1 of 1 3. 8 %, a 2-si de d 9 0 % c o nfi de nce i nter val f or t he differe nce i n 
l o g-tra nsf or me d Cma x bet wee n fe d a n d faste d will e xte n d n o m ore t ha n 0. 1 3 fr o m t he o bser ve d mea n differ e nce. As a n 
e xa m ple, if t he o bser ve d rati o bet wee n t he t w o re gi me ns is 1. 5, re prese nti n g a 5 0 % i ncrease i n e x p os ure d ue t o f o o d, 
t he n t he c o nfi de nce i nter val f or t he tr ue rati o will e xte n d fr o m 1. 3 2 t o 1. 7 1.
Pr o p ert y of T a k e d a: F or n o n- cc 
ci al u s e o nl y a n d
o h ort ( 6 a
h ort ( 6
first
rst-i ni n-h
t 3 was c h
was 
st 1 6 s u bj
1 6 s
%, a 2a 2-si de
si
will e xte n
ill e xt
 t w o re gi
w o re g
rati o wil
o w
d  
j e ct t o t h e a p pli c a bl e T er m s of U s e
A Es will 
Es will
a b orat or y
orat or
o st d ose, a
st d os
ose val ues
e val u
ns, a n d E C
ns, a n d E
ti me p oi n
i me p o
d Q T i nter
Q T i nter
eac h sc he
ac h sc h
fr o m base
o m ba
ca nt or n o
a nt or n
m sm s
d
c
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
3. 0 
S T U D Y R E F E R E N C E I N F O R M A TI O N
3. 1 
St u d y- Rel ate d Res p o nsi bilities
T he s p o ns or will perf or m all st u d y-r elate d acti vities wit h  t he e xce pti o n of t h ose i de ntifie d i n t he 
St u d y- Relate d Res p o nsi bilities te m plate. T he i d e ntifie d ve n d ors i n t he te m plate f or s pecific 
st u d y-relate d acti vities will perf or m t hese acti vities i n f ull or i n part ners hi p wit h t he s p o ns or.
3. 2 
Pri nci p al I n vesti g at or
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u b ct t o t h e a p pli c a bl e T er m s of U s e
n t he 
n t he 
fic c
p o ns or.
p o ns or
P P D

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
3. 3 
List of A b bre vi ati o ns
Ter m
Defi niti o n
5- H T 2 C
5- h y dr o x ytr y pta mi ne s u bt ype 2c
A E
a d verse e ve nt
A E t
t otal a m o u nt of dr u g e xcrete d i n uri ne fr o m ti me 0 t o ti me t
A L T
ala ni ne a mi n otra nsferase
A S T
as partate a mi n otra nsferase
A-t o- B
a pical-t o- bas olateral
A U C
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve
A U C 2 4
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs
A U C 9 6
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 9 6 h o urs
A U C ∞
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y.
A U C last
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n
A U C τ
area u n der t he plas ma c o nce ntrati o n-ti me c ur ve d uri n g a d osi n g i nter val, w here ta u ( τ) is 
t he le n gt h of t he d osi n g i nter val
B MI
b o d y mass i n de x
B-t o- A
b as olateral-t o-a pical
C- S S R S
C ol u m bia- S uici de Se verit y Rati n g Scale
C ma x
ma xi m u m o bser ve d plas ma c o nce ntrati o n
C N S 
ce ntral ner v o us s yste m
C R O
c o ntract researc h or ga nizati o n
C S
cli nicall y si g nifica nt
C S R
cli nical st u d y re p ort
C V
car di o vasc ular
C Y P
c yt oc hr o me P- 4 5 0
DI LI
dr u g-i n d uce d li ver i nj ur y
D L T
d ose-li miti n g t o xicit y
D N A
de o x yri b o n ucleic aci d
E C 5 0
hal f- ma xi mal res p o nse 
E C G
electr ocar di o gra m
e C R F
electr o nic case re p ort f or m 
e G F R
esti mate d gl o mer ular filtrati o n rate
E R C P
e n d osc o pic retr o gra de c h ola ni g o pa ncreat o gra p h y
F D A
F o o d a n d Dr u g A d mi nistrati o n
Fe
fracti o n of dr u g e xcrete d i n uri ne
Pr o p er  of T a k e d a: F or n o n- c o m m er c
ici de S
ci de 
m o bser ve d
o bser v
l ner v o us
ner v o
ntract res
tract re
cli nicall
cli nica
cli ni
cli
A
C 5 0
E C G
E C G
e C
 s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
0 t o 2 4 h o
0 t o 2 4
me 0 t o 9
e 0 t o
m ti me 0 t
ti me 0
fr o m ti me
o m ti m
c ur ve d u
ur ve d
C CI
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Ter m
Defi niti o n
FI H
first-i n- h u ma n
F S H
f ollicle-sti m ulati n g h or m o ne
G C P
G o o d Cli nical Practice
G G T
∀- gl uta m yl tra nsferase
G L P
G o o d La b orat or y Practice
G P C R
G- p r otei n-c o u ple d rece pt or
G P R 1 3 9
G- p r otei n-c o u ple d rece pt or 1 3 9
H Bs A g
he patitis B s urface a nti ge n
h C G
h u ma n c h ori o nic g o na d otr o pi n
H C V
he patitis C vir us
H E D
h u ma n e q ui vale nt d ose
h E R G
h u ma n et her-à- g o- g o – relate d ge ne
HI V
h u ma n i m m u n o deficie nc y vir us
I B
I n vesti gat or's Br oc h ure
I C5 0
5 0 % i n hi bit or y c o nce ntrati o n
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n
I N R
i nter nati o nal n or malize d rati o
I R B
i nstit uti o nal re vie w b oar d
I V
i ntra ve n o us
K i
i n hi biti o n c o nsta nt 
L F T 
li ver f u ncti o n test
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
MI NI
Mi ni I nter nati o nal Ne ur o ps yc hiatric I nter vie w
M R D
m ulti ple-risi n g d ose
m R N A
messe n ger R N A
N C S
n ot cli nicall y si g nifica nt
N O A E L
n o- o bser ve d-a d verse-effect le vel
N O E L
n o- o bser ve d-effect le vel
P A N S S
P ositi ve a n d Ne gati ve S y n dr o me Scale
P a p p
a p pare nt per mea bilit y c oefficie nt
P D
p har mac o d y na mic(s)
P- g p
P- gl yc o pr otei n
P K
p har mac o ki netic(s)
P O
p er os, oral
P O C
p r o of of c o nce pt
P ol y (I: C)
p ol yi n osi nic: ol yc yti d ylic aci d
P T E
p retreat me nt e ve nt
Q D
o nce dail y
Pr o p ert y of 
e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
isati o n
sati o n
o nar y f or 
nar y f o
nati o nal N
ti o nal 
e-risi n g d
risi n g
sse n ger R
e n ger 
n ot cli nic
t cli n
n o
n o -o b
n
P K
P K
P O
P O
P
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 2 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Ter m
Defi niti o n
Q Tc
c orrecte d Q T i nter val
Q Tc B
Q T i nter val wit h Bazett c orrecti o n met h o d
Q Tc F
Q T i nter val wit h Fri dericia c orrecti o n met h o d
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 ysis pla n
S E R T
ser ot o ni n tra ns p orter 
S R D
si n gle-risi n g d ose
S U S A R
s us pecte d u ne x pecte d seri o us a d verse reacti o n
t1/ 2z
ter mi nal dis p ositi o n p hase half-life
T E A E
treat me nt-e mer ge nt a d verse e ve nt
tma x
ti me t o ma xi m u m plas ma c o nce ntrati o n
U L N
u p per li mit o f n or mal
V A S
vis ual a nal o g ue scale
W B C
w hite bl o o d cell
W H O
W orl d Healt h Or ga nizati o n
3. 4  
C or p or ate I de ntific ati o n
T D C Asia
Ta ke da De vel o p me nt Ce nter Asia, Pte Lt d
T D C E ur o pe
Ta ke da De vel o p me nt Ce ntre E ur o pe Lt d.
T D C A mericas 
Ta ke da De vel o p me nt Ce nter A mericas, I nc.
T D C
T D C Ja pa n, T D C Asia, T D C E ur o pe a n d/ or T D C A mericas, as a p plica ble
Ta ke da
T D C Ja pa n, T D C Asia, T D C E ur o pe a n d/ or T D C A mericas, as a p plica ble
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n 
ct t o t h e a p pli c a bl e T er m s of U s e
i o n
o n
zati o n
ti o n
e vel o p me
vel o p m
a De vel o p
De vel o
ke da De v
da De
T D C Ja p
T D C J
T D C
T D
C CI
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 2 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
4. 0
I N T R O D U C TI O N
4. 1
B ac k gr o u n d
T A K -0 4 1 is a n orall y a vaila ble, s mall m o lec ule G- pr otei n -c o u ple d rece pt or 1 3 9 (G P R 1 3 9) a g o nist  
t hat d ose-de pe n de nt l y i m pr o ves s ocial i nteracti on i n a ni mal m odels o f s o cial deficit a n d has t he 
p ote nti al for t he treat m e nt of sc hiz o p hre nia, partic ularl y ne gat i ve s y m pt o ms, a n d dis or ders 
ass ociat e d wit h s o cial a nd c o g ni tive d ysf u nct i on.
G P R 1 3 9 i s a n o vel class A or p ha n rece pt or t hat is e x presse d nearl y e xcl usi vel y in t he ce ntral  
ner v o us s yste m ( C N S). H u ma n G P R 1 3 9 is e x presse d i n t he p uta me n, ca u date n uclei, 
e nt o pe d u nc ular n uclei, o lfact or y b ul bs, h y p ot hala mic n uclei, s u bsta ntia ni gra, cere bellar n uclei, 
vesti b ular n uclei a n d ha be n ular n uclei, w here it is pre d o mi na nt l y e x presse d i n S y na pt ota g mi n 6 
p osi tive ne ur o ns of t he me dial ha be n ula [ 1, 2]. T he ha be n ula is a ke y brai n str uct ure i n v ol ve d i n 
s pecific as pects of s ocial a n d c o g nit i ve be ha vi or t hat is d ysf u ncti o nal i n sc hiz o p hre nia a n d ot her 
ps yc hiatric dis or ders.
I n a series of assa ys, c haracterizati on of T A K -0 4 1 as a n a g o nist f or G P R 1 3 9 de m o nstrate d t he 
a bilit y of  T A K-0 4 1 t o sti m ulate e xtracell ular calci u m e ntr y  int o C hi nese ha mster o var y  cells 
e x pressi n g t he rec o m bi na nt m o use, rat, d o g, a n d h u ma n rece pt or at a c o nce ntrati o n pr o d uci n g a 
half -ma xi mal res p o nse ( E C 5 0) of 9 8 t o 1 0 2 n M, 8 8 t o 1 3 2 n M, 2 5 n M, a n d 2 3 t o 3 6 n M, 
res pecti vel y. M ore o ver, t he pre dicte d d o w nstrea m m o d ulat i on o f i n osit ol ph os p hate (I P 1) t ur n o ver 
was o bser ve d i n t he h u ma n rece pt or at a n E C 5 0 of  4 2 2 t o 4 6 1 n M. Bi n di n g affi nit y t o t he 
rec o m bi na nt d o g a n d h u ma n rece pt or e x hi bit e d a n i n hi bit i on diss ociat i on c o nsta nt ( K i) of 2 2 9 n M 
a n d 1 1 7 t o 3 0 1 n M, res pecti vel y.
T A K -0 4 1 select i vity was e val uate d a gai nst a pa nel of 7 8 e nz y mes, rece pt ors, a n d tra ns p orters t hat 
are f u nct i onall y rele va nt t o t he C N S circ uitr y  of G P R 1 3 9 usi n g e nz y me a n d bi n di n g assa ys. 
T A K -0 4 1 di d n ot s h o w a n y  acti vity a gai nst most of t he pr otei ns teste d wit h t he e xce pt i on of 
5- h y dr o x y tr ypta mi ne s u bt y pe 2c ( 5 -H T 2 C) a n d ser ot o ni n tra ns p orter ( S E R T). I nitial e val uati on 
s h o we d i n hi biti on at 9 5 % a n d 6 8 % of 5 -H T 2 C a n d S E R T, res pecti vel y, at 1 0 µ M of T A K -0 4 1. 
H o we ver, o nl y S E R T i n hi bit i on was c o nfir me d i n f o ll ow- u p e x peri me nts. T A K -0 4 1 i n hi bite d 
S E R T wit h a 5 0 % i n hi bit or y c o nce ntrati o n (I C 5 0) of 2. 2 9 µ M. T he res ults of t hese st u dies i n dicate 
t hat T A K-0 4 1 is a p o te nt a n d selecti ve a g o nist of G P R 1 3 9.
W hile i n vitr o st u dies use d cell -base d assa ys a n d me m bra nes pre pare d fr o m cells e x pressi n g 
G P R 1 3 9, i n vi v o st u dies e xa mi ni n g b ot h m o lec ular a n d be ha vi oral c o nse q ue nces of rece pt or 
acti vat i on were use d t o assess t he a bi lity of  T A K-0 4 1 treat m e nt t o i m pr o ve s ocial int eract i on 
deficits a n d c o g nit i ve d ysf u ncti on, w hic h are ass ociate d wit h ps yc hiatric dis or ders s uc h as 
sc hiz o p hre nia. I n vi v o st u dies e val uat i n g t he m olec ular effects of T A K-0 4 1 de m o nstrate d t hat 
c- f os, a n i m me diate earl y ge ne t hat is d o w nstrea m of G P R 1 3 9 acti vati o n, le vels were ele vate d i n a 
ti me- a n d d ose-de pe n de nt ma n ner after T A K -0 4 1 a d mi nistrati o n. As earl y  as 1 h o ur after a si n gle 
0. 3 -m g/ k g d ose, t here was a n o bser va ble, si g nifica nt ( p < 0. 0 5) i ncrease i n c -fos i m m u n oreacti vit y 
i n t his re gi on of t he brai n. M ore o ver, t he c -f os ele v atio n i n t he m e dial ha be n ula of treate d mice 
persiste d wit h s u bc hr o nic a d mi nistrati o n of T A K -0 4 1. T hese st u dies s u g gest t hat 
T A K - 0 4 1 e xcites t he me dial ha be n ula.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 2 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Be ha vi oral res p o nses were e xa mi ne d i n 2 differe nt m o use m o dels e x hi bit i n g s ocial i nteract i on 
deficits: t he Bal b/c m o del a n d t he p ol yi n osi nic: p ol yc yt i d ylic aci d ( p ol y [I: C]) mo d el . I n b ot h 
m o dels, 0. 1 m g/ k g T A K -0 4 1, d ose d ei t her ac utel y or s u bc hr o nicall y ( 1 5 da ys of treat me nt),
mit i gate d t he s ocial deficits t hat were eit her nat urall y occ urri n g ( Bal b/c) or p har mac ol ogi call y 
e v o ke d b y t he i nfla m mat or y st i m ul us ( p ol y [I/ C]). M ore o ver, hal o peri d o l, a d o pa mi ne D 2 rece pt or 
a nta g o nist, di d n ot pr o vi de t hera pe utic be nefit as a sta n d -alo ne treat m e nt i n t he p ol y (I: C) m o del 
a n d di d n ot a br o gate t he efficac y ass o ciate d wit h T A K-0 4 1. F urt her m ore, t he c o g nit i ve deficits 
ass ociat e d wit h s u bc hr o nic p he nc ycli di ne ( P C P) treat me nt i n a rat set s hifti n g tas k were 
sig nifica nt l y atte n uate d b y increas i n g d oses of T A K-0 4 1 f r o m 0. 3 t o 3 mg/ k g wi t h 4 h o urs of 
pretreat m e nt. T his res ult c o mpare d fa v ora bl y  t o ris perid o ne, a sec o n d ge nerat i on a nti ps yc h otic 
treat me nt. Acc or di n gl y, t he a vaila ble e x peri me ntal e vi de nce s u p p orts t he use of T A K-0 4 1, a 
G P R 1 3 9 a g o nis t, as a p ote ntial tr e at me nt for t he ne gati ve s y m pt o ms (i ncl u di n g a m ot i vati on, 
a n he d o nia, a n d as ocialit y)  a n d c o g nitive i m pair me nt ass ociate d wit h sc hiz o p hre nia, a de bilitat i n g 
di s or der wit h hi g h u n met me dical nee d.
T he P K pr o perties of T A K -0 4 1 ha ve bee n c h aracterize d i n vitr o a n d i n S pra g ue- Da wle y  rats a n d 
bea gle d o gs after oral ( P O) or i ntra ve n o us (I V) a d mi nistrati o n. P har mac o ki net ic e val uati ons were 
c o n d ucte d i n rats a n d d o gs beca use t hese were t he maj or s pecies use d i n t he t o xic o l og y  pr o gra m.
T A K -0 4 1 was a bs or be d after P O a d mi nistrati o n t o rats a n d d o gs, wit h pea k plas ma c o nce ntrati o ns 
ge nerall y occ urri n g wit hi n 4 t o 8 h o urs p ost d ose i n rats a n d 0. 5 t o 2 h o urs p ost d ose i n d o gs. T he 
pl as ma cleara nce of T A K-0 4 1 was l o w i n rats a n d m o derate t o hi g h i n d o gs ( ~ 4 a n d 
~ 1 1 m L/ mi n/ k g, res pecti vel y). T he ter mi nal eli mi nati o n half -life (t1/ 2) of T A K-0 4 1 after P O 
a d mi nistrati o n was 1. 5 t o 2. 8 h o urs i n d o gs, a n d u n defi ne d i n rats beca use of a p o orl y defi ne d 
ter mi nal p hase o bser ve d i n t his s pecies. T he oral bi oa vaila bility of  T A K-0 4 1 was hi g h ( 9 0. 8 % t o 
9 4. 2 % i n rats; i n d o gs, t he d ose -n or m alize d P O e x p os ures were greater t ha n o bser ve d after I V 
d osi n g, res ult i n g i n re p orte d bi oa vaila bility u p t o 1 0 0 % or greater. A bs or pti o n was n ot li kel y 
m o d ulate d b y  P-gl yc o pr otei n ( P - g p), beca use T A K-0 4 1 ha d a l o w P - g p effl u x rati o ( 0. 4), as 
d e m o nstrate d i n L L C -P K 1 -M D R 1 cells, i n dicat i n g t hat T A K-0 4 1 is n ot li kel y a s u bstrate f or P- g p. 
T A K -0 4 1 ( 1 a n d 1 0 µ M) plas ma pr otei n bi n di n g was 9 5. 9 %, 9 5. 4 t o 9 6. 5 %, 9 6. 8 t o 9 7. 3 %, 9 5. 3 t o 
9 5. 4 %, a n d 9 6. 8 t o 9 7. 1 % i n plas ma fr o m mice (teste d at 1 0 µ M o nl y), rats, d o gs, m o n ke ys, a n d 
h u ma ns, res pecti vel y. Re d bl o o d cell: plas ma rat i os of T A K-0 4 1 at 0. 1, 1, a n d 1 0 µ M were 
a p pr o xi matel y 0. 8, 0. 8, a n d 1. 1 i n rats; 0. 4, 0. 4, a n d 1. 0 i n d o gs; a n d 0. 7, 0. 6, an d 0. 8 i n h u ma ns, 
res pecti vel y. T A K-0 4 1 s h o we d n o i n hi bit or y effect o n t he Bile Salt E x p ort P u m p tra ns p orter i n rat 
a n d h u ma n vesicles u p t o 2 0 0 µ M a n d a m o derate i n hi bit or y effect i n d o g vesicles (I C 5 0 ~ 7 2 µ M).
I n vitr o meta b olis m st u dies with he pat ic micr os o mes a n d he pat oc ytes fr o m h u ma n d o n ors s h o we d 
trace a mo u nts of a fe w meta b o lites i ncl u di n g o xi dati ve N- deal k ylat i on t o f or m a n a mi de 
meta b o lite a n d o xidat i ons at t he o x o be nz otriazi ne m o iety t o for m  p ositio nal  is omeric str uct ures. 
S u bse q ue nt gl uc ur o ni da tio n of  t hese o xidat i ve is o meric str uct ures yiel de d t heir c orres p o n di n g 
gl uc ur o ni de c o nj u gate meta b o lites. I n a d ditio n t o t hese meta b o lites, a glut at hi o ne c o nj u gate of 
T A K -0 4 1 a n d o ne of its d o w nstrea m meta b o lites, a c ystei ne c o nj u gate, were als o detecte d i n rat 
a n d d o g he pat oc ytes. N o h u ma n-s pecific meta b olit es were o bser ve d. A n e val uat i on of t he 
c yt o c hr o me P-4 5 0 e nz y mes ( C Y Ps) res p o nsi ble f or t he meta b o lis m of T A K -0 4 1 has n ot y et bee n 
c o n d ucte d. Gl utat hi o ne-a d d uct -deri ve d t hi o l meta b olites t hr o u g h t he -lyase pat h wa y is 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 3 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
sig nifica nt i n d o g ( hi g her rate of m eta b o lis m a n d lac k of N-acet ylat i on det o xificat i on pat h wa y). 
Preli mi nar y h u ma n i n vitr o a n d i n vi v o data s u g gest si milar meta b o lic pat h wa ys b ut t o a m uc h 
lesser e xte nt. T he f or mati on of N -acet ylc ystei ne c o nj u gate was o bser ve d i n h u ma n as e vi de nt of 
N- acet ylat i on det o xificat i on pat h wa y. I n rat, h o we ver, gl uc ur o ni dati o n pat h wa y see ms t o be 
pre d o mi na nt.
A n assess me nt of c y t o c hr o me P-4 5 0 e nz y me ( C Y P) i n d uct i on was c o n d ucte d i n c ult ure d h u ma n 
he pat oc y tes, a n d in d ucti o n of  C Y P 2 B 6 a n d C Y P 3 A 4 messe n ger R N A ( m R N A) was o bser ve d. 
Treat me nt of c ult ure d h u ma n he pat oc y tes wit h u p t o 1 0 µ M T A K-0 4 1 ha d litt le or n o effect o n 
C Y P 1 A 2 m R N A le vels, w hile treat me nt wit h u p t o 1 0 µ M T A K -0 4 1 ca use d 
c o nce ntrati o n-de pe n de nt i ncreas es of > 2. 0-f ol d a n d > 2 0 % of t he p ositi ve c o ntr ol i n C Y P 2 B 6 a n d 
C Y P 3 A 4 m R N A le vels, res pecti vel y, i n all c ult ures teste d. T h us, T A K -0 4 1 was a mil d i n d ucer of 
C Y P 2 B 6 a n d C Y P 3 A 4 m R N A i n vitr o a n d C Y P i n d ucti o n base d D DI p ote ntial is c o nsi dere d l o w.
T A K -0 4 1 s h o we d n o re versi ble i n hi bit i on of C Y P 3 A 4/ 5 acti vit ies at c o nce ntrati o ns ra n gi n g u p t o 
1 0 0 M wit h a n I C 5 0 > 1 0 0 M.
I n t he C Y P 3 A 4/ 5 ti me-de pe n de nt i nact i vati on ( T DI) st u d y , t he 
perce nta ge of acti vit y re m ai ni n g i n sa m ples prei nc u bate d wit h T A K-0 4 1 s h o we d n o ti me-, 
c o nce ntrati o n-, or N A D P H-de pe n de nt C Y P 3 A 4/ 5 l oss of act i vity. T hese data s u g gest t hat 
p ote nti al re versi ble i n hi bitio n a n d T DI of C Y P 3 A 4/ 5 b y  T A K-0 4 1 are u nli kel y.
Uri nar y  e xcreti on of T A K -0 4 1 was i n vest i gate d i n d o gs after a si n gle I V d ose. After I V
a d mi nistrati o n t o 3 d o gs, T A K- 0 4 1 was detecta ble i n d o g uri ne, b ut at l o w le vels. T he a m o u nt of 
T A K -0 4 1 e xcrete d u nc ha n ge d i nt o d o g uri ne wit hi n 2 4 h o urs ra n ge d fr o m a p pr o xi matel y 0. 0 0 9 % 
t o 0. 0 1 5 7 % wit h mea n rec o ver y of 0. 0 1 3 5 % of t he gi ve n d ose. 
A c o m pr e he nsi ve series of n o ncli nical safet y st u dies ( G o o d La b orat or y Pr a ctices [ G L P]) ha ve 
bee n c o n d ucte d wit h T A K -0 4 1 t o s u p p ort earl y  hu ma n st u di es i ncl u di n g: h E R G, 
electr ocar dio gra p h y  in d o gs, res pi r at or y a n d C N S i n rats, ge netic t o xicity st u di es ( A mes, i n vit r o 
micr o n ucle us, i n vi v o micr o n ucle us), a n d i n vitr o p h ot ot o xicit y.  A n effect of T A K-0 4 1 was first 
o bser ve d at 1 µ M i n t he h u ma n et her - à- g o-g o – relate d ge ne ( h E R G) assa y (I C5 0 > 3 µ M); h o we ver, 
n o c ha n ges i n E C G para meters were o bser ve d i n t he i n vi v o d o g ca r dio vasc ular ( C V) or 4 -wee k 
re peat-d ose t o xicit y st u d y at 1 2 5 m g/ k g. I n t he d o g C V st u d y, a n i ncrease i n s yst olic bl o o d 
press ure ( 1 0 %) res ulti n g i n i ncreases i n mea n arterial a n d p ulse press ures wit h o ut a n y  ass ociate d 
c ha n ges i n heart rate at 0. 5 t o 6. 2 5 ho urs p ost d ose at 1 2 5 m g/ k g was o bser ve d. A di mi nis he d tre n d 
n ot of  bi ol ogical  si g nifica nce occ urre d at 1 5 m g/ k g wi t h n o effect o bser ve d at 5 m g/ k g. I n a d dit i on,  
dail y re peat -d ose t o xicit y st u di es o f 4-wee k a n d 1 3 -wee k d urati o n ha ve bee n c o n d ucte d i n rats a n d 
d o gs. T he oral d ose le vels i n t he 4 -wee k t o xicit y st u d y in rats were 5, 3 0, a n d 2 0 0 m g/ k g/ da y 
( males) a n d 3, 1 0, a n d 2 0 0 m g/ k g/ da y (fe males). I n t he 1 3 -wee k re peat -d ose t o xicit y st u d y  i n rats, 
t he oral d ose le vels were 1 0, 4 0 a n d 2 0 0 m g/ k g/ da y i n males a n d 2, 1 0, a n d 2 0 0 m g/ k g/ da y in 
fe males. I n t he 4- a n d 1 3-wee k t o xicit y st u dies i n d o gs, d osa ges were 5, 1 5, 5 0, a n d 1 2 5 m g/ k g/ da y 
f or t he 4-wee k st u d y a n d 1 5, 3 0 a n d 6 0 m g/ k g/ da y i n t he 1 3 -wee k st u d y . T he 
n o -o bser ve d -a d verse-effect le v el ( N O A E L) i n t he rat t o xicit y st u dies was t he ma xi m u m feasi ble 
d ose of 2 0 0 m g/ k g/ da y. T he N O A E L i n t he d o g t o xicit y st u dies was 1 5 m g/ k g/ da y i n males a n d 
5 0 m g/ k g/ da y i n fe males f or t he 4 -wee k st u d y. T he N O A E L was 3 0 m g/ k g/ da y f or b ot h males a n d 
fe males i n t he 1 3-wee k d o g t o xicit y st u d y, beca use of m or bi dity attri b ute d t o he patic c h o lestasis 
a n d re nal t u b ule de ge nerati o n c o nsi dere d sec o n dar y t o he patic c ha n ges at 6 0 m g/ k g/ da y, w hic h le d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 3 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
t o e ut ha nasia of 2 d o gs at Da y  8 5. T hese a ni mals ha ve ele vate d A L T, A S T, bile aci ds, B U N, 
creati ni ne, G G T, P H O S, a n d T BI LI bef ore e ut ha nasia, a n d i ncreases i n A L P a n d C H O L as earl y as 
D a y  1 4. T his fi n di n g was m o nit ora ble, base d o n plas ma c he mistr y c ha n ges at all d ose le vels a n d as 
earl y as D a y 1 4 i n t he hi g h d ose gr o u p, w hic h prece de d cli nical si g ns. After a 4-wee k 
treat me nt -free peri o d, t here was n o e vi de nce of rec o ver y of biliar y h y p er plasia, mul ti-n ucleate d 
cells, or mi xe d cell i nfiltrate a n d si n gle cell he pat ic necr osis; h o we ver, ele vat i ons i n plas ma 
c he mistr y val ues were lar gel y re versi ble (tre n di n g d o w n of ele vate d li ver f u ncti o n tests at all d ose 
le vels i n t he rec o ver y gr o u p d o gs).
D ue t o t his fi n di n g of c h olestatic li ver i nj ur y bei n g m o nit ora ble, partiall y re versi ble, a n d o bser ve d 
i n d o gs b ut n ot rats, t he selecte d d oses are pr ojecte d t o res ult i n plas ma e x p os ures of 
T A K - 0 4 1 bel o w t h ose ass ociate d wit h t he N O A E L i n t he d o g 1 3 -wee k t o xic ol o g y st u d y. F urt her 
i nf or mat i on fr om t he n o ncli nical st u dies, s u m marize d a b o ve, ca n be f o u n d i n t he c urre nt 
I n vesti gat or’s Br oc h ure. O verall, t he n o ncli nical P K a n d safety pac ka ge s u m marize d herei n 
pr o vi de s u p p ort f or t he cli nical e val uat i on of T A K - 0 4 1.
4. 2
R ati o n ale f or t he Pr o p ose d St u d y
T he n o ncli nical p har mac o l og y  a n d t o xicit y data s u p p ort t he pr o p ose d st u d y in healt h y s u bjects, 
w hic h will be t he first T A K -0 4 1 st u d y  in h u ma ns. T his st u d y  will e val uate t he safety,  t olera bilit y, 
a n d P K of T A K-0 4 1 f ol l owi n g si n gle or m ult i ple oral d ose a d ministrati o ns i n male a n d fe male 
healt h y s u bjects ( Part 1 a n d Part 2) a n d as a d d-o n t hera p y t o a nti ps yc h otics i n s u bjects wit h sta ble 
sc hiz o p hre nia (Part 4 ). I n a d diti o n, a n i m me diate release ta blet f or m ulati on f or T A K-0 4 1 was 
rece ntl y de vel o pe d. Part 3 of  this st u d y is desi g ne d t o assess t he oral bi oa vaila bilit y o f TA K -0 4 1 i n 
healt h y s u bjects a d mi nistere d as a 4 0 m g ta blet f or m ulati on r elat i ve t o t he 4 0 m g oral  s us pe nsio n  
f or mulat i on i n t he faste d state, a n d t o assess t he effect of a hi g h-fat, hi g h -calori e meal o n t he 
p har mac o ki net ics of  a si n gle d ose of t he 4 0 m g ta blet f or m ulati o n of T A K- 0 4 1.
Part 1 C o h orts 1 a n d 2, w hic h ha ve alrea d y bee n c o m plete d, partici pate d i n a 2 -p eri o d, al ter nati n g 
pa nel, d o u ble -bli n d desi g n t o e val uate si n gle -risi n g d oses of  T A K-0 4 1 or m atc he d place b o wit h a 
was h o ut peri o d of at least 7 da y s bet wee n treat me nt perio ds. F oll o wi n g si n gle oral d ose 
a d mi nistrati o ns of T A K-0 4 1 o ver t he d ose ra n ge of 5 t o 4 0 m g u n der faste d c o n dit i ons, 
T A K - 0 4 1 was ra pi dl y  a bs or be d wit h a me dia n t m a x of  1 t o 2 h o urs. Eli mi nati on of T A K -0 4 1 f r o m 
pl as ma was sl o w ( mea n t 1/ 2 a p pr o xi matel y 1 1 da ys). Area u n der t he plas ma c o nce ntrati o n -time 
c ur ve fr o m ti me 0 t o 2 4 h o urs ( A U C2 4) i ncrease d a p pr o xi matel y d ose pr o p orti o nall y fr om 
1 6 6 0 n g * hr/ m L at 5 m g t o 1 1 9 5 2 n g * hr/ m L at 4 0 m g. O ver t his d ose ra n ge, ma xi m u m o bser ve d 
pl as ma c o nce ntrati o n ( Cma x ) i ncrease d fr om 1 4 0 t o 7 4 7 n g/ m L. T he f o ll owi n g st u d y  safety 
i nf or mat i on is preli mi nar y a n d base d o n bli n de d a d verse e ve nt data re p orte d b y t he i n vesti gat or 
a n d bli n de d safet y e n d p oi nt data i n st u d y T A K-0 4 1 -1 0 0 1. Al t ho u g h n ot e x pecte d, t hese data are 
s u bject t o c ha n ge u p o n fi nalizat i on f oll owi n g st u d y  mo ni t orin g, s o urce data verificat i on, a n d 
di scre pa nc y q uer y ma na ge me nt prior t o data base l oc k. Preli mi nar y res ults i n dicat e t hat si n gle 
d oses of 5, 1 0, 2 0, a n d 4 0 m g T A K- 0 4 1 are well t olerate d a n d safe. Se ve n A Es were o bser ve d i n 
t his st u d y, c hest pai n fr om aci d refl u x, deja v u, e pista xis, a n d fat i g ue i n o ne s u bject, tire d ness, a n d 
u p per res pi rat or y infect i on i n o ne s u bject, a n d c o ntact der matit is fr o m E C G lea ds i n o ne s u bject; 
all se ve n A Es were mil d, were j u d ge d b y t he i n vestigat or t o be n ot relate d t o t he st u d y  dr u g, a n d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
res ol ve d wit h o ut treat me nt. T here were n o seri o us A Es or se vere A Es. T here were n o cli nicall y 
mea ni n gf ul a b n or malities i n safet y la b orat or y res ults (i ncl u di n g A L P, A S T, A L T, G G T, a n d 
T BI LI) a n d n o cli nicall y si g nifica nt a b n or malities i n p h ysical e xa mi nati o n, vital si g ns, or E C G 
res ults were re p orte d f or t he 1 6 s u bjects w h o recei ve d 5 t o 4 0 m g d oses of T A K- 0 4 1 or matc hi n g 
place b o i n T A K 0 4 1 1 0 0 1 C o h orts 1 a n d 2.
Base d o n t he preli mi nar y res ults fr o m t hese first 2 c o h orts ( C o h orts 1 t o 2) a n d d ue t o t he 
u ne x pecte d o bser vati o n of a p pr o xi matel y 1 1 da y t 1/ 2 of T A K- 0 4 1, healt h y s u bjects i n Part 1 
C o h orts 3 t o 5 a n d Part 2 C o h orts 1 o n war ds will partici pate i n a se q ue ntial pa nel, d o u ble- bli n d 
desi g n t o e val uate si n gle-risi n g d oses ( Part 1) or m ult i ple-risi n g d oses ( Part 2) of T A K- 0 4 1. T his is 
a d o u ble- bli n d st u d y; t heref ore, t he s u bject, t he trial site pers o n nel, a n d t he S p o ns or staff w h o are 
i n v ol ve d i n t he treat me nt or cli nical e val uati o n are bli n de d t o treat me nt or i nter ve nti o n. Certai n 
S p o ns or staff n ot directl y i n v ol ve d wit h t he treat me nt or e val uati o n ma y be u n bli n de d t o t he 
treat me nt or i nter ve nti o n.
F or t he e val uati o n of t he effect of f o o d o n t he T A K- 0 4 1 i m me diate release ta blet f or m ulati o n, 
si nce P D or efficac y will n ot be e val uate d, n o c o ntr ol gr o u p will be use d a n d t heref ore, a n 
o pe n-la bel st u d y desi g n will be utilize d.  A parallel desi g n is selecte d d ue t o t he pr ol o n ge d t 1/ 2 ( ~ 1 1
da ys) of T A K- 0 4 1. I n acc or da nce t o t he re g ulat or y g ui da nce o n t he bi oa vaila bilit y[ 3] a n d 
bi oe q ui vale nce assess me nt f or dr u gs wit h l o n g t 1/ 2, a 9 6- h o ur P K sa m pli n g peri o d is c o nsi dere d 
a de q uate t o e ns ure c o m pleti o n of gastr oi ntesti nal tra nsit a n d a bs or pti o n of T A K- 0 4 1 after oral 
a d mi nistrati o n. Si nce 9 6 h o urs p ost d ose is a c o m m o n sa m pli n g ti me p oi nt i n St u d y 
T A K- 0 4 1- 1 0 0 1, al o n g wit h C ma x , t he P K para meter A U C9 6 ca n be use d t o assess t he relati ve 
bi oa vaila bilit y bet wee n t he oral s us pe nsi o n f or m ul ati o n a n d t he oral ta blet f or m ulati o n. Base d o n
t he preli mi nar y P K a nal ysis, A U C9 6 was a p pr o xi matel y 2 3 % of A U C ∞f oll o wi n g a si n gle 2 0 or 4 0 
m g d ose of T A K- 0 4 1 via oral s us pe nsi o n, a n d t he c orres p o n di n g i nters u bject varia bilit y f or A U C 9 6
ra n ge d fr o m 9. 1 % t o 2 6. 8 %. 
Pr o p e
m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
c hi n g 
hi n g 
t he 
t he 
i n Part 
n Par
el, d o u bl
l, d o u
off T A K
T A
f
e S p o ns o
S p o ns
or i nter
or i nte
ma y be u
ma y be 
e diate re
diate r
p will be
will b
g n is sele
n is se
ui da nce 
i da nc
, a 9 6
a 9 6-h
nal tra nsi
l tra n
c o m m o
m m
para m
para m et
nsi o
si on n f of o
was a p p
was a
s pe nsi o
e nsi o n
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T 
of U s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
5. 0 
S T U D Y O B J E C TI V E S A N D E N D P OI N T S
5. 1 
St u d y  O bjecti ves
5. 1. 1 
Pri m ar y O bjecti ves
T o e val uate t he safet y a n d t olera bilit y of T A K- 0 4 1
!
F oll o wi n g or al si n gle a n d m ulti ple d oses i n healt h y s u bjects ( Parts 1, 2, a n d 3).
!
As a d d- o n t hera p y t o a nti ps y c h otics i n s u bjects wit h sta ble sc hiz o p hre nia ( Part 4).
T o assess t he or al bi oa vaila bilit y i n healt h y s u bjects of T A K – 0 4 1 a d mi nistere d as a 4 0 m g 
i m me diate release ta blet f or m ulati o n i n t he faste d state c o m pare d t o 4 0 m g oral s us pe nsi o n 
f or m ulati o n i n t he faste d state ( Part 3).
T o assess t he effect of f o o d o n t he p har mac o ki netics of 4 0 m g i m me diate release ta blet 
f or m ulati o n of T A K – 0 4 1 i n healt h y s u bjects ( Part 3).
5. 1. 2 
Sec o n d ar y O bjecti ve
T o e val uate t he P K of T A K- 0 4 1
!
A d mi nistere d u n der fasti n g c o n diti o ns f oll o wi n g or al si n gle a n d m ulti ple d oses i n healt h y 
s u bjects ( Parts 1 a n d 2).
!
As a d d- o n t hera p y t o a nti ps y c h otics i n s u bjects wit h sta ble sc hiz o p hre nia ( Part 4).
5. 1. 3 
E x pl or at or y O bjecti ves
Pr o p e
ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
.
(Part 4
Part 4 )
tere d as
ere d as
0 m g or
m g or a
m me diat
m me d
wi n g
wi n g oro
i n s u bje
n s u bj
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
5. 2 
E n d p oi nts f or P art 1 a n d P art 2 a n d P art 3 ( He alt h y S u bjects) a n d P art 4 ( S u bjects 
wit h Sc hiz o p hre ni a)
5. 2. 1 
Pri m ar y E n d p oi nts
T he pri mar y e n d p oi nt f or all parts of t his st u d y is t he c o m p osit e of safet y varia bles t o deter mi ne 
t he safet y a n d t olera bilit y of or al si n gle a n d m ulti ple d oses of T A K- 0 4 1 as well as d ose-li miti n g 
effects of T A K- 0 4 1. T he f oll o wi n g safet y para meter s will be a nal yze d f or eac h of t he st u d y parts 
as t he n u m ber a n d perce nta ge of s u bjects w h o:
!
E x perie nce at least 1 treat me nt- e mer ge nt a d verse e ve nt ( T E A E).
!
Dis c o nti n ue d ue t o a n a d verse e ve nt ( A E).
!
Meet t he mar ke dl y a b n or mal crit eria f or safet y la b orat or y tests at least o nce p ost d ose.
!
Meet t he mar ke dl y a b n or mal crit eria f or vit al si g n meas ure me nts at least o nce p ost d ose.
!
Meet t he mar ke dl y a b n or mal crit eria f or 1 2-lea d E C G para meters at least o nce p ost d ose.
!
E x perie nce cli nicall y si g nifica nt a b n or mal c ha n ges i n c o nti n u o us 1 2-lea d E C G meas ure me nts 
at least o nce p ost d ose (e xce pt Part 3).
T he pri mar y e n d p oi nts als o i ncl u de t he T A K- 0 4 1 plas ma P K para meters f or Part 3, ma xi m u m 
o bser ve d c o nce ntrati o n ( C ma x ) a n d area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 
9 6 h o urs ( A U C 9 6).
5. 2. 2 
Sec o n d ar y E n d p oi nts
T he sec o n dar y e n d p oi nts c o nsist of sta n dar d P K varia bles t o deter mi ne dr u g e x p os ure at eac h d ose 
i n eac h of t he st u d y parts. T he f oll o wi n g P K para meters f or T A K- 0 4 1 will be a nal yze d as 
sec o n dar y e n d p oi nts:
!
C ma x : ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Parts 1, 2 a n d 4 o nl y).
!
tma x : ti me t o Cma x .
!
A U C 2 4: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs.
!
A U C 9 6: area u n der t he plas ma c o nce ntrati o n-ti me cur ve fr o m ti me 0 t o 9 6 h o urs ( Parts 1, 2 a n d 
4 o nl y).
!
A U C last: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me of t he last 
q ua ntifia ble c o nce ntrati o n.
!
A U C ∞: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y ( Part 1 o nl y).
!
A U C τ: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve d uri n g a d osi n g i nter val, w here ta u (τ) 
is t he le n gt h of t he d osi n g i nter val ( Parts 2 a n d 4 o nl y).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
ects 
cts 
es t o de
es t o d
ll as d os
as d o
eac h of t
c h of
).
or y tests 
tests
y
meas
meas ure
a d E C G 
d E C G
l c ha n ge
c ha n ge
T A K
T A K -0
rea u n de
ea u n
oi nts
nts
s c o nsist
c o nsi
parts. T h
arts. T
nts:s:
i m u m
i m u m o
m
i me t o C
me t o
U C 2 4
2 4: a
A U C
A U
4 o
!
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
!
t1/ 2z: ter mi nal dis p ositi o n p hase half-life.
5. 2. 3 
E x pl or at or y E n d p oi nts
Pr o p e
s of U s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
6. 0 
S T U D Y D E SI G N A N D D E S C RI P TI O N
6. 1 
St u d y Desi g n
T his is a p hase 1, first-i n- h u ma n ( FI H), ra n d o mize d, place b o-c o ntr olle d, d o u ble- bli n d st u d y t o 
e val uate t he safet y, t olera bilit y, a n d P K of T A K- 0 4 1. T his st u d y desi g n i n t his a me n d me nt reflects 
a m o dificati o n of t he ori gi nal desi g n, d ue t o t he l o n ger t ha n e x pecte d half-life of T A K- 0 4 1 
o bser ve d after t he si n gle- d ose a d mi nistrati o n of t he c o m p o u n d t o healt h y s u bjects i n t he first 
2 c o h orts. T he st u d y is c o m p ose d of 4 parts: Pa rt 1 is a si n gle-risi n g d ose [ S R D] st u d y i n healt h y 
s u bjects, wit h a n alt er nati n g pa nel desi g n ( C o h orts 1 a n d 2) a n d a se q ue ntial pa nel desi g n ( C o h orts 
3 t o 5), Part 2 is a m ulti ple-risi n g d ose [ M R D], se q ue ntial pa nel desi g n i n healt h y s u bjects 
( C o h orts 1 t o 4), Part 3 is a ra n d o mize d, o pe n-la bel si n gle- d ose, parallel desi g n t o e val uate t he 
r elati ve bi oa vaila bilit y a n d f o o d effect o n t he P K of t he T A K- 0 4 1 i m me diate release ta blet 
f or m ulati o n i n healt h y s u bjects, Part 4 is a si n gle d ose c o h ort i n s u bjects wit h sta ble sc hiz o p hre nia. 
F or Part 1, C o h orts 1 a n d 2, d ose escalati o n a n d s u bse q ue nt d ose le vels will be deter mi ne d 
f oll o wi n g a f ull bli n de d re vie w of all a vaila ble safet y, t olera bilit y, a n d P K data fr o m t he pre vi o us 
d ose le vel. F or Part 1, C o h orts 3 t o 5, a n d all c o h ort s i n Part 2, d ose escalati o n a n d s u bse q ue nt d ose 
le vels will be base d o n a s p o ns or re vie w of at least 2 1 da ys of safet y, t olera bilit y, a n d a vaila ble P K 
data fr o m t he pre vi o us d ose le vels. F or Part 3, t he s u bjects will recei ve a si n gle 4 0 m g d ose of t he 
ta blet f or m ulati o n of T A K- 0 4 1 ( 1 x 4 0 m g ta blet) base d o n safet y/t olera bilit y of t he sa me d ose i n 
healt h y s u b jects fr o m Part 1 a n d Part 2. F or Part 4, t he d ose selecte d will n ot e xcee d t he hi g hest 
d ose e val uate d, dee me d safe, a n d well t olerate d i n Part 2. T he pr o p ose d wee kl y mai nte na nce d ose 
will ha ve a pre dicte d mea n a vera ge c o nce ntrati o n d uri n g a d osi n g i nter val, at stea d y state ( Ca v,ss) 
bel o w t he Ca v,ss o bser ve d at t he N O A E L d ose of 3 0  m g/ k g/ da y i n t he male a n d fe male d o gs fr o m 
t he 1 3- wee k t o xic ol o g y st u d y
A p pr o xi matel y e q u al n u m bers of male a n d fe male s u bjects will be e nr olle d at eac h d ose le vel. 
T A K- 0 4 1 a n d matc hi n g place b o will be a d mi nistere d as  a n oral s us pe nsi o n i n Parts 1, 2, a n d 4 a n d 
as a n i m me diate-release ta blet f or m ulati o n i n Part 3.
6. 1. 1 
P art 1 Si n gle- Risi n g D ose: He alt h y S u bjects
Part 1 will ha ve 5 c o h orts t o e val uate d ose escal ati o n. C o h orts 1 t o 5 will ha ve 8 s u bjects per c o h ort 
( 6 acti ve: 2 place b o). C o h orts 1 a n d 2 will partici pate i n a 2- p eri o d, alter nati n g- pa nel, d o u ble- bli n d 
st u d y desi g n t o e val uate si n gle-risi n g d oses of T A K- 0 4 1( 5, 1 0, 2 0, a n d 4 0 m g) or matc he d place b o 
Pr o p er
o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
y t o 
t o 
nt reflects
reflec
- 0 4 1 
0 4 1 
n t he fir
t he f
 st u d y
st u d y i
y
a nel desi
nel de
healt
ealt h y 
h y
desi g n
desi g
me diate
me dia
bjects wi
jects w
se le vels
se le ve
biliilit y
t y
i , a n
, a
rt 2, d os
2, d o
da ys of s
a ys of 
u bjects w
bjects
) baba se d o
se d 
art 4
rt 4, t he
, t he
rate d i n P
te d i n
ce ntrati o
ntrati
A E L d os
E L d o
of male
of ma
ace b o wi
e b o w
a blet f o
blet 
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
wit h a was h o ut peri o d of at least 7 da ys bet wee n treat me nt peri o ds ( Ta ble 6. a). As of A me n d me nt
0 4, after re vie w of t he data fr o m t hese i nitial c o h orts, C o h orts 3, 4, a n d 5 will partici pate i n a 
se q ue ntial- p a n el, d o u ble- bli n d st u d y desi g n t o e val uate si n gle-risi n g d oses of T A K- 0 4 1 or 
matc he d place b o. T his is a d o u ble- bli n d st u d y; t heref ore, t he s u bject, t he trial site pers o n nel, a n d 
t he S p o ns or staff w h o are i n v ol ve d i n t he treat me nt or cli nical e val uati o n are bli n de d t o treat me nt 
or i nter ve nti o n. Certai n S p o ns or staff n ot directl y i n v ol ve d wit h t he treat me nt or e val uati o n ma y be 
u n bli n de d t o t he treat me nt or i nter ve nti o n. T he pla n ne d d ose le vels of T A K- 0 4 1 t o be e val uate d i n 
C o h orts 3, 4, 5 are 8 0, 1 2 0, a n d 1 6 0 m g, res pecti vel y ( Ta ble 6. a). Alt h o u g h pla n ne d, all s u bse q ue nt 
d oses after t he d ose of 8 0  m g f or C o h ort 3 w ill be deter mi ne d base d o n t he e mer gi n g safet y, 
t olera bilit y, a n d P K data fr o m t he prece di n g c o h orts.
As t his is a n FI H st u d y, a se nti nel gr o u p will be use d f or Part 1 C o h ort 1 Peri o d 1 ( wit h t he i nit ial 
2 s u bjects recei vi n g eit her acti ve dr u g or place b o [ 1: 1]) t o e ns ure a de q uate safet y a n d t olera bilit y 
pri or t o d osi n g T A K- 0 4 1 t o t he re mai ni n g s u bjects i n t his c o h ort. I n Part 1 C o h ort 1 Peri o d 1, t he 
r e mai ni n g 6 s u bjects will be d ose d f oll o wi n g a re vie w of 2 4- h o ur p ost d ose safet y a n d t olera bilit y 
data a n d will o nl y occ ur f oll o wi n g a gree me nt bet wee n t he i n vesti gat or a n d Ta ke da. T he d ose 
a d mi nistere d f or s u bse q ue nt c o h orts will be base d o n a mi ni m u m of 2 1 da ys of e mer gi n g safet y, 
t olera bilit y, a n d a vaila ble P K data fr o m t he pre vi o us c o h orts (see sc he matic of st u d y d esi g n 
bel o w). T he hi g hest pla n ne d d ose is pre dicte d t o ha ve C ma x a n d A U C 2 4 val ues bel o w t he 
c orres p o n di n g e x p os ure o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ da y i n t he male a n d fe male 
d o gs fr o m t he 1 3- wee k t o xic ol o g y st u d y. Se nti nel  d osi n g ma y be use d f or a d diti o nal c o h orts if 
deter mi ne d t o be necessar y base d o n t he e mer gi n g safet y, t olera bilit y, a n d a vaila ble P K data fr o m 
t he prece di n g c o h orts.
B o n d- La der vis ual a nal o g scales will be perf or me d i n Part 1, Da y - 1, Da y 1 at 1, 3, 8, a n d 2 4 h o urs 
p ost d ose, Da y 5, a n d (if a p plica ble) a n d at Earl y Ter mi nati o n.
A sc he matic of t he Part 1 st u d y desi g n is s h o w n i n  Ta ble 6. a.
Pr o p ert y of T a k e d a: F or n o n
nal o g 
al o g 
a n d (if a
d (if 
o f f t h
t he Pa
e P
u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
a n d 
a n d 
eat me nt 
at me n
i oi on ma y
n m
e e val ua
e val u
d, all s u b
d, all s u
mer gi n g s
er gi n g
1 Peri o d
1 Peri o
e q uate s
e q uate 
I n Part 
n Part
o ur p ost d
o ur p os
n vest
vest i ga
i g
mi ni m u m
mi ni m u m
c o h orts (
o h ort
a ve C
e C mam
L d ose of
d ose
ti nel d os
nel d os
mer gi n g 
mer gi n g
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 3 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 6. a 
P art 1: St u d y Desi g n
P art 1 ( S R D)
N u m ber of 
S u bjects 
Peri o d 1 ( a)
W as h o ut Peri o d
( at le ast 7 d a ys) 
Peri o d 2 ( b)
C o h ort 1 ( n = 8), 
faste d
6
T A K- 0 4 1 5 m g
T A K- 0 4 1 2 0 m g
2
Place b o
Place b o
C o h ort 2 ( n = 8), 
faste d
6
T A K- 0 4 1 1 0 m g
T A K- 0 4 1 4 0 m g
2
Place b o
Place b o
C o h ort 3 ( n = 8), 
faste d
6
T A K- 0 4 1 8 0 m g
2
Place b o
C o h ort 4 ( n = 8), 
faste d
6
T A K- 0 4 1 1 2 0 m g
2
Place b o
C o h ort 5 ( n = 8), 
faste d
6
T A K- 0 4 1 1 6 0 m g
2
Place b o
(a) D oses pla n ne d t o be a d mi nistere d ra n ge fr o m 5 t o u p t o 1 6 0 m g. T he act ual d oses a d mi nistere d after 8 0 m g will be 
base d o n e mer gi n g safet y, t olera bilit y, a n d P K data fr o m t he pre vi o us c o h orts a n d ma y var y fr o m t he act ual d oses 
s h o w n i n t he ta ble a b o ve.
( b) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1.
O verall, Part 1 of t he st u d y will c o nsist of a Scr ee ni n g Visit ( Da ys - 2 1 t o - 2), a pre d ose C hec k-i n 
Da y f or all s u bjects ( Da y - 1) d uri n g w hic h baseli ne assess me nts will be c o n d ucte d, a n d a si n gle 
or al d ose a d mi nistrati o n ( Da y 1) w he n all s u bj ects will u n der g o st u d y-s pecific assess me nts. T he 
t otal c o nfi ne me nt peri o d f or eac h s u bject will be 5 da ys.
S u bjects fr o m Part 1 C o h orts 1 a n d 2 i n eac h peri o d will be re q uire d t o re mai n i n t he st u d y u nit f or 
at least 9 6 h o urs after d osi n g f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge. F or 
s u bjects fr o m Part 1 C o h orts 1 a n d 2 Peri o d 2, t he wee kl y f oll o w- u p safet y a n d P K o n-site visits 
will occ ur starti n g fr o m 7 da ys after last d ose a d mi nistrati o n u ntil T A K- 0 4 1 is n ot q ua ntifia ble i n 
plas ma. All s u bjects i n t he c o h orts will be br o u g ht bac k i n or der t o mai ntai n t he bli n d. S u bjects 
fr o m Part 1 C o h orts 3 t o 5 will be re q uire d t o re mai n i n t he st u d y u nit f or 9 6 h o urs after d osi n g. F or 
s u bjects fr o m Part 1 C o h orts 3 t o 5, t he wee kl y f o ll o w- u p safet y a n d P K o n-site visits will occ ur 
starti n g fr o m D a y 8 u ntil 6 wee ks after t he d ose. F or s u bjects fr o m Part 1 C o h orts 1 t o 5, a fi nal 
visit t hat c o m pletes t he st u d y will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K 
F oll o w- u p visit. T he sc he d ule f or Part 1 is s h o w n bel o w.
Pr o p er 
a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
m gg
m
o
4 1 4 0 m g
4 1 4 0 m
Place b o
ace b o
j e ct t o t h e a p pl
pli c a
j e c
act ual d os
ct ual d o
c o h orts a
o h orts a
ree ni n g 
e ni n g
baseli ne 
aseli ne
 s u bject
s u bje
ect will b
ct will
d 2 i n ea
2 i n e
or safet
safety
s 1 a n d 2
1 a n d 
da ys aft
da ys a
n t he c o h
he c o
3 t o 5 w
t o 5 
rt 1 C o h
1 C o h
D a y
D a y  8 u n
8 
y
o m pletes
m ple
u p visit. 
visit
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 6 . b
P art 1 C o h orts 1 t o 2: St u d y Sc he d ule f or E ac h Peri o d ( He alt h y S u bjects)
Scree ni n g
C hec k -i n
D osi n g ( a)
S afet y a n d P K 
Assess me nts
S afet y a n d P K 
Assess me nts
Disc h ar ge
Wee kl y 
F oll o w -u p
Visits ( b)
Fi n al Visit (c)
Da ys -2 1 t o -2
Da y  -1
Da y  1
Da ys 2 -5
Da y  5
T B D ( b)
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1.
( b) S u bjects will ret ur n t o t he site f or wee kl y safet y a n d P K F oll o w-u p Visits, starti n g fr o m 7 da ys after eac h C o h ort’s 
last treat me nt peri o d u ntil t he plas ma c o nce ntrati o n of T A K-0 4 1 is bel o w t he li mit of q ua ntitati o n.
(c) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K F oll o w-u p Visit.
T a ble 6. c 
P art 1 C o h orts 3 t o 5: St u d y Sc he d ule ( He alt h y S u bjects)
Scree ni n g
C hec k -i n
D osi n g ( a)
S afet y a n d P K 
Assess me nts
S afet y a n d P K 
Assess me nts
Disc h ar ge
Wee kl y 
F oll o w -u p
Visits ( b)
Fi n al Visit (c)
Da ys -2 1 t o -2
Da y  -1
Da y  1
Da ys 2 -5
Da y  5
Da ys 8, 1 5, 2 2, 
2 9, 3 6 a n d 4 3
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da y 1. S u bjects will be all o we d t o eat 4 h o urs p ost d ose.
( b) T he F oll o w -u p P K a n d safet y assess me nts will occ ur wee kl y fr o m 7 da ys u ntil 6 wee ks after t he d ose. All s u bjects 
will be br o u g ht bac k i n or der t o mai ntai n t he bli n d. If a b n or mal, cli nicall y si g nifica nt fi n di n gs are o bser ve d after 
disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or re -e val uati on per i n vesti gat or’s discreti o n.
(c) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last wee kl y safet y a n d P K F oll o w-u p Visit.
T he sc he d ule of pr oce d ures i n Part 1 ( healt h y s u bjects) is s h o w n i n A p pe n di x A.
6. 1. 2
P art 2 M ulti ple -Risi n g D ose: He alt h y S u bjects
Part 2 will c o nsist of a 4- c o h ort, se q ue nt ial-pa nel , d o u ble- bli n d, wee kl y d osi n g, M R D desi g n. T o 
assess T A K-0 4 1 plas ma e x p os ure a n d p ote ntial acc u m ulat i on i n Part 2, s u bjects will recei ve a n 
i nitial l oa di n g d ose of T A K-0 4 1 o n Da y  1 f oll owe d b y  a mai nte na nce d ose t hat is half t he i nitial 
d ose o n Da ys 8, 1 5, a n d 2 2 or will recei ve place b o o n all s t u d y d osi n g da ys. F o ur d ose c o h orts are 
c o nsi dere d a de q uate t o e x pl ore t he p har mac o l ogicall y act i ve e x p os ure ra n ge i n healt h y s u bjects. 
H o we ver, a d dit i onal c o h orts ma y be st u die d if dee me d necessar y  t o full y c haracterize t he 
p har mac o l ogi cal ex p os ure ra n ge. Eac h c o h ort will be c o m p ose d of 8 s u bjects w here 6 s u bjects will 
be ra n d o mize d t o recei ve T A K- 0 4 1 a n d 2 s u bjects will be ra n d oml y assi g ne d t o recei ve matc he d 
pl ace b o. T he st u d y p o p ulatio n f or Part 2 will be c o m p ose d of a t otal of u p t o a p pr o xi matel y  
3 2 he alt hy s u bjects. Part 2 ma y c o m me nce o nl y after 2 1 da ys o f safet y, t olera bilit y, a n d a vaila ble 
P K data ha ve bee n c o llecte d fr om Part 1 C o h ort 3.
T he d ose le vels f or Part 2 C o h orts 2 o n war ds will be base d o n e mer gi n g safet y/ t olera bilit y a n d 
a vaila ble P K data fr o m Part 1 a n d fr o m prece di n g c o h orts i n Part 2. D ose escalati on a n d 
s u bse q ue nt d ose le vels will be base d o n a s p o ns or re vie w o f at least 2 1 da ys of safety,  t olera bilit y, 
a n d a vaila ble P K data fr o m t he pre vi o us d ose re gi me n. T he hi g hest pla n ne d l oa di n g d ose i n Part 
2 will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, a n d well t olerate d i n Part 1. T he hi g hest 
pr o p ose d wee kl y mai nte na nce d ose will ha ve a pre dicte d mea n a vera ge c o nce ntrati o n d uri n g a 
d osi n g i nter val, at stea d y  state ( Ca v,ss) belo w t he C a v,ss o bser ve d at t he N O A E L d ose of 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 4 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
3 0  m g/ k g/ da y i n t he male a n d fe male d o gs fr o m t he 1 3- wee k t o xic ol o g y st u d y. T he st u d y 
sc he matic f or Part 2 is s h o w n i n Ta ble 6. d.
T a ble 6. d 
P art 2: St u d y Desi g n ( He alt h y S u bjects, C o h orts 1 t o 4)
4 0 m g o n D a y 1 a n d 2 0 
m g o n D a ys 8, 1 5, a n d 2 2
8 0 m g o n D a y 1 a n d 4 0 m g 
o n D a ys 8, 1 5, a n d 2 2
1 2 0 m g o n D a y 1 a n d 6 0 m g 
o n D a ys 8, 1 5, a n d 2 2
1 6 0 m g o n D a y 1 a n d 8 0 
m g o n D a ys 8, 1 5, a n d 2 2
C o h ort 1
( n = 8; 6 acti ve: 2 place b o)
C o h ort 2
( n = 8; 6 acti ve: 2 place b o)
C o h ort 3
( n = 8; 6 acti ve: 2 place b o)
C o h ort 4
( n = 8; 6 acti ve: 2 place b o)
O verall, f or healt h y s u bjects ( C o h orts 1 t o 4), Part 2 of t he st u d y will c o nsist of a Scree ni n g Visit 
( D a ys - 2 1 t o - 3), a pre d ose C hec k-i n Da y f or all s u bjects ( Da ys - 2) d uri n g w hic h baseli ne 
assess me nts will be c o n d ucte d, a n d m ulti ple oral d ose a d mi nistrati o ns ( Da ys 1, 8, 1 5, a n d 2 2) 
w he n all s u bjects will u n der g o st u d y-s pecific assess me nts.
S u bjects fr o m Part 2 C o h orts 1 t o 4 will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o 
D a y 3 ( 4 8 h o urs after t he first d ose) f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge. 
S u bjects will be re q uire d t o ret ur n o n Da y 5 f or a safet y a n d P K assess me nt. S u bjects will ret ur n o n 
Da y 7 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he sec o n d d ose o n Da y 8. S u bjects will 
r e mai n i n t he st u d y u nit fr o m Da y 7 t o Da y 1 0 ( 4 8 h o urs after t he sec o n d d ose). S u bjects will ret ur n 
o n Da y 1 4 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he t hir d d ose o n Da y 1 5. S u bjects will 
r e mai n i n t he st u d y u nit fr o m Da y 1 4 t o Da y 1 7 ( 4 8 h o urs after t he t hir d d ose). S u bjects will ret ur n 
o n Da y 2 1 t o o btai n safet y la b orat or y tests bef ore recei vi n g t he t hir d d ose o n Da y 2 2. S u bjects will 
r e mai n i n t he st u d y u nit fr o m Da y 2 1 t o Da y 2 4 ( 4 8 h o urs after t he f o urt h d ose). After disc har ge o n 
D a y 2 4, s u bjects will ret ur n t o t he cli nic o n Da ys 2 6, 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4 f or safet y a n d P K 
f oll o w u p visits. F or s u bjects fr o m Part 2 C o h orts 1 t o 4, a fi nal visit t hat c o m pletes t he st u d y will 
occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K f oll o w- u p visit. T he sc he d ule f or Part 2 is s h o w n 
bel o w.
B o n d- La der vis ual a nal o g scales will be perf or me d o n Da y - 1; Da ys 1, 8, 1 5, a n d 2 2 at 1, 3, 8, a n d 
2 4 h o urs p ost d ose, Da y 2 4, a n d (if a p plica ble) at Earl y Ter mi nati o n.
Pr o p er
o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
1 a n d 8 0 
a n d 8
, 1 5, a n d
1 5, a
T er
o h ort 4
h ort 4
acti ve: 2
acti ve: 
bl e
pli c
of a Scre
f a Sc
w hic h ba
hic h b
Da ys 1, 
Da ys 
t he st u d
he st u
d y asses
asse
y
P K asse
P K ass
he sec o n
he sec o
rs after t
s afte
ecei vi n g
cei vi n
( 4 8 h o ur
4 8 h o
f ore rece
re rec
a y 2 4 ( 4 8
y 2 4 
c o n Da y
c o n D
art 2 C o
art 2 C
safet
fety y a n
scales w
cales 
, a n d
a n
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 6 . e
P art 2: St u d y Sc he d ule ( He alt h y S u bjects, C o h orts 1 t o 4)
Scree ni n g
C hec k -i n
D ose
A d mi nistr ati o n ( a, b, c)
Fi n al
Disc h ar ge
F oll o w -u p
Visits ( d)
Fi n al
Visit
(e)
Da y  -2 1 t o -3
Da y  -2
Da ys 1, 8, 1 5, a n d 2 2
Da y  2 4
Da ys 2 6, 2 9, 3 6, 
4 3, 5 0, 5 7, 6 4
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da ys 1, 8, 1 5, a n d 2 2. O n all d osi n g da ys, s u bjects will be 
all o we d t o eat 4 h o urs p ost d ose.
( b) D osi n g o n Da ys 8, 1 5, a n d 2 2 will be pre dicate d o n t he re vie w of safet y la b orat or y res ults fr o m sa m ples o btai ne d 
t he da y bef ore (i.e., o n Da ys 7, 1 4, a n d 2 1).
(c) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y -2 t o Da y 3, Da y 7 t o Da y 1 0, Da y 1 4 t o Da y 1 7, a n d 
Da y  2 1 t o Da y 2 4.
( d) T he F oll o w-u p P K a n d safet y assess me nts will occ ur u ntil 6 wee ks after t he last d ose. If a b n or mal, cli nicall y 
si g nifica nt fi n di n gs are o bser ve d u p o n disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or re -e val uati o n per 
i n vesti gat or’s discreti o n.
(e) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K F oll o w-u p Visit.
T he Sc he d ule o f Pr oce d ures f or Part 2 is s h o w n i n A p pe n di x B ( healt h y s u bjects, C o h orts 1-4).
6. 1. 3
P art 3: Si n gle D ose: He alt h y S u bjects Rel ati ve Bi o a v ail a blit y a n d F o o d Effect St u d y
Part 3 i s a p hase 1, ra n d o mize d, o pe n -label, si n gle -d ose, si n gle -ce nter, parallel desi g n st u d y. T o 
e val uate t he oral bi oa vaila bilit y of  t he rece nt l y de vel o pe d T A K - 0 4 1 ta blet f or mulat i on relati ve t o 
t he oral s us pe nsio n  a n d effect of f o o d o n t he P K of t he ta blet f or m ulati on, healt h y s u bjects will be 
ra n d omize d t o recei ve o n Da y 1 a si n gle 4 0 m g d ose of  T A K-0 4 1 (as a si n gle 4 0 m g ta blet) aft er 
eit her at le ast 10- h o urs of o ver ni g ht fast or 3 0 mi n utes after starti n g i n gesti on of a hi g h -fat, 
hi g h -calori e brea kfast. Bl o o d sa m ples will be c o llecte d o ver 9 6 h o urs p ost -d ose t o meas ure 
T A K -0 4 1 pl as ma c o nce ntrati o ns. 
T he c o h ort will be ra n d o mize d w here 9 s u bjects will recei ve T A K- 0 4 1 i n t he faste d state a n d 9 
s u bjects t o recei ve i n t he fe d state. T he st u d y  p o p ulati on f or Part 3 will be c o m p ose d of 
a p pr o xi matel y 1 8 healt h y s u bjects ra n d o mize d i n a 1: 1 rati o t o recei ve T A K -0 4 1 i n t he faste d state 
or i n t he fe d state. T he st u d y sc he matic f or Part 3 is s h o w n i n Ta ble 6.f.
T a ble 6.f
P art 3: St u d y Desi g n ( He alt h y S u bjects
Re gi me n
N u m ber of 
S u bjects
D ose
Faste d o ver ni g ht 
mi ni m u m 1 0 hr
9
T A K -0 4 1 1 x 4 0 m g 
Ta blet F or m ulati o n
F e d hi g h -fat 
hi g h -cal orie 
br ea kfast (a)
9
T A K -0 4 1 1 x 4 0 m g 
Ta blet F or m ulati o n
(a) S u bjects ra n d o mize d t o t he fe d ar m will be d ose d 3 0 mi n utes after starti n g i n gesti o n of a hi g h -fat, hig h -cal orie 
br ea kfast.
S u bjects w h o satisf y t he Scree ni n g e val uat i on a n d select i on cri t eria ma y be e nr olle d i n t he st u d y. 
O n Da y  1, eli gi ble s u bjects will be ra n d o mize d t o recei ve T A K-0 4 1 as o ne 4 0 m g i m me diate 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
r elease ta blet a d mi nistere d orall y after eit her a n at least 1 0-h o urs of o ver ni g ht fast (i ncl u di n g n o 
me dicat i ons) or 3 0 mi n utes after starti n g i n gest i on of a hi g h -fat, hig h -calori e brea kfast
(a p pr o xi matel y 8 0 0-1 0 0 0 cal ori es wit h a p pr o xi matel y 5 0 % fr om fat), a n d will be re q uire d t o 
r e mai n i n t he st u d y u nit for at l east a n a d dit i on al  4 8 h o urs after d osi n g f or safet y a n d P K , wi t h 
a d ditio nal  visits for P K a n d safet y assess me nts o n Da y 4 a n d 5 a n d a fi nal F o ll ow- u p visit o n Da y 
1 7- 2 1. T he sc he d ule f or Part 3 is s h o w n i n  Ta ble 6. g.
T a ble 6. g
P art 3 T a blet F or m ul ati o n / F o o d Effect St u d y Sc he d ule ( He alt h y S u bjects)
Pretre at me nt
Tre at me nt Peri o d 
F oll o w u p
( a)
Scree ni n g
C hec k -i n
D osi n g a n d
St u d y Assess me nts
S afet y a n d P K 
Assess me nts
Da y -2 8 t o -2
Da y -1
Da y 1
Da ys 1 -3
Da ys 4 -5 
St u d y  Da y 
1 9 ( ± 2)
C o nfi ne me nt ( b)
(a) T he F oll o w-u p Visit will occ ur 1 9 ( ± 2) da ys p ost d ose.
( b) S u bjects will be release d fr o m c o nfi ne me nt after Da y 3 st u d y assess me nts are c o m plete.
O veral l, for heal t h y s u bjects, Part 3 of  t he st u d y will c o nsist of a Scree ni n g Visit ( Da ys -2 8 t o - 2), 
a pre d ose C hec k -i n Day f or all s u bjects ( Da y - 1) d uri n g w hic h baseli ne assess me nts will be 
c o n d ucte d, a n d a si n gle oral d ose a d mi nistrati o n ( Da ys 1) f oll owi n g w hic h all s u bjects will 
u n der g o st u d y -s pecific assess me nts. S u bjects fr o m Part 3 will be re q uire d t o re ma i n i n t he st u d y 
u nit u nt il a mi ni m u m 4 8 h o urs after t he first d ose f or safety,  P K, a n d st u d y assess me nts bef ore 
di sc har ge. S u bjects will be re q uire d t o ret ur n t o t he st u d y u nit f or safety a n d P K assess me nt s, a n d 
f or a fi nal F oll ow- u p visi t t hat c o mpletes t he st u d y a p pr o xi matel y 1 8 da ys after d o si n g. T he 
sc he d ule f or Part 3 is s h o w n i n A p pe n di x C.
6. 1. 4
P art 4 : Si n gle D ose: S u bjects wit h Sc hiz o p hre ni a
Part 4 will c o nsist of a d o u ble -bli n d, wee kl y d osi n g, parallel gr o u p desi g n. T we nt y- f our s u bjects 
wi t h sta ble sc hiz o p hre nia will be e nr olle d. T he 2 4 s u bjects are c o nsi dere d a de q uate t o e x pl ore t he 
p har mac o l ogi call y act i ve e x p os ure ra n ge i n s u bjects wit h sta ble sc hiz o p hre nia. T he s u bjects will 
be ra n d o ml y assi g ne d t o recei ve T A K -0 4 1 or pl ace b o i n a rati o of 2: 1. S u bjects will recei ve a n 
i nitial l oa di n g d ose of T A K-0 4 1 o n Da y  1 f oll owe d b y  a mai nte na nce d ose t hat will be half t he 
i nitial d ose o n Da ys 8, 1 5, a n d 2 2 or will recei ve place b o o n all st u d y  d osi n g da ys. Part 4 ma y 
c o m me nce o nl y after at least 2 1 da ys of safety,  t olera bility,  a n d a vaila ble P K data ha ve bee n 
c ollecte d at t he e q ui vale nt d ose c o h ort i n healt h y s u bjects i n Part 2.
T he d ose le vels f or Part 4 wil l be base d o n e mer gi n g safet y/ t olera bilit y a n d a vaila ble P K data of 
t he sa me d ose i n healt h y s u bjects fr o m Part 2. D ose escalat i on w ill be base d o n a s p o ns or re vie w of 
at least 2 1 da ys of safet y,  t olera bilit y, a n d a vaila ble P K data fr o m t he prece di n g c o h or t. T he 
hi g hest pl a n ne d loa di n g d ose i n P art 4 will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, 
a n d well t olerate d i n Part 2. S u bjects i n Part 4 will be a d mi nistere d a si n gle T A K -0 4 1 l oa di n g d ose 
or place b o o n Da y 1 a n d wee kl y mai nte na nce d oses o n Da ys 8, 1 5 a n d 2 2. T he 2 4 s u bjects will be 
ra n d omize d wit h 1 6 acti ve : 8 place b o. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 4 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
O verall, P art 4 of t he st u d y will c o nsist of a Sc ree ni n g Visit ( Da ys - 3 5 t o - 3), a pre d ose C hec k-i n 
D a y f or all s u bjects ( Da ys - 2) d uri n g w hic h s o me baseli ne assess me nts will be c o n d ucte d, Da y - 1 
d uri n g w hic h ot her baseli ne assess me nts will be c o n d ucte d, a n d 2 2 da ys of treat me nt w he n all 
s u bjects will be d ose d o n Da ys 1, 8, 1 5, a n d 2 2 as well as u n der g oi n g w he n all s u bjects will 
u n der g o st u d y-s pecific assess me nts. After 4 wee ks of d osi n g, s u bjects will ret ur n f or f oll o w- u p 
st u d y-s pecific assess me nts o n Da ys 2 6, 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4.
S u bjects will be re q uire d t o re mai n i n t he st u d y u n it fr o m Da y - 2 t o Da y 3 ( 4 8 h o urs after t he first 
d ose) f or safet y, P K, a n d all st u d y assess me nts be f ore disc har ge. S u bjects will ret ur n o n Da y 5 f or 
a safet y a n d P K assess me nt. S u bjects will ret ur n o n Da y 7 t o o btai n safet y la b orat or y tests bef ore 
recei vi n g t he sec o n d d ose o n Da y 8. S u bjects will re mai n i n t he st u d y u nit fr o m D a y 7 t o Da y 1 0 
( 4 8 h o urs after t he sec o n d d ose). S u bjects will ret ur n o n Da y 1 4 t o o btai n safet y la b orat or y tests 
bef ore recei vi n g t he t hir d d ose o n Da y 1 5. S u bjects will re mai n i n t he st u d y u nit fr o m D a y 1 4 t o 
D a y 1 7 ( 4 8 h o urs after t he t hir d d ose). S u bjects will ret ur n o n Da y 2 1 t o o btai n safet y la b orat or y 
tests bef ore recei vi n g t he t hir d d ose o n Da y 2 2. S u bjects will re mai n i n t he st u d y u nit fr o m Da y 2 1 
t o Da y 2 4 ( 4 8 h o urs after t he f o urt h d ose). After disc har ge o n Da y 2 4, s u bjects will ret ur n t o t he 
cli nic o n Da ys 2 6 , 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4 f or safet y a n d P K f oll o w u p visits. T he fi nal visit t hat 
c o m pletes t he st u d y will occ ur 1 2 t o 1 6 da ys after  t he last safet y a n d P K f oll o w- u p visit. T he 
sc he d ule f or Part 4 is s h o w n bel o w.
B o n d- La der vis ual a nal o g scales will be p erf or me d o n Da ys - 1, 1, 8, 1 5, a n d Da y 2 2 at 1, 3, 8, a n d 
2 4 h o urs p ost d ose, Da y 2 4, a n d (if a p plica ble) at Earl y Ter mi nati o n.
Pr o p ert y of T a k e d a: F
 o nl y
m
l y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
w- u p 
w- u p 
rs after t h
 after
et ur n o n 
ur n o
b orat or y
orat or
fr o m
o m
f
D
m
i n safet
n safe
he st u d y
e st u d y
y 2 1 t o o
2 1 t o 
y
mai n i n 
mai n i n
o n Da y
n Da y 2
y
d P K f o
d P K f
last safe
ast sa
e d o n D
e d o n
) at 
at Ear
E
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 6 . h
P art 4 : St u d y Sc he d ule ( S u bjects wit h Sc hiz o p hre ni a)
Scree ni n g
C hec k -i n
D ose
A d mi nistr ati o n ( a, b)
Fi n al
Disc h ar ge
(c)
F oll o w -u p
Visits ( d)
Fi n al
Visit
(e)
Da y  -3 5 t o -3
Da y  -2
Da ys 1, 8, 1 5, a n d 2 2
Da y  2 4
Da ys 2 6, 2 9, 3 6, 
4 3, 5 0, 5 7, 6 4
St u d y 
C o m pleti o n
(a) S u bjects will fast f or at least 8 h o urs bef ore d osi n g o n Da ys 1, 8, 1 5, a n d 2 2. O n all d osi n g da ys, s u bjects will be 
all o we d t o eat 4 h o urs p ost d ose.
( b) D osi n g o n D a ys 8, 1 5, a n d 2 2 will be pre dicate d o n t he re vie w of safet y la b orat or y res ults fr o m sa m ples o btai ne d 
t he da y bef ore (i.e., o n Da ys 7, 1 4, a n d 2 1).
(c) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y -2 t o Da y 3, Da y 7 t o Da y 1 0, Da y  1 4 t o Da y 1 7, a n d 
Da y  2 1 t o Da y 2 4.
( d) T he F oll o w-u p P K a n d safet y assess me nts will occ ur u ntil 6 wee ks after t he last d ose. If a b n or mal, cli nicall y 
si g nifica nt fi n di n gs are o bser ve d u p o n disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or r e-e val uati o n per 
i n vesti gat or’s discreti o n.
(e) T he Fi nal/ St u d y C o m pleti o n Visit will occ ur 1 2 t o 1 6 da ys after t he last safet y a n d P K F oll o w-u p Visit.
T he sc he d ule of p r oce d ures f or Part 4 is s h o w n i n A p pe n di x D /E .
6. 1. 5
E n d of Tri al
E n d -of -Tri al is defi ne d as t he last assess me nt of t he last s u bject (t he Fi nal St u d y C o mpleti o n 
Vi sit).
6. 1. 6
D ose Esc al ati o n
All decisi o ns c o ncer ni n g d ose escalat i on will be ma de b y Ta ke da (at a mi ni m u m, t he cli nical 
scie nce re prese ntati ve(s) a n d t he pri nci pal i n vesti gat or/ desi g nee). F or Part 1, C o h orts 1 a n d 2, d ose 
escalat i on a n d s u bse q ue nt d ose le vels will be deter mi ne d f o ll owi n g a f ull bli n de d re vie w o f all 
a vaila ble safet y,  t olera bility, a n d P K data fr o m t he pre vi o us d ose le vel. F or Part 1, C o h orts 3 t o 5, 
a n d all c o h orts i n Part 2, d ose escalat i on a n d s u bse q ue nt d ose le vels will be base d o n a s p o ns or 
re vie w of at least 2 1 da ys of safet y, t olera bilit y, a n d a vaila ble P K data fr o m t he pre vi o us d ose 
le vels. I n a d diti on t o t hi s d ose escalati o n re vie w, d uri n g t he c o n d uct of Part 1, C o h orts 3 t o 5, a n d 
all c o h orts i n Part 2, certai n s p o ns or staff n ot directl y  in v o l ve d with t he treat me nt or e val uati o n 
ma y be u n bli n de d t o t he treat me nt or i nter ve nt i on. D ose escalat i on fr om t he pre vi o us d ose le vel 
a n d will o nl y occ ur f ollo wi n g a gree me nt bet wee n t he i n vest i gat or a n d Ta ke da. T he s u bse q ue nt 
d ose l e vel ma y be hi g her, lo wer, or re mai n t he sa me as t he prece di n g d ose le vel.
Base d o n e mer gi n g safet y,  t olera bilit y, a n d a vaila ble P K data, t he pla n ne d d ose le vels ma y be 
m o difie d i n acc or da nce wit h t he f o ll owi n g:
F or Part 1, C o h orts 1 a n d 2:

D ose escalat i ons will be li mite d t o a n escalate d d ose t hat is pre dicte d t o gi ve n o greater t ha n a 
3 -f ol d i ncrease i n either C ma x or A U C. T he A U C of t he hi g hest pla n ne d d ose le vel is pre dicte d 
n ot t o e xcee d t he mea n, male -female c o m bi ne d A U C 2 4 (ie, a p pr o xi matel y 9 3, 0 7 0 n g∙hr/ m L) 
f or Part 1 or Ca v,ss ( 3, 8 7 8 n g/ m L) at t he N O A E L of t he 1 3-wee k t o xicit y st u d y (t he mor e 
sensit i ve s pecies) f or Part 2.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
F or Part 1, C o h orts 3 t o 5:

T he hi g hest pla n ne d d ose is pre dicte d t o ha ve C ma x a n d A U C 2 4 val ues bel o w t he c orres p o n di n g 
e x p os ure o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ da y i n t he male a n d fe male d o gs fr o m t he 
1 3- wee k t o xic ol o g y st u d y.
F or Part 2, All C o h orts:

D ose escalati o ns will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, a n d well t olerate d i n 
Part 1. T he hi g hest pr o p ose d wee kl y d ose after t he l oa di n g d ose will ha ve a pre dicte d mea n 
a vera ge c o nce ntrati o n d uri n g a d osi ng i nter val , at stea d y state ( Ca v,ss) t hat is bel o w t he Ca v,ss
o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ da y  in t he male a n d fe male d o gs fr o m t he 1 3-wee k 
t o xic o l og y  st u d y.

T h o u g h m o deli n g will be use d t o pre ve nt escalati o n t o d oses t hat c o ul d e xcee d t hese e x p os ures, 
f urt her escalati on w ill st o p if t he mea n Cma x or A U C fr o m a c o h ort e xcee ds t hese li mits. L o wer 
d oses ma y  be e x plore d at t hat ti me.

A d dit i onall y , Ta ke da a n d t he pri nci pal i n vesti gat or/ desi g nee ma y j oi ntl y deci de t o n ot escalate 
t he d ose f or a partic ular perio d/c o h ort, b ut rat her a d mi nister t he sa me or a l o wer d ose le vel t o 
t he ne xt c o h ort.
F or Part 3:

T he T A K -0 4 1 4 0 m g ta blet f or mulat i on is desi g ne d f or i m me diate dr u g release a n d ha s bee n 
ma n ufact ure d as 4 0-m g stre n gt h f or t he st u d y, base d o n safet y/t olera bility of  t he sa me d ose i n 
healt h y s u bjects fr o m Part 1 a n d 2.
F or Pa rt 4:

T he d ose will n ot e xcee d t he hi g hest d ose e val uate d, dee me d safe, a n d well t olerate d i n Part 1. 
T he hi g hest pr o p ose d wee kl y d ose after t he l oa di n g d ose will ha ve a pre d icte d mea n a vera ge 
c o nce ntrati o n d uri n g a d osi n g i nter val, at stea d y state ( Ca v,ss) t hat is bel o w t he Ca v,ss o bser ve d at 
t he N O A E L d ose of 3 0 m g/ k g/ da y i n t he male a n d fe male d o gs fr o m t he 1 3-wee k t o xic o l og y  
st u d y.

T he d ose le vel f or Part 4 will be base d o n e mer gi n g safet y/ t olera bilit y an d a vaila ble P K data of 
t he sa me d ose i n healt h y s u bjects fr o m Part 2.
Part 1 C o h orts 1 a n d 2, t here will be a mi ni m u m was h o ut peri o d/i nter val of 7 da ys bet wee n eac h 
d ose escalat i on t o all o w f or a f ull -bli n de d re vie w of all a vaila ble safet y,  t olera bilit y, a n d P K data. 
F or Part 1 C o h orts 3 t o 5, a n d Part 2, C o h orts 1 t o 4, t here will be a mi ni m u m i nter val o f 2 1 d a y s 
bet wee n eac h d ose escalat i on t o all o w f or a s p o ns or re vie w of all a vaila ble safet y,  t olera bilit y,  a n d 
a vaila ble P K  data. For eac h d ose l e vel a d mi nistere d/c o mplete d, t he pri nci pal i n vest i gat or a n d 
Ta ke da will deter mi ne w het her d osi n g s h o ul d st o p or c o nti n ue (a n d, if c o nt i n ue, at w hat d ose, 
i ncl u di n g w het her t o re peat t he pre vi o us d ose), a n d w het her a d dit i onal se q ue nt ial d osi n g s h o ul d be 
i m ple me nte d i n f ut ure peri o ds/c o h orts.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
All a d verse e ve nts re p orte d d uri n g t he Treat me nt Peri o d, b ot h wit hi n a n d acr oss c o h orts, u p t o t he 
ti me of disc har ge, will be e val uate d t o assess t he nee d f or s u bject a n d/ or st u d y  ter mi nati on i n 
acc or da nce wit h t he pres pecifie d criteria f or disc o nt i n uati on/ter mi nat i on ( Secti o n 6. 3. 1 ).
F o ll owi n g assess me nt of t he a d verse e ve nt data a n d pre defi ne d criteria f or st u d y ter mi nat i on, d ose 
escalat i on ma y be i nterr u pte d/st o p pe d if t hese criteria are met. Base d o n re vie w of st u d y data as 
o utli ne d a b o ve , Ta ke da i n c o ns ultati on wi t h t he pri nci pal in vest i gat or/ desi g nee will deci de if a n d 
h o w it i s a p pr o priate f or t he st u d y t o pr ocee d.
If a gree me nt re gar di n g a d ose escalati on decisi o n ca n n ot be reac he d bet wee n t he pri nci pal 
i n vesti gat or/ desi g nee a n d Ta ke da, t he st u d y will be st o p pe d.
T he pri nci pal i n v estigat or or desi g nee will c o m pre he nsi vel y e xa mi ne t he bli n de d safet y res ults 
( A Es, vital si g ns, ne ur ol ogical assess me nts, E C G fi n di n gs, a n d rec or ds of la b orat or y  tests) 
o btai ne d at all st u d y  e xa mi nati ons after t he start of st u d y  me dicatio n a d mi nistrati o n a n d t he n 
deter mi ne t he e ntr y  of t he ne xt perio d/c o h ort after disc ussi o n(s) wit h t he s p o ns or a n d me dical 
e x perts, as a p pr o priate.
Ot her criteria t o c o nsi der disc o nt i n uati on of t he d ose escalat i on or g o t o a l o wer d ose c o h ort are 
detaile d i n Sect i on  6. 3. 2 .
6. 2
J ustific ati o n f or St u d y Desi g n, D ose, a n d E n d p oi nts
6. 2. 1
St u d y Desi g n
A pri mar y  o bjecti ve of t he st u d y is t o c haracterize t he safety a n d t olera bilit y of 
T A K - 0 4 1 f oll owi n g oral  si n gle a n d m ulti ple d ose a d mi nistrati o ns i n health y s u bjects a n d s u bjects 
wi t h sta ble sc hiz o p hre nia. As re pr o d ucti ve t o xicity st u di es ha ve n ot bee n c o m p lete d, fe male 
s u bjects of c hil d beari n g p ote ntial will n ot be eli gi ble f or e nr oll me nt a n d male s u bjects w h o are 
se x uall y acti ve wit h a fe male part ner of  c hil d beari n g p ote ntial will be re q uire d t o use a n acce pta ble 
f or m of c o ntrace ptio n.
Part 1 , 2 a n d 4 of  t his st u d y will be d o u ble-bli n d a n d place b o -c o ntr olle d t o a v oi d s u bjecti ve bias i n
t he assess me nt of t he safet y,  t olera bilit y, a n d p har mac olo gi cal effects of T A K- 0 4 1.
A n alter nati n g pa nel desi g n is pr o p ose d f or Part 1 S R D C o h orts 1 a n d 2 beca use it pr o vi des a n 
efficie nt a n d r o b ust assess me nt of wit hi n-s u bject varia bility o n t he safet y /tol era bilit y a n d d ose 
pr o p orti o nali t y.
St u d y  T A K- 0 4 1-1 0 0 1 has e nr o lle d a n d d ose d a t otal of 1 6 s u bjects ( 1 2 acti ve a n d 4 place b o) i n a n 
alter nati n g pa nel desi g n ( 2 c o h orts) at 5, 1 0, 2 0 a n d 4 0 m g. ( C o h ort 1 recei ve d 5 a n d 2 0 m g d oses 
a n d C o h ort 2 recei ve d 1 0 a n d 4 0 m g d oses) wi t h a was h o ut perio d of  at least 7 da ys bet wee n t he 
2 treat me nt perio ds .
Base d o n t he preli mi nar y res ults fr o m t hese first 2 c o h orts ( C o h orts 1 t o 2) a n d d ue t o t he 
u ne x pecte d o bser vati o n o f a p pr o xi matel y 1 1 d a y  t1/ 2, Part 1 C o h orts 3 to 5, Part 2, a n d Part 4 will 
parti ci pate i n a se q ue nt ial pa nel, d o u ble-bli n d desi g n t o e val uate t he safet y,  t olera bilit y, a n d P K 
f oll owi n g si n gle - or m ul tiple -risi n g d oses of T A K-0 4 1 or m atc he d place b o. I n vest i gat or a n d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
s u bjects will be ke pt bli n de d t hr o u g h o ut t he st u d y. F or Part 2, a wee kl y d osi n g re gi me n with a 
t wice as hi g h l oa di n g d ose o n Da y 1, f o ll owe d b y wee kl y d osi n g o n Da ys 8, 1 5, a n d 2 2 is pla n ne d. 
T he hi g her l oa di n g d ose is i nc or p orate d t o s h orte n t he ti me necessar y t o attai n stea d y -state plas ma 
c o nce ntrati o ns of T A K-0 4 1. A p o p ul at i on p har mac o ki net ic m o d el  was de velo pe d usi n g t he 
a vaila ble data fr o m Part 1 C o h orts 1 a n d 2, a n d base d o n m o deli n g a n d si m ulat i ons, a p pr o xi matel y 
9 2 % t o 9 3 % of t he esti mate d stea d y -state Cma x levels will be attai n e d b y t he last wee kl y d ose o n 
D a y  2 2.
F or Part 1 C o h orts 1 a n d 2 Peri o d 2, t he F oll o w -u p peri o d was e xte n de d d ue t o t he u ne x pecte dl y 
l on g half -life of T A K - 0 4 1. F or Part 1 C o h orts 3 t hr o u g h 5, Part 2, a n d Part 4 of  t his st u d y, a 
6- wee k F oll o w -u p peri o d (a p p r o xi matel y 4 half li ves of T A K-0 4 1) f o ll owi n g t he l ast d ose is 
pr o p ose d t o f ull y  c haracterize t he si n gle - a n d m ult i ple -d ose P K of T A K -0 4 1. It is e x pecte d t hat 
t he p o p ulatio n mea n plas ma c o nce ntrati o n at t he e n d of t he F oll o w -u p peri o d will be at or bel o w 
9 % of t he c orres p o n di n g C ma x val ue f o ll ow a si n gle d ose ( Part 1) or t he last d ose o n Da y 2 2 ( Part 2 
a n d P art 4 ). All s u bjects a d mi nisteri n g place b o will be f oll owe d a n d plas ma sa m ples c o llecte d 
i de nticall y t o s u bjects a d mi nistere d T A K- 0 4 1.
T he pri mar y  o bje ct i ve of Part 3 t he st u d y is t o deter mi ne t he oral bi oa vaila bilit y of  T A K- 0 4 1 i n 
healt h y s u bjects a d mi nistere d as a 4 0 m g i m me diate release ta blet f or mulat i on i n t he faste d state
c o mpare d t o 4 0 m g oral s us pe nsi o n f or m ulat i on i n t he faste d state a n d t o esti mate t he effect of 
f oo d o n t he p har mac o ki net ics of  a si n gle d ose of 4 0 m g i m me diate release ta blet f or mulat i on of 
T A K - 0 4 1 i n healt h y s u bjects. 
6. 2. 2
D ose Selecti o n
A c o m pre he nsi ve series of n o ncli nical safet y st u dies ( G L P) ha ve bee n c o n d ucte d wit h T A K - 0 4 1 t o 
s up p ort earl y h u ma n st u dies: h E R G, electr ocar di o gra p h y  in d o gs, res pi r at or y a n d C N S i n rats, 
ge net ic t o xicity st u dies ( A mes, i n vitr o micr o n ucle us, i n vi v o micr o n ucle us), or i n vi v o 
p h ot ot o xi cit y. A n effect of T A K-0 4 1 was first o bser ve d at 1 µ M i n t he h u ma n h E R G assa y  
(I C5 0 > 3 µ M); h o we ver, n o c ha n ges i n E C G para meters were o bser ve d i n t he i n vi v o d o g C V or 
4- wee k re peat -d ose t o xicit y st u d y at 1 2 5 m g/ k g. I n t he d o g C V st u d y, a n i ncrease i n s yst olic bl o o d 
press ure ( 1 0 % relat i ve t o pre d ose val ues) res ulti n g i n i ncreases i n mea n arterial a n d p ulse 
press ures wit h o ut a n y ass ociate d c ha n ges i n heart rate at 0. 5 t o 6. 2 5 h o urs p ost d ose at 1 2 5 m g/ k g. 
I n a d diti on, dail y  re peat-d ose t o xicit y st u di es o f u p 1 3 -wee ks i n d urat i on ha ve bee n c o n d ucte d i n 
rats a n d d o gs. T he ma xi m u m oral d ose a d mi nistere d i n t he 4-wee k t o xi cit y st u d y in rats was t he 
ma xi m u m feasi ble d ose of 2 0 0 m g/ k g/ da y. Oral d oses i n d o gs were 5, 1 5, 5 0, a n d 1 2 5 m g/ k g/ da y 
i n t he 4-wee k st u d y  a n d 1 5, 3 0, a n d 6 0 m g/ k g/ da y i n t he 1 3-wee k st u d y .
I n t he rece ntl y c o mplete d 1 3 -wee k t o xicit y st u dies, t here were n o pat h ol o gical fi n di n gs i n rats, a n d 
t he N O A E L was t he hi g hest d ose teste d of 2 0 0 m g/ k g/ da y .
T he N O A E L i n t he d o g t o xicit y st u dies was 1 5 mg/ k g/ da y  in males a n d 5 0 m g/ k g/ da y i n fe males 
f or t he 4-wee k st u d y. T he N O A E L was 3 0 m g/ k g/ da y f or b ot h males a n d fe males i n t he 1 3 -wee k 
d o g t o xicit y st u d y, d ue t o mar ke d c h olestatic li ver i nj ur y at 6 0 m g/ k g/ day,  w hic h le d t o e ut ha nasia 
of  2 d o gs at da y 8 5 d ue t o ja u n dice a n d m ori b u n dit y.  T his fi n di n g was m o nit ora ble, base d o n 
pl as ma c he mistr y c ha n ges at all d ose le vels a n d as earl y as Da y 1 4 i n t he hi g h d ose gr o u p, w hic h 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 4 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
prece de d cli nical si g ns. Ele vat i ons i n plas ma c he mistr y v alues were als o l ar gel y re versi ble 
(tre n di n g d o w n of ele vate d li ver f u ncti on tests at all d ose le vels i n t he rec o ver y  gr o u p d o gs). 
Hi st o pat h olo g y  was n ot defi niti vel y re versi ble after o ne mo nt h, h o we ver gi ve n t he re d ucti o n i n 
pl as ma he pat o biliar y mar kers (e g , A L P, G G T, T BI LI), rec o ver y  of hist o pat h olo gical  c ha n ges 
mi g ht ha ve occ urre d after a l o n ger rec o ver y  p erio d.
D ue t o t his fi n di n g of c h olestatic li ver i nj ur y bei n g m o nit ora ble, partiall y re versi ble, a n d o bser ve d 
i n d o gs b ut n ot rats, t he selecte d d oses are pr ojecte d t o be res ult i n plas ma e x p os ures of 
T A K - 0 4 1 bel o w t h ose ass ociate d wit h t he N O A E L i n t he d o g 1 3 -wee k t o xic ol o g y st u d y. F urt her 
i nf or mat i on fr om t he n o ncli nical st u dies, s u m marize d a b o ve, ca n be f o u n d i n t he c urre nt 
I n vesti gat or’s Br oc h ure. O verall, t he n o ncli nical P K a n d safet y pac ka ge s u m marize d herei n 
pr o vi de s u p p ort f or t he cli nical e val uat i on of T A K - 0 4 1.
T a ble 6.i
Fi n di n gs a b o ve t he N O A E L
S pecies
St u d y
N O A E L D ose 
( m g/ k g/ d a y)
D a y E x p os ure ( a)
Fi n di n gs a b o ve N O A E L
C m a x
( n g/ m L)
A U C 0- 2 4
( n g. hr/ m L)
Rat
4 -wee k
2 0 0
N o ne of t o xic ol o gical 
si g nifica nce.
1 3 -wee k
2 0 0
2 2 9 8 4
3 4 4, 6 4 4
N o ne of t o xic ol o gical 
si g nifica nce.
D o g
4 -wee k
1 5 ( male)
5 0 (fe male)
1 male a ni mal e ut ha nize d o n Da y 
2 4 i n m ori b u n d c o n diti o n; bl o o d 
c he mistr y ele vati o ns c o nsiste nt 
wit h c h olestasis a n d altere d re nal 
f u ncti o n
1 3 -wee k ( b)
3 0
8 5 2 8
9 3, 0 7 0
2 a ni mals e ut ha nize d o n Da y 8 5 
f or ja u n dice, m ori b u n dit y; bl o o d 
c he mistr y ele vati o ns c o nsiste nt 
wit h c h olestasis a n d altere d re nal 
f u ncti o n.
(a) Mea n of male a n d fe male f or e x p os ure at t he e n d of t he re peat d osi n g peri o d.
( b) 3 male a n d 3 fe male per d osi n g gr o u p i n eac h of t he mai n ( 1 3-wee k) a n d rec o ver y ( 4 -a d diti o nal -wee k) st u dies
Base d o n t he a vaila ble data fr o m t he c o mplete d Part 1 C o h orts 1 a n d 2, a si n gle d ose u p t o 4 0 m g 
T A K - 0 4 1 was safe a n d well t olerate d, a n d P K of T A K-0 4 1 a p peare d t o be li near o ver t he d ose 
ra n ge of 5 t o 4 0 m g. A t w o-f ol d d ose i ncre me nt t o 8 0 m g is pr o p ose d f or Part 1 C oh ort 3. 
De pe n di n g o n t he e mer gi n g safet y,  t olera bility a n d P K data fr o m t he c o mplete d c o h orts, t he d ose 
i n Part 1 ma y be f urt her i ncrease d t o 1 2 0 a n d 1 6 0 m g i n C o h orts 4 a n d 5, res pecti vel y. At t he 
hi g hest pl a n ne d d ose i n C o h ort 5 ( 1 6 0 m g), t he e x pecte d C m a x is 2 9 0 3 n g/ m L a n d A U C2 4
4 7, 8 2 8 h. n g/ m L, re prese nt i n g a 2. 9- a n d 1. 9-f ol d mar gi n, res pecti vel y, c om pare d t o t he C ma x,ss a n d 
A U C 2 4,ss val ues at N O A E L of 3 0 m g/ k g/ da y fr o m t he rece nt l y c om p lete d 1 3-wee k t o xic o l og y  
st u d y in d o gs.
F or Part 2 of t his st u d y , t he pla n ne d starti n g d ose i n C o h ort 1 is 4 0 m g o n Da y 1 f oll owe d b y 
wee kl y d oses of 2 0 m g o n Da ys 8, 1 5 a n d 2 2 ( 4 0/ 2 0). Alt h o u g h a si n gle d ose of 4 0 m g was s h o w n 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 5 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
t o be safe a n d well t olerate d, t o f urt her e ns ure t he safet y of t he s u bjects f oll o wi n g m ulti ple d oses of 
T A K- 0 4 1, Part 2 C o h ort 1 will be i nitiate d after t he d ose escalati o n safet y re vie w of 2 1- da ys of 
safet y, t olera bilit y, a n d a vaila ble P K data fr o m Part 1 C o h ort 3 ( 8 0 m g). T he e x p os ure o ver t he 1 st
wee k of d osi n g f oll o wi n g t he l oa di n g d ose i n Part 2 is e x pecte d t o be si milar t o t hat fr o m Part 1 at 
t he sa me d ose, a n d t he e x p os ure o ver eac h s u bse q ue nt d osi n g i nter val is esti mate d t o be l o wer 
c o m pare d t o t hat i n t he 1 st d osi n g i nter val. D ue t o t he differe nt d osi n g i nter vals i n Part 2 of t his 
st u d y ( wee kl y) a n d t o xic ol o g y st u dies i n d o gs ( dail y), C a v,ss will be use d t o c o m pare t he esti mate d 
cli nical e x p os ure a n d stea d y-state e x p os ure at N O A E L i n d o gs. At t he pla n ne d d oses i n C o h orts 
1 ( 4 0/ 2 0), 2 ( 8 0/ 4 0), 3 ( 1 2 0/ 6 0), a n d 4 ( 1 6 0/ 8 0) of Part 2, C a v,ss is esti mate d t o be 5 4 3, 1 0 6 9, 1 5 9 4, 
a n d 2 1 5 1 n g/ m L, re prese nti n g a 7. 3-, 3. 6-, 2. 4-, a n d 1. 8-f ol d mar gi n, res pecti vel y, c o m pare d t o t he 
mea n C a v,ss at N O A E L ( 3 0 m g/ k g/ da y) fr o m t he 1 3- wee k t o xic ol o g y st u d y i n d o gs.
T he T A K- 0 4 1 4 0 m g t a blet f or m ulati o n is desi g ne d f or i m me diate dr u g release a n d has bee n 
ma n ufact ure d as 4 0- m g stre n gt h f or t he st u d y, base d o n safet y/t olera bilit y of t he sa me d ose i n 
healt h y s u b jects fr o m Part 1 a n d 2.
T he hi g hest pla n ne d l oa di n g d ose i n Part 4  will n ot e xc ee d t he hi g hest d ose e val uate d, dee me d safe, 
a n d well t olerate d i n Part 1 a n d Part 2. T he hi g hest pr o p ose d wee kl y mai nte na nce d ose will ha ve a 
pre dicte d mea n a vera ge c o nce ntrati o n d uri n g a d osi n g i nter val,  at stea d y state ( Ca v,ss) bel o w t he 
C a v,ss o bser ve d at t he N O A E L d ose of 3 0  m g/ k g/ da y i n t he male a n d fe male d o gs fr o m t he 1 3- wee k 
t o xic ol o g y st u d y.
O verall, t he pr o p ose d d ose ra n ge of T A K- 0 4 1 t o be e x pl ore d i n t his FI H st u d y is a ntici pate d t o 
ac hie ve s ufficie nt ra n ge of plas ma e x p os ures wit h a mar gi n a b o ve a n d be y o n d t he pre dicte d 
p har mac ol o gicall y acti ve e x p os ures/c o nce ntrati o ns esta blis he d i n precli nical m o dels. T he 
preli mi nar y safet y/t olera bilit y a n d P K data, as well as P D i nf or mati o n will facilitate t he desi g n of a 
pr o of- of- c o nce pt ( P O C) st u d y i n a patie nt p o p ulati o n. O verall, data fr o m t his st u d y i n c o nj u ncti o n 
wit h data fr o m ot her st u dies will be use d t o i nf or m d ose selecti o n a n d re gi me n f or t he P O C st u d y.
6. 2. 3 
E n d p oi nts
T he pri mar y e n d p oi nts f or t his st u d y are t he c o m p osit e of safet y varia bles t o deter mi ne t he safet y 
a n d t olera bilit y of oral si n gle a n d m ulti ple d oses  of T A K- 0 4 1 as well as d ose li miti n g effects of 
T A K- 0 4 1. T he sec o n dar y e n d p oi nts c o nsist of sta n dar d P K varia bles t o deter mi ne dr u g e x p os ure 
at eac h d ose t o facilitate d ose escalati o n. T he e n d p oi nts f or e val uati o n of t he T A K- 0 4 1 ta blet 
f or m ulati o n ( Cma x a n d A U C 9 6) i n Part 3 are sta n dar d e x p os ure metrics t o assess t he oral 
bi oa vaila bilit y of T A K- 0 4 1 a n d esti mate t he effect of f o o d o n T A K- 0 4 1 e x p os ures. T he use of 
sta n dar d n o nc o m part me nt al P K para meters are c o nsiste nt wit h F D A bi oa vaila bilit y a n d f o o d 
effect g ui da nce [ 3].
Pr o p er 
f T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
1 t
t 1 at 
 at 
o wer 
wer 
2 of t hi
2 of 
t he esti m
he est
oses i n C
oses i n 
be 5 4 3, 1
e 5 4 3,
i vel y, c o
el y, c o
d y i
y n d o g
n d o
r u g relea
r u g rele
era bili
ra bilit y
ti
t he hi g he
he hi g h
ose d we
se d w
n g i nter v
g i nter
a y i n t he 
i n t he
0 4 1 t o be
1 t o b
s ures wi
ures w
c o nce ntr
c o nce nt
P K data
P K dat
n a pat
a pa ie
will be u
will be
oi nts f or 
nts f or
of oral s
f oral 
he sec o n
e sec o
se t o fac
t o f
ti oo n (
n ( C
vaila bilit
aila b
a n dar d n
a n dar d
effect g
effect
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 5 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Pr o p er
U s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 5 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
6. 3 
P re m at ure Ter mi n ati o n or S us pe nsi o n of St u d y or I n vesti g ati o n al Site
6. 3. 1  
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he St u d y
T he st u d y will b e c o m plete d as pla n ne d u nless o ne  or m ore of t he f oll o wi n g crit eria are satisfie d 
t hat re q uire te m p orar y s us pe nsi o n or earl y ter mi nati o n of t he st u d y:
1.  Ne w i nf or mati o n or ot her e val uati o n re gar di n g t he safet y or efficac y of t he st u d y me dicati o n 
t hat i n dicates a c ha n ge i n t he k n o w n ris k/ be nefit pr ofile f or T A K- 0 4 1, s uc h t hat t he ris k/ be nefit 
pr ofile f or T A K- 0 4 1 is n o l o n ger acce pta ble f or s u bjects partici pati n g i n t he st u d y.
2. Si g nifica nt vi olati o n of G o o d Cli nical Practice ( G C P) t hat c o m pr o mises t he a bilit y t o ac hie ve 
t he pri mar y st u d y o bjecti ves or c o m pr o mises s u bject safet y.
3. T w o or m ore s u bjects i n a n y si n gle c o h ort or acr oss m ore t ha n 1 c o h ort e x perie nce a n y of t he 
Ta ke da Me dicall y Si g nifica nt e ve nts (as o utli ne d i n  Ta ble 1 0. a). *
4.  A b n or mal li ver f u ncti o n:
a) T w o or m ore s u bjects at a n y si n gle d ose le vel or acr oss d ose le vels e x perie nce ala ni ne 
a mi n otra nsferase ( A L T) a n d/ or as partate a mi n otra nsferase ( A S T) ele vati o ns > 5 × 
u p per li mit of n or mal ( U L N) i n t he a bse nce of a c o nc o mit a nt bilir u bi n i ncrease. *
b)  O ne or m or e s u bjects at a n y si n gle d ose le vel or acr oss d ose le vels e x perie nce A L T 
a n d/ or A S T ele vati o ns > 3 × U L N i n t he prese nce of a t otal bilir u bi n i ncrease > 2 × U L N 
or a n i nter nati o nal n or malize d rati o (I N R) > 1. 5 wit h o ut fi n di n gs of c h olestasis or ot her 
alter nati ve eti ol o g y t o e x plai n t he ele vati o ns (ie, “ H y’s La w cases”).
c) T w o or m ore s u bjects i n a n y si n gle d ose le vel or acr oss d ose le vels e x perie nce A L T 
a n d/ or A S T ele vati o ns > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, 
ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia ( > 5 %). *
d)  O ne or m ore s u bjects at a n y si n gle d ose le vel or acr oss d ose le vels e x perie nce A L P 
ele vati o ns > 1. 5 × U L N i n c o nj u ncti o n wit h ele vate d t otal bilir u bi n > 1. 5 × U L N or 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct
vesti g
esti g
o n of t h
n of t
m ore of t
ore of
o n of
n of  t he
t h
f
n g t he sa
g t he
be nefit pr
nefit p
pta ble f o
ta ble f
ical Prac
cal Pra
c o m pr o m
o m pr
y  si n gle 
si n g
y
fica nt e v
ca nt e
ti oo n:n:
m ore s u b
ore s
otra nsfer
ra nsfe
per li mit
per li m
O ne or
O ne o
a n d/
a n d
o
U s e
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
ele vate d 5’ n ucle otidase > 2 × U L N or ele vate d G G T > 5 × U L N or ele vate d A S T/ A L T 
> 3 × U L N.
e)
O ne or m ore s u bjects at a n y  si n gle d ose le vel or acr oss d ose le vels e x perie nce A L P 
ele vat i ons > 2 × U L N t hat persists f or l o n ger t ha n 3 da y s.
f)
O ne or m ore s u bjects at a n y  si n gle d ose le vel or acr oss d ose le vels e xp eri e nce A L P 
ele vat i ons > 3 × U L N.
* Please n ote t hat t he st u d y ma y be ter mi nate d earl y pri or t o f ull attai n me nt of t hese criteria (e g, if 
j ust 1 s u bject e x perie nces 1 of t hese e ve nts) if warra nte d b y safety data fr o m  t he ot her s u bjects 
d ose d i n t he st u d y  to date.
6. 3. 2
St u d y -S pecific D ose Esc al ati o n a n d St o p pi n g R ules
1.
D ose escalati o n bet wee n c o h orts a n d wit hi n a c o h ort will be deci de d after eit her a f ull - bli n de d 
( Part 1, C o h orts 1 a n d 2) or a s p o ns or partial u n bli n de d ( Part 1, C o h orts 3 t o 5, a n d Part 
2, C o h ort 1 o n war ds, w here certai n s p o ns or staff n ot direct l y i n v ol ve d wit h t he treat me nt or 
e val uat i on ma y be u n bli n de d t o t he treat me nt or i nter ve nt i on) re vie w of at least 2 1 da y s of 
safety,  t olera bilit y, a n d a vaila ble P K data fr o m t he pre vi o us d ose. T he selecti on of  eac h 
s u bse q ue nt d ose will be ma de j oi ntl y a n d a gree d u p o n b y t he s p o ns or a n d t he pri nci pal 
i n vesti gat or/ desi g nee a n d after caref ul e val uati on of all a vaila ble data fr o m pre vi o us d oses .
2.
D ose escalat i on will be st o p pe d at a d ose le vel (ie, o ne escalat i on ste p) bel o w t he d ose t hat is 
pre di cte d t o gi ve a T A K-0 4 1 A U C 2 4 or C ma x t hat e xcee ds t he mea n A U C 2 4,ss or C ma x,ss 
( Part 1) or Ca v,ss t hat e xcee ds Ca v,ss ( Part 2) at t he N O A E L d ose o f 3 0 m g/k g/ da y i n t he male 
a n d fe male d o gs fr o m t he 1 3 wee k t o xic o l og y  st u d y.
3.
Escal at i on will st o p o nce t he ma xi m u m t olerate d d ose has bee n reac he d or pre vi o usl y defi ne d 
t o xic o ki net ic e x p os ure li mits are met.
4.
D ose escalat i on ma y n ot pr ocee d if a n y o f t he f o ll owi n g occ ur at t he pre vi o us d ose c o h ort, 
alt ho u g h d osi n g m a y be res u me d at a lo wer d ose i n t he s u bse q ue nt c o h ort:
a)
Si g nifica nt st u d y  dr u g-r elate d a d verse e ve nts of se vere i nte nsit y i n ≥3 s u bjects.
b)
O ne or m ore s u bjects e x perie nce cli nicall y si g nifica nt E C G a b n or malit ies or effects o n 
vit al si g ns i n dicati n g d ose-li miti n g i nt olera nce.
c)
O ne o r m o re s u bjects e x perie nce cli nicall y si g nifica nt c ha n ges i n ne ur ol o gical 
assess me nts i n dicat i n g d ose-li miti n g i nt olera nce.
d)
O ne or m ore s u bjects i n a c o h ort e x perie nces a st u d y dr u g -relate d seri o us a d verse e ve nt 
( S A E).
e)
O ne or m ore s u bjects has a b n or mal li ver f u nct i on tests as descri be d i n Sect i on  6. 3. 1
t hat ca n be c o nsidere d rel ate d t o st u d y dr u g.
f)
S u bject e x perie nces a n y of t he Ta ke da Me dical Si g nifica nt E ve nts (Ta ble 1 0. a ) t hat 
ca n be c o nsi dere d relate d t o st u d y dr u g.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
5.
Wit hi n eac h d ose le vel, if at least 1 s u bject de vel o ps a d ose -li miti n g t o xicit y ( D L T) liste d i n 
Ta ble 6.j w hic h is c o nfir me d b y  re peat test if a p plica ble, n o f urt her d osi n g will occ ur i n t hat 
s u bject if t he s u bject has recei ve d T A K- 0 4 1.
T a ble 6.j
Defi niti o n of D L Ts
T o xicit y
Defi niti o n
Le u k o pe nia
T otal le u k oc yt e c o u nt < 2 5 0 0 cells/ m m 3 ( 2. 5 x 1 09/ L)
Ne utr o pe nia
A bs ol ute ne utr o p hil c o u nt < 1 5 0 0/ m m 3 ( 1. 5 x 1 09/ L)
T hr o m b oc yt o pe nia
Platelet c o u nt < 1 0 0 x 1 0 9/ L
L y m p h o pe nia
L y m p h oc y te c o u nt < 1 0 0 0 cells/ m m3 ( 1 x 1 09/ L)
A ne mia
Re d bl o o d cell c o u nt < 3. 5 x 1 0 1 2/ L ( me n) or <3. 0 x 1 0 1 2/ L ( w o me n)
L o w He m o gl o bi n
He m o gl o bi n < 1 1 g/ d L ( me n) or < 1 0. 5 g/ d L ( w o me n)
Se vere I nfecti o n 
Seri o us i nfecti o n re q uiri n g h os pitalizati o n, i ntra ve n o us a nti bi otics, s yste mic 
a ntif u n gal or a nti viral i nter ve nti o n
Q Tc
Q Tc > 5 0 0 msec
6.
After re vie w o f t he safet y dat a a n d disc ussi o n/a gree m e nt bet wee n t he i n vest i gat or a n d Ta ke da, 
t he sa me d ose ma y be gi ve n a gai n or a lo wer d ose ma y be gi ve n i n s u bse q ue nt peri o ds/c o h ort 
t o i ncrease data wit hi n t he d ose ra n ge.
7.
T he d ose i ncre me nts a n d pla n ne d d oses ma y be c h a n ge d as t he st u d y pr o gresses de pe n de nt 
u p o n e mer gi n g P K, safet y, a n d t olera bilit y d ata. A n y decisi o n t o alter t he pla n ne d d ose sc he me 
a n d t he decisi o n o n w hic h d oses t o use will be ma de j oi nt l y a n d a gree d u p o n b y t he 
i n vesti gat or a n d Ta ke da after caref ul e val uatio n of  all a vaila ble data.
8.
S h o ul d si g nifica nt a d verse e ve nts occ ur, a n y  decisi o n t o res u me d osi n g at t he c urre nt d ose 
le vel or t o escalate t he d ose will be ma de j oi ntl y b y t he i n vesti gat or a n d Ta ke da after caref ul 
e val uat i on of all a vaila ble data a n d will be c o m m u nicate d t o t he I nst itut i on al  Re vie w B oar d 
(I R B).
6. 3. 3
Criteri a f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of I n vesti g ati o n al Sites
A st u d y  site ma y be ter mi nate d pre mat urel y or s us pe n de d if t he site (i ncl u di n g t he i n vesti gat or) is 
f ou n d i n si g nifi c a nt viol at i on of G C P, pr ot oc ol, or c o ntract ual a gree me nt, is u na ble t o e ns ure 
a de q uate perf or ma nce of t he st u d y, or as ot her wise per mitte d b y t he c o ntract ual a gree me nt.
6. 3. 4
Pr oce d ures f or Pre m at ure Ter mi n ati o n or S us pe nsi o n of t he St u d y or t he 
P artici p ati o n o f I n vesti g ati o n al Site(s)
I n t he e ve nt t hat t he s p o ns or, a n i nstit uti o nal re vie w b oar d (I R B)/ i n de pe n de nt et hics c o m mittee, or 
re g ulat or y a ut h orit y elects t o ter mi nate or s us pe n d t he st u d y or t he partici pat i on of a n 
i n vesti gati onal site, a st u d y -s pecific pr oce d ure f or earl y ter mi nati on or s us pe nsi o n will be 
pr o vi de d b y  t he s p o ns or; t he pr oce d ure will be f oll o we d b y a p plica ble i n vesti gati onal sites d uri n g 
t he c o urse of ter mi nat i on or st u d y  s us pe nsio n .
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
7. 0
S E L E C TI O N A N D DI S C O N TI N U A TI O N/ WI T H D R A W A L O F S U B J E C T S
All e ntr y crit eria, i ncl u di n g test res ults, nee d t o be c o nfir me d pri or t o ra n d o mizat i on or first d ose.
7. 1
I ncl usi o n Criteri a
7. 1. 1
He alt h y s u bjects a n d s u bjects wit h sc hiz o p hre ni a
S u bject eli gi bilit y is deter mi ne d acc or di n g t o t he f oll o wi n g criteria pri or t o e ntr y int o t he st u d y: 
1.
I n t he o pi ni o n of t he i n vest i gat or, t he s u bject is ca pa ble of u n dersta n di n g a n d c o m pl yi n g with 
pr ot oc ol  r e q uire me nts.
2.
T he s u bject si g ns a n d dates a writte n, i nf or me d c o nse nt f or m a n d a n y  re q uire d pri vac y 
a ut h orizat i on pri or t o t he i nit iati o n of a n y st u d y pr oce d ures i ncl u di n g re q uesti n g t hat a s u bject 
fast f or a n y la b orat or y e val uatio ns.
3.
T he s u bject is willi n g t o c o m pl y  wit h st u d y restrictio n s (see Secti ons  7. 3 a n d 7. 4 f or a 
s u m mar y of restricti o ns).
4.
T he s u bject is a n a d ult ma n or w o ma n ( of n o n -c hil d beari n g p ote ntial). *
5.
T he s u bject is j u d ge d t o be i n g o o d healt h b y t he i n vesti gat or, base d o n cli nical e val uati ons 
i ncl u di n g la b orat or y safety tests, me dical hist or y, p h ysical e xa mi nati on, 1 2- lea d E C G, a n d 
vit al si g n meas ure me nts perf or me d at t he Scree ni n g Visit a n d pri or t o a d mi nistrati o n of  t he 
i nitial d ose of st u d y dr u g.
6.
T he s u bject is a ge d 1 8 t o 5 5 years, i ncl usi ve, at t he ti me of i nf or me d c o nse nt.
7.
T he s u bject wei g hs at least 4 5 k g ( 9 9 l b) a n d has a b o d y  mass i n de x ( B MI) fr o m 1 8 u p t o 
3 2 k g/ m 2 f or health y s u bjects a n d u p t o 4 0 . 5 k g/ m 2 f or s u bjects wit h sc hiz o p hre nia, i ncl usi ve at 
Scree ni n g.
8.
A male s u bject w h o is n o n -sterilize d * a n d se x uall y acti ve wit h a fe male part ner of  c hil d beari n g 
p ote nti al * a grees t o use a de q uate c o ntrace pti o n * fr o m si g ni n g of i nf or me d c o nse nt t hr o u g h o ut 
t he d urat i on of t he st u d y a n d f or 1 4 5 da ys (ie, 9 0 da ys after 5 half -li ves) ha ve ela pse d si nce t he 
last d ose of st u d y dr u g.
* Defi nit i ons a n d acce pta ble met h o ds of c o ntrace pti o n are defi ne d i n 
Secti o n 9. 1. 1 0 C o nt race pti o n a n d Pre g na nc y A v oi da nce Pr oce d ure a n d re p orti n g 
res p o nsi bilities are defi ne d i n Secti o n 9. 1. 1 1 Pre g na nc y.
7. 1. 2
S u bjects wit h sc hiz o p hre ni a o nl y
All e ntr y crit eria, i ncl u di n g test res ults, nee d t o be c o nfir me d pri or t o ra n d o mizat i on.
1.
T he s u bject is o n a sta ble d ose of a n a nti ps yc h otic me dicat i on f or at least 2 mo nt hs as 
d oc u m e nte d b y me dical hist or y a n d assesse d b y sit e staff ( ot her t ha n t h ose e xcl u de d i n Ta ble 
7. b ).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
2.
T he s u bject meets sc hiz o p hre nia criteria as defi ne d b y  t he D S M-5 b y t he Mi ni I nter nat i onal 
Ne ur o ps yc hiatric I nter vie w ( MI NI).
3.
T he s u bject has P A N S S t otal sc ore ≤9 0 a n d P A N S S Ne gati ve S y m pt o m Fact or Sc ore ( N S F S; 
S u m  of P A N S S N 1, N 2, N 3, N 4, N 6, G 7, a n d G 1 6) ≥1 5 at scree ni n g a n d baseli ne ( Da y -1).
4.
T he s u bject has sta ble scree ni n g a n d baseli ne ( Da y -1) P A N S S a n d N S F S t otal sc ores ( < 2 0 % 
c ha n ge).
7. 2
E xcl usi o n Criteri a
7. 2. 1
He alt h y s u bjects
N ote : S u bjects wit h sc hiz o p hre ni a w h o meet a n y of t he criteri a liste d bel o w wit h t he 
e xce pti o n of N u m ber 9, a n d 1 4 will als o n ot q u alif y f or e ntr y i nt o t he st u d y. F or criteri a t h at 
are als o re prese nte d i n Secti o n  7. 2. 2 f or s u bjects wit h sc hiz o p hre ni a, t h ose criteri a 
s u perse de t he criteri a i n t his secti o n ( Secti o n 7. 2. 1).
A n y s u bject w h o meets a n y  of t he f oll owi n g cri teria will n ot q ualif y for e ntr y  int o t he st u d y : 
1.
T he s u bject has recei ve d a n y i n vest i gati onal c o m p o u n d wit hi n 3 0 da ys pri or t o t he fir st d ose of 
st u d y dr u g, or d ue t o t he half-life of t he i n vesti gati o nal dr u g is li kel y t o still ha ve detecta ble 
pl as m a le vels o f t hat c o mp o u n d.
2.
T he s u bject is a n i m me diate fa mil y me m ber, st u d y site e m pl o yee, or i s i n a de pe n de nt 
r elat i ons hi p wit h a st u d y site e m pl o y ee w h o is i n v o l ve d i n t he c o n d uct of  this st u d y (e g, s p o use, 
pare nt, c hil d, si bli n g) or ma y c o nse nt u n der d uress.
3.
T he s u bject has a k n o w n h y perse nsit i vity t o a n y  c o m p o ne nt of t he f or m ulati on of T A K - 0 4 1.
4.
T he s u bject has a p ositi ve uri ne/ bl o o d dr u g res ult f o r dr u gs of  ab use ( defi ne d as a n y illicit dr u g 
use) at Scree ni n g or Da y  - 1.
5.
T he s u bject has ta ke n a n y e xcl u de d me dicat i on, s u p ple me nts, or f o o d pr o d ucts d uri n g t he ti me 
p eri o ds liste d i n t he E xcl u de d Me dicati o ns a n d Dietar y  Pr o d ucts (Ta ble 7. a f or health y 
s u bjects a n d Ta ble 7. b f or s u bjects wit h sc hiz o p hre nia i n Secti on  7. 3 ) or is u na ble t o refrai n 
fr om or a nti ci pates t he use of a n y me dicat i on (e xce pt t h ose prescri be d) as d escri be d i n (Ta ble 
7. a f or healt h y s u bjects a n d Ta ble 7. b f or s u bjects wit h sc hiz o p hre nia i n Secti on  7. 3 ).
6.
T he s u bject is lact ose i nt olera nt ( Part 3 o nl y ).
7.
If fe male, t he s u bject is of c hil d beari n g p ote ntial (e g, pre me n o pa usal, n ot sterilize d).
8.
If male, t he s u bject i nte n ds t o d o nate s per m d uri n g t he c o urse of t his st u d y or f or 1 4 5 da ys (ie, 
9 0 da y s after 5 half-li ves) ha ve ela pse d si nce t he last d ose of st u d y dr u g.
9.
T he s u bject has e vi de n ce of c urre nt acti ve car di o vasc ular, ce ntral ner v o us s yste m, 
he pat o biliar y  disease i ncl u di n g hist or y of biliar y tree dis or ders, gallst o nes, e n d osc o pic 
retr o gra de c h ola n gi o pa ncreat o gra p h y ( E R C P), a n d/ or c h olec ystect o m y, he mat o p oiet ic 
di sease, re nal d ysf u nctio n, m eta b o lic or e n d ocri ne d ysf u ncti on, seri o us aller g y , ast h ma, 
h y p o xe mia, h y perte nsi o n, seiz ures, or aller gic s ki n ras h. T here is a n y fi n di n g i n t he s u bject’s 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
me dical hist or y , p h ysical e xa mi nati on, or safet y la b orat or y test res ults (i nclu di n g ele vate d 
A L P, ele vate d bilir u bi n, ele vate d G G T, or ele vate d 5’ -n ucle oti dase) t hat i n t he j u d g me nt of t he 
pri nci pal i n vesti gat or re prese nts a reas o na ble s us pici o n of a disease t hat w o ul d c o ntrai n dicate 
ta ki n g T A K-0 4 1, or t hat mi g ht i nterfere wit h t he c o n d uct of t he st u d y. T his i ncl u des, b ut is n ot 
li mite d t o, pe ptic ulcer disease, c h olestasis, seiz ure dis or ders, a n d car diac arr h yt hmias.
1 0. T he s u bject has c urre nt or rece nt ( wit hi n 6 m o nt hs) gastr oi ntest i nal disease t hat w o ul d be 
e x pecte d t o i nfl ue nce t he a bs or pti o n of dr u gs (ie, a hist or y of mala bs or pti o n, es o p ha geal refl u x, 
pe pti c ulcer disease, er osi ve es o p ha gitis, fre q ue nt [ m ore t ha n o nce per wee k] occ urre nce of 
heart b ur n, or a n y  s ur gical int er ve nt i on).
1 1. Ha d maj or s ur ger y , or d o nate d or l ost 1 u nit of bl oo d (a p pr o xi mat el y 5 0 0 m L) wit hi n 4 wee ks 
pri or t o Scree ni n g.
1 2. T he s u bject has a hist or y  of ca ncer, e xce pt basal cell carci n o ma t hat has bee n i n re missi on f or 
at least 5 ye ars prior t o Da y  1.
1 3. T he s u bject has a p ositi ve test res ult f or he pat itis B s urface a nti ge n ( H Bs A g), he patitis C vir us 
( H C V) a nti b o d y at Scree ni n g or a k n o w n hist or y of hu ma n i m m u n o deficie nc y  vir us ( HI V) 
i nfecti on.
1 4. T he s u bject has use d nic oti ne -c o ntai ni n g pr o d ucts (i ncl u di n g but n ot li mite d t o ci garettes, 
pi p es, ci gars, c he wi n g t o bacc o, nic oti ne patc h or nic oti ne g u m) wit hi n 2 1 da ys pri or t o 
C hec k -i n o n Da y -1. C oti ni ne test is p osit i ve at Scree ni n g or Da y -1. 
1 5. T he s u bject has p o or peri p heral ve n o us access.
1 6. T he s u bject ha d a tr a nsf usi o n of a n y  blo o d pr o d uct wi t hi n 3 0 da ys prior t o Da y  1.
1 7. T he s u bject has a Scree ni n g or C hec k -i n a b n or mal (cli nicall y si g nifica nt) E C G. E ntr y of a n y 
s u bject wit h a n a b n or mal ( n ot cli nicall y si g nifica nt) E C G m ust be a p pr o ve d, a n d d oc u me nte d 
b y si g nat ure of t he pri nci pal i n vesti gat or or a me dicall y q ualifie d s u b-i n vesti gat or.
1 8. T he s u bject has a s ustai ne d resti n g heart rate o utsi de t he ra n ge 4 0 t o 1 0 0 beats per mi n ute 
( b p m), c o nfir me d o n re peat testi n g wit hi n a ma xi m u m of 3 0 mi n utes, at Scree ni n g or C hec k -i n.
1 9. T he s u bject has a Q T i nter val wit h Fri dericia c orrecti o n met h o d ( Q Tc F) > 4 5 0 ms or P R o utsi d e 
t he ra n ge 1 2 0 t o 2 2 0 ms, c o nfir me d o n re peat testi n g wit hi n a ma xi m u m of 3 0 mi n utes, at t he 
Scree ni n g Visit or C hec k -i n.
2 0. T he s u bject has a b n or mal Scree ni n g or C hec k -i n la b orat or y val ues ( > U L N f or t he res pecti ve 
ser u m c he mistries) of A L T, A S T, T BI LI, A L P, G G T, 5’ n ucle oti dase ( Scree ni n g o nl y) a n d/ or 
a b n or mal uri ne os mol alit y, c o nfir me d u p o n re peat testi n g.
2 1. T he s u bject has a cli nicall y si g nifica nt hist or y of hea d i nj ur y or tra u ma ass ociate d wit h l oss of 
c o nsci o us ness f or > 1 5 mi n utes.
2 2. T he s u bject is c o nsi dere d b y t he i n vest i gat or t o be at i m mi ne nt ris k of s uici de or i nj ur y t o self, 
ot hers, or pr o pert y , or s u bjects w h o wit hi n t he past year pri or t o Scree ni n g ha ve att e mpte d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
s uicide. S u bj ects w h o ha ve p osit i ve a ns wers o n ite m 4 or 5 o n t he C-S S R S ( base d o n t he past 
year) pri or t o ra n d o mizat i on are e xcl u de d.
2 3. T he s u bject has a hist or y o f si g nifica nt s ki n reacti ons ( h y perse nsit i vity) t o a d hesi ves, metals or 
pl astic; t his crit erio n a p plies o nl y t o s u bjects partici pat i n g i n t he st u d y of t he t w o weara ble 
di gi t al de vices.
2 4. T he s u bject is u ns uita ble f or i ncl usi o n i n t he trial i n t he o pi ni on of t he i n vest i gat or or s p o ns or.
7. 2. 2
S u bjects wit h sc hiz o p hre ni a o nl y
N ote: S u bjects wit h sc hi z o p hre ni a m ust n ot meet a n y of t he criteri a liste d i n Secti o n  7. 2. 1 f or 
he alt h y s u bjects wit h t he e xce pti o n of N u m ber 9 a n d 1 4 , as well t he criteri a liste d bel o w. T he 
criteri a liste d bel o w s u perse de t he criteri a i n Secti o n  7. 2. 1.
All e ntr y crit eria, i ncl u di n g test res ults, nee d t o be c o nfir me d pri or t o ra n d o mizat i on.
A n y s u bject wit h sc hiz o p hre nia w h o meets a n y of t he f o ll owi n g cri t eria will n ot q ualif y for e ntr y  
i nto t he st u d y : 
1.
T he s u bject has a n u n detecta ble le vel o f baseli ne a nt i ps yc h otic me dicati on at Scree ni n g.
2.
T he s u b ject has a lifeti me dia g n osis of sc hiz oaffecti ve dis or der; a lifeti me dia g n osis of bi p olar 
di s or der; or a lifeti me dia g n osis of o bsessi ve c o m p ul si ve dis or der base d o n t he MI NI 
c o m bi ne d wit h t he ge neral ps yc hiatric e val uat i on. As a n e xce pt i on, s u bjects wit h a hist orical 
pri or lifet i me dia g n osis of sc hiz oaffecti ve dis or der ma y be e nr olle d i n t he st u d y with s p o ns or 
or desi g nee a p pr o val pr o vi de d t hat t he pri nci pal i n vesti gat or ca n attest t hat t he s u bject’s 
o verall hist or y  a n d c urre nt cli nical prese ntati o n a n d hist or y is most c o nsi ste nt wit h 
sc hiz o p hre nia, n ot sc hiz oaffecti ve dis or der.
3.
T he s u bject has a rece nt ( wit hi n t he last 6 m o nt hs) dia g n osis of pa nic dis or der, de pressi ve 
e pis o de, or ot her c o m or bi d ps yc hiatric c o n dit i ons re q uiri n g cli nical atte nti o n base d o n t he 
MI NI f or D S M -5 a n d t he ge neral ps yc hiatric e val uati o n.
4.
T he s u bject has a hist or y of dr u g a b use ( defi ne d as a n y illicit dr u g use) or a hist or y of alc o h ol 
a b use ( defi ne d as 4 or m ore alc o h o lic be vera ges per da y) wit hi n 1 year pri or t o t he Scree ni n g 
Vi sit or i s u n willi n g t o a gree t o a bstai n fr o m alc o h ol a n d dr u gs t hr o u g h o ut t he st u d y. 
5.
T he s u bject has a dia g n osis of s u bsta nce use dis or der ( wit h t he e xce pt i on of nic oti ne 
de pe n de nce) wit hi n t he prece di n g 6 m o nt hs base d o n t he MI NI f or D S M -5 a n d t he ge neral 
ps yc hiatric e val uat i on.
6.
T he s u bject has e vi de nce or hist or y  of c urre nt cli nicall y si g nifica nt car di o vasc ular disease, 
i ncl u di n g u nc o ntr olle d h yperte nsi o n  (sta n di n g or s u pi ne diast olic bl o o d press ure > 9 0 m m H g 
a n d/ or sta n di n g or s u pi ne s yst olic bl o o d press u re > 1 4 5 m m H g, wit h or wit h o ut treat me nt), 
s y m pt o mat ic isc he mic heart disease, u nc om pe nsate d heart fail ure or rece nt ( past 1 2 m o nt hs) 
ac ute m yocar dial  infarct i on or b y pass s ur ger y . C o ntr olle d esse ntial h y perte nsi o n, 
n o n- cli nicall y sig nifica nt si n us bra d yca r dia a n d si n us tac h yc ar dia will not be c o nsi dere d 
sig nifica nt me dical ill nesses a n d w o ul d n ot e xc l u de a s u bject fr om t he st u d y. Ot her 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 5 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
well -c o ntr olle d me dical ill nesses ma y be per mitte d t hat d o n ot i ncrease he pat ic ris ks or ot her 
safety ris ks t o t he s u bject's partici pat i on i n t he j u d ge me nt of t he i n vesti gat or i n c o ns ultati on 
wi t h t he s p o ns or or desi g nee.
7.
T he s u bject has e vi de nce of cli nicall y  si g nifica nt e xtra p yra mi dal s y m pt o ms as meas ure d b y a 
Si ms o n -A n g us Scale ( S A S) sc ore > 6.
8.
T he s u bject has e vi de nce of d e pressio n  as meas ure d b y a Cal gar y  De pressio n  Sc ore (C D S S )
sc ore > 9.
9.
T he s u bject has recei ve d T A K- 0 4 1 i n a pre vi o us cli nical st u d y; or has pre vi o usl y  or is 
c urre ntl y part ici pati n g i n t his st u d y; has recei ve d treat me nt wit h ot her e x peri me ntal t hera pies 
wi t hi n t he prece di n g 6 0 da ys or < 5 half-li ves prior t o ra n d o mizat i on, w hic he ver is l o n ger; has 
parti ci pate d i n 2 or m ore cli nical st u dies wit hi n 1 2 m o nt hs pri or t o Scree ni n g; or has 
parti ci pate d i n a cli nical st u d y f or a ps yc hiatric c o n dit i on t hat is e xcl u sio n ar y per t his pr ot oc ol.
7. 3
E xcl u de d Me dic ati o ns a n d Diet ar y Pr o d ucts
Use of t he a ge nts i n  Ta ble 7. a ( prescripti o n or n o n prescri pt i on) i s pr o hi bite d fr om t he ti me p oi nts 
s pecifie d u ntil c om p leti on of all st u d y act i vities (e g, u ntil s u bject is disc har ge d fr o m t he u nit).
T a ble 7. a 
E xcl u de d Me dic ati o ns a n d Diet ar y Pr o d ucts f or he alt h y s u bjects ( P arts 1, 2 
a n d 3 )
2 1 d a ys pri or t o C hec k -i n
7 d a ys pri or t o C hec k -i n
7 2 h o urs pri or t o C hec k -i n
Prescri pti o n me dicati o ns
O T C me dicati o ns (a)
Pr o d ucts c o ntai ni n g caffei ne or xa nt hi ne
N utrace uticals (e g, St. J o h n’s w ort, gi nse n g, 
ka va ka va, gi n k g o bil o ba, C hi nese her bs, a n d 
melat o ni n)
Vita mi n s u p ple me nts
P o p p y see ds
I m m u nizati o n/ Vacci nes ( b)
F o o ds or be vera ges c o ntai ni n g gra pefr uit 
or gra pefr uit j uice or star fr uit or star fr uit 
j uice or Se ville-t ype (s o ur) ora n ges a n d 
mar mala de, a p ple, ora n ge, or pi nea p ple 
j uices, ve geta bles fr o m t he m ustar d gree n 
fa mil y (e g, kale, br occ oli, watercress, 
c ollar d gree ns, k o hlra bi, Br ussels s pr o uts, 
m ustar d), a n d c har br oile d meats
Nic oti ne -c o ntai ni n g pr o d ucts
Alc o h ol -c o ntai ni n g pr o d ucts
I nta ke of k n o w n O T C i n hi bit ors/i n d ucers of 
C Y Ps 3 A 4/ 5, 2 C 9, 2 C 1 9, 2 D 6, 1 A 2, 2 B 6, 
2 E 1, a n d 2 A 6 (c)
Me dici nes i n t he stati n class ( d)
H or m o nal c o ntrace pti ves
O T C = o ver -t he-c o u nter.
(a) Occasi o nal use of aceta mi n o p he n/ paraceta m ol (1 g/ da y) or ot her me dicat i o n as a p pr o ve d b y Ta ke da o n a case- b y-case basis is 
all o we d. Aceta mi n o p he n/ paraceta m ol is pr o hi bite d o n Da y 1 i n Part 1 a n d o n Da ys 1, 8, 1 5 a n d 2 2 i n Part 2.
( b) I ncl usi ve of, b ut n ot li mite d t o, H 1 N 1 a n d fl u vacci nati o ns.
(c) O me praz ole, la ns o praz ole, ci meti di ne, ra niti di ne, a n d c hl or p he nira mi ne.
( d) at or vastati n, fl u vastati n, l o vastati n, pita vastati n, pra vastati n, r os u vastati n, a n d si m vastati n.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 7 . b
E xcl u de d Me dic ati o ns a n d Diet ar y Pr o d ucts f or S u b jects wit h Sc hiz o p hre ni a 
(P art 4 )
Dr u g Cl ass
Dis all o we d ( X) D uri n g t he St u d y
(secti o ns wit h o ut [ X] i n dic ate n o restricti o n)
C hr o nic Use
E pis o dic Use
C o m me nts or E xce pti o ns
A n y i n vesti gati o nal dr u g
X
X
< 6 0 da ys bef ore Scree ni n g or 5 half -li ves –
w hic he ver is l o n ger
Narc otic a nal gesics
X
X
A n ore xia nts (e g, p he nter mi ne, be nz p heta mi ne, 
p he n di metrazi ne, met ha m p heta mi ne, 
a m p heta mi ne, sti m ula nts, si b utra mi ne, Bel vi q 
(l orcaseri n), Qs y mia ( p he nter mi ne/t o pira mate)
X
X
M ust be disc o nti n ue d f or ≥3 0 da ys pri or t o 
Scree ni n g
A ntiarr h yt h mics of 1 C class, q ui ni di ne
X
X
A nti bi otics
X
A ntic h oli ner gics
X
X
Ma xi m u m d ose of c hr o nic a ntic h oli ner gic 
treat me nt is 2 m g/ da y of be nztr o pi ne or 
e q ui vale nt.
A ntit hr o m bic a ge nts a n d a ntic oa g ula nts 
(e xcl u di n g warfari n, w hic h is e xcl u de d)
X
A ntic o n v ulsa nts 
X
X
E xce pti o n: ga ba pe nti n a n d pre ga bali n are 
per mitte d if t he y are prescri be d at a sta ble 
d ose f or ≥2 m o nt hs pri or t o Scree ni n g a n d 
t hr o u g h o ut st u d y treat me nt. S u bjects ta ki n g 
ot her a ntic o n v ulsa nts s h o ul d n ot be 
c o nsi dere d f or partici pati o n i n t he st u d y, as 
t heir disc o nti n uati o n c o ul d lea d t o s y m pt o m 
i nsta bilit y.
A nti de pressa nts (e xcl u di n g tric yclic 
a nti de pressa nts, M A OIs, a n d RI M As)
X
Tric yclic a nti de pressa nts, M A OIs, a n d 
RI M As are e xcl u de d, a n d s u bjects ta ki n g 
t he m s h o ul d n ot be c o nsi dere d f or 
partici pati o n i n t he st u d y, as t heir 
disc o nti n uati o n c o ul d lea d t o s y m pt o m 
i nsta bilit y. All ot her a nti de pressa nts are 
all o we d wit h c hr o nic a d mi nistrati o n
A nti hista mi nes
X
X
E xce pt l orata di ne, desl orata di ne, cetirizi ne, 
le v ocetirizi ne, miz olasti ne, a n d 
fe x ofe na di ne.
A nti h y perte nsi ves
Cl o ni di ne N O T all o we d.
A nti ps oriatic a ge nts
X
X
T o pical a ge nts are all o we d.
A nti ps yc h otics
X
P he n ot hiazi nes (c hl or pr o mazi ne, 
per p he nazi ne, pr oc hl or perazi ne, 
t hi ori dazi ne), hal o peri d ol, a n d cl oza pi ne are 
e xcl u de d a n d m ust be disc o nti n ue d 6 0 da ys 
pri or t o scree ni n g; all ot her treat me nts m ust 
a d here t o re q uire me nts o utli ne d i n t he st u d y 
e ntr y criteria.
As a n e xce pti o n, occasi o nal use of a n 
a d diti o nal d ose of t he bac k gr o u n d 
a nti ps yc h otic ma y be per mitte d wit h s p o ns or 
or desi g nee a p pr o val.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Dr u g Cl ass
Dis all o we d ( X) D uri n g t he St u d y
(secti o ns wit h o ut [ X] i n dic ate n o restricti o n)
C hr o nic Use
E pis o dic Use
C o m me nts or E xce pti o ns
Her bal re me dies, w hic h are ps yc h oacti ve (e g, St 
J o h ns W ort, ka va ka va, valeria n, gi n k g o bil o ba, 
melat o ni n)
X
X
M ust be disc o nti n ue d ≥7 da ys pri or t o 
Scree ni n g.
Se dati ve h y p n otics 
Bar bit uates are e xcl u de d. C hr o nic treat me nt 
wit h B Zs is all o we d u p t o 3 m g/ da y 
l oraze pa m or e q ui vale nt ( B Z e q ui vale nce 
sta n dar ds will be pr o vi de d i n a site refere nce 
d oc u me nt).
I ns uli n
X
X
M o o d sta bilizers 
X
X
Me dicati o ns t hat ma y i nterfere wit h c o g niti ve 
f u ncti o n
X
X
S uc h as c ol d me dici nes c o ntai ni n g 
a nti hista mi ne or de xtr o m or p ha n as a c o u g h 
s u p pressa nt are restricte d 
T o bacc o a n d Nic oti ne c o ntai ni n g pr o d ucts
N ot restricte d, e xce pt f or 2 h o urs pri or t o a n d 
d uri n g baseli ne assess me nts a n d d uri n g P D 
testi n g ( u nless t he s u bject e x hi bits nic oti ne 
wit h dra wal s y m pt o ms t hat p ose a ris k t o t he 
st u d y P D assess me nts i n t he j u d g me nt of t he 
i n vesti gat or.
Ps yc h otr o pic a ge nts k n o w n t o affect c o g niti o n
X
X
S uc h as l o n g -acti n g slee p ai ds,
a m p heta mi nes, bar bit urates, lit hi u m, 
met h y l p he ni date, a ntic h oli ner gics, 
a nti de pressa nts
Ster oi ds
S y ste mic oral or 
i njecta ble
X
X
As a n e xce pti o n, treat me nt wit h l ocal ster oi d 
i njecti o ns f or ort h o pe dic c o n diti o ns ma y be 
per mitte d wit h s p o ns or or desi g nee a p pr o val.
T o pical
I n hala nt
Sti m ula nts
X
X
M ust be disc o nti n ue d f or ≥3 0 da ys pri or t o 
Scree ni n g. D oes n ot i ncl u de s u bsta nces 
c o ntai ni n g caffei ne or nic oti ne.
U G T e nz y me i n hi bit ors ( pr o be neci d a n d val pr oic 
aci d)
N ot wit hi n 1 4 da ys of d osi n g.
B Z = be nz o diaze pi ne, M A OI = m o n oa mi ne o xi dase i n hi bit or, RI M A =re versi ble i n hi bit or of m o n oa mi ne o xi dase t y pe A, 
U G T = uri di ne 5' -di p h os p hate -gl uc ur o n os yltra nsferase.
S u bjects fr o m Parts 1, 2, a n d 3 m ust be i nstr ucte d n ot t o ta ke a n y  me dicatio ns i ncl u di n g 
o ver -t he- c o u nter pr o d ucts, wit h o ut first c o ns ult i n g wi t h t he i n vesti gat or.
7. 4
Diet, Fl ui d, a n d Acti vit y C o ntr ol
S u bjects will be c o nfi ne d t o t he u nit f or t he d urati o n of eac h treat me nt peri o d i n Parts 1, 2, 3 a n d 
Part 4 as descri be d i n A p pe n di x A , A p pe n di x B , A p pe n di x C , a n d A p pe n di x D /E res pecti vel y. 
S u bjects fr o m Part 1 will be re q uire d t o re mai n i n t he st u d y u nit d uri n g eac h treat me nt peri o d fr o m 
C hec k -i n, Da y 1 f or si n gle d ose a d mi nistrati o n, a n d wit h C o h orts 1-5 at least 9 6 h o urs p ost d ose f or 
a t otal c o nfi ne me nt peri o d f or eac h treat me nt  peri o d of 5 da ys. S u bjects fr o m Part 2 C o h orts 1 t o 4, 
a n d Part 1 C o h orts 1 a n d 2, will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y -2 t o Da y 3, Da ys 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
7 t o 1 0, Da y 1 4 t o Da y 1 7, a n d Da y 2 1 t o Da y 2 4 ( 4 8 h o urs after eac h d ose i n Part 2) f or safet y, P K, 
a n d all st u d y assess me nts bef ore disc har ge. I n a d diti o n, s u bjects will ret ur n t o t he cli nic o n Da ys 5, 
2 6, 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4 f or safet y a n d P K f o ll o w u p visits. S u bjects wit h sc hiz o p hre nia (Part 
4 ) will als o u n der g o part-s pecific assess me nts o n Da ys 2 9 a n d 4 3. A Fi nal Visit t hat c o m pletes t he 
st u d y will occ ur 1 2 t o 1 6 da ys after t he last safety a n d P K F o ll ow- u p Visit. O n t he da ys of d osi n g, 
s u bjects will be a d mi nistere d T A K-0 4 1/ m atc he d place b o at a p pr o xi matel y 0 8 0 0 h o urs f o ll owi n g a 
fast of at least 8 h o urs a n d will c o nti n ue t o fast f or a n a d dit i onal 4 h o urs p ost d ose. 
S u bjects fr o m st u d y  Parts 1, 2 a n d 4 ma y c o ns u me water a d li bit u m with t he e xce pti o n o f 1 h o ur 
bef ore a n d 1 h o ur after dr u g a d mi nistrati o n. T he meal start a n d st o p ti mes a n d t he a mo u nt 
c o ns u me d will be rec or de d i n t he s o urce d oc u me nt a n d a p pr o priate electr o nic case re p ort f or m 
(e C R F) pa ge f or all meals ser ve d o n t he d osi n g da ys. D uri n g c o nfi ne me nt o n n o n d osi n g da ys, 
s u bjects will be gi ve n 3 meals a n d a n e ve ni n g s nac k eac h c o ntai nin g a p pr o xi matel y  3 0 % fat 
(relati ve t o t he t otal cal ories). Brea kfast will n ot be ser ve d o n d osi n g da ys.
S u bjects fr o m all st u d y parts s h o uld r e m ai n u prig ht (seate d, sta n di n g, or a m b ulat or y ) for 4 h o urs 
f oll owi n g d ose a d mi nistrati o n, e xce pt as necessitate d b y t he occ urre nce of a n A E / or st u d y  
pr oce d ure (e g, o btai ni n g 1 2 -lea d E C G). S u bjects s h o ul d refrai n fr om stre n u o us e xercise fr o m 
7 2 h o urs bef ore C hec k -i n a n d t hr o u g h o ut t he e ntire c o urse of t he st u d y.
7. 4. 1
P art 3 Diet a n d Fl ui d C o ntr ol
S u bjects i n Part 3 will b e re q uire d t o re mai n i n t he st u d y u nit for a c o nfi ne me nt peri o d of 3 da y s. 
T he s u bjects will be ra n d o mize d f or T A K - 0 4 1 i m me diate release ta blet a d mi nistrati o n at 
a p pr o xi matel y 0 8 0 0 h o urs eit her fol l owi n g a n o ver ni g ht fast ( n o f o o d, n o dri n k ot her t ha n wate r,
n o me dicat i ons) of  at least 1 0 h o urs or 3 0 mi n utes after starti n g i n gest i on of a hi g h -fat, 
hi g h -calori e brea kfast as descri be d i n 2 0 0 2 F D A F o o d-Effect G ui da nce (t he meal c o m p osit i on 
s h o uld deri ve of a p pr o xi matel y  1 5 0, 2 5 0, a n d 5 0 0 t o 6 0 0 cal ories fr om pr otei n, car b o h y drate, a n d 
fat, res pecti vel y, i n t otal of a p pr o xi matel y 8 0 0 t o 1 0 0 0 cal ories). 
Per F D A g ui da nce, s u bjects will be ser ve d t he sta n dar d F D A brea kfast t o be i n geste d a n d 
c o m p letely c o ns u me d o ver 3 0 mi n utes. T A K -0 4 1 4 0 m g ta blet s h o uld be a d mi nistere d 
i m me diatel y after brea kfast wit h a glass of water.
S u bst ituti o ns t o t he c o nte nts of t his hi g h -fat, hig h -calori e meal ca n be ma de as lo n g as t he sa m e 
meal is ser ve d t o all s u bjec ts a n d a n utritio nist at t he site e ns ures t hat t he test m eal pr o vides a 
si milar a m o u nt of cal ories fr o m pr otei n, car b o h y drates a n d fat a n d has c o m para ble meal v o l ume 
a n d visc osit y.  T he cli nical site will d oc u me nt t he a m o u nt of  pr otei n car b o h y drates a n d fat a n d t otal 
calori e c o nte nt of t he test meal f or t he st u d y file a n d pr o vi de a c o p y t o t he s p o ns or. T he date a n d 
ti me of t he meal will als o be rec or de d o n t he e C R F.
Fast i n g s u bjects will als o be a d mi nistere d t he 4 0 m g ta blet wit h a glass of water. B ot h fastin g a n d 
fe d s u bjects will ha ve n o f o o d, n o dri n ks (e xce pt water) a n d n o me dicati o ns f or 4 h o urs after d ose 
a d mi nistrati o n. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
7. 5
Criteri a f or Disc o nti n u ati o n or Wit h dr a w al of a S u bject
T he pri mar y  reas o n f or disc o nti n uati on or wi t hdra wal  of t he s u bject fr o m t he st u d y or st u d y 
me dicat i on s h o ul d be rec or de d i n t he e C R F usi n g t he f o ll owi n g cate g ori es. F or scree n fail ure 
s u bjects, refer t o Secti o n 9. 1. 2 1 .
1.
Pret reat me nt e ve nt ( P T E) or A E. T he s u bject has e x perie nce d a P T E or A E t hat re q uires earl y 
ter mi nati o n beca use c o nti n ue d partici pati on i m p oses a n u nacce pta ble ris k t o t he s u bject’s 
healt h or t he s u bject is u n willi n g t o c o nti n ue beca use of t he P T E or A E.

Li ver F u nct i on Test ( L F T) A b n or malit ies
St u d y  me dicatio n s h o ul d be disc o nt i n ue d i m me diatel y wit h a p pr o priate cli nical f oll ow- u p 
(incl u di n g re peat la b orat or y  tests, u ntil a s u bject’s la b orat or y pr ofile has ret ur ne d t o 
n or m al/ baseli ne stat us, see Secti o n 9. 1. 9 ), if a n y of t he f oll owi n g circ u msta nces occ ur at 
a n y ti me d uri n g st u d y me dicat i on treat me nt:
–
A L T or A S T > 8 × U L N.
–
A L T or A S T > 5 × U L N a n d per sists f or m ore t ha n 2 wee ks.
–
A L T or A S T > 3 × U L N i n c o nj u nct i on wi t h ele vate d t otal bilir u bi n > 2 × U L N or I N R 
> 1. 5.
–
A L T or A S T > 3 × U L N wit h a p peara nce of fat i g ue, na usea, v omit i n g, ri g ht u p per 
q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia ( > 5 %).
–
A L P ele vati o ns > 1. 5 × U L N i n c o nj u nct i on w ith e le vate d t otal bilir u bi n > 1. 5 × U L N or 
ele vate d 5’ n ucle otidase > 2 × U L N or ele vate d G G T > 5 x U L N or ele vate d A S T/ A L T 
> 3 × U L N or ele vate d A L P > 2 × U L N, persist i n g f or l o n ger t ha n 3 da ys.
–
A L P > 3 × U L N.
2.
Si g nifica nt pr ot oc ol de viat i on. T he disc o ver y p ostra n d o mizat i on t hat t he s u bject faile d t o meet  
pr ot oc ol  e ntr y crit eria or did n ot a d here t o pr ot oc ol re q uire me nts, a n d c o nti n ue d partici pati o n 
p oses a n u nacce pta ble ris k t o t he s u bject’s healt h.
3.
L ost t o f oll o w -u p. T he s u bject di d n ot ret ur n t o t he u nit a n d atte m pts t o c o ntact t he s u bject 
were u ns uccessf ul. Atte m pts t o c o ntact t he s u bject m ust be d oc u me nte d.
4.
V ol u nt ar y  wit hdra wal. T he s u bject wis hes t o wit h dra w fr o m t he st u d y . T he reas o n f or 
wi t hdra wal , if pr o vid e d, s h o uld be rec or de d i n t he e C R F.
N ote: All atte m pts s h o ul d be ma de t o deter mi ne t he u n derl yi n g reas o n f or t he wit h dra wal a n d, 
w here p ossi ble, t he pri mar y  u n derl yi n g reas o n s h o ul d be rec or de d (ie, wit h dra wal d ue t o a n 
A E).
5.
St u d y  ter mi nati on. T he s p o ns or, I R B, i n de pe n de nt et hics c o m mittee, or re g ulat or y a ge nc y 
ter mi nates t he st u d y.
6.
Ot her.
N ote: T he s pecific reas o ns s h o ul d be rec or de d i n t he “s pecif y” fiel d of t he e C R F.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
N ote: S ki n react i ons (c uta ne o us h y perse nsit i vity) t o o ne of t he weara ble di gital de vices will 
lea d t o re m o val of that de vice f or t he re mai n der of t he st u d y, a n d de pe n de nt o n PI assess me nt, 
t he s u bject w o ul d n ot be re q uire d t o disc o nt i n ue t he st u d y.
7. 6
Pr oce d ures f or Disc o nti n u ati o n or Wit h dr a w al of a S u bject
T he i n vest i gat or ma y disc o nti n ue a s ubject’s st u d y partici pat i on at  a n y ti me d uri n g t he st u d y w he n 
t he s u bject meets t he st u d y ter mi nati o n criteria descri be d i n Secti o n  7. 5 . I n a d diti on, a s u bject ma y 
di sc o nti n ue his or her partici pat i on wi t ho ut gi vi n g a reas o n at a n y  ti me d uri n g t he st u d y. S h o uld a 
s u bject’s partici pati on be di sc o nti n ue d, t he pri mar y crit erio n f or ter mi nat i on m ust be rec or de d b y  
t he i n vest i gat or. I n a d diti on, eff orts s h o ul d be m a de t o perf or m all pr oce d ures sc he d ule d f or t he 
Earl y Ter mi nat i on Visit. S u bjects w h o dr o p o ut f or n o nsafet y reas o ns ma y b e r e place d o n a 
case- b y-case basis at t he discret i on of t he s p o ns or i n c o ns ultat i on wi t h t he i n vesti gat or. S u bjects 
w h o dr o p o ut f or safet y reas o ns will n ot be re place d.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
8. 0
C LI NI C A L T RI A L M A T E RI A L M A N A G E M E N T
T his sect i on c o ntai ns i nf or mat i on re gar di n g all me dicat i on a n d m at erials pr o vid e d di rectl y b y t he 
s p o ns or, a n d/ or s o urce d b y ot her mea ns, t hat are re q uire d b y t he st u d y pr ot ocol , i ncl u di n g 
i m p orta nt secti o ns descri bi n g t he ma na ge me nt of cli nical trial material.
8. 1
St u d y Me dic ati o n a n d M ateri als
8. 1. 1
D os a ge F or m, M a n uf act uri n g, P ac k a gi n g, a n d L a beli n g
T he T A K -0 4 1 oral cr ystalli ne s us pe nsi o n will be use d i n t his st u d y Parts 1, 2 a n d 4 . T he T A K -0 4 1 
cr ystalli ne dr u g s u bsta nce ( mille d) will be la bele d i n a n o pe n-label fas hi o n a n d c o m p o u n de d i nt o 
or al  s us pe nsio n s t hat will be la bele d i n a bli n de d fas hi on f or t hir d part y dis pe nsi n g. A n u n bli n de d 
p har macist will ma na ge a n d pre pare d oses as nee de d t hr o u g h o ut t he st u d y . T he oral s us pe nsio ns 
will c o ntai n 5 t o 1 6 0 m g of T A K -0 4 1 per d ose. C o m p o u n di n g i nstr ucti o ns will be pr o vi de d t o t he 
cli nical site usi n g t he c o m p o u n di n g w or ks heet or a si milar d oc u me nt.
T he oral  s us pe nsio n  c o ntai ni n g cr ystalli ne T AK- 0 4 1 ( mille d) will be pre pare d at t he site b y  
w ei g hi n g a n a p pr o pri ate a mo u nt of  cr ystalli ne T A K-0 4 1 ( mille d) i nt o a d osi n g b ottle a n d mi xi n g 
wi t h 7 0 mL of 0. 5 % T wee n 8 0 i n 0. 5 % met h ylcell ul ose ve hicle ( T wee n/ M C ve hicle). T he 
c o mp osi tio n of  t he T wee n/ M C vehicle is i n  Ta ble 8. a . T he c o m p ositi on of cr ystalli ne 
T A K - 0 4 1 or al  s us pe nsio n  is liste d i n Ta ble 8. b.
T a ble 8. a
C o m p ositi o n of 0. 5 % T wee n 8 0 i n 0. 5 % ( w/ v) Met h ylcell ul ose Ve hicle
C o m p o ne nt
C o m p ositi o n per 1 0 0 m L of W ater
Met h y lcell ul ose, U S P
5 0 0 m g
T wee n 8 0, N F
5 0 0 m g
Sterile water f or irri gati o n, U S P
1 0 0 m L 
T a ble 8 . b
C o m p ositi o n of Cr yst alli ne T A K -0 4 1 Or al S us pe nsi o n
C o m p o ne nt
Q u a ntit y per D ose 
Cr y stalli ne T A K-0 4 1 ( mille d)
(a) m g
T wee n/ M C ve hicle
7 0 m L 
(a) A m o u nt s hall be i n t he ra n ge of 5 m g t o 1 6 0 m g, w hic h c orres p o n ds t o a d ose of 5 t o 1 6 0 m g T A K-0 4 1, a n d a 
c o nce ntrati o n ra n ge of 0. 0 7 t o 2. 2 9 m g/ m L T A K -0 4 1.
A pl ace b o s us pe nsi o n will be pre pare d b y wei g hi n g a n a p pr o priate a m o u nt of H P M C A S -M i nt o a 
d osi n g b ottl e. A d d 7 0 m L of 0. 5 % met h ylcell ul o se ( M C) ve hicle ( M C ve hicle) a n d mi x well. T he 
c o mp osi tio n of  t he place b o s us pe nsi o n is i n Ta ble 8. c.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 6 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 8. c  
C o m p ositi o n of Pl ace b o t o T A K- 0 4 1 Or al S us pe nsi o n
C o m p o ne nt
Q u a ntit y per D osi n g B ottle 
H y dr o x y pr o p yl met h ylcell ul ose acetate s ucci nate- me di u m 
gra de ( H P M C A S- M), N F
(a) m g
0. 5 % M C ve hicle ( M C ve hicle)
7 0 m L
(a) A m o u nt deter mi ne d b y t he acti ve d ose use d i n t he c o h ort a n d peri o d. T he a m o u nt s hall be t he sa me as t hat i n t he 
acti ve d ose i n t he sa me c o h ort a n d peri o d, i n a ra n ge of 5 t o 1 6 0 m g.
T he T A K- 0 4 1 4 0 m g ta blet will be use d i n t his st u d y f or Part 3. T he ta blet f or m ulati o n is desi g ne d 
f or i m me diate dr u g release 
T he ta blets are r o u n d a n d fil m c oate d. 
8. 1. 1. 1 S p o ns or- S u p plie d Dr u g
F or Parts 1, 2, a n d 4, t he T A K- 0 4 1 cr ystalli ne dr u g s u bsta nce ( mille d) will be s u p plie d i n a p o w der 
f or m, i n a p pr o priate pac ka gi n g, a n d eac h c o ntai ner will bear a si n gle pa nel la bel t hat i ncl u des all 
perti ne nt st u d y i nf or mati o n.
T he T A K- 0 4 1 4 0 m g i m me diate release ta blet will be use d i n t his st u d y f or health y s u bjects i n Part 
3. T he ta blets are pac ka ge d i n a m ber glass b ottles. Eac h b ottle will c o ntai n a la bel t hat i ncl u des 
perti ne nt st u d y i nf or mati o n a n d ca uti o n state me nts.
8. 1. 2 
St or a ge
I n vesti gati o nal dr u g  m ust be ke pt i n a n a p pr o priate, li mit e d-access, sec ure place u ntil it is use d or 
ret ur ne d t o t he s p o ns or or desi g nee f or destr ucti o n. I n vesti gati o nal dr u g  m ust be st ore d u n der t he 
c o n diti o ns s pecifie d o n t he la bel, a n d re mai n i n t he ori gi nal c o ntai ner u ntil dis pe nse d.
T A K- 0 4 1 cr ystalli ne dr u g s u bsta nce ( mille d) a n d 4 0 m g ta blets are st ore d at c o ntr olle d r o o m 
t e m perat ure ( 2 0°- 2 5° C wit h e xc ursi o ns all o we d fr o m 1 5°- 3 0° C).
8. 1. 3  
D ose a n d Re gi me n
T he pla n ne d i nitial d ose of T A K- 0 4 1 f or Part  1 S R D C o h ort 1 Peri o d 1 is 5 m g. D oses f or 
s u bse q ue nt peri o ds/c o h orts will be deter mi ne d base d o n t he a vaila ble safet y, t olera bilit y, a n d P K 
data fr o m t he prece di n g peri o d/c o h ort. T he d oses will be a d mi nistere d t o t he s u bjects b y t he 
i n vesti gat or or t he i n vesti gat or’s desi g nee. S u bjects will recei ve t he d oses b y dri n ki n g t he e ntire 
s us pe nsi o n fr o m t he d osi n g b ottle. T he d osi n g b ottle will t he n be ri nse d wit h 3 5 m L of water a n d 
t he ri nse will be a d mi nistere d i n t he sa me ma n ner as t he s us pe nsi o n. T he ri nse a n d a d mi nistrati o n 
will be re peate d o ne m ore ti me.
Eli gi ble s u bjects i n P art 3  will be ra n d o mize d t o recei ve a si n gle d ose of T A K- 0 4 1 as o ne 4 0 m g 
ta blet a d mi nistere d orall y after eit her a n o ver ni g ht fast of at least 1 0 h o urs or 3 0 mi n utes after 
starti n g i n gesti o n of a hi g h-fat a n d hi g h-cal orie brea kfast as rec o m me n de d i n t he 2 0 0 2 F D A 
F o o d- Effect G ui da nce [ 3] (t he meal s h o ul d deri ve of a p pr o xi matel y 1 5 0, 2 5 0 a n d 5 0 0 t o 6 0 0 
cal ories fr o m pr otei n, car b o h y drate a n d fat, res pecti vel y, i n t otal of a p pr o xi matel y 1 0 0 0 cal ories). 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e 
li c a bl e T er m s of U s e
T e
e
e as t hat i n
as t hat
ulatat i oi on i
n
ille d) wi
le d) w
a si n gle 
a si n g
use d i n t h
se d i n
Eac h b o
ac h b
nts.ts.
a p pr o p
a p pr o p
f or destr
or des
a n d re m
a n d re
bsta nce 
sta nce
it h e xc u
h e xc
Re gi me n
e gi m
all d ose 
d os
l
eri o ds/c o
eri o ds/
t he prece
he pre
at or or t
or or
e nsi o n fr
nsi o n f
e ri nse w
e ri nse
will be 
will b
Eli
El
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he ta blet m ust be a d mi nistere d wit h a glass of water (a p pr o xi matel y  2 4 0 m L). It s h o uld be 
s wallo we d as a w h ol e a n d n ot be ma ni p ulate d i n a n y w a y.
8. 1. 4
O ver d ose
A n o ver d ose is defi ne d as a k n o w n deli berate or acci de ntal a d mi nistrati o n of i n vest i gati onal dr u g, 
t o or b y a st u d y s u bject, at a d ose a b o ve t hat w hic h is assi g ne d t o t hat i n di vi d ual s u bject acc or di n g 
t o t he st u d y pr ot oc ol.
All cases of o ver d ose ( wit h or wit h o ut ass ociate d A Es) will be d o c u me nte d o n a n O ver d ose pa ge 
of  t he e C R F, i n or der t o ca pt ure t his i m p orta nt safet y inf or mati o n c o nsiste nt l y i n t he data base. 
Cases of o ver d ose wit h o ut ma nifeste d si g ns or s y m pt o ms are n ot c o nsi dere d A Es. A Es ass ociate d 
wi t h a n o ver d ose will be d oc u me nte d o n A E C R F(s) acc or di n g t o Secti o n  1 0. 0 , Pretreat me nt 
E ve nts a n d A d verse E ve nts.
S A Es ass ociate d wit h o ver d ose s h o ul d be re p orte d acc or di n g t o t he pr oce d ure o utli ne d i n 
Secti o n 1 0. 2. 2 , C ollecti on a n d Re p orti n g of S A Es.
I n t he e ve nt of dr u g o ver d ose, t he s u bject s h o ul d be treate d s y m pt o maticall y.
8. 2
I n vesti g ati o n al Dr u g Assi g n me nt a n d Dis pe nsi n g Pr oce d ures
S u bjects will be assi g ne d, i n t he or der i n w hic h t he y are ra n d o mize d i nt o t he st u d y, t o recei ve t heir 
treat me nt acc or di n g t o t he ra n d o mizat i on sc he d ule all ocate d t o t he site. T he Ra n d o mizati o n 
Se q ue nce N u m ber will be e ntere d o nt o t he e C R F.
I n vesti gati onal dr u g m ust be st ore d u n der t he c o n dit i ons s pecifie d o n t he la bel, a n d re mai n i n t he 
ori gi nal  c o ntai ner u ntil dis pe nse d. S u bjects are t o fast o ver ni g ht f or at least 8 h o urs pri or t o d osi n g 
o n Da y  1 (in Part 1) a n d o n Da ys 1, 8, 1 5 a n d 2 2 (i n Part 2 a n d Part 4 ). S u bjects i n P art 3 will be 
ra n d omize d t o recei ve T A K-0 4 1 as o ne 4 0 m g ta blet a d mi nistere d orall y  after at least 1 0 h o urs of  
o ver ni g ht fast or 3 0 mi n utes after starti n g i n gesti on of a hi g h-fat, hi gh- calori e breakf ast . O n all 
d osi n g da ys, s u bjects i n all st u d y parts will be all o we d t o eat 4 h o urs p ost d ose. Descri pt i ons o f the 
st u d y s u p plie d meals a n d dietar y fat c o nte nt, a n d ti mi n g of assess me nts i n relati on t o d osi n g ca n be 
f ou n d i n Secti o n  7. 4 .
S u bjects w h o dr o p o ut f or n o n -safety reas o ns ma y be re place d o n a case - b y-case basis at t he 
di scretio n of  t he s p o ns or i n c o ns ultati o n wit h t he i n vesti gat or. S u bjects w h o re place dr o p o uts will 
be all ocate d t o t he sa me treat me nt as t he s u bject t he y  re place. S u bjects w h o dr o p o ut f or safety 
reas o ns will n ot be re place d.
F or eac h d osi n g c o h ort i n Parts 1, 2, 3, a n d 4, ra n d o mize d s u bjects will be assi g ne d a 4-di gi t 
ra n d omizat i on n u m ber i n t he or der t he y  are e nr olle d. Ra n d o mizati o n se q ue nce n u m bers will be 
X Y 0 1 t o X Y 0 8 f or Parts 1 a n d 2, X Y 0 1 t o X Y 1 8 f or Part 3 , a n d X Y 0 1 t o X Y2 4 f or Part 4 , w here 
X refers t o st u d y  part ( 1, 2, 3 or 4) a n d Y refers t o c oh ort n u m ber. 
F or e xa m ple:

S u bjects i n Part 1 C o h ort 1 will ha ve ra n d o mizat i on se q ue nce n u m bers 1 1 0 1 t o 1 1 0 8 a n d 
s u bjects i n Part 1 C o h ort 2 will ha ve ra n d o mizat i on se q ue nce n u m bers 1 2 0 1 t o 1 2 0 8.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8

S u bjects i n Part 2 C o h ort 1 will ha ve ra n d o mizat i on se q ue nce n u m bers 2 1 0 1 t o 2 1 0 8, s u bjects 
i n Part 2 C o h ort 2 will ha ve ra n d omizat i on se q ue nce n u m bers 2 2 0 1 t o 2 2 0 8, a n d s u bjects i n 
Part 2 C o h ort 3 will ha ve n u m bers 2 3 0 1 t o 2 3 0 8.

S u bjects i n Part 3 will ha ve ra n d o mizat i on se q ue nce n u m bers 3 1 0 1 t o 3 1 1 8.

S u bjects i n Part 4 will ha ve ra n d o mizat i on se q ue nce n u m bers 4 1 0 1 t o 4 1 2 4.
T his 4 -di gi t n u m ber will be use d b y t he cli nical site t o facilitate t he pre-la beli n g of P K sa m ples, 
a n d will be t he o nl y s u bject i de nt ifier use d o n all P K sa m ple c ollecti ons. It s h o ul d als o be 
co ntai ne d o n t he P K tra ns p ort vials s hi p pe d t o t he bi oa nal yt ical la b orat or y, a n d will be use d b y t he 
la b orat or y t o re p ort t he s u bject data res ults. T his 4-di gi t n u m ber s h o uld o nl y be use d f or t he 
p ur p oses descri be d i n t his sect i on. It d oes n ot re place t he 3 -di git s u bject n u m ber w hic h is assi g ne d 
at t he ti me t he i nf or me d c o nse nt is o btai ne d a n d w hic h is use d f or all ot her pr oce d ures t o i de nt if y 
t he s u bjects t hr o u g h o ut t he st u d y.
If a s u bject nee ds t o be re place d, t he re place me nt s u bject will recei ve t he sa me treat me nt or 
treat me nt se q ue nce o f t he s u bject bei n g re place d. T he re place me nt ra n d o mizat i on n u m ber will be 
5 0 lar ger t ha n t he ra n d o mizati o n n u m ber of t he s u bject w h o is bei n g re place d. F or e xa m ple, 
ra n d omizat i on n u m ber 1 2 5 1 will be use d f or t he s u bject w h o re pl aces t he s u bject w h o ha d 
ra n d omizat i on n u m ber 1 2 0 1, usi n g t he sa me treat me nt or treat me nt se q ue nce i n Part 1 C o h ort 2.
St u d y  dr u gs will be dis pe nse d i n t he u nit u n der t he s u per visi on of t he i n vest i gat or or desi g nee.
8. 3
R a n d o miz ati o n C o de Cre ati o n a n d St or a ge
T D C A mericas A nal y tical Scie nces De partme nt  or desi g nee will ge nerate t he ra n d o mizati on 
sc he d ule a n d a c o p y will be pr o vide d t o t he si te p har macist prior t o t he start of t his st u d y . All 
ra n d omizat i on i nf or mati on will  be st ore d i n a sec ure d area, acce ssi ble o nl y b y a ut h orize d 
pers o n nel.
8. 4
I n vesti g ati o n al Dr u g Bli n d M ai nte n a nce 
T he i n vest i gati o nal dr u g bli n d is mai ntai ne d t hr o u g h a ra n d omizat i on sc he d ule hel d b y t he 
di s pe nsi n g p har macist a n d t he ra n d o mizat i on stati sticia n.
8. 4. 1
U n bli n di n g Pr oce d ure
T he i n vest i gati o nal dr u g bli n d s hall n ot be br o ke n b y t he i n vesti gat or u nless i nf or mati on 
c o ncer ni n g t he i n vest i gati onal dr u g is necessar y f or t he me dical treat me nt of t he s u bject. All st u d y 
assess me nts a n d ca usalit y s h o uld be perf or me d, if p ossi ble, pri or t o u n bli n di n g. I n t he e ve nt of a 
me dical e mer ge nc y, if p ossi ble, t he me dical m o nit or or desi g nee s h o ul d be c o ntacte d bef ore t he 
i n vesti gati onal dr u g bli n d is br o ke n t o disc uss t he nee d f or u n bli n di n g.
T he s p o ns or m ust be n otifie d as s o o n as p ossi ble if t he i n vesti g atio n al  dr u g bli n d is br o ke n. T he 
date, ti me, a n d reas o n t he bli n d is br o ke n m ust be rec or de d i n t he s o urce d oc u me nts a n d t he sa me 
i nf or mat i on (e xce pt t he ti me) m ust be rec or de d o n t he e C R F.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 6 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
If a n y site pers o n nel are u n bli n de d, i n vesti gati onal dr u g m ust be st o p pe d i m me diatel y a n d t he 
s u bject m ust be wit h dra w n fr o m t he st u d y.
N o c ha n ge s h o ul d be ma de t o a n y  assess me nt of t he s u bject after u n bli n di n g.
8. 5
Acc o u nt a bilit y a n d Destr ucti o n of S p o ns or- S u p plie d Dr u gs
Dr u g s u p plies will be c o u nte d a n d rec o ncile d at t he site bef ore bei n g ret ur ne d t o t he s p o ns or or 
desi g nee.
T he i n vest i gat or or desi g nee m ust e ns ure t hat t he s p o ns or-s u p plie d dr u gs are use d i n acc or da nce 
wi t h t he pr ot oc ol a n d is dis pe nse d o nl y t o s u bjects e nr olle d i n t he st u d y. T o d oc u me nt a p pr o priate 
use of s p o ns or-s u p plie d dr u g ( T A K-0 4 1 a n d matc he d pl ace b o), t he i n vest i gat or or desi g nee m ust 
mai ntai n rec or ds of all s p o ns or -s u p plie d dr u g deli ver y t o t he sit e, site i n ve nt or y, dis pe nsati on a n d 
use b y eac h s u bject, a n d ret ur n t o t he s p o ns or or desi g nee.
U p o n re cei pt of s p o ns or -s u p plie d dr u g, t he i n vest i gat or or desi g nee m ust verif y t he c o nte nts of t he 
s hi p me nts a gai nst t he pac ki n g list. T he verifier s h o ul d e ns ure t hat t he q ua ntity is c orrect, a n d t he 
me dicat i on is i n g o o d c o n dit i on. I f q ua ntity a n d c o n dit i ons ar e acce pta ble, i n vest i gat or or desi g nee 
s h o uld ac k n o wl e d ge t he receipt of  t he s hi p me nt b y sig ni n g b ott o m  half of t he pac ki n g list a n d 
e maili n g per i nstr ucti o ns pr o vi de d o n t he f or m. If t here are a n y discre pa ncies bet wee n t he pac ki n g 
list vers us t he act ual pr o d uct recei ve d, Ta ke da m ust be c o ntacte d t o res ol ve t he iss ue. T he pac ki n g 
list s h o ul d be file d i n t he i n vesti gat or’s esse ntial d o c u m e nt file.
T he i n vest i gat or or desi g nee m ust mai ntai n 1 0 0 % acc o u nta bility f or all s p o ns or-s u p plie d dr u gs 
recei ve d a n d dis pense d d uri n g his or her e ntire partici pat i on i n t he st u d y.

C o nti n u o usl y m o nit ori n g e x pirati o n dates if e x pir y date/retest date is pr o vi de d t o t he 
i n vesti gat or or desi g nee.

Fre q ue nt l y verif yi n g t hat act ual i n ve nt or y  matc hes d oc u me nte d i n ve nt or y.

Verif yi n g t h at t he lo g is c o m plete d f or t he dr u g l ot use d t o pre pare eac h d ose.

Verif yi n g t hat all c o ntai ners use d are d oc u me nte d acc uratel y o n t he l o g.

Verif yi n g t hat re q uire d fiel ds are c o m p lete d acc uratel y a n d le gi bl y.

A site re prese ntati ve or u n bli n de d p har mac y m o nit or, ot her wise u ni n v o l ve d with st u d y  
c o n d uct, will re vie w t he ra n d o mizati o n sc he d ule a n d s u bject d osi n g l o g pri or t o Da y 1 f or all 
C o h orts/ Peri o ds d osi n g a n d f o ll owi n g d osi n g t o e ns ure all s u bjects recei ve d t he c orrect d ose of 
st u d y me dicat i on.

If a n y dis pe nsi n g err ors or discre pa ncies are disc o vere d, t he s p o ns or m ust be n otifie d 
i m me diatel y.
T he i n vest i gat or or desi g nee m ust rec or d t he c urre nt i n ve nt or y of all s p o ns or-s u p plie d dr u gs 
( T A K-0 4 1 a n d m atc he d place b o) o n a s p o ns or -a p pr o ve d dr u g acc o u nta bilit y l og. T he f oll o wi n g 
i nf or mat i on will be rec or de d at a mi ni m u m: pr ot oc ol n u m ber a n d tit le, name of i n vest i gat or, site 
i de ntifier a n d n u m ber, descri pti on of s p o ns or -s u p plie d dr u gs, e x pir y a n d/ or retest dates, date a n d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
a mo u nt dis pe nse d, i ncl u di n g i nit ials, seal, or si g nat ure of  t he pers o n dis pe nsi n g t he dr u g, a n d t he 
date a n d a m o u nt ret ur ne d t o t he site b y t he s u bject, i ncl u di n g t he i nitials of t he pers o n recei vi n g t he 
s p o ns or-s u p plie d dr u g. T he l o g s h o ul d i ncl u de all re q uire d i nf or mat i on as a se parate e ntr y f or eac h 
s u bject t o w h o m s p o ns or-s u p plie d dr u g is dis pe nse d.
Pri or t o si t e clos ure or at a p pr o pri ate i nter vals, a re prese ntati ve fr o m t he s p o ns or or its desi g nee 
will perf or m s p o ns or-s u p plie d dr u g acc o u nta bilit y a n d rec o nciliat i on bef ore s p o ns or-s u p plie d 
dr u gs are ret ur ne d t o t he s p o ns or or its desi g nee f or destr ucti o n. T he i n vest i gat or or desi g nee will 
retai n a c o p y of t he d oc u me nt atio n re gar di n g s p o ns or-s u p plie d dr u g acc o u nta bilit y,  ret ur n, a n d/ or 
destr ucti o n, a n d ori gi nals will be se nt t o t he s p o ns or or desi g nee.
T he i n vest i gat or will be n otifie d of a n y e x pir y date or retest date e xte nsi on of s po ns or -s u p plie d 
dr u g d uri n g t he st u d y c o n d uct. O n e x pir y date n otificat i on fr o m t he s p o ns or or desi g nee, t he site 
m ust c o m plete all  instr ucti o ns o utli ne d i n t he n otificati o n, i ncl u di n g se gre gat i on of e x pire d 
s p o ns or-s u p plie d dr u g f or ret ur n t o t he s p o ns or or its desi g nee f or destr ucti o n.
I n t he e ve nt of e x pir y date e xte nsi on of s u p plies alrea d y  at t he st u d y sit e, s p o ns or-s u p plie d dr u gs
ma y be rela bele d wit h t he ne w e x pir y date at t hat site. I n s uc h cases, Ta ke da or its desi g nee will 
pre pare a d dit i onal la bels , certificates of a nal yses, a n d all necessar y d oc u me ntati o n f or c o m pleti on 
of  t he pr oce d ure at t he sites.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 0
S T U D Y P L A N
9. 1
St u d y Pr oce d ures
T he f o ll owi n g sect i ons descri be t he st u d y pr oce d ures a n d data t o be c ollecte d. F or eac h pr oce d ure, 
s u bjects are t o be assesse d b y t he sa me i n vesti gat or or site pers o n nel w he ne ver p ossi ble. T he 
Sc he d ules of St u d y  Pr oce d ures are locate d i n A p pe n di x A , A p pe n di x B , A p pe n di x C a n d 
A p pe n di x D a n d A p pe n di x E f or Parts 1, 2, 3, a n d 4 res pecti vel y, of t he st u d y.
9. 1. 1
I nf or me d C o nse nt Pr oce d ure
T he re q ui re me nts of t he i nf or me d c o nse nt are descri be d i n Secti on  1 5. 2 .
I nf or me d c o nse nt must be o btai ne d pri or t o t he s u bject e nteri n g i nt o t he st u d y , a n d before a n y 
pr ot oc ol -di recte d pr oce d ures are perf or me d, i ncl u di n g re q uesti n g t hat a s u bject fast f or la b orat or y 
e val uat i ons.
P arti cip ati o n i n t he weara ble de vice st u d y  c o mp o ne nt is o pti o nal f or t he st u d y  s u bjects.
A u ni q ue s u bject i de nt ificati on n u m ber (s u bject n u m ber) will be assi g ne d t o eac h s u bject at t he 
ti me t hat i nf or me d c o nse nt is o btai ne d; t his s u bject n u m ber will be use d t hr o u g h o ut t he st u d y.
9. 1. 1. 1
P h ar m ac o ge n o mic I nf or me d C o nse nt Pr oce d ure
P har mac o ge n o mics i nf or me d c o nse nt is a c o mp o ne nt of t he o verall st u d y  inf or me d c o nse nt. T he 
re q uire me nts are descri be d i n Secti o n 1 5. 2 .
T he p har mac o g e n o mic sa m ple c o llecti on is ma n dat or y .
9. 1. 2
De m o gr a p hics, Me dic al Hist or y, a n d Me dic ati o n Hist or y Pr oce d ure
D e m o gra p hic i nf or mat i on t o be o btai ne d will i ncl u de date of birt h, se x, His pa nic et h nicit y,  a n d 
race as descri be d b y t he s u bject, alc o h ol a n d caffei ne hist or y, a n d s mo ki n g stat us of t he s u bject at 
Scree ni n g.
Me dical hist or y  t o be o btai ne d will i ncl u de deter mi ni n g w het her t he s u bject has a n y si g nifica nt 
c o n ditio ns or di seases rele va nt t o t he disease t hat st o p pe d at or pri or t o si g ni n g of t he i nf or me d 
c o nse nt. O n g oi n g c o n dit i ons are c o nsi dere d c o nc urre nt me dical c o n dit i ons (see Secti o n 9. 1. 8 ).
Me dicat i on hist or y  inf or mat i on t o be o btai ne d i ncl u de s a n y me dicati on rel e va nt t o eli gi bilit y 
criteria st o p pe d at or wit hi n 2 8 da ys pri or t o si g ni n g of i nf or me d c o nse nt.
9. 1. 3
P h ysic al E x a mi n ati o n Pr oce d ure a n d Ne ur ol o gic al E x a mi n ati o n
A p h ys ical e xa mi nati on will c o nsist of t he f o ll owi n g b o d y  s yste ms: ( 1) e yes; ( 2) ears, n ose, t hr oat; 
( 3) car dio vasc ular s yste m; ( 4) res pirat or y  s yste m; ( 5) gastr oi ntesti nal s yste m; ( 6) der mat ol o gic 
s yste m; ( 7) e xtre mities; ( 8) m usc ul os keletal s yste m; ( 9) ner v o us s yste m; ( 1 0) l y m p h n o des; a n d 
( 1 1) ot her.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
As part of t he p h ysical e xa mi n at i on, ne ur o l ogi cal assess me nts will be i ncl u de d o n t he 
Ne ur ol o gi cal E xa m e C R F a n d i nclu de ( 1) Basic Me ntal  Stat us; ( 2) Cra nial ner ves II-XII; 
( 3) M ot or e xa mi nat i on; ( 4) Dee p Te n d o n Refle xes ; ( 5) Se ns or y e xa mi nati on; ( 6) Cere bellar 
f u ncti on. T he B o n d -La der vis ual a nal o g ue scale ( V A S) ( Secti o n  9. 1. 1 3 ) a n d t he C-S S R S ( Secti o n 
9. 1. 1 4 ) will als o be a d mi nistere d.
A n y a b n or mal fi n di n g o n a pretreat me nt p h ysical e xa mi nat i on assess me nt m ust be assesse d as N ot 
Cli nicall y Si g nifica nt ( N C S) or Cli nicall y Si g nifica nt ( C S) b y t he i n vest i gat or a n d rec or de d i n t h e 
s o urce d oc u me nt a n d e C R F. All C S fi n di n gs/c ha n ges will be rec or de d as a P T E or c o nc urre nt 
me dical c o n dit i on i n t he s o urce d oc u me nt a n d o n t he a p pr o priate e C R F descri be d i n Secti o n 
1 0. 0 or Secti o n  9. 1. 8 .
O n s u bse q ue nt e xa mi nat i ons, a n y  a b n or mal c ha n ge fr o m t he pretreat me nt p h ysical e xa mi nati on 
(incl u di n g ne ur ol o gical) assess me nt occ urri n g i m me diatel y pri or t o t he start of t he i n vest i gati o nal
dr u g ( Da y  -1) m ust be assesse d as N C S or C S b y  t he i n vesti gat or a n d rec or de d i n t he s o urce 
d oc u m e nt a n d e C R F. A n y C S c ha n ge or ne w dia g n osis as a res ult of a C S c ha n ge, as deter mi ne d 
b y t he i n vest i gat or, will be rec or de d as a n A E i n s o urce d oc u me ntati o n an d o n t he P T E/ A E e C R F 
descri be d i n Secti o n 1 0. 0 .
9. 1. 4
Wei g ht, Hei g ht, a n d B MI
A s u bject s h o ul d ha ve wei g ht a n d hei g ht meas ure d w hile weari n g i n d o or cl ot hi n g a n d wit h s h oes 
off. T he B MI is calc ulate d usi n g metric u nit s wit h t he f or mula pr o vi de d bel o w:
T he Ta ke da sta n dar d f or c ollect i n g hei g ht is ce nti meters wit h o ut deci mal places a n d f or wei g ht it 
is kil o gra ms ( k g) wit h 1 deci mal place. B MI s h o ul d be deri ve d as:
Metri c:
B MI = wei g ht ( k g)/ hei g ht ( m) 2
N ote t hat alt h o u g h hei g ht is re p orte d i n ce nti meters, t he f o r mula uses meters f or hei g ht; meters ca n 
be deter mi ne d fr o m ce nt i meters b y di vi di n g b y 1 0 0. T h us, f or e xa m ple, if hei g ht = 1 7 6 c m 
( 1. 7 6 met ers) a n d wei g ht = 7 9. 2 k g, t he n B MI = 7 9. 2/ 1. 7 6 2= 2 5. 5 6 8 1 8 k g/ m 2.
T he val ues s h o ul d be re p orte d t o 1 deci mal place b y r o u n di n g. T h us, i n t he a b o ve e xa m ple B MI 
w o ul d be re p orte d as 2 5. 6 k g/ m 2. H o we ver, if t he B MI is use d as e ntr y crit eria base d o n a B MI 
bet wee n 1 8 a n d 3 2 k g/ m 2, t he n t his deter mi nati on m ust be ma de after r o u n di n g.
9. 1. 5
Vit al Si g n Pr oce d ure
Vi t al si g ns will incl u de oral  bo d y  t e mperat ure m eas ure me nt, s u pi ne a n d sta n di n g bl o o d press ure, 
res pirati on rate, a n d p ulse ( beats per mi n ute). P ulse a n d bl o o d press ure will be m eas ure d after 
5 mi n utes s u pi ne a n d a gai n at 1 a n d 3 mi n utes after sta n di n g f or all sc he d ule d ti me p o i nts.
Vi t al si g ns ma y be re peate d. All meas ure me nts will be rec or de d o n t he s o urce d oc u me nts a n d i n 
t he e C R F. See A p pe n di x A , B, C a n d D / E f or t he sc he d ules of vital si g n assess me nts i n Part 1 , 2, 3, 
a n d 4 res pecti vel y, of t he st u d y.
If a vital si g n is f o u n d t o be a b n or mal p ost d ose, it ma y be c ollecte d e ver y 3 0 mi n utes if cli nicall y 
sig nifica nt.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 7 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Vit al si g ns s h o ul d b e meas ure d at t he sa me ti me of  t he da y acr oss visits, if p ossi ble. W he n 
p ost d ose vital si g ns are sc he d ule d at t he sa me ti me as bl o o d dra ws, t he bl o o d dra w will ta ke 
pri orit y a n d vit al si g ns will be o btai ne d wit h i n 0. 5 h o ur bef ore or after t he sc he d ule d bl o o d dra w.
9. 1. 6  
We ar a ble De vice Pr oce d ure
9. 1. 7  
D oc u me nt ati o n of C o nc o mit a nt Me dic ati o ns
C o nc o mita nt me dicati o n is a n y dr u g gi ve n i n a d di ti o n t o t he st u d y me dicati o n. T hese ma y be 
prescri be d b y a p h ysicia n or o btai ne d b y t he s u bject o ver t he c o u nter. C o nc o mita nt me dicati o n is 
n ot pr o vi de d b y Ta ke da. At eac h st u d y visit, s u b jects will be as ke d w het her t he y ha ve ta ke n a n y 
me dicati o n ot her t ha n t he st u d y me dicati o n ( use d fr o m si g ni n g of i nf or me d c o nse nt t hr o u g h t he 
e n d of t he st u d y), a n d all me dicati o n i ncl u di n g vita mi n s u p ple me nts, o ver-t he-c o u nter me dicati o ns, 
a n d oral her bal pre parati o ns, m ust be rec or de d i n t he e C R F. D oc u me ntatio n will i ncl u de ge neric 
me dicati o n na me, d ose, u nit, fre q ue nc y, r o ute of a d mi nistrati o n, start a n d e n d dates, a n d reas o n f or 
use.
9. 1. 8  
D oc u me nt ati o n of C o nc urre nt Me dic al C o n diti o ns
C o nc urre nt me dical c o n diti o ns are t h ose si g nifica nt o n g oi n g c o n diti o ns or diseases t hat are prese nt 
at si g ni n g of i nf or me d c o nse nt. T his i ncl u des cli nicall y si g nifica nt la b orat or y, E C G, or p h ysical 
e xa mi nati o n a b n or malities n ote d at scree ni n g a n d/ or Baseli ne ( Da y - 1) e xa mi nati o n. T he 
c o n diti o n (ie, dia g n osis) s h o ul d be descri be d.
9. 1. 9 
Pr oce d ures f or Cli nic al L a b or at or y S a m ples
All sa m ples will be c ollecte d i n acc or da nce wit h acce pta ble la b orat or y pr oce d ures. La b orat or y 
sa m ples will be ta ke n f oll o wi n g a n o ver ni g ht fast of at least 8 h o urs o n t he da ys sti p ulate d i n t he 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al
mit a nt
mit a n
dr u g gi v
dr u g 
o btai ne
btai n
At eac h 
t eac h
t he st u d y
he st u d
n d all me
all m
re parat
e parat i o
a me, d ose
me, d o
D oc u
D oc
o nc urre n
o nc urre
at si
at s g n
e xa m
e x
c
er m s of U s e
w.
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Sc he d ules of St u d y  Pr oce d ures ( A p pe n di x A, B, C, a n d D / E f or Part 1, 2, 3 a n d 4 res pecti vel y, of 
t he st u d y.
Ta ble 9. a lists t he tests t hat will be o btai ne d f or eac h la b orat or y s peci me n.
T a ble 9. a
Cli nic al L a b or at or y Tests
He m at ol o g y
Ser u m C he mistr y
Uri n al ysis
Re d bl o o d cells ( R B C)
W hite bl o o d cells
( W B C) wit h 
differe ntial 
He m o gl o bi n
He mat ocrit
Platelets
P T/I N R
a P T T
A L T
Al b u mi n
Al kali ne p h os p hatase
A S T
T otal bilir u bi n
Direct bilir u bi n
T otal pr otei n
Creati ni ne
Bl o o d urea nitr o ge n ( B U N)
Creati ne ki nase 
- Gl uta m yl tra nsferase ( G G T)
P otassi u m
S o di u m
Gl uc ose
C hl ori de
Bicar b o nate
Calci u m
T otal ser u m c h olester ol
Tri gl yceri des
e G F R
5’- n ucle oti dase
Bile aci ds
p H
S pecific gra vit y
Pr otei n
Gl uc ose
Bl o o d 
Nitrite
Le uc oc yte esterase
Os m olalit y
Micr osc o pic A nal ysis ^ :
R B C/ hi g h p o wer fiel d
W B C/ hi g h p o wer fiel d
E pit helial cells, casts, etc.
^ T o be perf or me d if a b n or mal
Di a g n ostic Scree ni n g:
Ser u m
Uri ne/ Bl o o d
A nti ps yc h otic me dicati o n le vel ( perf or me d at Scree ni n g , 
Da y  2 1 a n d Da y 5 0. )
Dr u g scree n, i ncl u di n g a m p heta mi nes, bar bit urates, 
be nz o diaze pi nes, ca n na bi n oi ds, c ocai ne, o piates, alc o h ol, 
a n d c oti ni ne
He patitis pa nel, i ncl u di n g H Bs A g a n d a nti -H C V
Fe male s u bjects o nl y:
h u ma n c h ori o nic g o na d otr o pi n ( h C G) f or pre g na nc y
F ollicle -sti m ulati n g h or m o ne (F S H )
if me n o pa use is s us pecte d a n d s u bject is n ot s ur gicall y 
sterile
a P T T =acti vate d Partial T hr o m b o plasti n Ti me, e G F R =esti mate d gl o mer ular filtrati o n rate, P T = pr ot hr o m bi n ti me, 
I N R =i nter nati o nal n or malize d rati o.
T he l o c al  la b orat or y will p erfor m  la b orat or y tests f or he mat olo g y , ser u m c he mistries, a n d 
uri nal ysis. T he res ults of la b orat or y tests will be ret ur ne d t o t he i n vest i gat or, w h o is res p o nsi ble f or 
re vie wi n g a n d fili n g t hese res ults.
If s u bjects e x perie nce a n y of t he f oll owi n g:
1.
A L T or A S T > 3 × U L N
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
2.
A L P el e vat i ons > 1. 5 × U L N i n c o nj u nct i on wi t h ele vate d t otal bilir u bi n > 1. 5 × U L N or 
ele vate d 5’ n ucle oti dase > 1. 5 × U L N or ele vate d G G T > 5 x U L N or ele vate d A S T/ A L T > 1. 5 × 
U L N A L P > 2 × U L N persist i n g f or lo n ger t ha n 3 da ys
3.
A L P > 3 × U L N
f oll ow- u p l a b orat or y tests (at a mi ni m u m, ser u m A L P, A L T, A S T, t otal bilir u bi n, GG T, 
5’- n ucle oti dase, I N R, a n d t he s pecific assess me nt t hat meets o ne of t hese criteria if n ot i n t his list) 
s h o uld be perf or m e d wit hi n a ma xi m u m of 7 da ys a n d prefera bl y wit hi n 4 8-7 2 h o urs after t he 
a b n or malit y was n ote d.
Pl ease refer t o Secti o n  7. 5 f or disc o nti n uati on cri t eria, a n d Secti o n 1 0. 2. 3 f or t he a p pr o priate 
g ui da nce o n Re p orti n g of A b n or mal Li ver F u nct i on Tests i n relat i on t o t he ele vate d li ver e nz y me 
val ues liste d a b o ve. I nit iate close o bser vat i on f or s u bjects e nr olle d wit h Baseli ne ele vati ons i n 
li ver e nz y mes t hat are n ot > 3 × U L N, yet  w orse n b y 2-f ol d i ncreases a b o ve Baseli ne val ues after 
st u d y dr u g e x p os ure.
If t he A L T, A S T, or A L P re mai ns ele vate d > 3 × U L N o n t hese 2 c o nsec uti ve occasi ons, t he 
i n vesti gat or m ust c o ntact t he Me dical M o nit or f or c o nsi derati o n of a d diti onal test i n g, close 
m o nit ori n g, p ossi ble disc o nt i n uati on o f stu d y me dicati o n, disc ussi o n o f the rele va nt s u bject details 
a n d p ossi ble alter nat i ve eti ol ogi es. T he a b n or malit y s ho ul d be rec or de d as a n A E ( please refer t o 
Secti o n  1 0. 2. 3 Re p orti n g of A b n or mal Li ver F u ncti o n Tests f or re p orti n g re q uire me nts).
All la b orat or y safety data will be tra nsferre d electr o nicall y t o Ta ke da or desi g nee i n t he f or m 
s pecifie d b y Ta ke da. T he i n vest i gat or will mai ntai n a c o p y of t he la b orat or y accre dit atio n a n d 
a p plica ble refere nce ra n ges f or t he la b orat or y  use d.
La b orat or y  re p orts must be si g ne d a n d date d b y  t he pri nci pal i n vesti gat or or s u bi n vesti gat or 
i n dicati n g t hat t he re p ort has bee n re vie we d a n d a n y a b n or malit ies ha ve bee n assesse d f or cli nical 
sig nifica nce. A n y  a b n or malities i de nt ifie d pri or t o first d ose will re q uire clear a n d c om p lete 
d oc u m e nt atio n i n t he s o urce d oc u me nts as t o t he i n vesti gat or’s assess me nt of n ot cli nicall y 
sig nifica nt bef ore pr ocee di n g wit h e nr oll me nt/ra n d o mizat i on.
All cli nicall y si g nifica nt la b orat or y a b n or malities m ust be rec or de d as a P T E/ A E i n t he s u bject’s 
s o urce d oc u me nts a n d o n t he a p pr o priate e C R F. A cli nicall y si g nifica nt la b orat or y a b n or mality 
that has bee n verifie d b y retesti n g will be f o ll owe d u ntil t he a b n or malit y ret ur ns t o a n acce pta ble 
le vel or a satisfact or y e x pla nati on has bee n o btai ne d.
9. 1. 9. 1
Re n al F u ncti o n
I n a d diti on t o t he c o m m o n la b orat or y  tests of kid n e y  fu n cti o n ( B U N, creati ni ne, uri nal ysis), a n d 
e G F R will be deter mi ne d i n all st u d y parts, see Ta ble 9. a . F or t he Sc he d ule of Pr oce d ures, see 
A p pe n di x A, B, C a n d D / E f or Part 1, 2, 3 a n d 4, res pecti vel y.
9. 1. 1 0
C o ntr ace pti o n a n d Pre g n a nc y A v oi d a nce Pr oce d ure
Fr o m  si g ni n g of i nf or me d c o nse nt, t hr o u g h o ut t he d urati o n of t he st u d y, a n d f or a peri o d of 
1 4 5 d a y s (ie, 9 0 d a y s after 5 half-li ves) after t he last d ose of st u d y dr u g, n o nsterilize d * * male 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
s u bjects w h o are se x uall y act i ve wit h a fe male part ner of c hil d beari n g p ote ntial * m ust use barrier 
c o ntrace pti o n (e g, c o n d o m wit h s per mici dal crea m or jell y). I n a d dit i on, t he y  must be a d vise d n ot 
t o d o nate s per m d uri n g t his peri o d.
* Fe males N O T of c hil d beari n g p ote ntial are defi ne d as t h ose w h o ha ve bee n s ur gicall y sterilize d 
( h ysterect o m y, bilateral o o p h orect o m y or t u bal li gati o n) or w h o are p ost me n o pa usal (e g, defi ne d 
as at least 2 years si nce last re g ular me nses wit h a n F S H > 4 0 I U/ L or at least 5 y ears si nce last 
re g ular me nses, c o nfir me d bef ore a n y st u d y me dicatio n is i m ple me nte d).
* * Sterilize d males s h o ul d be at least 1 y ear p ost vasect o m y a n d ha ve c o nfir me d t hat t he y ha ve 
o btai ne d d oc u me ntati o n of t he a bse nce of s per m i n t he ejac ulate.
A n acce pta ble met h o d of c o ntrace pti o n is defi ne d as o ne t hat has n o hi g her t ha n a 1 % fail ure rate. 
I n t his st u d y, w here me dicati ons a n d de vices c o ntai ni n g h or m o nes are e xcl u de d, t he o nl y 
acce pta ble met h o ds of c o ntrace pti o n are barrier met h o ds f or male s u bjects w h o are se x uall y acti ve 
wi t h a fe male part ner of c hil d beari n g p ote ntial:
B arrier met h o ds (e ac h ti me t he s u bject h as i nterc o urse):

Male c o n d o m P L U S s per mici de.

Ca p ( pl us s per mici dal crea m or jell y) P L U S male c o n d o m a n d s per mici de.

Di a p hra g m ( pl us s per mici dal crea m or jell y) P L U S male c o n d o m a n d s per mici de.
F or fe male s u bjects, oral c o ntrace pti ves are pr o hi bite d f or 3 0 da ys pri or t o C hec k -i n ( Da y -2) u ntil 
5 5 da y s (ie, 5 half -li ves) after t he last d ose of st u d y dr u g.
S u bjects will be pr o vi de d i nf or mat i on o n acce pta ble met h o ds of c o ntrace pti o n as part of t he 
s u bject i nf or me d c o nse nt pr ocess a n d will be as ke d t o si g n a c o nse nt f or m stati n g t hat t he y 
u n dersta n d t he re q uire me n ts for a v oi da nce of pre g na nc y, d o nati o n of o va, a n d s per m d o nati o n
d uri n g t he c o urse of t he st u d y .
I n a d diti on t o a ne gat i ve ser u m h C G pre g na nc y test at Scree ni n g, fe male s u bjects als o m ust ha ve a 
ne gat i ve ser u m h C G pre g na nc y test o n Da y - 2 a n d St u d y E xit/Earl y  Ter mi nati on f or all st u d y 
parts.
I n a d diti on, m ale s u bjects must be a d vise d n ot t o d o nate s per m fr o m si g ni n g of i nf or me d c o nse nt 
u nt il 1 4 5 da ys (ie, 9 0 da ys after 5 half-li ves) ha ve ela pse d si nce t he last d ose of st u d y dr u g.
9. 1. 1 1
Pre g n a nc y
W o me n of c hil d b eari n g p ote ntial will n ot be i ncl u de d i n t his st u d y.
T here are n o n o ncli nical terat o ge nicit y/ fet ot o xicit y data o n T A K-0 4 1 as n o e m br y o- fetal 
de vel o p me nt t o xicit y st u dies ha ve bee n c o n d ucte d wit h t he c o m p o u n d. Base d o n t he res ults of 
n o ncli nical t o xicit y stu di es, T A K-0 4 1 was n ot m uta ge nic or cl ast o ge nic.
As s uc h , t he effect of T A K-0 4 1 o n fetal  de velo p me nt is u n k n o w n at t his ti me. T A K -0 4 1 has n ot 
bee n a d mi nistere d t o w o me n w h o are pre g na nt or lactati n g. N o n o ncli nical re pr o d ucti ve a n d 
de vel o p me ntal t o xicit y st u dies ha ve bee n c o n d ucte d. T A K -0 4 1 s h o ul d n ot be a d mi nistere d t o 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
pre g na nt or l actati n g w o me n at t his sta ge i n de vel o p m e nt. Base d o n t his, it is rec o m me n de d t hat 
w o m e n of c hil d beari n g p ote ntial be e xcl u de d fr o m t his st u d y. Male s u bjects w h o are se x uall y 
acti ve with a w o m a n of c hil d beari n g p ote ntial s h o ul d use a hi g hl y effecti ve met h o d of 
c o ntrace pti o n ( < 1 % fail ure rate/ year), w hic h has lo w  user de pe n de nc y w hile partici pati n g i n t his 
st u d y (see Secti on  9. 1. 1 0 ). T hese re q uire me nts will a p pl y d uri n g treat me nt a n d f or a peri o d of 
1 4 5 d a y s (ie, 9 0 da ys after 5 half-li ves) da ys after t he last d ose of st u d y dr u g.
If a n y s u bject is f o u n d t o be pre g na nt d uri n g t he st u d y s he s h o uld be wi t hdra w n a n d a n y 
s p o ns or-s u p plie d dr u g s h o ul d be i m me diatel y disc o nti n ue d. I n a d dit i on, a n y pre g na ncies i n t he 
part ner of a male s u bject d uri n g t he st u d y  or 1 4 5 da ys (ie, 9 0 da ys after 5 half-li ves) after t he last 
d ose of st u d y  dr ug, s h o ul d als o be rec or de d f oll o wi n g a ut h orizat i on fr om t he s u bject’s part ner.
If the pre g na nc y occ urs d uri n g a d mi nistrati o n of acti ve st u d y me dicat i on, e g, after Da y 1 or wit hi n 
1 4 5 da ys (ie, 9 0 da ys after 5 half -li ves) ha ve ela pse d si nce t he last d ose of act i ve st u d y me dicati on, 
t he pre g na nc y s h o ul d be re p orte d i m me diatel y, usi n g a pre g na nc y n otificat i on f or m, t o t he c o ntact 
liste d i n Secti o n 1. 0 .
S h o ul d t he pre g na nc y  occ ur d uri n g or after a d mi nistrati o n of bli n de d dr u g, t he i n vesti gat or m ust 
i nf or m t he s u bject of t heir ri g ht t o recei ve treat me nt i nf or mati o n. If t he s u bject c h o oses t o recei ve 
u n bli n de d treat me nt i nf or mat i on, t he i n di vi d ual bli n d s h o ul d be br o ke n b y t he i n vest i gat or. 
S u bjects ra n d o mize d t o place b o nee d n ot be f o ll owe d.
If t he fe male part ner of a male s u bject a grees t o t he pri mar y care p h ysicia n bei n g i nf or me d, t he 
i n vesti gat or s h o ul d n otif y t he pri mar y care p h ysicia n t hat t he male part ner was partici pati n g i n a 
cli nical st u d y at t he ti me s he beca me pre g na nt a n d pr o vi de details of treat me nt t he s u bject recei ve d 
( bli n de d or u n bli n de d, as a p plica ble).
All re p orte d pre g na ncies will be f o ll owe d u p t o fi nal o utc o me, usi n g t he pre g na nc y f or m. T he 
o utc o m e, i ncl u di n g a n y pre mat ure ter mi nati on, m ust be re p orte d t o t he s p o ns or. A n e val uat i on 
after t he birt h of t he c hil d will als o be c o n d ucte d.
9. 1. 1 2
E C G Pr oce d ure
A sta n dar d 1 2 -lea d E C G will be rec or de d. T he i n vesti gat or ( or a q ualifie d o bser ver at t he 
in vesti gat i onal site) will i nter pret t he E C G usi n g o ne of t he f o ll owi n g cate g ori es: wit hi n n or mal 
li mits, a b n or mal b ut n ot cli nicall y si g nifica nt, or a b n or mal a n d cli nicall y si g nifica nt. T he 
f oll owi n g para meters will be rec or de d o n t he e C R F fr o m t he s u bject ’s E C G trace: heart rate, P R 
i nter val, Q T i nter val, Q R S i nter val, a n d Q T c, a n d Q Tc F.
All st atio nar y  1 2-lea d E C G mac hi nes will be s u p plie d b y t he site. S u bjects s h o ul d be i n a s u pi ne 
p osi tio n f ol l owi n g a n a p pr o xi mate 1 0 -mi n ute rest peri o d f or E C G rec or di n gs . S h o uld tec h nical 
diffic ult ies occ ur d uri n g rec or di n g of t he E C G, a reas o na ble atte m pt s h o ul d be ma de t o re peat t he 
E C G s h ortl y after t he faile d atte m pt.
E C G res ults (i ncl u di n g electr o nic traci n g) will be ca pt ure d electr o nicall y a n d re vie we d i n t he site’s
ele ctr o nic s o urce data s yst e m, Cli n Base, a n d n ot pri nte d. E C Gs ca n be pri nte d if nee de d.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 7 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
E C Gs will be a d mi nistere d acc or di n g t o t he sc he d ules i n all stu d y  parts as s h o w n i n A p pe n di x A, B, 
C a n d D/ E . Si n gle E C Gs will be ta ke n at all ti me p oi nts.
C o nti n u o us 1 2- lea d H olter E C G m o nit ori n g will als o be c o n d ucte d i n Part 2 o nl y  fr om Da y -1 u ntil 
2 4 h o urs p ost d ose o n Da y  1. Triplicate 1 2 -lea d E C Gs will be e xtracte d fr o m t he H -1 2 flas h car d 
a p pr o xi matel y 1 mi n ute a part fr o m o ne a n ot her (f or eac h ti me p oi nt, tri plicate E C Gs wit h 1 0 sec. 
e xtractio n) at t he f oll o wi n g ti me p oi nts: Da y  -1 ( 2 3, 2 2, 2 0, 1 6, 1 2 h o ur bef ore d osi n g), a n d Da y  
1 i m me diatel y bef ore d osi n g [ 0 hr, wit hi n 4 5 mi n of d osi n g], a n d at 1, 2, 4, 8, 1 2, a n d 2 4 h o urs 
p ost d ose. A wi n d o w of ± 1 0 mi n utes ar o u n d eac h sc he d ule d t i me p oi nt ca n be utilize d i n or der f or 
t he ce ntral rea der t o o btai n t he necessar y E C Gs. H ol ter rec or di n gs will be als o st ore d b y Ta ke da, 
use d f or a d dit i onal a nal yses, a n d ma y be se nt t o a ce ntral E C G a nal ysis la b orat or y f or retr os pecti ve
e x pert re vie w a n d est i mati on of E C G i nter vals at a n a p pr o priate ti me f or t he T A K -0 4 1 pr o gra m  
d uri n g or after c o m plet i on of t he prese nt st u d y .
W he n a n E C G is sc he d ule d at t he sa me ti me as bl o o d dra ws or vital si g ns, t he n t he bl o o d dra ws 
a n d vital si g ns will ta ke pri orit y a n d t he E C G will be o btai ne d wit hi n 0. 5 h o ur bef ore or after t he 
sc he d ule d bl o o d dra w/ vital si g n assess me nt. If a n E C G c oi nci des wit h a m eal, E C G will ta ke 
prece de nce f o ll owe d b y t he meal.
9. 1. 1 2. 1 H olter E C G M o nit ori n g ( P art 2, He alt hy S u bject C o h orts)
T o e ns ure hi g h -q ualit y data rec or di n g, pri or t o electr o de place me nt, t he a nat o mical sites m ust be 
pre pare d t o all o w f or pr o per s ki n/electr o de i nterface. A n y hair o n t he electr o de sites m ust be 
s ha ve n. A n y oils, loti o ns, or dea d s ki n s h o ul d be re m o v e d fr o m t he electr o de sites usi n g a n 
a brasi ve alc o h o l pre p pa d desi g ne d f or t his p ur p ose. A n i n deli ble s ki n mar ker m ust be use d t o 
mar k t he e xact electr o de place me nt site s o t hat t he electr o de p osit i ons will re mai n c o nsta nt 
t hr o u g h o ut eac h treat me nt peri o d. T he electr o des s h o ul d al wa ys be attac he d t o t he H olter 
c o n necti n g ca ble pri or t o s ki n place me nt.
All H olter rec or di n gs will be o btai ne d o n 1 0 0 0 s ps flas h car ds usi n g a 1 2 -lea d H olter rec or der. T he 
flas h car ds will be c o uriere d t o t he ce ntral car diac c ore lab orat or y . Alter nati vel y, H olter rec or di n gs 
will be di gitall y  tra ns mitte d t o t he ce ntral car diac c ore la b orat or y, as a p pr o priate.
Eac h 1 2 -lea d H olter E C G ac q uisit i on wi n d o w will be a p pr o xi matel y 1 0 mi n utes i n d urat i on, fr o m 
w hic h car diac data a nal ysis la b orat or y will e xtract 1 0- sec o n d E C Gs i n tri plicate. T his wi n d o w will 
be prece de d b y  1 0 mi n utes of q uiet s u pi ne rest.
S u bjects will be s u per vise d w hile re mai ni n g at rest, q uiet, a wa ke, a n d i n a s u pi ne p osit i on fr o m at 
least 1 0 mi n utes pri or t o t he be gi n nin g of  eac h E C G e xtractio n ti me p oi nt a n d will re mai n q uiet, 
a wa ke, moti o nless, a n d s u pi ne f or at least 1 0 mi n utes after t he be gi n ni n g of eac h E C G e xtracti o n 
ti me p oi nt.
E C Gs deri ve d fr o m H ol t er mo ni t ori n g are n ot i nte n de d t o be a nal yze d f or real-ti me safety 
m o nit ori n g b ut m a y be use d f or f ut ure retr os pecti ve E C G a nal yses, u nless a n earlier a nal ysis is 
warra nte d b y  e mer gi n g safet y inf or m at i on.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 7 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 3 
B o n d- L a der Vis u al A n al o g ue Sc ale
T he B o n d- La der V A S will be a d mi nistere d at desi g nate d ti me p oi nts s h o w n i n A p pe n di x D.
B o n d- La der V A S of M o o d a n d Alert ness [ 1 3] c o nsists of a q uesti o n naire of 1 6 a nal o g ue scales 
t hat deri ve 3 fact ors t hat assess c ha n ge i n Self- Rate d Alert ness, Self- Rate d Cal m ness, a n d 
Self- Rate d C o nte nt me nt. It has pr o ve n se nsiti vit y t o a wi de ra n ge of c o m p o u n ds. I n t he ori gi nal 
versi o ns, rati n gs were perf or me d b y t he s u bject b y mar ki n g a p oi nt o n a 1 0 c m li ne t hat is mea nt t o 
re prese nt t he f ull ra n ge of t he partic ular di me nsi o n (f or e xa m ple, alert- dr o ws y). Ni ne ite ms assess 
alert ness, 5 ite ms assess c o nte nte d ness, a n d 2 ite ms assess cal m ness.  A mar k o n t he far left si de or 
far ri g ht si de of t he scale re prese nts e xtre mes wit h re gar d t o t he a djecti ves o n eac h si de of t he li ne 
(e g, a hi g her or m ore ri g ht war d sc ore o n a scale mar ke d a wa ke — dr o ws y i n dicates t hat t he s u bject 
feels dr o wsier).
W he n B L- V A S assess me nts are sc he d ule d at t he sa me ti me as bl o o d dra ws, vital si g ns, or E C Gs, 
t he y will be c o m plete d wit hi n 2 h o urs bef ore or after t he bl o o d dra ws, vital si g ns, a n d E C Gs.
I n t his st u d y, t he B o n d- La der V A S is c o nsi dere d a safet y meas ure.
9. 1. 1 4  
C- S S R S
S uici dalit y will be assesse d b y t he use of t he C- S S R S. T he C- S S R S is a 3- part scale t hat meas ures 
s uici d al i deati o n (e g, s u bject e n d orses t h o u g hts a b o ut a wis h t o be dea d or has ot her t h o u g hts of 
s uici de), i nte nsit y of i deati o n (fre q ue nc y, d uratio n, c o ntr olla bilit y, deterre nts, a n d reas o ns f or 
i deati o n), a n d s uici dal be ha vi or (act uall y, i nterr u pte d, a n d a b orte d atte m pts at s uici de) [ 1 4].
T w o versi o ns of t he C- S S R S will be use d i n t his st u d y: t he Scree ni n g/ Baseli ne C- S S R S Lifet i me 
a n d t he Si nce- Last- Visit C- S S R S. T hese will be a d mi nistere d acc or di n g t o t he sc he d ules s h o w n i n 
A p pe n di x A, B, C a n d D/ E f or Part 1, 2, 3, a n d 4, res pecti vel y.
T he C- S S R S was de vel o pe d b y researc hers at C ol u m bia U ni versit y as a t o ol t o hel p s yste maticall y 
assess s uici dal i deati o n a n d be ha vi or i n s u bjects d uri n g partici pati o n i n a cli nical trial of 
ce ntrall y- acti n g dr u gs [ 1 4]. T he C- S S R S is c o m p ose d of 3 q uesti o ns a d dressi n g s uici dal be ha vi or 
a n d 5 q uesti o ns a d dressi n g s uici dal i deati o n, wit h s u b q uesti o ns assessi n g t he se verit y. T he t o ol is 
a d mi nistere d via i nter vie w wit h t he s u bject.
9. 1. 1 5
Pr o p ert
or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
les s 
ori gi nal
ori gi n
at is mea
t is me
Ni ne ite m
Ni ne ite
n t he far 
t he fa
n eac h s
eac h s
i n dicate
n dicat
o o d dra w
o d dra
dra ws, v
dra ws,
meas ure
eas ure
S R S. T he
S. T h
s a b o ut a
a b o ut 
urati o n, c
rati o n
y , i nterr u
i nterr
use d i n 
use d i n
T hese w
T hese 
Part 1, 2
Part 1
d b y res
b y re
a n d be h
n d be h
s [ 1 4]
[ 1 4]. T
d dressi n g
dressi n
a i nter v
a i nter
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 6  
C o g niti v e Assess me nts
Pr o p
l
U s e
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 7  
Ot her Ps yc hi atric/ Ne ur o l o gic al R ati n g Sc ales
S u bjects wit h sc hiz o p hre nia ( Part 4) will als o recei ve t he MI NI, 
. A trial ma n ual descri bi n g t he pr oce d ures t o be use d wit h t hese 
assess me nts will be s u p plie d t o t he site. T hese assess me nts will be a d mi nistere d acc or di n g t o t he 
sc he d ule s h o w n i n A p pe n di x D/ E. T he assess me nts are briefl y descri be d bel o w:
9. 1. 1 7. 1  MI NI I nter n ati o n al Ne ur o psyc hi atric I ntervie w
T he MI NI I nter nati o nal Ne ur o ps yc hiatric I nter v ie w ( MI NI) is a s h ort str uct ure d dia g n ostic 
i nt er vie w de vel o pe d j oi ntl y b y ps yc hiatrists a n d cli nicia ns i n t he U nite d States a n d E ur o pe f or 
D S M-I V a n d I nter nati o nal Classificati o n of Diseases 1 0t h Re visi o n ps yc hiatric dis or ders  wit h a n 
a d mi nistrati o n ti me of a p pr o xi matel y 1 5  mi n utes, it was desi g ne d t o meet t he nee d f or a s h ort b ut 
acc urate str uct ure d ps yc h iatric i nter vie w f or m ultice nter cli nical trials a n d e pi de mi ol o g y st u dies. 
T he cli nicia n res p o nsi ble f or t he s u bject m ust a d mi nister t he MI NI [ 2 0- 2 2].
9. 1. 1 7. 2
)
Pr o p er
j e ct t o t h e a p pli c a bl e T er m s of U s e
t o t he 
t o t he
d dia g n o
dia g n
tes a n d E
s a n d 
hiatric d
atric 
meet t he n
et t he
als a n d e
s a n
NII [ 2 0- 2
[ 2 0-
)
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 8 
P h ar m ac o ge n o mic S a m ple C ollecti o n
9. 1. 1 8. 1  D N A S a m ple C ollecti o n
Pr o p e
F o
 S a m p
 S a m p
s e
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 8. 2 R N A S a m ple C ollecti o n – P art 1
9. 1. 1 8. 3 R N A S a m ple C ollecti o n – P ar t 2, P art 3 a n d P art 4
9. 1. 1 9 
P h ar m ac o ki netic S a m ple C ollecti o n
9. 1. 1 9. 1 C ollecti o n of Pl as m a f or P h ar m ac oki netic S a m pli n g
Bl o o d sa m ples ( o ne 4- m L sa m ple per sc he d ule d ti me) f or P K a nal ysis of T A K- 0 4 1 will be 
c ollecte d i nt o c hille d Vac utai ners c o ntai ni n g a ntic oa g ula nt K 2E D T A. Place b o sa m ples will n ot be 
a nal yze d b y t he bi oa nal ytical la b orat or y e xce pt 2 sa m ples per s u bject recei vi n g place b o, 1 pre d ose 
a n d t he ot her ar o u n d t he e x pecte d ti me at w hic h C ma x occ urre d (as e mer gi n g fr o m t he act ual 
meas ure me nt of t he sa m ples of t he first d ose gr o u p) t o e ns ure fr o m a safet y pers pecti ve t hat n o 
a d diti o nal s u bjects c o ul d ha ve bee n o n acti ve treat me nt . I nstr ucti o ns f or sa m ple pr ocessi n g a n d 
s hi p me nt will be pr o vi de d i n t o t he site i n t he La b orat or y Ma n ual.
S erial bl o o d s a m pl es f or deter mi nati o n of T A K- 0 4 1 i n Part 1 will be c ollecte d acc or di n g t o 
Ta ble 9. c, a n d Ta ble 9. d,  a n d i n A p pe n di x A.
Pr o p ert y of T a k e d a: F or n
ac o ki n
c o ki n
ollecti o n
lecti o
a mm ples 
ples
m
ecte d i nt o
cte d i n
nal yze d b
nal yze d
a n d t he
a n d t h
mea
me
a
e  
 of U s e
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 8 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9 . c  
C ollecti o n of Bl o o d S a m ples f or P h ar m ac o ki netic A n al ysis i n P art 1, C o h orts 
1 a n d 2
A n al yte
M atri x
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K -0 4 1
Plas ma
Da y  1 of Peri o d 1Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 0. 2 5, 0. 5, 1, 1. 5, 2, 3, 4, 8, 
1 2, 2 4, 3 6, 4 8, 7 2, a n d 9 6 h o urs p ost d ose.
T A K -0 4 1
Plas ma
Da y  1 of Peri o d 2Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 0. 2 5, 0. 5, 1, 1. 5, 2, 3, 4, 8, 
1 2, 2 4, 3 6, 4 8, 7 2, a n d 9 6 h o urs p ost d ose, a n d at eac h wee kl y 
F oll o w -u p Visit
T a ble 9 . d  
C ollecti o n of Bl o o d S a m ples f or P h ar m ac o ki netic A n al ysis i n P art 1, C o h orts 
3 t o 5
A n al yte
M atri x
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K -0 4 1
Plas ma
1
Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 0. 2 5, 0. 5, 1, 1. 5, 2, 3, 4, 8, 
1 2, 2 4, 3 6, 4 8, 7 2, a n d 9 6 h o urs p ost d ose, a n d at eac h wee kl y 
F oll o w -u p Visit ( Da y s 8, 1 5, 2 2, 2 9, 3 6 a n d 4 3).
S eri al bl o o d sa m ples f or deter mi nati on o f TA K -0 4 1 i n Part 2 a n d Part 4 will be c ollecte d acc or di n g 
t o Ta ble 9. e a n d i n A p pe n di x B f or Part 2 a n d i n A p pe n di x D a n d A p pe n di x E f or Part 4. 
T a ble 9. e  
C ollecti o n of Bl o o d S a m ples f or P K A n al ysis i n P art 2 a n d P art 4
A n al yte
M atri x
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K -0 4 1
Plas ma
1
Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 0. 5, 1, 1. 5, 2, 3, 4, 8, 1 2, 2 4, 
4 8, a n d 9 6 h o urs p ost d ose.
T A K -0 4 1
Plas ma
8 a n d 1 5
Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 1, 2 a n d 4 h o urs p ost d ose. 
T A K -0 4 1
Plas ma
2 2
Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), a n d 0. 5, 1, 1. 5, 2, 3, 4, 8, 
1 2, 2 4, a n d 4 8 h o urs p ost d ose, a n d at eac h F oll o w -u p Visit ( D a ys 2 6, 
2 9, 3 6, 4 3, 5 0, 5 7, 6 4 a n d 7 0).
S eri al blo o d s a m ples f or deter mi nat i on of T A K -0 4 1 i n P art 3 will be c ollecte d acc or di n g t o  Ta ble 
9 .f, a n d i n A p pe n di x C.
T a ble 9 .f
C ollecti o n of Bl o o d S a m ples f or P h ar m ac o ki netic A n al ysis i n P art 3
A n al yte
M atri x
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K -0 4 1
Plas ma
1
Pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 0. 2 5, 0. 5, 1, 1. 5, 2, 3, 4, 6, 
8, 1 2, 2 4, 3 6, 4 8, 7 2, a n d 9 6 h o urs p ost d ose, a n d at F oll o w -u p Visit 
( Da y 1 9).
Base d o n e mer gi n g P K data fr o m pre vi o us c o h orts, t he act ual ti mes ma y c ha n ge b ut t he n u m ber of 
sa m ples will re mai n t he sa me. All eff orts will be ma de t o o btai n t he P K sa m ples at t he e xact 
n o mi nal t i me relati ve t o d osi n g. W he n t he ti mi n g of safety meas ure me nts c oi nci des wit h a P K 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
bl o o d c ollecti o n, t he or der s h o ul d be safet y assess me nts f oll o we d b y P K bl o o d sa m ple c ollecti o n 
at t he n o mi nal ti me. T he act ual ti mes of sa m ple c ollecti o n will be rec or de d o n t he s o urce 
d oc u me nts a n d e C R F.
S a m pli n g ti me p oi nts ma y be a dj uste d base d o n t he preli mi nar y e mer gi n g P K data c ollecte d fr o m 
pri or peri o d/c o h ort(s), b ut t he t otal n u m ber of sa m ples c ollecte d per s u bject s h o ul d n ot e xcee d t he 
pla n ne d n u m ber.
9. 1. 1 9. 2 C ollecti o n of Uri ne f or P h ar m ac oki netic S a m pli n g
S erial uri ne sa m ples f or deter mi nati o n of T A K- 0 4 1 i n Part 1 will be c ollecte d acc or di n g t o 
Ta ble 9. g a n d i n A p pe n di x A.
T a ble 9. g  
C ollecti o n of Uri ne S a m ples f or P h ar m ac o ki netic A n al ysis f or P art 1
A n al yte  
M atri x  
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K- 0 4 1  
Uri ne
1 
Pre d ose (- 1 2 t o 0), 0 t o 6, 6 t o 1 2, 1 2 t o 2 4, 2 4 t o 4 8, 4 8 t o 7 2, a n d 7 2 
t o 9 6 h o urs p ost d ose.
S erial uri ne sa m ples f or deter mi nati o n of T A K- 0 4 1 i n Part 2 will be c ollecte d acc or di n g t o 
Ta ble 9. h a n d i n A p pe n di x B.
T a ble 9. h  
C ollecti o n of Uri ne S a m ples f or P h ar m ac o ki netic A n al ysis f or P art 2 
A n al yte  
M atri x  
D osi n g D a y
Sc he d ule d Ti me ( h o urs)
T A K- 0 4 1  
Uri ne
1 
Pre d ose (- 1 2 t o 0), a n d 0 t o 6, 6 t o 1 2, 1 2 t o 2 4, 2 4 t o 4 8 h o urs 
p ost d ose.
T A K- 0 4 1  
Uri ne
2 2 
Pre d ose (- 1 2 t o 0), a n d 0 t o 6, 6 t o 1 2, 1 2 t o 2 4, 2 4 t o 4 8 h o urs 
p ost d ose.
I n Part 2 a n d Part 4 o nl y, 1 0 m L ali q u ots s h o ul d be ta ke n fr o m t he uri ne c ollecti o ns o n Da ys 1 a n d 
2 2 ( pre d ose a n d 1 2 t o 2 4 h o urs p ost d ose) f or meas ure me nt of 6 β - h y dr o x yc ortis ol/c ortis ol r ati o t o 
assess C Y P 3 A 4 i n d ucti o n.
W he n Earl y Ter mi nati o n occ urs o n a n o n- P K bl o o d c ollecti o n da y, P K bl o o d a n d uri ne sa m ples 
s h o ul d be c ollecte d.
Uri ne sa m ples f or s u bjects ra n d o mize d t o place b o will n ot be a nal yze d.
Uri ne v ol u me will be rec or de d wit hi n 2 h o urs of t he e n d of t he c ollecti o n peri o d. I nstr ucti o ns f or 
sa m ple pr ocessi n g a n d s hi p me nt will be pr o vi de d t o t he site i n t he La b orat or y Ma n ual.
 
.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
d fr o
d fr o m m 
xcee d t h
cee d t
e d acc or d
d acc or
A n al ysi
A n al y
ule d Ti me
d Ti
t t
 6 t o 1 2, 
6 t o 1 2
e c
s u
 i n Part 
n Par
es f or P
f or P
s e
Pre d
Pr
p
l u
2 2
er
m
nl y
nl y , 1 0 m
, 1 0
2 t o 2 4
t o 2 4 h
4 i n d ucti
i n d uc
y Ter mi n
Ter m
e c ollec
c olle
ne sa m pl
e sa m p
Uri ne v o
Uri ne v
sa m p
sa m
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 8 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 1 9. 3 Bi o a n alytic al Met h o ds
Pl as ma a n d uri ne c o nce ntrati o ns of T A K -0 4 1 will be meas ure d b y  hi g h-p erf or m a nce li q uid 
c hr o mat o gra p h y  wit h ta n de m mass s pectr o metr y at P P D la b orat ories.
9. 1. 2 0
P h ar m ac o ki netic P ar a meters
T he P K para meters of T A K - 0 4 1 will be deter mi ne d fr o m t he c o nce ntrati o n-ti me pr ofiles f or all 
e val ua ble s u bjects i n all st u d y parts. Act ual sa m pli n g ti mes, rat her t ha n sc he d ule d sa m pli n g ti mes, 
will be use d i n all c o m p utati o ns i n v o l vi n g sa m pli n g ti mes. T he f oll owi n g P K para meters will be 
calc u late d f or plas ma c o nce ntrati o n val ues of T A K - 0 4 1:
T a ble 9.i
P h ar m ac o ki netic P ar a meters
S y m b ol/ Ter m
Defi niti o n
Pl as m a
A U C 2 4
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m t he ti me 0 t o ti me 2 4 h o urs. N ote: If a 
ti me peri o d ot her t ha n 2 4 h o urs is nee de d, t his will ha ve t o be s pecifie d (e g, A U C7 2 f or ti me 0 
t o 7 2 h o urs).
A U C 9 6
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m t he ti me 0 t o ti me 9 6 h o urs. 
A U C τ
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve d uri n g a d osi n g i nter val, w here ta u (τ) is t he 
le n gt h of t he d osi n g i nter val.
A U C last
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o ti me of t he last q ua ntifia ble 
c o nce ntrati o n.
A U C ∞
Area u n der t he plas ma c o nce ntra ti o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y, calc ulate d as 
A U C ∞= A U C t+ C last/ λz
R ac( A U C)
Acc u m ulati o n rati o ( base d o n A U C), calc ulate d as d ose n or malize d A U C τ at stea d y state/ d ose 
n or malize d A U C τ after a si n gle d ose.
R ac( C ma x)
Acc u m ulati o n fact or ( base d o n C ma x ), calc ulate d as d ose n or malize d Cma xss / d ose n or malize d 
C ma x after a si n gle d ose.
C a v,ss
A vera ge plas ma c o nce ntrati o n at stea d y state, calc ulate d as A U C τ/τ.
C last
Last o bser ve d q ua ntifia ble plas ma c o nce ntrati o n.
C ma x
Ma xi m u m o bser ve d plas ma c o nce ntrati o n.
C ma x,ss
Ma xi m u m o bser ve d stea d y -state plas ma c o nce ntrati o n d uri n g a d osi n g i nter val.
C tr o u g h
Tr o u g h plas ma c o nce ntrati o n ( meas ure d c o nce ntrati o n at t he e n d of a d osi n g i nter val at 
stea d y state ta ke n directl y bef ore ne xt a d mi nistrati o n.
C L / F
A p pare nt cleara nce after e xtra vasc ular a d mi nistrati o n, calc ulate d as = D ose/ A U C ∞after a 
si n gle d ose a n d as D ose/ A U C τ after m ulti ple d osi n g (at stea d y state).
t1/ 2z
Ter mi nal eli mi nati o n half -life, calc ulate d as l n( 2)/ λz.
tma x
Ti me t o reac h C ma x .
V z/ F
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi nal p hase after e xtra vasc ular a d mi nistrati o n, 
calc ulate d as ( C L/ F)/ λz.
T he f o ll owi n g uri ne P K para meters of T A K -0 4 1 will  be deri ve d fr o m uri ne c o nce ntrati o ns of 
T A K - 0 4 1:
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 8 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9.j  
Uri ne P ar a meters P art 1, P art 2 a n d P art 4
Uri ne
Ae t
T otal a m o u nt of dr u g e xcrete d i n uri ne fr o m ti me 0 t o ti me t.
fe
Fracti o n of dr u g e xcrete d i n uri ne, calc ulate d as ( Ae t/ d ose) × 1 0 0. M olec ular wei g ht a dj ust me nt 
nee de d f or meta b olites.
C L R
Re nal cleara nce, calc ulate d as Ae/ A U C.
9. 1. 2 1 
P h ar m ac o d y n a m ic P ar a meters
9. 1. 2 1. 1
9. 1. 2 2 
E x pl or at or y Bi o m ar ker S a m ple C ollecti o n
Pr o p
l u
m ple C
m ple C
e a p pli c a bl e T er m s of U s e
s
me nt 
me nt 
a b
C CI
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 8 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 1. 2 3
D oc u me nt ati o n of Scree n F ail ure
I n vesti gat ors m ust acc o u nt f or all s u bjects w h o si g n i nf or me d c o nse nt. If t he s u bject is f o u n d t o be 
n ot eli gi ble at t his visit, t he i n vesti gat or s h o ul d c o m plete t he e C R F scree n fail ure f or m.
T he pri mar y  reas o n f or scree n fail ure is rec or de d i n t he e C R F usi n g t he f oll o wi n g cate g ories:

P T E/ A E.

Di d n ot m eet i nclusi o n  crit eria or did meet e xcl usi o n criteria (s pecif y  reas o n).

Si g nifica nt pr ot oc ol  de viati on.

L ost t o f oll o w - u p.

V ol u nt ar y  wit hdra wal (s pecif y  reas o n).

St u d y  ter mi nati on.

Ot her (s pecif y reas o n).
S u bject n u m bers assi g ne d t o s u bjects w h o fail scree ni n g s h o ul d n ot be re use d.
9. 1. 2 4
D oc u me nt ati o n of R a n d o miz ati o n
O nl y s u bjects w h o meet all of  t he i nclusi o n  crit eria a n d n o ne of t he e xcl usi o n cri t eria are eli gi ble 
f or ra n d o mizati on i nto t he treat me nt p hase.
If t he s u bject is f o u n d t o be n ot eli gi ble f or ra n d o mizati on, t he i n vest i gat or s h o ul d rec or d t he 
pri mar y  reas o n f or fail ure o n t he a p plica ble e C R F.
9. 2
M o nit ori n g S u bject Tre at me nt C o m pli a nce
St u d y  me dicati on w ill be a d mi nistere d w hile s u bjects are u n der o bser vati o n i n t he cli nical researc h 
u nit. F oll o wi n g a d mi nistrati o n of t he st u d y me dicati o n, a p pr o priate m o ut h a n d/ or ha n d c hec ks will 
be perf or m e d t o e ns ure t hat t he d ose is s wall o we d a n d n ote d i n t he s o urce d oc u me nt. T he date a n d 
ti me of eac h d ose will be rec or de d i n t he s o urce d oc u me nts a n d o n t he e C R Fs. A n i n ve nt or y of t he 
st u d y me dicat i on s u p plies dis pe nse d will be perf or me d b y  t he site p har macist or a ut h orize d st u d y 
desi g nee a n d rec or de d o nt o t he Dr u g Acc o u nta bilit y L o g i n t he s u bject’s s o urce d oc u me nt rec or ds 
or e q ui vale nt. T he e xact d ose ti me of c o nsec ut i ve s u bjects ma y be sta g gere d t o facilitate lo gi stics 
at t he site.
9. 3
Sc he d ule of O bser v a ti o ns a n d Pr oce d ures

T he sc he d ules f or all st u d y -r elate d pr oce d ures i n Part 1, Part 2, Part 3 a n d Part 4 are s h o w n i n 
A p pe n di x A , A p pe n di x B , A p pe n di x C a n d A p pe n di x D /E , res pecti vel y. Assess me nts s h o uld 
be c o m p lete d at t he desi g nate d visit/ti me p oi nt(s).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 8 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
9. 3. 1
Disc h ar ge
P art 1 D a y 5 ( Disc h ar ge)

P h ysical e xa mi nat i on a n d ne ur o l ogi cal e xa mi nat i on.

Vi t al si g ns.

Wei g ht.

C o nc o mita nt me dicat i ons.

1 2- Lea d E C G.

S af et y lab orat or y  tests.

S er u m  pre g na nc y test ( h C G) (fe male s u bjects o nl y) ( C o h orts 1 a n d 2 o nl y)

P K bl o o d c ollect i on.

P K uri ne c o llecti on.

A E assess me nt.

C- S S R S ( Si nce Last Visit).

B o n d -La der V A S.
P art 2 a n d P art 4 D a ys 3, 1 0, 1 7, a n d 2 4 ( Fi n al Disc h ar ge)

P h ysic al e xa mi nati on a n d ne ur o l ogi cal e xa mi nat i on.

Vi t al si g ns.

C o nc o mita nt me dicat i ons.

1 2- Lea d E C G.

S af et y lab orat or y  tests.

P K bl o o d c ollect i on ( Da ys 3 a n d 2 4 o nl y).

P K uri ne c o llecti on ( Da ys 3 a n d 2 4 o nl y).

A E assess me nt.

C- S S R S ( Si nce Last Visit).

B o n d -La de r V A S.
P art 3 D a y 1 9 ( F oll o w -u p )

P h ysical e xa mi nat i on a n d ne ur o l ogi cal e xa mi nat i on.

Vi t al si g ns.

C o nc o mita nt me dicat i ons.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 9 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8

1 2 -Lea d E C G.

S af et y lab orat or y  tests.

P K bl o o d c ollect i on

A E assess me nt.

C- S S R S ( Si nce Last Visit).
F or all s u bjects recei vi n g st u d y me dicat i on, t he i n vesti gat or m ust c o m plete t he E n d of  St u d y e C RF 
pa ge.
9. 3. 2
E arl y Ter mi n ati o n
T he reas o n f or disc o nti n uat i on m ust be d oc u me nte d i n t he s o urce d oc u me nt a n d e C R F . T he 
f oll owi n g pr oce d ures will be perf or me d a n d d oc u me nte d:
W he n earl y  ter mi nati on is wit hi n 1 h o ur of a sc he d ule d P K sa m ple c ollecti on a n d t he st u d y  dr u g 
has bee n a d mi nistere d, t he P K sa m ple s h o ul d be c ollecte d. T he site ma y see k g ui da nce. F or 
e xa m ple, c ollect sa m ples if earl y wit h dra wal is d ue t o a n A E a n d/ or if se veral h o urs ela pse d si nce 
last blo o d dra w.
F or all s u bjects recei vi n g st u d y dr u g, t he i n vest i gat or m ust c o m plete t he E n d-of -St u d y  e C R F pa ge. 
E n d -of -St u d y  is defi ne d as t he F oll o w-u p assess me nt or Earl y  Ter mi natio n.
9. 4
Bi ol o gic al S a m ple Rete nti o n a n d Destr ucti o n
I n t his st u d y, s peci me ns f or ge n o me/ ge ne a nal ysis will be c ollecte d as descri be d i n Secti o n 9. 1. 1 5 , 
Ot her Pr oce d ures. T he ge net ic material will be preser ve d a n d retai ne d at C o va nce Bi ore p osit or y  
f or u p t o b ut n ot l o n ger t ha n 1 5 years or as re q uire d b y a p plica ble la w. T he s p o ns or has p ut i nt o 
pl ace a s yste m t o pr otect t he s u bjects’ pers o nal i nf or mati o n t o e ns ure o pti mal c o nfi de nt iality a n d 
defi ne d sta n dar d pr ocesses f or sa m ple a n d data c ollect i on, st ora ge, a nal ysis, a n d destr ucti o n.
T he sa m ples will be se nt t o a ce ntral la b orat or y  t hat pr ocesses t he bl o o d sa m ple a n d ser ves as a 
sec ure st ora ge facility. T he sa m ples will be i nit iall y st ore d at C o va nce Ce ntral La b orat or y Ser vices, 
I n dia na p olis, I N. T he S p o ns or a n d researc hers w or ki n g wit h t he S p o ns or will ha ve access t o t he 
sa m ples c ollecte d a n d a n y test res ults. All sa m ples c ollecte d d uri n g t he st u d y will be st ore d 
sec urel y wit h li mite d access a n d t he S p o ns or will re q uire a n yo n e w h o w or ks wit h t he sa mples t o 
a gree t o h ol d t he researc h i nf or mat i on a n d a n y res ults i n c o nfi de nce.
T he sa m ple will be la bele d wit h a u ni q ue sa m ple i de nt ifier si milar t o la beli n g i n t he mai n st u d y b ut 
usi n g a c o de t hat is differe nt fr o m t he c o de attac he d t o t he healt h i nf or mati o n a n d ot her cli nical test 
res ults c ollecte d i n t he st u d y. T he sa m ple a n d data are li n ke d t o pers o nal healt h i nf or mati on wi t h 
c o de n u m bers; t he sa m ples are stri p pe d of all pers o nal i de ntif yi n g i nf or mati o n b ut a ke y li n ki n g 
t he sa mples t o cli nical a nal ysis data e xists. T his li n k mea ns t hat t he s u bject ma y  b e ide nt ifie d b ut 
o nl y  in direct l y. T he c o de n u m bers will be ke pt sec ure b y or o n be half of t he S p o ns or.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
S u bjects w h o c o nse nte d a n d pr o vi de d a p har mac o ge n o mic sa m ple f or D N A a n d R N A a nal ysis ca n 
wit h dra w t heir c o nse nt a n d re q uest dis p osal of a st ore d sa m ple at a n y ti me pri or t o a nal ysis. N otif y 
s p o ns or of c o nse nt wit h dra wal.
9. 5 
Bl o o d V ol u me
T otal bl o o d sa m pli n g v ol u me f or a n i n di vi d ual s u bject i n Part 1 is s h o w n i n  Ta ble 9. k.
T a ble 9. k  
A p pr o xi m ate Bl o o d V ol u me f or P art 1 C o h ort 1
S a m ple T y pe
S a m ple V ol u me 
( m L)
N u m ber of S a m ples
T ot al
V ol u me ( m L)
Scree ni n g
Peri o d
F oll o w- u p 
Visits ( a)
Fi n al 
Visit
1
2
3
4
Safet y la b orat or y tests
2 0. 2 m L at 
scree ni n g
1 1. 7 m L at ot her 
visits
1
 
3
3
3
3
 
7
 
1
2 5 4. 2
5’ n ucle oti dase (a) 
3. 5 m L 
1 ( b) 
3 ( b) 
3 ( b) 
3 ( b) 
3 ( b) 
7 ( b) 
1 ( b)
1 4 ( a)
P K bl o o d c ollecti o n
4
0 
1 5 
1 5 
1 5 
1 5 
7
0
2 6 8
e G F R (c)
3. 5
0 
2 (c) 
2 (c) 
2 (c) 
0 
0
0
1 0. 5 (c)
T ot al A p pr o xi m ate Bl o o d S a m pli n g  V ol u me 
5 6 2. 7
(a) N u m ber of sa m ples base d o n 7 wee kl y safet y a n d P K F oll o w- u p Visits pla n ne d.
( b) T he bl o o d re q uire d f or 5’ n ucle oti dase will be c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y 2, Da y 5, at 
t he wee kl y safet y F oll o w- u p Visits a n d at t he Fi nal Visit. O n Da y 1 a se parate 3. 5 m L sa m ple will be c ollecte d.
(c) T he bl o o d re q uire d f or t he pre d ose e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples o n Da y - 1. T he 
p ost d ose e G F R 3. 5 m L sa m ple will be c ollecte d 6 ( ± 2) h o urs p ost d ose.
T he ma xi m u m v ol u m e of bl o o d i n a n y si n gle da y is a p pr o xi matel y 5 8 m L. T he t otal v ol u me of 
bl o o d f or eac h s u bject i n C o h ort 1 is a p pr o xi matel y 5 6 2. 7 m L. Direct ve ni p u nct ure or i n d welli n g 
cat heter ma y be use d f or bl o o d c ollecti o n.
T ot al bl o o d sa m pli n g v ol u me f or a n i n di vi d ual s u bject i n Part 1 C o h ort 2 is s h o w n i n  Ta ble 9.l.
Pr o p ert y of T a k e d a: F or
m
r n o n- c o m m er ci al u s e o 
bj e ct t o t h e a p pli c a bl e T er m s of U s e
pl
u p 
s ( a)
( a)
FiF
a p
e
7
t h
bj e
3 ( b)
( b)
bj
1 5
o
2 (c)
(c)
2 (
2
o
s e
u
a n d P K F o
d P K F
be c ollecte
e c ollec
e Fi nal Vi
Fi nal V
G F R sa m pl
R sa m
c ollecte d 
ollecte
bll
f
o o d i
o o d
t i n C o h o
i n C o
e d f or bl
f or b
pli n g v
pli n g 
m
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9.l  
A p pr o xi m ate Bl o o d V ol u me f or P art 1 C o h ort 2
S a m ple T y pe
S a m ple V ol u me 
( m L)
N u m ber of S a m ples
T ot al V ol u me 
( m L)
Scree ni n g
Peri o d
F oll o w- u p
Visits ( a) 
Fi n al Visit
1
2
 
3
Safet y l a b orat or y tests
2 0. 2 m L at 
scree ni n g
1 1. 7 m L at ot her 
visits
1
3
3
3
 
7
 
1
2 1 9. 1
5’ n ucle oti dase (a)
3. 5 
1 ( b) 
3 ( b) 
3 ( b) 
3 ( b) 
7 ( b) 
1 ( b)
1 0. 5 ( a)
P K bl o o d c ollecti o n
4
0 
1 5 
1 5 
1 5 
7
0
2 0 8
e G F R (c)
3. 5
0 
2 (c) 
2 (c) 
2 (c) 
0
0
1 0. 5 (c)
T ot al A p pr o xi m ate Bl o o d S a m pli n g V ol u me 
4 6 4. 1
(a) N u m ber of sa m ples base d o n 7 wee kl y safet y a n d P K F oll o w- u p Visits pla n ne d.
( b) T he bl o o d re q uire d f or 5’ n ucle oti dase will be c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y 2, Da y 5, at 
t he wee kl y safet y F oll o w- u p Visits a n d at t he Fi nal Visit. O n Da y 1 a se parate 3. 5 m L sa m ple will be c ollecte d.
(c) T he bl o o d re q uire d f or t he pre d ose e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples o n Da y - 1. T he 
p ost d ose e G F R 3. 5 m L sa m ple will be c ollecte d 6 ( ± 2) h o urs p ost d ose.
Si milar t o Part 1 C o h ort 1, t he ma xi m u m v ol u me of bl o o d c ollecte d f or C o h ort 2 i n a n y si n gle da y 
is a p pr o xi matel y 5 8  m L. T he t otal v ol u me of bl o o d f or eac h s u bject i n C o h ort 2 is a p pr o xi matel y 
4 6 4. 1 m L. Direct ve ni p u nct ure or i n d welli n g cat heter ma y be use d f or bl o o d c ollecti o n.
T otal bl o o d sa m pli n g v ol u me f or a n  i n di vi d ual s u bject i n Part 1 C o h orts 3 t o 5 is s h o w n i n Ta ble 
9. m.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t 
li c a bl e T er m s of U s e
me e 
L))
m
2 1 9. 1
9 1
T e
li c
li c
0
m ate Bl o o d
ate Bl o
j e c
u bj
a n ne d.
n ne d.
afet y la b or
fet y la b
e parate 3. 5
arate 3
d as part o
as part
d ose.
d ose
me of b
me of b
o f f bl o o d
bl o o
elli n g ca
elli n g 
n i n di vi d
i n di v
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9. m  
A p pr o xi m ate Bl o o d V ol u me f or P art 1 C o h orts 3 t o 5
S a m ple T y pe
S a m ple 
V ol u me 
( m L)
V ol u me per S u bject ( m L)
T ot al V ol u me 
per S u bject per 
C o h ort ( m L)
Scree ni n g
D a y
- 2 1 t o - 2
D a y
F oll o w- u p 
Visits
Fi n al 
Visit
D a y 
- 1
1
2
3
4
5
E T
Safet y la b orat or y 
sa m ples
2 0 m L at 
scree ni n g
1 2 m L at 
ot her visits
2 0 
1 2 
1 2
1 2 
1 2 
1 2 ( 7 2)(a) 
1 2 
1 4 0
5’ n ucle oti dase 
3. 5 
( b)
( b)
( b) 
( b) 
( b) 
( b) 
0
P K sa m ples 
4
4 0 
8 
4 
4 
4 
4 
4 ( 2 4)(a)
8 4
e G F R
3. 5
(c) 
(c)
(c)
(c)
0
T ot al Bl o o d S a m pli n g V ol u me
2 4 5
(a) T he n u m bers re prese nt v ol u me re q uire d per visit a n d i n pare nt hesis, t he v ol u me re q uire d f or 6 visits ( Da ys 8, 1 5, 2 2, 2 9, 36, a n d 
4 3).
( b) T he blo o d re q uire d f or 5’ n ucle oti dase will be  c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y - 1, Da y 2, Da y
5, at Earl y Ter mi nati o n, at t he wee kl y safet y f oll o w- u p visits, a n d at t he Fi nal Visit.
(c) T he bl o o d re q uire d f or e G F R will be c ollecte d as part of t he safet y la b orat or y sa m ples at Da y - 1, Da y 2, Da y 5, a n d at t he wee kl y 
safet y f oll o w- u p visits.
T he ma xi m u m v ol u me of bl o o d c ollecte d f or C o h orts 3 t o 5 i n a n y si n gle da y is a p pr o xi matel y 
4 0  m L. T he t otal v ol u me of bl o o d f or eac h s u bject i n C o h orts 3 t o 5 is a p pr o xi matel y 2 4 5 m L. 
Direct ve ni p u nct ure or i n d welli n g cat heter ma y be use d f or bl o o d c ollecti o n.
T ot al bl o o d s a m pli n g v ol u me f or a n i n di vi d ual s u bject i n Part 2 is s h o w n i n  Ta ble 9. n.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o  
pli c a bl e T er m s of U s e
me 
me 
ect per 
ect per 
ort ( m L)
rt ( m L
m
1 4 0
1 4
e T
i c
( b)
b)
4 ( 2 4)(a)
(
(c)
(c
ct
l Bl o o d S
Bl o o d 
ctctct
bj e
me re q uire d
e re q uire
et y la b orat
t y la b or
Fi nal Visi
i nal V
la b orat or y
b orat o
C o h orts 
o h orts
s u bject 
u bjec
ter ma y 
er ma y
n i n di vi d
i n di v
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9. n  
A p pr o xi m ate Bl o o d V ol u me f or P art 2 C o h orts 1 t o 4
S a m ple T y pe
S a m ple 
V ol u me 
( m L)
V ol u me per S u bject ( m L)
T ot al 
V ol u me 
per 
S u bject 
per 
C o h ort 
( m L)
Scree ni
n g
D a y
Fi n al 
Disc h a
r ge 
D a y 2 4 E T
F oll o w-
u p Peri o d 
S afet y 
P K F/ u 
visits
D a y 
- 2 
1- 3 
5 
7 
8 
1 4 
1 5 
2 1 
2 2 
2 3
Safet y 
la b orat or y 
sa m ples
2 0 m L at 
scree ni n g
1 2 m L at 
ot her 
visits
2 0 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 1 2 ( 8 4)(a) 
2 1 2
5’ n ucle oti das
e (a)
3. 5 
( b) 
( b)
( b) 
( b) 
( b)
( b) 
( b) 
( b) 
0
P K sa m ples 
4
4 4 
4 
1 6 
1 6 
3 6 
4 
4 
4 
4 ( 2 8) (a) 
1 5 2
e G F R
3. 5
(c) 
(c) 
(c) 
(c) 
(c)
(c) 
0
T otal Bl o o d Sa m pli n g V ol u me 
4 5 5
T he t otal bl o o d v ol u me of 5 2 8. 5 ml will be ta ke n o ver a peri o d of 2. 5 m o nt hs
(a) T he n u m bers re prese nt v ol u me re q uire d per visit a n d i n pare nt hesis, t he v ol u me re q uire d f or 7 visits ( Da ys 2 6, 2 9, 3 6, 4 3, 5 0, 5 7 , 
a n d 6 4).
( b) T he blo o d re q uire d f or 5’ n ucle oti dase will be  c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y - 2, Da y 7, Da y 
1 4, Da y 2 1, Da y 2 4, Earl y Ter mi nati o n, a n d at t he wee kl y safet y f oll o w- u p visits.
(c) T he bl o o d re q uire d f or e G F R will be c ollecte d as part of t he safet y la b orat or y sa m ples at Da ys - 2, 7, 1 4, 2 1, a n d at t he wee kl y 
safet y f oll o w- u p visits.
T he ma xi m u m v ol u me of bl o o d c ollecte d o n a n y si n gle da y is a p pr o xi matel y 1 0 8. 5 m L. T he t otal 
v ol u me of bl o o d t o be c ollecte d fr o m eac h s u bject i n Part 2 C o h orts 1 t o 4 is a p pr o xi matel y 
4 5 5  m L, a n d will be ta ke n o ver a peri o d of 2. 5 m o nt hs. Direct ve ni p u nct ure or i n d welli n g cat heter 
ma y be use d f or bl o o d c ollecti o n .
T ot al bl o o d s a m pli n g v ol u me f or a n i n di vi d ual s u bject i n Part 3 is s h o w n i n  Ta ble 9. o.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al l
(c)
(c
al
ci a
er
be ta ke n o
e ta ke n
uire d per v
ire d pe
le oti dase 
oti das
er mi nati o n
mi nati o
e G F R 
G F R wi
m  v
 v
m
olol u m
ul
bl o o d t o
bl o o d
L, a n d wi
a n d w
be use d 
be use d
T ot al
T ot al  bl
bl
o
e ct t o t h e a p pli c a bl e T er m s of U s e
T ot al 
T ot al 
V ol u me
V ol u m
per
S u
S
T
eri o d 
ri o d 
S afet y 
afet y 
P K F/ u 
P K F/ u
visit
vis
m
p p
bl e
m
1 21 2
1 2 
1 2 
p p
p p
t o
e
p p
e
t
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9. o  
A p pr o xi m ate Bl o o d V ol u me f or P art 3
S a m ple 
T y pe
S a m ple 
V ol u me
N u m ber of S a m ples
T ot al 
V ol u me
Scree ni n g
D a y
- 1
D a y 
1
D a y 
2
D a y 
3
D a y 
4
D a y 
5
E T 
F oll o w
- u p 
D a y 1 9
Safet y 
La b orat or y 
Sa m ples
2 0 
1 
1 
- 
- 
1 
- 
- 
1 
1 
8 0
5’ 
n ucle oti dase
3. 5 
( b) 
( b)
( b) 
( b) 
0
P K Sa m ples 
4
- 
- 
1 1 
2 
1 
1 
1 
1 
1 
6 8
e G F R
3. 5
(c)
(c) 
(c) 
0
T otal Bl o o d Sa m pli n g V ol u me ( ml)
1 5 9
(a) T he n u m bers re prese nt v ol u me re q uire d per visit.
( b) T he bl o o d re q uire d f or 5’ n ucle oti dase will be c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y - 1, Earl y 
Ter mi nati o n, a n d at t he F oll o w- u p visit.
(c) T he bl o o d re q uire d f or e G F R will be c ollecte d as part of t he safet y la b orat or y sa m ples at Da y - 1, E T or F oll o w- u p visit.
T he ma xi m u m v ol u me of bl o o d c ollecte d f or a s u bject i n Part 3 i n a n y si n gle da y is a p pr o xi matel y 
5 5  m L. T he t otal v ol u me of bl o o d f or eac h s u bject i n Part 3 is a p pr o xi matel y 1 5 9  m L. Direct 
ve ni p u nct ure or i n d welli n g cat heter ma y be use d f or bl o o d c ollecti o n.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t 
li c a bl e T er m s of U s e
ot al 
al 
V ol u me
V ol u me
s
m s
8 08
T e
bl e
( b)
( b)
b
1
Bl o o d Sa
Bl o o d S
t t
ct
a b orat
b orat or y 
or
rat or y
at or y sa m
sa
y
ct i n
t i n Par
Pa
ct i n Part
t i n Pa
e d f or b
d f or b
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T a ble 9. p  
A p pr o xi m ate Bl o o d V ol u me f or P art 4
S a m ple T y pe
S a m ple 
V ol u me 
( m L)
V ol u me per S u bject ( m L)
T ot al 
V ol u me 
per 
S u bject 
per 
C o h ort 
( m L)
Scree n-
i n g
D a y
Fi n al 
Disc h a
r ge 
D a y 2 4 E T
F oll o w-
u p Peri o d 
S afet y 
P K F/ u 
visits
D a y 
- 2 
1- 3 
5 
7 
8 
1 4 
1 5 
2 1 
2 2 
2 3
Safet y 
la b orat or y 
sa m ples
2 0 m L at 
scree ni n g
1 2 m L at 
ot her 
visits
2 0 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 
1 2 1 2 ( 8 4)(a) 
2 1 2
5’ n ucle oti das
e (a)
3. 5 
( b) 
( b)
( b) 
( b) 
( b)
( b) 
( b) 
( b) 
0
P K sa m ples 
4
4 4 
4 
1 6 
1 6 
3 6 
4 
4 
4 
4 ( 2 8) (a) 
1 5 2
e G F R
3. 5
(c) 
(c) 
(c) 
(c) 
(c)
(c) 
0
T otal Bl o o d Sa m pli n g V ol u me 
4 5 5
(a) T he n u m bers re prese nt v ol u me re q uire d per visit a n d i n pare nt hesis, t he v ol u me re q uire d f or 7 visits ( Da ys 2 6, 2 9, 3 6, 4 3, 5 0, 5 7, 
a n d 6 4).
( b) T he blo o d re q uire d f or 5’ n ucle oti dase will be  c ollecte d as part of t he safet y la b orat or y sa m ples at Scree ni n g, Da y - 2, Da y 7, Da y 
1 4, Da y 2 1, Da y 2 4, Earl y Ter mi nati o n, a n d at t he wee kl y safet y f oll o w- u p visits.
(c) T he bl o o d re q uire d f or e G F R will be c ollecte d as part of t he safet y la b orat or y sa m ples at Da ys - 2, 7, 1 4, 2 1, a n d at t he wee kl y 
safet y f oll o w- u p visits.
T he ma xi m u m v ol u m e of bl o o d c ollecte d o n a n y si n gle da y is a p pr o xi matel y 1 0 8 m L. T he t otal 
v ol u me of bl o o d t o be c ollecte d fr o m eac h s u bject i n P art 4 is a p pr o xi matel y 4 5 5  m L, a n d will be 
ta ke n o ver a peri o d of 2. 5 m o nt hs. Direct ve ni p u nct ure or i n d welli n g cat heter ma y be use d f or 
bl o o d c ollecti o n.
6
o
(c)
o
s e
u s
it a n d i n pa
a n d i n 
ll be c ollec
be c oll
n d at t he w
d at t he
e c ollecte
c ollec
of blbl
f
o o d
o o
be c ollec
e c ol
o d of 2. 5
d of 2
o n.n.
 t h e a p pli c a bl e T er m s of U s e
e 
er 
u bject 
u bject 
per 
pe
C o h o
C
( m
u u
itsts
m
bl e
m
2 ( 8 4)(a)
2 ( 8 4)(a
a b
e
p p
b
( b)
( b)
(
e
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 9 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 0. 0
P R E T R E A T M E N T E V E N T S A N D A D V E R S E E V E N T S
1 0. 1
Defi niti o ns
1 0. 1. 1 P T Es
A P T E i s defi ne d as a n y u nt o war d me d ical occ urre nce i n a cli nical i n vesti gati on s u bject w h o has 
sig ne d i nf or m e d c o nse nt t o partici pate i n a st u d y b ut prior t o a d mi nistrati o n of a n y st u d y  
me dicat i on; i t d oes n ot necessaril y ha ve t o ha ve a ca usal relati ons hi p wi t h st u d y partici pat i on.
1 0. 1. 2
A Es
A n A E i s defi ne d as a n y u nt o war d me dical occ urre nce i n a cli nical i n vest i gati on s u bject 
a d mi nistere d a dr u g or d ue t o a st u d y pr oce d ure; it d oes n ot necessaril y ha ve t o ha ve a ca usal 
r elat i ons hi p wit h t his treat me nt.
A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (e g, a cli nicall y si g nifica nt a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a st u d y dr u g or d ue 
t o a st u d y pr oce d ure, w het her or n ot it is c o nsi dere d relate d t o t he st u d y dr u g.
1 0. 1. 3
A d diti o n al P oi nts t o C o nsi der f or P T Es a n d A Es
A n u nt o war d fi n di n g ge nerall y ma y:

I n dicate a ne w dia g n osis or u ne x pecte d w orse ni n g of a pre-e xist i n g c o n diti on. (I nter mitte nt 
e ve nts f or pre-e xist i n g c o n diti ons u n derl yi n g disease s h o ul d n ot be c o nsi dere d P T Es or A Es.)

Necessitate t hera pe utic i nter ve nt i on.

Re q ui re a n i n vasi ve dia g n ostic pr oce d ure.

Re q ui re disc o nti n uati o n or a c ha n ge i n d ose of st u d y me dicati on or a c o nc o mita nt me dicat i on.

Be c o nsi dere d u nfa v ora ble b y t he i n vest i gat or f or a n y reas o n. 

P T Es/ A Es ca use d b y a st u d y pr oce d ure (e g, a br uise after bl o o d dra w) s h o ul d be rec or de d as a 
P T E/ A E.
Di a g n oses vs si g ns a n d s y m pt o ms:

Eac h e ve nt s h o ul d be rec or de d t o re prese nt a si n gle  dia g n osis. Acc om pa n yi n g si g ns (i ncl u di n g 
a b n or mal la b orat or y val ues or E C G fi n di n gs) or s ym pt o m s s h o uld N O T be rec or de d as 
a d ditio nal  AEs. If  a dia g n osis is u n k n o w n, si g n(s) or s y m pt o m(s) s h o ul d be rec or de d 
a p pr o priatel y as a P T E(s) or as a n A E(s).
La b orat or y  val ues a n d E C G fi n di n gs:

C ha n ges i n la b orat or y val ues or E C G para meters are o nl y c o nsi dere d t o be P T Es or A Es if t he y 
are ju d ge d t o be cli nicall y si g nifica nt (ie, if s o me acti o n or i nter ve nt i on is re q uire d or if t he 
i n vesti gat or j u d ges t he c ha n ge t o be be yo n d t he ra n ge of n or mal p h ysi o l ogic fl uct uati o n). A 
la b orat or y r e-test a n d/ or c o nti n ued m o ni t ori n g of a n a b n or mal val ue are n ot c o nsi dere d a n 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 9 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
i nter ve nt i on. I n a d dit i on, re peate d or a d dit i onal n o ni n vasi ve testi n g f or verificat i on, e val uati o n 
or m o ni t ori n g of a n a b n or mality is n ot c o nsi dere d a n i nter ve nt i on.

If a b n or mal la b orat or y val ues or EC G fi n di n gs are t he res ult of pat h ol o g y f or w hic h t here is a n 
o verall dia g n osis (e g, i ncrease d creat i ni ne i n re nal fail ure), t he dia g n osis o nl y s h o ul d be 
re p orte d a p pr o priatel y as a P T E or as a n A E.
Pre -e xist i n g c o n diti ons:

Pre -e xist i n g c o n diti ons ( prese nt at  t he ti me of sig ni n g of i nf or me d c o nse nt) are c o nsi dere d 
c o nc urre nt me dical c o n dit i ons a n d s h o ul d N O T be rec or de d as P T Es or A Es. Baseli ne 
e val uat i ons (e g, l a b orat or y tests, E C G, X-ra ys etc.) s h o ul d N O T be rec or de d as P T Es u nless 
r elate d t o st u d y pr oce dures. H o we ver, if t he s u bject e x perie nces a w orse ni n g or c o m plicati o n 
of  s uc h a c o nc urre nt c o n diti on, t he w orse ni n g or c o m plicat i on s h o ul d be rec or de d 
a p pr o priatel y as a P T E ( w orse ni n g or c o m plicati on occ urs bef ore start of st u d y me dicat i on) or 
a n A E ( w orse ni n g or c o m plicat i on occ urs after start of st u d y me dicat i on). I n vesti gat ors s h o ul d 
e ns ure t hat t he e ve nt ter m rec or de d ca pt ures t he c ha n ge i n t he c o n dit i on (e g, “ w orse ni n g 
of …”).

If a s u bject has a pre-e xist i n g e pis o dic c o n diti on (e g, ast h ma, e pile ps y) a n y occ urre nce of a n 
e pis o de s h o ul d o nl y be ca pt ure d as a P T E/ A E if t he e pis o des bec o me m o re fre q ue nt, seri o us or 
se vere i n nat ure, t hat is, i n vest i gat ors s h o ul d e ns ure t hat t he A E ter m rec or de d ca pt ures t he 
c ha n ge i n t he c o n dit i on fr om Baseli ne (e g “ w orse ni n g of …”).

If a s u bject has a de ge nerati ve c o nc urre nt c o n diti o n (e g, cataracts, r he u mat oi d art hritis), 
w orse ni n g of t he c o n dit i on s h o ul d o nl y  be ca pt ure d as a P T E/ A E if occ urri n g t o a greater 
e xte nt t o t hat w hic h w o ul d be e x pecte d. A gai n, i n vesti gat ors s h o u l d e ns ure t hat t he A E ter m 
rec or de d ca pt ures t he c ha n ge i n t he c o n diti on (e g, “ w orse ni n g o f …”).
W o rse ni n g of P T Es or A Es:

If the s u bject e x perie nces a w orse ni n g or c o m plicati o n o f a P T E after starti n g a d mi nistrati o n of 
t he st u d y me dicat i on, t he w orse ni n g o r c o mplicat i o n s h o ul d be rec or de d a p pr o priatel y as a n 
A E. I n vest i gat ors s h o ul d e ns ure t hat t he A E ter m rec or de d ca pt ures t he c ha n ge i n t he c o n dit i on 
(e g, “ w orse ni n g of …”).

If t he s u bject e x perie nces a w orse ni n g or c o m plicati o n of a n A E after a n y c ha n ge i n st u d y 
me dicat i on, t he w orse ni n g or c o m plicat i on s h o ul d be rec or de d as a ne w A E. I n vesti gat ors 
s h o uld e ns ure t hat t he A E ter m rec or de d ca pt ures t he c ha n ge i n t he c o n dit i on (e g, “ w orse ni n g 
of …”).
C ha n ges i n se verit y of  AEs / Seri o us P T Es:

If t he s u bject e x perie nces c ha n ges i n se verity of  a n A E/serio us P T E, t he e ve nt s h o ul d be 
ca pt ure d o nce wit h t he ma xi m u m se verit y rec or de d.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 9 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Pr e pla n ne d s ur geries or pr oce d ures:
!
Pr e pla n ne d pr oce d ures (s ur geries or t hera pies) t hat were sc he d ule d pri or t o si g ni n g of 
i nf or me d c o nse nt are n ot c o nsi dere d P T Es or A Es. H o we ver, if a pre pla n ne d pr oce d ure is 
perf or me d earl y (e g, as a n e mer ge nc y) d ue t o a w orse ni n g of t he pre-e xisti n g c o n diti o n, t he 
w orse ni n g of t he c o n diti o n s h o ul d be ca pt ure d a p pr o priatel y as a P T E or a n A E. C o m plicati o ns 
res ulti n g fr o m a n y pla n ne d s ur ger y s h o ul d be rep orte d as A Es.
Electi ve s ur geries or pr oce d ures:
!
Electi ve pr oce d ures perf or me d w here t here is n o c ha n ge i n t he s u bject’s me dical c o n diti o n 
s h o ul d n ot be rec or de d as P T Es or A Es, b ut s h o ul d be d oc u me nte d i n t he s u bject’s s o urce 
d oc u me nts. C o m plicati o ns res ulti n g fr o m a n electi ve s ur ger y s h o ul d be re p orte d as A Es.
O ver d ose:
!
Cases of o ver d ose wit h a n y me dicati o n wit h o ut ma nifeste d si de effects are N O T c o nsi dere d 
P T Es or A Es, b ut i nstea d will be d oc u me nte d o n a n O ver d ose pa ge of t he e C R F. A n y 
ma nifeste d si de effects will be c o nsi dere d P T Es  or A Es a n d will be rec or de d o n t he A E pa ge of 
t he e C R F.
E ve nts detecte d b y weara ble di gital de vices:
1 0. 1. 4 
S A Es
A n S A E is defi ne d as a n y u nt o war d me dical occ urre nce t hat at a n y d ose:
1. Res ults i n D E A T H.
2. Is LI F E T H R E A T E NI N G.
!
T he ter m “life t hreate ni n g” refers t o a n e ve n t i n w hic h t he s u bject was at ris k of deat h at t he 
ti me of t he e ve nt; it d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h 
if it were m ore se vere.
3. Re q uires i n patie nt H O S PI T A LI Z A TI O N or pr ol o n gati o n of e xisti n g h os pit alizati o n.
4. Res ults i n persiste nt or si g nifica nt DI S A BI LI T Y/I N C A P A CI T Y.
5. Lea ds t o a C O N G E NI T A L A N O M A L Y/ BI R T H D E F E C T.
6. Is a n I M P O R T A N T M E DI C A L E V E N T t hat satisfies a n y of t he f oll o wi n g:
!
Ma y re q uire i nter ve nti o n t o pre ve nt ite ms 1 t hr o u g h 5 a b o ve.
!
Ma y e x p ose t he s u bject t o da n ger, e ve n t h o u g h t he e ve nt is n ot i m me diatel y life 
t hreate ni n g or fatal or d oes n ot res ult i n h os pitalizati o n.
Pr o p ert y of T a k e d a: F or n o n- c o m m er c
nt o war d
nt o war
A T E NI N
T E NI
m “life t h
“life
of t he e v
f t he 
itit were 
wer
Re q ui
e q uires 
res
i
4. Res ul
4. Res u
5.5.
L
6
a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
, t he 
 t he 
plicat
licati oi n
m e dical 
e dica
t he s u bje
he s u bj
d be re p o
d be re
siside eff
de ef
er d ose pa
d ose p
s a n d w
a n d w
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8

I ncl u des a n y e ve nt or s y n o n y m descri be d i n t he Ta ke da Me dicall y Si g nifica nt A E List 
(Ta ble 1 0. a ).
T a ble 1 0. a 
T a ke d a Me dic all y Si g nific a nt A E List
Ter m
Ac ute res pirat or y fail ure/ac ute res pirat or y distress 
s yn dr o me
He patic necr osis
T orsa de de p oi ntes/ ve ntric ular fi brillati o n / ve ntric ular 
tac h ycar dia
Ac ute li ver fail ure
A na p h y lactic s h oc k
Mali g na nt h y perte nsi o n
Ac ute re nal fail ure
C o n v ulsi ve seiz ure
P ul m o nar y h y perte nsi o n
A gra n ul oc yt osis
P ul m o nar y fi br osis
A plastic a ne mia
C o nfir me d or s us pecte d e n d ot o xi n s h oc k
T o xic e pi der mal necr ol ysis/ Ste ve ns -J o h ns o n s y n dr o me C o nfir me d or s us pecte d tra ns missi o n of i nfecti o us a ge nt b y a 
me dici nal pr o d uct
Ne ur ole ptic mali g na nt s y n dr o me/ mali g na nt h y pert her mia
S p o nta ne o us a b orti on/still birt h a n d fetal deat h
P T Es t hat f ulfill 1 or m ore of t he seri o us criteria a b o ve are als o t o be c o nsi dere d S A Es a n d s h o ul d 
be re p orte d a n d f o ll owe d u p i n t he sa me ma n ner (see Secti o ns  1 0. 2. 2 a n d 1 0. 3 ).
1 0. 1. 5
Se verit y of P T Es a n d A Es
T he differe nt cate g ories o f i nte nsit y (se verit y)  are c haracterize d as f oll o ws:
Mil d:
T he e ve nt is tra nsie nt a n d easil y t olerate d b y t he s u bject.
M o derate:
T he e ve nt ca uses t he s u bject disc o mf ort a n d i nterr u pts t he s u bject’s us ual acti vities.
Se vere:
T he e ve nt ca uses c o nsi dera ble i nterfere nce wit h t h e s u bject’s us ual acti vities.
1 0. 1. 6
C a us alit y of A Es
T he rel at i ons hi p of eac h A E t o st u d y  me dicatio n(s) will be assesse d usi n g t he f o ll owi n g 
cate g ories:
Relate d:
A n A E t hat f oll o ws a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of a dr u g (i ncl u di n g t he 
c o ur se after wit h dra wal of t he dr u g), or f or w hic h p ossi ble i n v ol ve me nt of t he dr u g ca n n ot be 
r ule d o ut, alt h o u g h fact ors ot her t ha n t he dr u g, s uc h as u n derl yi n g diseases, c o m plicati o ns, 
c o nc o mita nt dr u gs a n d c o nc urre nt treat me nts, ma y als o be res p o nsi ble.
N ot Relate d:
A n A E t hat d oes n ot f oll o w a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of a dr u g a n d/ or 
t hat ca n reas o na bl y be e x plai ne d b y ot her fact ors, s uc h as u n derl yi n g diseases, c o m plicati o ns, 
c o nc o mita nt dr u gs a n d c o nc urre nt treat me nts.
1 0. 1. 7
Rel ati o ns hi p t o St u d y Pr oce d ures
Relati o ns hi p (ca usalit y)  t o st u d y pr oce d ures s h o ul d be deter mi ne d f or all P T Es a n d A Es.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he relati o ns hi p s h o ul d be assesse d as Relate d if t he i n vesti gat or c o nsi ders t hat t here is reas o na ble 
p ossi bilit y t hat a n e ve nt is d ue t o a st u d y pr oce d ure. Ot her wise, t he relati o ns hi p s h o ul d be assesse d 
as N ot Relate d.
1 0. 1. 8
St art D ate
T he start date of t he A E/ P T E is t he date t hat t he first si g ns/s y m pt o ms were n ote d b y  t he s u bject 
a n d/ or p h ysicia n.
1 0. 1. 9
St o p D ate
T he st o p date of  the A E/ P T E is t he date at w hic h t he s u bject rec o vere d, t he e ve nt res ol ve d b ut wit h 
or wi t ho ut se q uel ae or t he s u bject die d.
1 0. 1. 1 0 Fre q ue nc y
E pis o di c A Es/ P T E (e g, v o mit i n g) or t h ose w hic h occ ur re peate dl y o ver a peri o d of c o nsec uti ve 
da ys are i nter mitte nt. All ot her e ve nts are c o nti n u o us .
1 0. 1. 1 1 Acti o n C o ncer ni n g St u d y Me dic ati o n

Dr u g wit h dra w n – a st u d y me dicat i on is st o p pe d d ue t o t he partic ular A E.

D ose n ot c ha n ge d – t he partic ular A E di d n ot re q uire st o p pi n g a st u d y me dicat i on.

U n k n o w n – o nl y  t o be use d if it has n ot bee n p ossi ble t o deter mi ne w hat acti o n has bee n ta ke n.

N ot A p plica ble – a st u d y me dicatio n was st o p pe d f or a reas o n ot her t ha n t he partic ular A E 
e g, t he st u d y has bee n ter mi nate d, t he s u bject die d, d osi n g wit h st u d y me dicat i on was alrea d y 
st o p pe d bef ore t he o nset of t he A E.

D ose I nterr u pte d – t he d ose was i nterr u pte d d ue t o t he partic ular A E.
1 0. 1. 1 2 O utc o me

Rec o vere d/ Res ol ve d – S u bject ret ur ne d t o first assess me nt stat us wit h res pect t o t he A E/ P T E.

Rec o veri n g/ Res o l vi n g – t he i nte nsit y is l owere d b y  o ne or more sta ges: t he di a g n osis or 
sig ns/s y m pt o m s has al m ost disa p peare d; t he a b n or mal la b orat or y v alue i m pr o ve d, b ut has n ot 
ret ur ne d t o t he n or mal ra n ge or t o baseli ne; t he s u bject die d fr o m a ca use ot her t ha n t he 
parti c ular A E/ P T E wit h t he c o n dit i on re m ai ni n g “rec o veri n g/resol vi n g”.

N ot rec o vere d/ n ot res ol ve d – t here is n o c ha n ge i n t he dia g n osis, si g ns or s y m pt o ms; t he 
i nte nsit y of t he dia g n osis, sig ns/ s y m pt o m s or la b orat or y val ue o n t he last da y of t he o bser ve d 
st u d y p erio d has g ot w orse t ha n w he n it starte d; is a n irre ver si ble c o n ge nital a n o mal y; t he 
s u bject die d fr om a n ot her ca use wit h t he partic ular A E/ P T E state re mai ni n g “ N ot 
rec o vere d/ n ot res ol ve d”.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8

Res o l ve d wit h se q uelae – t he s u bject rec o vere d fr o m a n ac ute A E/ P T E b ut was left wit h 
p er m a ne nt/sig nifica nt i m pair me nt (e g, rec o vere d fr o m a car di o vasc ular acci de nt b ut wit h 
s o me persisti n g paresis.

Fatal  – t he A Es/ P T Es t hat are c o nsi dere d as t he ca use of deat h.

U n k n o w n – t he c o urse of t he A E/ P T E ca n n ot be f oll o we d u p d ue t o h os pital c ha n ge or 
reside nce c ha n ge at t he e n d of t he s u bject’s partici pati o n i n t he st u d y.
1 0. 2
Pr oce d ures
1 0. 2. 1 C ollecti o n a n d Re p orti n g of A Es
1 0. 2. 1. 1 P T E a n d A E C ollecti o n Peri o d
C ollect i on of P T Es will c o m me nce fr o m t he ti me t he s u bject si g ns t he i nf or me d c o nse nt t o 
parti ci pate i n t he st u d y a n d c o nti n ue u ntil t he s u bject is first a d mi nistere d st u d y me dicat i on 
( pre d ose o n Da y 1) or u ntil scree n fail ure. F or s u bjects w h o disc o nti n ue pri or t o st u d y me dicati on 
a d mi nistrati o n, P T Es are c ollecte d u nt il t he s u bject disc o nti n ues st u d y partici pati o n.
C ollect i on of A Es will c o m me nce fr o m t he ti me t hat t he s u bject is first a d mi nistere d st u d y 
me dicat i on ( Da y  1). R o uti ne c ollecti on of A Es will c o nti n ue u nt il t he F oll o w-u p Assess me nt.
1 0. 2. 1. 2 P T E a n d A E Re p orti n g
At  eac h st u d y visit, t he i n vestigat or will assess w het her a n y  s u bjecti ve A Es ha ve occ urre d. A 
ne utral  q uesti on, s uc h as “ H o w ha ve y o u bee n feeli n g si nce y o ur last visit ?” ma y be as ke d. 
S u bjects m a y re p ort A Es occ urrin g at a n y  ot her ti me d uri n g t he st u d y. S u bjects e x perie nci n g a 
serio us P T E m ust be m o nit ore d u ntil t he s y m pt o ms s u bsi de a n d a n y cli nicall y rele va nt c ha n ges i n 
la b orat or y val ues ha ve ret ur ne d t o baseli ne or t here is a sat isfact or y e x pla natio n f or t he c ha n ge. 
N o n -serio us P T Es, rel ate d or u nrelate d t o t he st u d y pr oce d ure, nee d n ot t o be f oll o we d-u p f or t he 
p ur p oses of t he pr ot o c ol .
All s u bjects e x perie nci n g A Es, w het her c o nsi dere d ass ociate d wit h t he use of t he st u d y me dicat i on 
or n ot, m ust be m o ni t ore d u ntil t he s y m pt o ms s u bsi de a n d a n y cli nicall y rele va nt c ha n ges i n 
la b orat or y val ues ha ve ret ur ne d t o baseli ne or u ntil t here is a satisfact or y e x pla nati on f or t he 
c ha n ges o bser ve d. All P T Es a n d A Es will be d oc u me nte d i n t he P T E/ A E pa ge of t he e C R F, 
w het her or n ot t he i n vest i gat or c o ncl u des t hat t he e ve nt is relate d t o t he dr u g treat me nt. T he 
f oll owi n g i nf or mat i on will be d oc u me nt e d f or eac h e ve nt:
1.
E ve nt ter m .
2.
Start a n d st o p date [a n d ti me].
3.
Fre q ue nc y.
4.
Se verit y.
5.
I n vesti gat or’s o pi ni on of t he ca usal relat i ons hi p bet wee n t he e ve nt a n d a d mi nistrati o n of st u d y 
me dicat i on(s) as (relate d or n ot relate d) ( n ot c o m plete d f or P T Es).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
6.
I n vesti gat or’s o pi ni o n of t he ca usal relat i ons hi p t o st u d y  pr oce d ure(s), i ncl u di n g t he details of 
t he s us pecte d pr oce d ure.
7.
Act i on ta ke n c o ncer ni n g st u d y  me dicat i on ( n ot a p plica ble f or P T Es).
8.
O utc o m e of e ve nt.
9.
S eri o us ness .
1 0. 2. 2
C ollecti o n a n d Re p orti n g of S A Es
W he n a n S A E occ urs t hr o u g h t he A E c ollecti o n peri o d it s h o ul d be re p orte d acc or di n g t o t he 
f oll owi n g pr oce d ure:
A Ta ke da S A E f or m m ust be c o m p lete d, i n E n glis h, a n d si g ne d b y t he i n vesti gat or i m me diatel y or 
wi t hi n 2 4 h o urs of first o nset or n otificati o n of t he e vent . T he i nf or mati on s h o ul d be c o m p lete d as 
f ull y as p ossi ble b ut c o ntai n, at a mi ni m u m:

A s h ort descri pt i on of t he e ve nt a n d t he reas o n w h y  t he e ve nt is cate g orize d as seri o us.

S u bject i de ntificat i on n u m ber.

I n vesti gat or’s na me.

N a m e of t he st u d y me dicat i on(s).

Ca usalit y assess me nt.
T he S A E f or m s h o ul d be tra ns mitte d wit hi n 2 4 h o urs t o t he atte nti o n of t he c o ntact liste d i n 
Secti o n  1. 0 .
A n y S A E s p o nta ne o usl y re p orte d t o t he i n vesti gat or f oll owi n g t he A E c ollect i on peri o d s h o ul d be 
re p orte d t o t he s p o ns or if c o nsi dere d relate d t o st u d y partici pat i on.
Re p orti n g of Seri o us P T Es will f o ll o w t he pr oce d ure descri be d f or S A Es.
1 0. 2. 3
Re p orti n g of A b n or m al Li ve r F u ncti o n Tests
If a s u bject is n ote d t o ha ve A L T, A S T, or A L P ele vate d > 3 × U L N o n 2 c o nsec uti ve occasi o ns 
(ie, sc he d ule d visit, re peat test 4 8 h o urs a part), t he a b n or malit y s h o uld be rec or de d as a n A E. I n 
a d ditio n, a n L F T I ncreases e C R F m ust be c o m p lete d pr o vi di n g a d dit i onal i nf or mat i on o n rele va nt 
rece nt hist or y, ris k fact ors, cli nical si g ns a n d s y m pt o ms a n d res ults of a n y a d ditio n al dia g n ostic 
tests perf or me d.
If a s u bject is n ote d t o ha ve A L T, A S T, A L P > 3 × U L N a n d t otal bilir u bi n > 2 × U L N f or w hic h a n 
a lter nat i ve eti ol og y  has n ot bee n ide nt ifie d, t he e ve nt s h o ul d be rec or de d as a n S A E a n d re p orte d 
as per Sectio n  1 0. 2. 2 . T he i n vesti gat or m ust c o nt a ct t he Me dical M o nit or f or disc ussi on of t he 
r ele va nt s u bject details a n d p ossi ble alter nati ve eti ol o gies, s uc h as ac ute viral he pat itis A or B or 
ot her ac ute li ver disease or me dical hist or y /c o nc urre nt me dical c o n ditio n s. F oll ow- u p l a b orat or y 
tests as describe d i n Sect i on  9. 1. 9 m ust als o be perf or me d. I n a d dit i on, a n L F T I ncreases e C R F 
m ust be c o m plete d a n d tra ns mitte d wit h t he Ta ke da S A E f or m (as per Secti o n  1 0. 2. 2 ).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 0. 3
F oll o w -u p of S A Es
If i nf or mati on is n ot a vaila ble at t he ti me of t he first re p ort bec o mes a vaila ble at a later date, t he 
i n vesti gat or s h o uld c o m plete a f oll o w -u p S A E f or m  or pr o vide ot her wri tte n d oc u me ntatio n a n d 
fa x it i m me diatel y withi n 2 4 h o urs of recei pt. C o pies of a n y rele va nt data fr o m t he h os pital n otes 
(e g, E C Gs, la b orat or y tests, disc har ge s u m mar y, p ost m orte m res ults) s h o ul d be se nt t o t he 
a d dressee, if re q ueste d.
All S A Es s h o ul d be f o ll owe d u p u nt il res ol uti on o r p er m a ne nt o utc o me of t he e ve nt. T he ti meli nes 
a n d pr oce d ure f or f oll o w -u p re p orts are t he sa me as t h ose f or t he i nit ial re p ort.
1 0. 3. 1 S afet y Re p orti n g t o I n vesti g at ors, I R Bs or I E Cs, a n d Re g ul at or y A ut h orities 
T he s p o ns or will be res p o nsi ble f or re p orti n g all s us pecte d u ne x pecte d seri o us a d verse react i ons 
( S U S A Rs) a n d a n y ot her a p plica ble S A Es t o re g ulat or y a ut h orities, i n vest i gat ors a n d I R Bs as 
a p plica ble, i n acc or da nc e wit h n atio n al  re g ulati ons i n t he c o u ntries w here t he st u d y  is c o n d ucte d. 
Relati ve t o t he first a ware ness o f t he e ve nt b y/ or furt her pr o visi o n t o t he s p o ns or or s p o ns or’s 
desi g nee, S U S A Rs will be s u b mitte d t o t he re g ulat or y a ut h orities as e x pe dite d re p ort wit hi n 7 da ys 
f or fatal a n d life-t hreate ni n g e ve nts a n d 1 5 da ys f or ot her seri o us e ve nts, u nless ot her wise re q uire d 
b y nati o n al  re g ulati ons. T he s p o ns or will als o pre pare a n e x pe dite d re p ort f or ot her safet y iss ues 
w here t hese mi g ht materiall y  alter t he curre nt be nefit -ris k assess me nt of a n i n vesti gati o nal 
me dici nal pr o d uct or t hat w o ul d be s ufficie nt t o c o nsi der c ha n ges i n t he i n vest i gati onal me dici nal 
pr o d ucts a d mi nistrati o n or i n t he o verall c o n d uct of t he trial. T he i n vest i gati onal site als o will 
f or war d a c o p y of all e x pe dite d re p orts t o his or her I R B.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 1. 0
S T U D Y -S P E CI FI C C O M MI T T E E S
N o steeri n g c o m mittee, data safet y  mo ni t ori n g c o m mittee, or cli nical e n d p oi nt c o m mittee will be 
use d i n t his st u d y .
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 2. 0
D A T A H A N D LI N G A N D R E C O R D K E E PI N G
T he f ull details of pr oce d ur es f or data ha n dli n g will be d oc u me nte d i n t he Data Ma na ge me nt Pla n. 
A Es, P T Es, me dical hist or y, a n d c o nc urre nt c o n dit i o ns will be c o de d usi n g t he Me dical Dicti onar y 
f or Re g ulat or y Acti vit ies ( Me d D R A). Dr u gs will be c o de d usi n g t he W orl d Healt h Or ga nizati on 
( W H O) Dr u g Dicti o nar y.
1 2. 1
C R Fs ( Electr o nic)
C o m plete d e C R Fs are re q uire d f or eac h s u bject w h o si g ns a n i nf or me d c o nse nt.
T he s p o ns or or its desi g nee will s u p pl y i n vesti gati ve sites wit h access t o e C R Fs . T he s p o ns or will 
ma ke arra n ge me nts t o trai n a p pr o priate site staff i n t he use of t he e C R F. T hese f or ms are use d t o 
tra ns mit t he i nf or mati on c o llecte d i n t he perf or ma nce of t his st u d y t o t he s p o ns or a n d re g ulat or y 
a ut h orities. e C R Fs m ust be c o m plete d i n En glis h.
After c o m plet i on of t he e ntr y pr ocess, c o m p uter l o gic c hec ks will be r u n t o i de ntif y ite ms, s uc h as 
i nc o nsiste nt dates, missi n g data, a n d q uesti o na ble val ues. Q ueries ma y be iss ue d b y Ta ke da 
pers o n nel ( or desi g nees) a n d will be a ns were d b y t he site .
C orrecti o ns t o e C R Fs are rec or de d i n a n a u dit trail t hat ca pt ures t he ol d i nf or mati o n, t he ne w 
i nf or mat i on, i de nt ificati on of t he pers o n ma ki n g t he c orrecti o n, t he date t he c orrecti o n was ma de, 
a n d t he reas o n f or c ha n ge. Reas o ns f or si g nifica nt c orrectio ns s h o ul d a d di tio nall y be i ncl u de d.
T he pri nci pal i n vest i gat or m ust re vie w t he e C R Fs f or c o m plete ness a n d acc urac y a n d m ust si g n 
a n d date t he a p pr o priate e C R Fs as i n dicate d. F urt her m ore, t he i n vesti gat or m ust retai n f ull 
res p o nsi bility f or t he accurac y  a n d a ut he nticity of  all data e ntere d o n t he e C R Fs.
After t he loc k of t he c li nical st u d y data base, a n y c ha n ge of, m o dificat i on of, or a d dit i on t o t he data 
o n t he e C R Fs s h o uld b e m a de b y t he i n vestig at or wi t h use of c ha n ge a n d m o dificati on rec or ds of 
the e C R Fs. T he pri nci pal i n vesti gat or m ust re vie w t he data c ha n ge f or c o m plete ness a n d acc urac y, 
a n d m ust si g n a n d date.
T he e C R Fs will be re vie we d f or c o m plete ness a n d acce pta bilit y at t he st u d y  site d uri n g perio dic 
visit s b y st u d y mo ni t ors. T he s p o ns or or its desi g nee will be per mitte d t o re vie w t he s u bject’s 
me dical a n d h os pital rec or ds perti ne nt t o t he st u d y  t o e ns ure acc urac y of t he e C R Fs. T he 
c o mplete d e C R Fs are t he s ole pr o pert y  of t he s p o ns or a n d s h o ul d n ot be ma de a vaila ble i n a n y 
f or m t o t hir d parties, e xce pt f or a ut h orize d re prese ntati ves of a p pr o priate g o ver n me ntal healt h or 
re g ulat or y a ut h orities, wit ho ut wri tte n per missi on of t he s p o ns or.
1 2. 2
Rec or d Rete nti o n
T he i n vest i gat or a grees t o kee p t he rec or ds sti p ulate d i n Secti o n 1 2. 1 a n d t h ose d oc u me nts t hat 
i ncl u de ( b ut are n ot li mite d t o) t he st u d y-s pecific d oc u me nts, t he i de ntificati on l og of  all 
parti ci pat i n g s u bjects, me dical rec or ds, te m p orar y me dia s uc h as t her mal se nsit i ve pa per, s o urce 
w or ks heets, all ori gi nal si g ne d a n d date d i nf or me d c o nse nt f or ms, s u bject a ut h orizat i on f or ms 
re gar di n g t he use of pers o nal health i nf or mati o n (if se parate fr o m t he i nf or me d c o nse nt f or ms), 
q uer y  res p o nses/ ele ctr o nic c o p y of e C R Fs, i ncl u di n g t he a u dit trail, a n d detaile d rec or ds of dr u g 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 0 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
di s p ositio n t o e na ble e val uat i ons or a u dits fr o m re g ulat or y a ut h orities, t he s p o ns or or its desi g nees. 
A n y s o urce d oc u me ntati o n pri nte d o n de gra da ble t her mal se nsit i ve pa per s h o ul d be p h ot oc o pie d 
b y t he site a n d file d wit h t he ori gi nal i n t he s u bject’s c hart t o e ns ure l o n g -t er m le gi bilit y. 
F urt her m or e, I n ter natio nal C o nfere nce o n Har m o nisati o n (I C H) E 6 Secti o n 4. 9. 5 re q uires t he 
i n vesti gat or t o retai n esse ntial d oc u me nts s pecifie d i n I C H E 6 ( Secti o n 8) u ntil at least 2 years after 
t he last a p pr o val of a mar keti n g a p plicati o n f or a s pecifie d dr u g i n dicat i on bei n g i n vest i gate d or, if 
a n a p plicat i on is n ot a p pr o ve d, u ntil at least 2 year s after t he i n vesti gati on is disc o nti n ue d a n d 
r eg ul at or y a ut h orities are n otifie d. I n a d diti on, I C H E 6 Secti o n 4. 9. 5 states t hat t he st u d y  rec or ds 
s h o uld be retai ne d u nt il a n a m o u nt of ti me s pecifie d b y a p plica ble re g ulat or y re q uire me nts or f or a 
ti me s pecifie d i n t he Cli nical St u d y Site A gree me nt bet wee n t he i n vesti gat or a n d s p o ns or.
Refer t o t he P hase 1 Site S pecificat i ons d oc u m e nt for t he s p o ns or’s re q uire me nts o n rec or d 
rete ntio n. T he i n vest i gat or s h o ul d c o ntact a n d recei ve writte n a p pr o val fr om t he s p o ns or bef ore 
di s p osi n g of a n y s uc h d oc u me nts.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 0 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 3. 0 
S T A TI S TI C A L M E T H O D S
1 3. 1 
St atistic al a n d A n al ytic al Pl a ns
A statistic al a nal ysis pla n ( S A P) will be pre pare d a n d fi nalize d pri or t o u n bli n di n g of s u bject’s 
treat me nt assi g n me nt. T his d oc u me nt will pr o vi de f urt her details re gar di n g t he defi niti o n of 
a nal ysis varia bles a n d a nal ysis met h o d ol o g y t o a d dress all st u d y o bjecti ves.
1 3. 1. 1  A n al ysis Sets 
T he a nal ysis sets will be defi ne d se paratel y f or eac h part of t he st u d y.
S afety Set
T he safet y a nal ysis set will c o nsist of all s u bjects w h o are e nr olle d a n d recei ve d 1 d ose of st u d y 
dr u g. S u b jects i n t his a nal ysis set will be use d f or de m o gra p hic, baseli ne c haracteristics, a n d safet y 
s u m maries.
P K Set
T he P K set will c o nsist of all s u bjects w h o recei ve st u d y dr u g a n d ha ve at least 1 meas ura ble 
plas ma c o nce ntrati o n or a m o u nt of dr u g i n t he uri ne.
If a n y s u bjects are f o u n d t o be n o nc o m plia nt i n d osi n g sc he d ule or wit h i nc o m plete data, a 
decisi o n will be ma de o n a case- b y- case basis as t o t heir i ncl usi o n i n t he a nal ysis b ut will be 
prese nte d i n t he s u bject listi n gs.
P D Set
1 3. 1. 2  
A n al ysis of De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics
F or eac h part of t he st u d y, descri pti ve statistics  ( N,  mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) 
will be ge nerate d f or c o nti n u o us de m o gra p hic varia bles a n d baseli ne c haracteristics varia bles (a ge, 
hei g ht, wei g ht, a n d B MI) f or p o ole d place b o, eac h T A K- 0 4 1 d ose le vel, T A K- 0 4 1 o verall, a n d 
o verall t otal. F or eac h Part, t he n u m ber a n d perce nta ge of s u bjects i n eac h class of t he cate g orical 
d e m o gra p hic varia bles a n d baseli ne c haracteristics varia bles (se x, et h nicit y, a n d race) will be 
ta b ulate d f or p o ole d place b o gr o u p, eac h T A K- 0 4 1 d ose le vel, T A K- 0 4 1 o verall, a n d o verall t otal. 
Place b o data will be p o ole d acr oss t he c o h orts wit hi n eac h part.
F or eac h Part, de m o gra p hic varia bles of scree n fail ure s u bjects a n d reas o ns f or scree n fail ures will 
be s u m marize d o verall f or s u bjects w h o are scree ne d b ut n ot e nr olle d i n t he st u d y. I n di vi d ual 
d e m o gra p hic c haracteristics, date of i nf or me d c o nse nt, a n d reas o n f or scree n fail ure will be liste d.
1 3. 1. 3 
P h ar m ac o ki ne tic A n al ysis
C o nce ntrati o ns of T A K- 0 4 1 i n plas ma will be s u m marize d b y d ose o ver eac h sc he d ule d sa m pli n g 
ti me usi n g descri pti ve statistics f or eac h st u d y part. A m o u nt of T A K- 0 4 1 e xcrete d i n uri ne will be 
Pr o p ert y of T a k e d a: F or n o n- c o 
l u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
ct’s 
ct s 
of 
of
n d recei
n d rece
aseli ne c h
seli ne 
d y dr u g 
dr u g
y
e.
d osi n g 
d osi n g
s as t o t
as t o
m o gr a p h
m o gr
st u d y
u d y , de
, d
f or c o nti
r c o n
a n d B M
a n d B
F or eac
F or ea
p hic vari
hic v
te d f or p
d f or p
ce b o dat
ce b o da
F or eac
F or ea
be s u
be s
d e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 0 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
s u m marize d b y d ose o ver eac h sc he d ule d sa m pli n g i nter val usi n g descri pti ve statistics f or eac h 
st u d y part. I n di vi d ual P K data will be prese nte d i n a data listi n g. P K para meters of T A K- 0 4 1 will 
be s u m marize d b y d ose usi n g descri pti ve statistics f or eac h st u d y part. D ose pr o p orti o nalit y will be 
assesse d gra p hicall y ( d os e- n or malize d C ma x a n d A U C vers us d ose) i n Part 1 a n d Part 2. T o assess 
d ose pr o p orti o nalit y of si n gle d osi n g ( Part 1), a p o wer m o del will be use d. T he m o del will i ncl u de 
t he nat ural l o g-tra nsf or me d A U C a n d Cma x as res p o nse varia ble a n d t he nat ural l o g-tra nsf or me d 
d ose [l n( d ose)] as a c o nti n u o us c o variate. N o f or mal statist ical c o m p aris o ns will be c o n d ucte d. F or 
Part 2, d ose pr o p orti o nalit y will be assesse d usi n g a n a nal ysis of v aria nce ( A N O V A) m o d el 
se paratel y f or d ose- n or malize d A U C a n d C ma x o n Da y 2 2 wit h treat me nt (as a cate g orical varia ble) 
as a fi xe d effect. T he d ose- n or malize d para meters will be nat ural l o g-tra nsf or me d pri or t o t he 
a nal ysis. All treat me nt differe nces a n d c orres p o n di n g t w o-si d e d 9 0 % CIs will be e xtracte d fr o m 
t he m o d el, bac k-tra nsf or me d, a n d e x presse d as ce ntral val ue rati os.
T he effect of f o o d o n T A K- 0 4 1 e x p os ure will be e val uate d i n Part 3 usi n g a n A N O V A o n t he 
nat ural l o g-tra nsf or me d T A K- 0 4 1 C ma x a n d  A U C 9 6 wit h re gi me n ( hi g h-fat vs. faste d) as a fi xe d 
effect. T he L S mea n differe nce bet wee n re gi me ns a n d t he c orres p o n di n g t w o-si de d 9 0 % CI will be 
e xtracte d fr o m t he m o del, bac k-tra nsf or me d, a n d e x presse d as ce ntral val ue rati os of T A K- 0 4 1 
e x p os ure after t he hi g h-fat me al vers us t he faste d state. 
T he relati ve bi oa vaila bilit y of T A K- 0 4 1 a d mi nistere d as a 4 0 m g i m me diate release ta blet 
f or m ulati o n c o m pare d t o t he 4 0 m g oral s us pe nsi o n f or m ulati o n i n t he faste d state will als o be 
assesse d usi n g a n A N O V A m o del. S u bjects a d mi nistere d t he 4 0 m g oral s us pe nsi o n i n Part 1 a n d 
Part 2 ( Da y 1 data o nl y) will be p o ole d t o get her a n d treate d as t he refere nce re gi me n f or t his 
a nal ysis; s u bjects treate d wit h t he T A K- 0 4 1 4 0 m g ta blet f or m ulati o n u n der t he faste d c o n diti o n i n 
Part 3  will be t he test re gi me n. T he A N O V A will be perf or me d o n t he nat ural l o g-tra nsf or me d Da y 
1 T A K- 0 4 1 C ma x a n d  A U C 9 6 wit h re gi me n as a fi xe d effect. T he L S mea n differe nce bet wee n 
re gi me ns a n d t he c orres p o n di n g t w o-si d e d 9 0 % CI will be e xtracte d fr o m t he m o d el, 
bac k-tra nsf or me d, a n d e x presse d as ce ntral val ue rati os.
1 3. 1. 4 
E x pl or at or y A n al yses
Pr o p e
c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
be e 
ssess 
sess 
i ncl u de 
i ncl u d
sfsfor m
or m
f
e d
o n d ucte d
n d uct
V A) m
V A) m o d
cate g oric
ate g ori
f or me d p
me d p
s will be
will b
t 33 usi n g
usi n
n ( hi g h
n ( hi g h
orres p o n d
res p o n
e d as ce
e d as c
. 
re d as a 
e d as 
si oo n n f of or
a d mi nist
mi ni
get her a n
et her
0 4 1 4 0 
0 4 1 4 0
A N O V A 
N O V
re gi me n 
e gi me
n g t w o
g t w o -si
esse d as
sse d a
n al ys
al y
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 1 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 3. 1. 5 
S afet y A n al ysis
S afet y data will be prese nte d b y T A K- 0 4 1 d ose a n d place b o f or eac h part.
T E A Es will be s u m marize d b y place b o, eac h T A K- 0 4 1 d ose le vel, a n d T A K- 0 4 1 o verall f or eac h 
st u d y part.
Cli nical la b orat or y varia bles, vital si g ns, a n d E C G para meters will be s u m marize d wit h 
descri pti ve statistics f or baseli ne, p ost d ose, a n d c ha n ge fr o m baseli ne t o p ost d ose val ues b y d ose 
a n d sc he d ule d ti me p oi nt f or eac h st u d y part. I n Part 2, c o nti n u o us H olt er E C G m o nit ori n g 
para meters will be e xtracte d i n tri plicate a n d t he a vera ge of t he 3 val ues at eac h ti me p oi nt will be 
calc ulate d a n d use d f or all statist ical a nal yses a n d s um maries. U nc orrecte d a n d c orrecte d Q T 
i nt er vals, P R, a n d Q R S i nter vals a n d heart rate, as well as t heir c ha n ges fr o m baseli ne will be 
s u m marize d at eac h sc he d ule d ti me p oi nt.
P ote ntial Q T pr ol o n gati o n will be assesse d usi n g t he H olter E C G meas ure me nts i n Part 2. A li near 
mi xe d effect m o del f or re peate d meas ures will be use d. T he res p o nse varia ble i n t he m o del will be 
t he c ha n ge fr o m t he ti me- mat c he d baseli ne i n t he a vera ge of t he tri plicate c orrecte d Q T i nter vals 
( Q Tc). T he ti me- matc he d baseli nes will c o me fr o m t he E C Gs ta ke n o n Da y - 1 ( 2 3, 2 2, 2 0, 1 6, a n d 
1 2 h o urs bef ore d osi n g). T he  m o d el will i ncl u de treat me nt, ti me (as a cate g orical varia ble), a n d t he 
treat me nt- b y-ti me i nt eracti o n as fi xe d effects, s u bject as a ra n d o m effect, baseli ne as a c o variate, 
a n d t he baseli ne- b y-ti me i nt eracti o n as a n a d diti o n al fi xe d effect. T he L S mea n c ha n ge fr o m 
ti me- matc he d baseli ne f or eac h treat me nt a n d t he ass ociate d sta n dar d err or a n d t w o-si de d 9 5 % CI 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e
K -0 4 1 d
0 4 1
place b o,
ace b o
bles, vita
les, vi
f or baseli
r base
e p oi nt f o
p oi nt 
be e xtra
e e xtr
d use d f o
d use d 
P R, a n d 
R, a n
rize d at 
ze d at
e nti
nti alal QQl
mi xe d ef
mi xe d e
t h
t he c h
e 
( Q
s e
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
will be e xtracte d f or eac h treat me nt at eac h ti me p oi nt, as well as differe nces fr o m place b o a n d 
ass ociate d sta n dar d err ors, t w o -si de d 9 5 % CIs, a n d p - values.
A se parate li near mi xe d effects m o del will be use d t o assess t he relat i ons hi p bet wee n t he c ha n ge 
fr om t i me-matc he d baseli ne i n Q Tc a n d T A K -0 4 1 e x p os ure i n Part 2. T he res p o nse varia ble i n t he 
m o d el  will be t he c ha n ge fr o m ti me-matc he d baseli ne i n Q T c. T he mo d el  will i ncl u de T A K- 0 4 1 
pl as ma c o nce ntrati o n (as a c o nti n u o us varia ble) as a fi xe d effect a n d s u bject as a ra n d o m effect. 
Pl ace b o s u bjects will be i ncl u de d i n t he a nal ysis wit h a pl as ma c o nce ntrati o n of 0. T he esti mate d 
re gressi o n li ne a n d t he 9 0% c o nfi de nce ba n d f or t he re gressi o n li ne will be e xtracte d fr o m t he 
m o d el . T h e r elat i ons hi p bet wee n t he c ha n ge fr o m ti me-matc he d baseli ne i n Q Tc a n d T A K - 0 4 1 
pl as ma c o nce ntrati o n will als o be e xa mi ne d gra p hicall y usi n g a scatter pl ot. T he re gressi o n li ne 
a nd 9 0 % c o nfi de nce ba n d f or t he re gressi o n li ne esti mate d fr o m t he m o del will be o verlai d o nt o 
t he scatter pl ot.
T he n u m ber a n d perce nta ge of s u bjects wit h p ost d ose val ues meeti n g Ta ke da’s criteria f or 
mar ke dl y  a b n or mal val ues f or cli nical la b orat or y v aria bles, vital si g ns, a n d E C G para meters will 
be prese nte d b y d ose. Ne ur ol o gical assess me nts will be j u d ge d n or mal, a b n or mal, C S or N C S. All 
s u m maries will be perf or me d b y p o ole d place b o wit hi n c o h ort a n d T A K- 0 4 1 d ose l e vel. P h ysical 
e xa mi nat i on fi n di n gs will be prese nte d i n data list i n gs. I n di vi d ual res ults of B L-V A S a n d t he 
C- S S R S will be liste d.
All A Es will be c o de d usi n g Me d D R A. Data will be s u m marize d usi n g preferre d ter m a n d pri mar y 
s yste m or ga n class.
1 3. 2
I nteri m A n al ysis a n d Criteri a f or E arl y Ter mi n ati o n
Se ctio n  6. 1. 6 descri bes safet y,  t olera bilit y, a n d P K re vie ws t hat will ta ke place after c o m pleti on of 
eac h c o h ort/ peri o d a n d pri or t o t he ne xt d ose e scalati o n sta ge i n t he st u d y. St u d y-s pecific d ose 
escalat i on a n d st o p pi n g r ules are descri be d i n Secti o n  6. 3. 2.
A n u n bli n de d i nteri m a nal ysis ma y be p erf or m e d i n Part 4. T he p ur p ose of  the a nal ysis w o ul d be t o 
assess safet y a n d efficac y of T A K -0 4 1 i n t he case of sl o wer t ha n a nt ici pate d e nr oll me nt of  s u bjects 
wi t h sc hiz o p hre nia.
1 3. 3
Deter mi n ati o n of S a m ple Size
T he sa m ple size c h ose n of 8 s u bjects per c o h o rt ( 6 acti ve: 2 place b o) i n Part 1 C o h orts 1-5 a n d Part 
2 C o h orts 1 -4 is base d u p o n prece de nts of ot her first -i n-h u ma n trials rat her t ha n a f or mal 
assess me nt of statistical p o wer. T his sa m ple size is c o nsi dere d s ufficie nt f or i n vest i gati n g t he 
o bj ect i ves of t he st u d y a n d c haracterizi n g a n y p ote ntial effects o n safet y para meters.
F or Part 3, wit h a sa m ple size of 1 6 s u bjects ( 8 per re gi me n), ass u mi n g a c oefficie nt of variat i on 
( %) f or t he Cma x of  T A K-0 4 1 of 1 3. 8 %, a t w o -si de d 9 0 % c o nfi de nce i nter val f or t he differe nce i n 
l og- tra nsf or me d C ma x bet wee n fe d a n d faste d will e xte n d n o m ore t ha n 0. 1 3 fr o m t he o bser ve d 
mea n differe nce. As a n e xa m ple, if t he o bser ve d rati o bet wee n t he t w o re gi me ns is 1. 5, 
re prese nti n g a 5 0 % i ncrease i n e x p os ure d ue t o f o o d, t he n t he co nfi de nce i nter val f or t he tr ue rati o 
will e xte n d fr o m 1. 3 2 t o 1. 7 1. Si milarl y, if t he o bser ve d rati o is 1. 0, re prese nt i n g n o effect of f o o d, 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 1 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
t he n t he c o nfi de nce i nter val f or t he tr ue rati o will e xte n d fr o m 0. 8 8 t o 1. 1 4. T he e x pecte d 
varia bilit y i n t he A U C 9 6 of T A K- 0 4 1 is lar ger t ha n i n C ma x . I n a w orst-case sce nari o, ass u mi n g a 
c oefficie nt of variati o n ( %) f or A U C 9 6 of 2 6. 8 %, t he c o nfi de nce i nter v al will e xte n d n o m ore t ha n 
0. 2 5 fr o m t he o bser ve d mea n differe nce. If t he o bser ve d rati o bet wee n t he t w o re gi me ns is 1. 5, 
re prese nti n g a 5 0 % i ncrease i n e x p os ure d ue t o f o o d, t he n t he c o nfi de nce i nter val f or t he A U C 9 6 
r ati o will e xte n d fr o m 1. 1 7 t o 1. 9 3. If t he o bser ve d rati o is 1. 0, re prese nti n g n o effect of f o o d, t he n 
t he c o nfi de nce i nter val will e xte n d fr o m 0. 7 8 t o 1. 2 8. Ta ke n t o get her, t hese res ults are c o nsi dere d 
t o re prese nt a de q uate precisi o n f or t he esti mate d f o o d effect. T he ass u me d varia bilit y i n Cma x a n d 
A U C 9 6 are esti mates fr o m t he c o m plete d c o h orts i n Part 1 of t his st u d y. T o acc o u nt f or p ote ntial
disc o nti n uati o ns, 1 8 s u bjects ( 9 per re gi me n) will be e nr olle d.
S u bjects w h o dr o p o ut f or n o n-safet y reas o ns ma y be re place d o n a case- b y-case basis at t he 
discreti o n of t he s p o ns or i n c o ns ultati o n wit h t he i n vesti gat or. S u bjects w h o re place dr o p o uts will 
be all ocate d t o t he sa me C o h ort as t he s u bject t he y re place. S u bjects w h o dr o p o ut f or safet y 
reas o ns will n ot be re place d.
Pr o p ert y of T a k e d a: F or n o n- c o m m er
afetet y y
o ns ultati o
ns ulta
o h ort as 
h ort a
ace d.
e d.
a p pli c a bl e T er m s of U s e
a n n 
. 5, 
5, 
A U C
A U C 9 6 
9 6
f f o o d, t h
f o o d
are c o nsi
e c o n
ilit
ility y i n 
i n C
c o u nt f or
o u nt f
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 4. 0
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E
1 4. 1
St u d y -Site M o nit ori n g Visits
M o ni t ori n g visits t o t he st u d y site will be ma de perio dicall y  d uri n g t he st u d y t o e ns ure t hat all 
as pects of t he pr ot oc ol are f o ll owe d. S o urce d oc u me nts will be re vie we d f or verificat i on of data 
rec or de d o n t he e C R Fs. S o urce d oc u me nts are defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds. 
T he i n vest i gat or a n d i nstitut i on g uara ntee access t o s o urce d oc u me nts b y  t he s p o ns or or its 
desi g nee ( C R O) a n d b y  t he I R B or I E C.
All as pects of t he st u d y a n d its d oc u me ntati o n will be s u bject t o re vie w b y t he s p o ns or or de sig nee 
(as lo n g as bli n di n g is n ot je o par dize d), i ncl u di n g b ut n ot li mite d t o t he I n vest i gat or’s Bi n der, 
st u d y me dicat i on, s u bject me dical rec or ds, i nf or me d c o nse nt d oc u me ntati o n, d oc u me ntati o n of 
s u bject a ut h orizati on t o use pers o nal healt h i nf or mati o n (if se parate fr om t he i nf or me d c o nse nt 
f or ms), a n d re vie w of e C R Fs a n d ass ociate d s o urce d oc u me nts. It is i m p orta nt t hat t he i n vest i gat or 
a n d ot her st u d y pers o n nel are a vaila ble d uri n g t he m onit ori n g visits a n d t hat s ufficie nt ti me is 
de v ote d t o t he pr ocess.
1 4. 2
Pr ot oc ol De vi ati o ns
T he i n vest i gat or s h o ul d n ot de viate fr om t he pr ot oc ol, e xce pt w here necessar y t o eli mi nate a n 
i m me diate hazar d t o st u d y s u bjects. S h o ul d ot her u ne x pecte d circ u msta nces arise t hat will re q uire 
de viat i on fr om pr ot oc ol -s pecifie d pr oce d ures, t he i n vesti gat or s h o ul d c o ns ult wit h t he s p o ns or or 
desi g nee (a n d I R B or I E C, as re q uire d) t o deter mi ne t he a p pr o priate c o urse of  acti o n. T here will be 
n o e xe m pt i ons (a pr os pecti vel y a p pr o ve d de viat i on) fr o m t he i ncl usi o n or e xcl usi o n cri t eria.
T he site s h o uld d oc u me nt all pr ot oc ol de viat i ons i n t he s u bject’s s o urce d oc u me nts. I n t he e ve nt of 
a sig nifica nt de vi at i on, t he si te s h o uld n otif y  t he s p o ns or or its desig nee (a n d I R B or I E C, as 
re q uire d). Sig nifica nt de vi at i ons i ncl u de, b ut are n ot li mite d t o, t h ose t hat i n v o l ve fra u d or 
misc o n d uct, i ncrease t he healt h ris k t o t he s u bject, or c o nf o u n d i nter pretati o n of pri mar y st u d y 
assess me nt. T he Si g nifica nt Pr ot oc ol De viat i on e C R F is t o be c o m plete d f or de viat i ons t hat are 
i de ntifie d as si g nifica nt b y t he s p o ns or.
E ver y  att e mpt will be m a de t o c ollect eac h p har mac o ki net ic bl o o d sa m ple at t he desi g nate d ti m e 
p oi nt, a n d t he act ual t i me of eac h bl o o d sa m ple will be rec or de d o n t he s o urce d oc u me nt a n d 
e C R F.
1 4. 3
Q u alit y Ass ur a nce A u dits a n d Re g ul at or y A ge nc y I ns pecti o ns
T he st u d y  site als o ma y be s u bject t o q ualit y ass ura nce a u dits b y t he s p o ns or or desig nees. I n t his 
circ u msta nce, t he s p o ns or-desi g nate d a u di t or will c o ntact t he site i n a d va nce t o arra n ge a n 
a u ditin g visit. T he a u dit or ma y as k t o visit t he facilit ies w here la b orat or y sa m ples are c ollecte d, 
w here t he me dicati o n is st ore d a n d pre pare d, a n d a n y ot her facilit y use d d uri n g t he st u d y . I n 
a d ditio n, t here is t he p ossi bilit y t hat t his st u d y ma y be i ns pecte d b y re g ulat or y a ge ncies, i ncl u di n g 
t hose of f orei g n g o ver n me nts (e g, t he F D A, t he U nite d Ki n g d o m Me dici nes a n d Healt hcare 
pr o d ucts Re g ulat or y  A ge nc y, t he P har mace uticals a n d Me dical De vices A ge nc y o f Ja pa n). If t he 
st u d y site is c o ntacte d f or a n i ns pecti on b y a re g ulat or y  b o d y, t he s p o ns or s h o ul d be n otifie d 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
i m mediatel y . T he i n vesti gat or a n d i nstitut i on g uara ntee access f or q ualit y a ss ura nce a u dit ors t o all 
st u d y d o c u me nts as descri be d i n Secti o n  1 4. 1 .
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 5. 0
E T HI C A L A S P E C T S O F T H E S T U D Y
T his st u d y  will be c o n d ucte d wit h t he hi g hest res pect f or t he i n di vi d ual partici pa nts (ie, s u bjects) 
acc or di n g t o t he pr ot oc ol, t he et hical pri nci ples t hat ha ve t heir ori gi n i n t he Declarat i on o f Helsi n ki, 
a n d t he I C H Har m o nise d Tri parti t e G uideli ne f or G C P. Eac h i n vest i gat or will c o n d uct t he st u d y 
acc or di n g t o a p plica ble l ocal or re gi o nal re g ulat or y re q uire me nts a n d ali g n his or her c o n d uct i n 
acc or da nce wit h t he “ Res p o nsi bilit ies of t he I n vesti gat or” t hat are liste d i n A p pe n di x F . T he 
pri nci ples of Helsi n ki are a d dresse d t hr o u g h t he pr ot oc ol a n d t hr o u g h a p pe n dices c o ntai ni n g 
re q uire me nts f or i nf or me d c o nse nt a n d i n vesti gat or res p o nsi bilities.
1 5. 1
I R B a n d/ or I E C A p pr o v al
I R Bs a n d I E Cs m ust be c o nstit ute d acc or di n g t o t he a p plica ble state a n d fe deral/l ocal re q uire me nts 
of  t he partici pati n g re gi on. T he s p o ns or or desi g nee will re q uire d oc u me ntati o n n oti n g all na mes 
a n d tit les of me m bers w h o ma ke u p t he res pecti ve I R B or I E C. If a n y me m ber of t he I R B or I E C 
has di rect partici pat i on i n this st u d y , writte n n otificati o n re gar di n g his or her a bsti ne nce fr om 
v oti n g m ust als o be o btai ne d. T h ose A mericas sites u n willi n g t o pr o vi de na mes a n d tit les of all 
me m bers d ue t o pri vac y  a n d c o nflict of i nterest c o ncer ns s h o ul d i nstea d pr o vi de a Fe deral Wi de 
Ass ura nce N u m ber or c o m para ble n u m ber assi g ne d b y t he De part me nt of Healt h a n d H u ma n 
Ser vices.
T he s p o ns or or desi g nee will s u p pl y rele va nt d oc u me nts f or s u b missi o n t o t he res pecti ve I R B or 
I E C f or t he pr ot oc ol’s re vie w a n d a p pr o val. T his pr ot oc ol, t he I n vesti gat or’s Br oc h ure, a c o p y of 
t he i nf or me d c o nse nt f or m, a n d, if a p plica ble, s u bject recr uit me nt  materials a n d/ or a d vertise me nts 
a n d ot her d oc u me nts re q uire d b y all a p plica ble la ws a n d re g ulati o ns, m ust be s u b mitte d t o a 
ce ntral or lo c al  I R B or I E C for a p pr o val. T he I R B’s or I E C’s writte n a p pr o val of t he pr ot oc ol a n d 
s u bject i nf or me d c o nse nt m ust be o btai ne d a n d s u b mitte d t o t he s p o ns or or desi g nee bef ore 
c o m me nce me nt of t he st u d y (ie, bef ore s hi p me nt of t he s p o ns or -s u p plie d dr u g or st u d y s pecific 
scree ni n g acti vit y). T he I R B or I E C a p pr o val m ust refer t o t he st u d y  b y e xact pr ot oc ol title, 
n u m ber, a n d versi o n date; i de nt if y versi o ns of ot her d oc u me nts (e g, i nf or me d c o nse nt f or m) 
re vie we d; a n d state t he a p pr o val date. T he s p o ns or will s hi p dr u g a n d n otif y site o nce t he s p o ns or 
has c o nfir me d t he a de q uac y  of sit e r e g ulat or y d oc u me ntatio n a n d, w he n a p plica ble, t he s p o ns or 
has recei ve d per missi o n fr om c o m pete nt a ut h orit y t o be gi n t he trial.
Si t es must a d here t o all re q uire me nts sti p ulate d b y  t heir res pecti ve I R B or I E C. T his ma y i ncl u de 
n otificati o n t o t he I R B or I E C re gar di n g pr ot oc ol a me n d me nts, u p dates t o t he i nf or me d c o nse nt 
f or m, r e cr uit me nt mat erials i nte n de d f or vie wi n g b y s u bjects, lo c al  s af et y re p ortin g re q uire me nts, 
re p orts a n d u p dates re gar di n g t he o n g oi n g re vie w of t he st u d y  at i nter vals s pecifie d b y t he 
res pecti ve I R B or I E C, a n d s u b missi on of t he i n vesti gat or’s fi nal stat us re p ort t o I R B or I E C. All 
I R B a n d I E C a p pr o vals a n d rele va nt d oc u me ntati o n f or t hese ite ms m ust be pr o vi de d t o t he 
s p o ns or or its desi g nee.
S u bject i nce nti ves s h o ul d n ot e xert u n d ue i nfl ue nce f or partici pat i on. Pa y me nts t o s u bjects m ust 
be a p pr o ve d b y t he I R B or I E C a n d s p o ns or.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 5. 2
S u bject I nf or m ati o n, I nf or me d C o nse nt, a n d S u bject A ut h oriz ati o n
Wr itte n c o nse nt d oc u me nts will e m b od y  t he ele me nts of i nf or me d c o nse nt as descri be d i n t he 
Declarati o n of Helsi n ki a n d t he I C H G ui deli nes f or G C P a n d will be i n acc or da nce wit h all 
a p plica ble la ws a n d re g ulati o ns. T he i nf or me d c o nse nt f or m, s u bject a ut h orizat i on f or m (if 
a p plica ble), a n d s ubject i nf or mat i on s heet (if a p plica ble) descri be t he pla n ne d a n d per mitte d uses, 
tra nsfers, a n d discl os ures of t he s u bject’s pers o nal a n d pers o nal healt h i nf or mat i on f or p ur p oses of 
c o n d ucti n g t he st u d y. T he i nf or me d c o nse nt f or m a n d t he s u bject i nf or mat i on s heet (if a p plica ble) 
f urt her e x plai n t he nat ure of  the st u d y, its o bject i ves, a n d p ote ntial ris ks a n d be nefits, as well as t he 
date i nf or me d c o nse nt is gi ve n. T he i nf or me d c o nse nt f or m will detail t he re q uire me nts of t he 
parti ci pa nt a n d t he fact t hat he or s he is free t o wit h dra w at a n y  ti me wit ho ut gi vi n g a reas o n a n d 
wi t ho ut prej u dice t o hi s or her f urt her me dical care.
T he i n vest i gat or is res p o nsi ble f or t he pre parati o n, c o nte nt, a n d I R B or I E C a p pr o val of t he 
i nf or me d c o nse nt f or m a n d if a p plica ble, t he s u bject a ut h orizati o n f or m. T he i nf or me d c o nse nt 
f or m, s u bject a ut h orizati on f or m (if a p plica ble), a n d s u bject i nf or mati o n s heet (if a p plica ble) m ust 
be a p pr o ve d b y b ot h t he I R B or I E C a n d t he s p o ns or pri or t o use.
T he i nf or me d c o nse nt f or m, s u bject a u t hori zat i on f or m (if a p plica ble), a n d s u bject i nf or mati on 
s heet (if a p plica ble) m ust be writte n i n a la n g ua ge f ull y c o m pre he nsi ble t o t he pr os pecti ve s u bject. 
It is t he res p o nsi bility of  t he i n vesti gat or t o e x plai n t he detaile d ele me nts of t he i nf or me d c o nse nt 
f or m, s u bject a ut h orizati on f o r m (if a p plica ble), a n d s u bject i nf or mati on s heet (if a p plica ble) t o t he 
s u bject. I nf or mati o n s h o ul d be gi ve n i n b ot h oral a n d writte n f or m w he ne ver p ossi ble a n d i n t he 
ma n ner dee me d a p pr o priate b y t he I R B or I E C. I n t he e ve nt t he s u bject is n ot ca pa ble of re n deri n g 
a de q uate writte n i nf or me d c o nse nt, t he n t he s u bject’s le gall y  acce pta ble re prese ntati ve ma y 
pr o vi de s uc h c o nse nt f or t he s u bject i n acc or da nce wit h a p plica ble la ws a n d re g ulat i ons.
T he s u bject, or t he s u bject’s le gall y acce pta ble re prese ntati ve, m ust be gi ve n a m ple o p p ort u nity t o : 
( 1) i n q uire a b o ut details of t he st u d y a n d ( 2) deci de w het her or n ot t o partici pate i n t he st u d y. If t he 
s u bject, or t he s u bject’s le gall y acce pta ble re prese ntati ve, deter mi nes he or she will part ici pate i n 
t he st u d y, t he n t he i nf or me d c o nse nt f or m a n d s u bject a ut h orizati on f or m (if a p plica ble) must be 
sig ne d a n d date d b y  t he s u bject, or t he s u bject’s le gall y acce pta ble re prese ntati ve, at t he ti me of 
c o nse nt a n d pri or t o t he s u bject e nt eri n g i nt o t he st u d y. T he s u bject or t he s u bject’s le gall y 
acce pta ble re prese ntati ve s h o ul d be i nstr ucte d t o si g n usi n g t heir le gal na mes, n ot nic k na mes, 
usi n g bl ue or blac k ball p o i nt i n k. T he i n vesti gat or m ust als o si g n a n d date t he i nf or me d c o nse nt 
f or m a n d s u bject a ut h orizat i on (if a p plica ble) at t h e ti me of c o nse nt a n d pri or t o s u bject e nteri n g 
i nto t he st u d y; h o we ver, t he s p o ns or ma y  allo w a desi g nee of t he i n vest i gat or t o si g n t o t he e xte nt 
per mitte d b y  a p plica ble la w.
O nce si g ne d, t he ori gi nal i nf or m e d c o nse nt f or m, s u bject a ut h oriz atio n f or m  (if a p plica ble), a n d 
s u bject i nf or mati on s heet (if a p plica ble) will be st ore d i n t he i n vest i gat or’s site file. T he 
i n vesti gat or m ust d oc u me nt t he date t he s u bject si g ns t he i nf or me d c o nse nt i n t he s u bject’s 
me dic al rec or d. C o pies of t he si g ne d i nf or me d c o nse nt f or m, t he si g ne d s u bject a ut h orizati o n f or m 
(if a p plica ble), a n d s u bject i nf or mat i on s heet (if a p plica ble) s hall be gi ve n t o t he s u bject.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
All re vise d i nf or me d c o nse nt f or ms m ust be re vie we d a n d si g ne d b y rel e va nt s u bjects or t he 
r ele va nt s u bject’s le gall y acce pta ble re prese ntati ve i n t he sa me ma n ner as t he ori gi nal i nf or me d 
c o nse nt. T he date t he re vise d c o nse nt was o btai ne d s h o uld be rec or de d i n t he s u bject’s me dical 
rec or d, a n d t he s u bject s h o ul d recei ve a co p y  of t he re vise d i nf or me d c o nse nt f or m.
S u bjects w h o c o nse nte d a n d pr o vi de d a p har mac o ge n o mic sa m ple f or D N A a n d R N A a nal ysis ca n 
wi t hdra w t heir c o nse nt a n d re q uest dis p osal of a st ore d sa m ple at a n y ti me pri or t o a nal ysis. N otif y 
s p o ns or of c o nse nt wit hdra wal.
1 5. 3
S u bject C o nfi de nti alit y
T he s p o ns or a n d desi g nees affir m a n d u p h old t he pri nci ple of t he s u bject’s ri g ht t o pr otecti o n 
a gai nst i n vasi o n of pri vac y. T hr o u g h o ut t his st u d y , a s u bject’s s o urce data will o nl y be li n ke d t o 
t he s p o ns or’s cli nical st u d y data base or d oc u me ntati o n via a u ni q ue i de nt ificati on n u m ber. As 
per mitte d b y all a p plica ble la ws a n d re g ulat i ons, li mite d s u bject attri b utes, s uc h as se x, a ge, or date 
of  birt h, a n d s u bject i nitials ma y be use d t o verif y t he s u bject a n d acc urac y of the s u b ject’s u ni q ue 
i de ntificati on n u m ber.
T o c o m pl y wit h I C H G ui deli nes f or G C P a n d t o verif y c o m p lia nce wit h t his pr ot oc ol, t he s p o ns or 
re q uires t he i n vesti gat or t o per mit its m o nit or or desi g nee’s m o nit or, re prese ntati ves fr om a n y 
re g ulat or y a ut h orit y (e g, F DA, Me dici nes a n d Healt hcare pr o d ucts Re g ulat or y  Age nc y, 
P har mace ut icals a n d Me dical De vices A ge nc y), t he s p o ns or’s desi g nate d a u dit ors, a n d t he 
a p pr o priate I R Bs a n d I E Cs t o re vie w t he s u bject’s ori gi nal me dical rec or ds (s o urce data or 
d oc u m e nts), i ncl u di n g , b ut n ot li mite d t o, la b orat or y test res ult re p orts, E C G re p orts, a d missi on 
a n d disc har ge s u m maries f or h os pital a d missi o ns occ urri n g d uri n g a s u bject’s st u d y partici pati o n, 
a n d a ut o ps y re p orts. Access t o a s u bject’s ori gi nal me dical rec or ds re q uires t he s pecific 
a ut h orizat i on of t he s u bject as part of t he i nf or me d c o nse nt pr ocess (see Secti o n  1 5. 2 ).
C o pi es of a n y s u bject s o urce d oc u me nts t hat are pr o vi de d t o t he s p o ns or m ust ha ve certai n 
pers o nall y i de nt ifia ble i nf or mati on re m o ve d (ie, s u bject na me, a d dress, a n d ot her i de nt ifier fiel ds 
n ot c ollecte d o n t he s u bject’s e C R F).
S u bjects w h o decli ne t o partici pate i n t his weara ble de vice o pti o nal c o m p o ne nt, or w h o c o nse nte d 
a n d later wit h dra w fr o m t his part of t he st u d y, ma y c o ntin ue t o partici pate i n t he re mai n der of t he 
st u d y. 
1 5. 4
P u blic ati o n, Discl os ure, a n d Cli nic al Tri al Re gistr ati o n P olic y
1 5. 4. 1 P u blic ati o n a n d Discl os ure
T he i n vesti gat or is o bli ge d t o pr o vi de t he s p o ns or wi t h c o m plete test res ults a n d all data deri ve d b y 
t he i n vest i gat or fr o m t he st u d y. D uri n g a n d after t he st u d y, o nl y t he s p o ns or ma y ma ke st u d y 
i nf or mat i on a vaila ble t o ot her st u d y in vest i gat ors or t o re g ulat or y a ge ncies, e xce pt as re q uire d b y 
la w or re g ulat i on. E xce pt as ot her wise all o wa ble i n t he cli nical st u d y  site a gree me nt, a n y p u blic 
di s clos ure (i ncl u di n g p u blicl y accessi ble we bsites) relate d t o t he pr ot oc ol or st u d y res ults, ot her 
t ha n st u d y recr uit me nt mat erials a n d/ or a d vertise me nts, is t he s ole res p o nsi bilit y of t he s p o ns or.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he s p o ns or ma y p u blis h a n y data a n d i nf or mat i on fr o m t he st u d y (i ncl u di n g data a n d i nf or mati o n 
ge nerate d b y  t he i n vesti gat or) wit h o ut the c o nse nt of t he i n vest i gat or. Ma n uscri pt a ut h ors hi p f or 
a n y peer -re vie we d p u blicati on will a p pr o priatel y reflect c o ntri b ut i ons t o t he pr o d ucti o n a n d 
re vie w of t he d oc u me nt. All p u blicati ons a n d prese ntati o ns m ust be pre pare d i n acc or da nce wit h 
t his sectio n a n d t he Cli nical St u d y  Site A gree me nt. I n t he e ve nt of a n y discre pa nc y bet wee n t he 
pr ot oc ol  a n d t he Cli nical St u d y Site A gree me nt, t he Cli nical St u d y Site A gree me nt will pre vail.
T he s p o ns or ma y p u blis h a n y data a n d i nf or mat i on fr o m t he st u d y (i ncl u di n g data a n d i nf or mati o n 
ge nerate d b y  t he i n vesti gat or) wit h o ut t he c o nse nt of t he i n vesti gat or.
1 5. 4. 2
Cli nic al Tri al Re gistr ati o n
I n or der t o e ns ure t hat i nf or mati on o n cli nical trials reac hes t he p u blic i n a ti mel y ma n ner a n d t o 
c o mpl y  wit h a p plica ble la ws, re g ulat i ons, a n d g ui da nce, Ta ke da will, at a mi ni m u m re gister 
i nter ve nt i onal cli nical trials it s p o ns ors a n y w here i n t he w orl d o n Cli nical Trials. g o v or ot her 
p u blicl y  accessi ble we bsites bef ore start of st u d y, as defi ne d i n Ta ke da P olic y/ Sta n dar d. Ta ke da 
c o ntact i nf or mati on, al o n g wit h i n vest i gat or’s city,  st at e (f or A merica n i n vesti gat ors), c o u ntr y, a n d 
recr uiti n g stat us will be re gistere d a n d a vaila ble f or p u blic vie wi n g. F or s o me re gistries, Ta ke da 
will assist callers i n l ocati n g trial sites cl osest t o t heir h o me s b y pr o vi di n g t he i n vesti gat or na me, 
a d dress, a n d p h o ne n u m ber t o t he callers re q uest i n g trial i nf or mati on. O nce s u bjects recei ve 
i n vesti gat or c o ntact i nf or mati o n, t he y ma y call t h e site re q uesti n g e nr oll me nt i nt o t he trial. T he 
i n vesti gati ve sites are e nc o ura ge d t o ha n dle t he trial i n q uiries acc or di n g t o t heir esta blis he d s u bject 
scree ni n g pr ocess. If t he caller as ks a d dit i onal q uesti o ns be y o n d t he t o pic of trial e nr oll me nt, t he y 
s h o uld be referre d t o t he s p o ns or. A n y  in vest i gat or w h o o bjects t o Ta ke da pr o vi di n g t his 
i nf or mat i on t o callers m ust pr o vi de Ta ke da wit h a writte n n otice re q uest i n g t hat t heir i nf or mati on 
n ot be liste d o n t he re gistr y  sit e.
1 5. 4. 3
Cli nic al Tri al Res ults Discl os ure
Ta ke da will p ost t he res ults of cli nical trial s o n Cli nical Trials. g o v or ot her p u blicl y  accessi ble 
we bsites, as re q uire d b y Ta ke da P olic y/ Sta n dar d, a p plica ble la ws a n d/ or re g ulat i ons.
1 5. 5
I ns ur a nce a n d C o m pe ns ati o n f or I nj ur y
Eac h s u bject i n t he st u d y  must be i ns ure d i n acc or da nce wit h t he re g ulati o ns a p plica ble t o t he site 
w her e t he s u bject is partici pat i n g. If a l ocal u n der writer is re q uire d, t he n t he s p o ns or or s p o ns or’s 
desi g nee will o btai n cli nical st u d y  ins ura nce a gai nst t he ris k o f i nj ur y t o cli nical st u d y s u bjects. 
Refer t o t he Cli nical St u d y  Site A gree me nt re gar di n g t he s p o ns or’s p olic y o n s u bject 
c o mpe nsat i on a n d treat me nt f or i nj ur y. If t he i n vesti gat or has q uesti o ns re gar di n g t his p o lic y, he or 
s he s h o ul d c o ntact t he s p o ns or or s p o ns or’s desi g nee.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 1 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 6. 0
R E F E R E N C E S
1.
S hi F, S he n J K, C he n D, F o g K, T hirstr u p K, He ntzer M, et al. Disc o ver y a n d S A R o f a Series 
of  A g o nists at Or p ha n G Pr otei n-C o u pl e d Rece pt or 1 3 9. A C S Me d C he m Lett 
2 0 1 1; 2( 4): 3 0 3 - 6.
2.
Mats u o A, Mats u m ot o S, Na ga n o M, Mas u m ot o K H, Ta kasa ki J, Mats u m ot o M, et al. 
M olec ular cl o ni n g a n d c haracteriza tio n of  a n o vel G q-c o u ple d or p ha n rece pt or G P R g 1 
e xcl usi vel y e x presse d i n t he ce ntral ner v o us s yste m. Bi oc he m Bi o p h ys Res C om m u n 
2 0 0 5; 3 3 1( 1): 3 6 3 - 9.
3.
G ui da nce f or I n d ustr y : F o o d-Effect Bi oa vaila bilit y a n d Fe d Bi oe q ui vale nce St u dies. U S De pt 
of  Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, Ce nter f or Dr u g E val uat i on 
a n d Researc h. Dece m ber 2 0 0 2.
4.
Cl a mor A , Li nc ol n T M, T ha yer J F, K oe ni g J. Resti n g va gal acti vity i n sc hiz o p hre nia: 
meta -a nal ysis o f heart rate varia bilit y as a p ote ntial e n d o p he n ot yp e. Br J Ps yc hiatr y 
2 0 1 6; 2 0 8( 1): 9 - 1 6.
5.
Bara basi A L, G ul ba hce N, L oscalz o J. Net w or k me dici ne: a net w or k -base d a p pr oac h t o h u man 
di sease. Nat Re v Ge net 2 0 1 1; 1 2( 1): 5 6-6 8.
6.
Ni else n J. S yste ms biol o g y  of meta b o lis m: a dri ver f or de vel o pi n g pers o nalize d a n d precisi o n 
me dici ne. Cell Meta b 2 0 1 7; 2 5( 3): 5 7 2 - 9.
7.
Sc h nei der H C, Kla b u n de T. U n dersta n di n g dr u gs a n d diseases b y s yste ms bi o l og y? Bi o or g 
Me d C he m Lett 2 0 1 3; 2 3( 5): 1 1 6 8 -7 6.
8.
B uffi n gt o n S A, Di Prisc o G V, A uc ht u n g T A, Aja mi NJ, Petr osi n o J F, C osta- Matti o li M. 
Micr o bi al rec o nst ituti o n re verses mater nal diet -i n d uce d s ocial a n d s y na ptic deficits i n 
offs pri n g. Cell 2 0 1 6; 1 6 5( 7): 1 7 6 2 - 7 5.
9.
Bra v o J A, F ors y t he P, C he w M V, Escara va ge E, Sa vi g nac H M, Di na n T G, et al. I n gest i on of 
Lact o bacill us strai n re g ulates e m oti o nal be ha vi or a n d ce ntral G A B A rece pt or e x pressi o n i n a 
m o use via t he va g us ner ve. Pr oc Natl Aca d Sci U S A 2 0 1 1; 1 0 8( 3 8): 1 6 0 5 0 - 5.
1 0. Cl a yt o n T A, Ba ker D, Li n d o n J C, E verett J R, Nic h ols o n J K. P har mac o meta b o n o mic 
i de ntificati on of a si g nifica nt h ost -micr o bi o me meta b o lic i nteractio n affect i n g h u ma n dr u g 
meta b o lis m. Pr oc Natl Aca d Sci U S A 2 0 0 9; 1 0 6( 3 4): 1 4 7 2 8- 3 3.
1 1. G o o dri c h J K, Waters J L, P o ole A C, S utter J L, K ore n O, Ble k h ma n R, et al. H u ma n ge net ics 
s ha pe t he g ut micr o bi ome. Cell 2 0 1 4; 1 5 9( 4): 7 8 9- 9 9.
1 2. Vet iz ou M, Pi tt J M, Daillere R, Le pa ge P, Wal dsc h mitt N, Fla me nt C, et al. A ntica ncer 
i m m u n ot hera p y b y C T L A-4 bl oc ka de relies o n t he g ut micr o bi ota. Scie nce 
2 0 1 5; 3 5 0( 6 2 6 4): 1 0 7 9 - 8 4.
1 3. B o n d A, La der M. T he use of a nal o g ue scales i n rati n g s u bject i ve feeli n gs. Br J Me d Ps y c h o l 
1 9 7 4; 4 7: 2 1 1 -8.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 2 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 4. P os ner K, Br o w n G K, Sta nle y B, Bre nt D A, Yers h o va K V, O q ue n d o M A, et al. T he 
C ol u m bia -S uici de Se verit y Rat i n g Scale: i nitial vali dity a n d i nter nal c o nsiste nc y fi n di n gs fr o m 
t hree mul tisit e st u dies wit h a d olesce nts a n d a d ults. A m J Ps yc hiatr y 2 0 1 1; 1 6 8( 1 2): 1 2 6 6- 7 7.
1 5. Ka y S R, O pler L A, Fis bei n A. P osit i ve a n d Ne gati ve S y n dr ome Scale Ma n ual. N ort h 
T o na wa n da, N Y: M ult i-Heal t h S yste ms; 1 9 9 4.
1 6. O pl ar L A, Ka y S S R, Li n de n ma yer J P, Fisz bei n A. Str uct ure d Cli nical I nter vie w f o r t he 
P osi tive a n d Ne gat i ve S y n dr ome Scale ( S CI -P A N S S). T or o nt o: M ult i-Heal t h S yste ms; 1 9 9 2.
1 7. Per ki ns D O, Str o u p T S, Lie ber ma n J A. Ps yc h otic dis or ders meas ures. I n: Ha n d b o o k of 
Ps y c hi atric Meas ures. Was hi n gt o n, D C: A merica n Ps yc hiatric Ass ociat i on; 2 0 0 0 , p. 4 8 5-5 1 3.
1 8. Keefe R S, G ol d ber g T E, Har ve y P D, G ol d J M, P oe M P, C o u g he n o ur L. T he Brief Assess me nt 
of  C o g nitio n i n Sc hiz o p hre nia: relia bilit y,  se nsitivit y , a n d c o mparis o n wi t h a sta n dar d 
ne ur oc o g nit i ve batter y. Sc hiz o p hr Res 2 0 0 4; 6 8( 2-3): 2 8 3 - 9 7.
1 9. At ki ns A S, Tse n g T, Va u g ha n A, T wa mle y E W, Har ve y P, Patters o n T, et al. Vali dati o n of t he 
ta blet -a d mi nistere d Brief Assess me nt of C o g nit i on ( B A C A p p). Sc hiz o p hr Res 
2 0 1 7; 1 8 1: 1 0 0 - 6.
2 0. Lecr u bier Y, S hee ha n D V, Weiller E, A m ori m P, B o n ora I, S hee ha n K H, et al. T he 
Mi ni -I nter natio nal Ne ur o ps y c hi atric I nter vie w ( MI NI). A s h ort dia g n ostic str uct ure d 
i nter vie w: relia bilit y a n d vali dit y acc or di n g t o t he CI DI. E ur o pea n Ps yc hiat 1 9 9 7( 1 2): 2 2 4- 3 1.
2 1. S hee ha n D V, Lecr u bier Y, S hee ha n K H, Ja na vs J, Weiller E, Kes ki ne r A, et al. T he vali dity o f 
t he Mi ni I nter nat i onal Ne ur o ps yc hiatric I nter vie w ( MI NI) acc or di n g t o t he S CI D -P a n d its 
relia bility. E ur Ps y c hi atr y 1 9 9 7; 1 2: 2 3 2- 4 1.
2 2. S hee ha n D V, Lecr u bier Y, S hee ha n K H, A m ori m P, Ja na vs J, Weiller E, et al. T he 
Mi ni -I nter natio nal Ne ur o ps y c hi atric I nter vie w ( M.I. N.I.): t he de vel o p me nt a n d vali dat i on of a 
str uct ure d dia g n ostic ps yc hiatric i nter vie w f or D S M-I V a n d I C D-1 0. J Cli n Ps yc hiatr y  
1 9 9 8; 5 9 S u p pl 2 0: 2 2 -3 3; q uiz 4 - 5 7.
2 3. Kir k patric k B, Stra uss G P, N g u y e n L, Fisc her B A, Da niel D G, Cie nf ue g os A, et al. T he brief 
ne gat i ve s y m pt o m scale: ps yc h omet ric pr o perties. Sc hiz o p hr B ull 2 0 1 1; 3 7( 2): 3 0 0 - 5.
2 4. G u y  W. Cli nical Gl obal I m pressi o n ( C GI), E C D E U Versi o n. I n: E C D E U Assess me nt Ma n ual 
f or Ps yc h o p har mac o l og y . Re vise d e d. R oc k ville, M D: U. S. De pt. of Healt h, E d ucati o n, a n d 
Welfare; 1 9 7 6; D H E W p u blicat i on n o. ( A D M) 7 6 -3 3 8, p. 2 1 8 -2 2.
2 5. Gar d D E, Gar d M G, Kri n g A M, J o h n O P. A ntici pat or y a n d c o ns u m mat or y c o m p o ne nts of t he 
e x perie nce o f pl eas ure: A scale de vel o p me nt st u d y. J o ur nal of Re searc h i n Pers o nality 
2 0 0 6; 4 0( 6): 1 0 8 6 - 1 0 2.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 2 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x A
Sc he d ule of St u d y Pr oce d ures P art 1
Pr oce d ure
Scree ni n g
C o h ort 1 Tre at me nt Peri o ds 1 a n d 2
C o h ort 2 Tre at me nt Peri o ds 1 a n d 2
C o h orts 3 t o 5
E T ( b)
F oll o w -u p Peri o d
Fi n al Visit
St u d y D a y
D a ys
-2 1 t o - 2
C hec k -i n 
D a y - 1
D a y 1 
D a y 2
D a y 3  
D a y 4 
D a y 5
( Disc h ar ge)
Wee kl y S afet y P K 
F oll o w -u p Visits ( a)
St u d y C o m pleti o n
I nf or me d c o nse nt 
X
I ncl usi o n/e xcl usi o n 
criteria
X
X
De m o gra p hics 
(i ncl u di n g s m o ki n g 
stat us) a n d me dical 
hist or y
X
Me dicati o n hist or y
X
P h y sical e xa mi nati o n 
a n d ne ur ol o gical 
e xa mi nati o n (c)
X
X
X 
X
X
X
X
Vital si g ns ( d)
X
X
X
X
X
X
X
X
X
X
Hei g ht, wei g ht, a n d 
B MI (e)
X
X
X
X
X
C o nc o mita nt 
me dicati o ns 
X
X
X
X
X
X
X
X
X
C o nc urre nt me dical 
c o n diti ons
X
X
1 2 -lea d E C G (f)
X
X
X
X
X
X
Safet y la b orat or y 
c ollecti o ns ( g) 
X
X
X
X
X
X
X
e G F R ( h)
X
X
X
X
Ur i ne, c oti ni ne, a n d 
dr u g scree n
X
X
Ser u m pre g na nc y test 
( h C G)(i)
X
X
X (i)
X
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x A Sc he d ule of St u d y Pr oce d ures P art 1 (c o nti n ue d)
Pr oce d ures
Scree ni n g
C o h ort 1 Tre at me nt Peri o ds 1 a n d 2
C o h ort 2 Tre at me nt Peri o ds 1 a n d 2
C o h orts 3 t o 5
E T 
( b)
F oll o w- u p 
Peri o d
Fi n al Visit
St u d y D a ys
D a ys
- 2 1 t o - 2
C hec k-i n 
D a y - 1  
D a y 1  
D a y 2  
D a y 3  
D a y 4 
D a y 5
( Disc h ar ge)
Wee kl y 
S afet y P K 
F oll o w- u p 
Visits ( a) 
St u d y C o m pleti o n
F S H (j) 
X
He patitis pa nel ( k)  
X
P K bl o o d c ollecti o n 
( n) 
X
X
X
X
 
X
 
X
 
X
P K uri ne c ollecti o n 
( o)
X
X
X
X
X
 
X
 
X
T A K- 0 4 1/ matc hi n g 
place b o d osi n g ( p)
X
C o nfi ne me nt ( q)
X  
X  
X  
X  
X
X
P T E assess me nt
X
X  
X
A E assess me nt (r)
X  
X  
X  
X
X  
X  
X
C- S S R S (s)
X
X  
X
X  
X  
X
B o n d- La der V A S (t)
X  
X  
X
X  
X
F o ot n otes are o n t he f oll o wi n g pa ge.
Pr o p ert y of T
l o wi n g
l o wi n
- c o m m er ci al u s e o 
bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
li cc
a
c
D a y 5
D a y 5
( Disc h ar
Disc h
h e  
e c
bj
X
e
X
e
s e
l u
r
X
r c
er
X
m ee
X
m m
X
o m
c
C CI
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A E =a d verse e ve nt, B MI = b o d y mass i n de x, C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scale, D N A = de o x yri b o n ucleic aci d, e G F R = esti mate d  gl o mer ular 
filtrati o n rate, E T = Earl y Ter mi nati o n, E C G =electr ocar di o gra m, F S H = f ollicle-sti m ulati n g h or m o ne, h C G = h u ma n c h ori o nic g o na d otr o pi n, P K = p har mac o ki netics, 
, P T E = pretreat me nt e ve nt, R N A = ri b o n ucleic aci d, V A S = vis ual a nal o g ue scale.
(a) Wee kl y safet y a n d P K F oll o w- u p Visits will occ ur starti n g fr o m 7 da ys after d osi n g ( Da y 8 ± 2 da ys) i n eac h C o h ort’s last treat me nt peri o d u ntil t he 
c o nce ntrati o n of T A K- 0 4 1 i n plas ma is n ot q ua ntifia ble i n eac h s u bject ( C o h orts 1 a n d 2) or 6 wee ks after t he d ose ( C o h orts 3 t o 5) t o assess safet y a n d P K a n d 
w h et her a n y c o nc o mita nt me dicati o ns were use d si nce Disc har ge o n Da y 5. If a b n or mal, cli nicall y si g nifica nt fi n di n gs are o bser v e d u p o n disc har ge, s u bjects ma y 
be br o u g ht bac k t o t he st u d y u nit f or re-e val uati o n per i n vesti gat or’s discreti o n.
( b) W he n earl y ter mi nati o n occ urs o n a n o n- P K bl o o d c ollecti o n da y, P K bl o o d a n d uri ne sa m ples s h o ul d be c ollecte d.
(c) P h ysical a n d ne ur ol o gical e xa mi nati o ns will be ma de at Scree ni n g, Da y 1, Da y 1, Da y 2, at Disc har ge o n Da y 5 or Earl y Ter mi nati o n, at eac h wee kl y safet y a n d 
P K F oll o w- u p Visit, a n d at t he Fi nal Visit.
( d) Vital si g ns will i ncl u de oral b o d y te m perat ure meas ure me nt, bl o o d press ure, res pirati o n rate, a n d p ulse ( beats per mi n ute). P ulse a n d bl o o d press ure will be 
meas ure d after 5 mi n utes s u pi ne a n d a gai n at 1 a n d 3 mi n utes after sta n di n g f or all sc he d ule d ti me p oi nts. Vital si g ns will be rec or de d at Scree ni n g, C hec k-i n 
( Da y - 1), Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 1, 2, 4, 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs p ost d ose or Earl y Ter mi nati o n, a n d at eac h wee kl y safet y 
a n d P K F oll o w- u p Visit, a n d at t he Fi nal Visit.
(e) Hei g ht a n d B MI will be meas ure d at scree ni n g o nl y. 
(f) F or C o h orts 1 a n d 2, sta n dar d 1 2-lea d E C Gs will be rec or de d at Scree ni n g, C hec k-i n ( Da y - 1), Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 1, 2, 
4, 8, 1 2, 2 4, 4 8, 7 2, a n d 9 6 h o urs p ost d ose or Earl y Ter mi nati o n, a n d at eac h wee kl y safet y a n d P K F oll o w- u p Visit. F or C o h orts  3 t o 5, sta n dar d 1 2-lea d E C Gs will 
be rec or de d at Scree ni n g, Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 2, 2 4, a n d 9 6 h o urs p ost d ose, a n d at Earl y Ter mi nati o n. Si n gle E C Gs will be 
ta ke n at t hese ti me p oi nts.
( g) C ollecti o ns f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis para meters will occ ur u p o n risi n g after a fast of at least 8 h o urs at Scree ni n g, C hec k-i n ( Da y - 1), 
Da y 2, at Disc har ge o n Da y 5, Earl y Ter mi nati o n, at eac h wee kl y safet y a n d P K F oll o w- u p Visit, a n d at t he Fi nal Visit.
( h) e G F R: F or C o h orts 1 a n d 2, t he bl o o d re q uire d f or t he Da y - 1 e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples o n Da y - 1. F or C o h orts 1 
a n d 2, o n Da y 1, 3. 5 m L of bl o o d will be dra wn 6 ( ± 2) h o urs p ost d os e. F or C o h orts 3 t o 5, t he bl o o d re q uire d f or t he Da y - 1 e G F R sa m ple will be c ollecte d as part 
of t he safet y la b orat or y sa m ples o n Da y - 1, Da y 2, Da y 5, a n d at eac h wee kl y safet y a n d P K f oll o w- u p visit.
(i) Ser u m pre g na nc y tests f or fe male s u bjects o nl y will be d o ne at Scree ni n g, Da y - 1 ( C hec k i n), a n d o n Disc har ge o n Da y 5 (f or C o h orts 1 a n d 2 o nl y), Earl y 
Ter mi nati o n, a n d at t he Fi nal Visit.
(j) A n F S H le vel will be o btai ne d f or p ost me n o pa usal w o me n ( defi ne d as c o nti n u o us a me n orr hea of at least 2 years).
( k) He patitis pa nel, i ncl u di n g H Bs A g a n d a nti- H C V.
(l)
 
( m)
 
( n) P K bl o o d sa m ples f or t he deter mi nati o n of T A K- 0 4 1 plas ma c o nce ntrati o ns will be c ollecte d o n Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d ose]) a n d at 0. 2 5, 
0. 5, 1, 1. 5, 2, 3, 4, 8, 1 2, 2 4, 3 6, 4 8, 7 2, a n d 9 6 h o urs p ost d ose, a n d at eac h  wee kl y safet y a n d P K F oll o w- U p Visit ( u ntil t he c o nce ntrati o n of T A K- 0 4 1 i n plas ma is 
n ot q ua ntifia ble i n eac h s u bject f or Peri o d 2 i n Part 1 C o h orts 1 a n d 2, a n d Da ys 8, 1 5, 2 2, 2 9, 3 6, a n d 4 3 f or Part 1 C o h orts 3 t hr o u g h 5).
( o) Uri ne sa m ples f or t he deter mi nati o n of T A K- 0 4 1 c o nce ntrati o ns i n uri ne will be c ollecte d pre d ose o n Da y - 1 t hr o u g h Da y 1 t o j ust bef ore d osi n g (- 1 2 t o 0 h o urs) 
Pr o p ert y of T a k e 
o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
ci d, e G F R
i d, e G F
i o nic g o n
o nic g o
C o h ort’s 
o h ort’s 
d ose ( C o h
ose ( C
nt fi n di n g
nt fi n di n
o ul d be c o
ul d be c
har ge o n D
ar ge o
ate, a n d p
e, a n d p
le d ti me p
le d ti me
, 7 2, a n d 
7 2, a n
C hec k
hec k -i n 
i n
wee kl y sa
e kl y
i n g]), a n d
n g]), 
ra meters w
meters
y safet y a
safet y
y -1 e G F R
1 e G F
rs p ost d o
 p ost d
5, a n d at 
, a n d a
ill bb e d o n
e d o
pa usal w
a usal
nti -H C V.
H C V
deter mi na
eter m
, 3 6, 4 8, 7
3 6, 4 8,
s u bject f o
u bject 
t he deter m
he dete
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
a n d at ( 0 t o 6), ( 6 t o 1 2), ( 1 2 t o 2 4), ( 2 4 t o 4 8), ( 4 8 t o 7 2), a n d ( 7 2 t o 9 6) h o ur i nter vals p ost d ose. 
( p) S u bjects will be a d mi nistere d t he T A K- 0 4 1 or matc hi n g place b o at a p pr o xi matel y 0 8 0 0 h o urs f oll o wi n g a 8- h o ur fast a n d will c o nti n ue t o fast f or a n a d diti o nal 
4 h o urs p ost d ose. S u bjects ma y c o ns u me water a d li bit u m wit h t he e xce pti o n of 1 h o ur bef ore a n d 1 h o ur after dr u g a d mi nistrati o n.
( q) F or eac h treat me nt peri o d, s u bjects will be c o nfi ne d t o t he st u d y u nit fr o m Da y - 1 u ntil disc har ge o n Da y 5.
(r) A Es will be ca pt ure d fr o m t he first d ose of st u d y dr u g a n d will c o nti n ue u ntil t he Fi nal Visit.
(s) C- S S R S: T he Scree ni n g/ Baseli ne C- S S R S will be a d mi nistere d at Scree ni n g a n d t he Si nce Last Visit C- S S R S will be a d mi nistere d at C hec k-i n o n Da y - 1, 
Disc har ge o n Da y 5 or Earl y Ter mi nati o n, a n d F oll o w- u p Visits as a p pr o priate (if cli nicall y si g nifica nt at Disc har ge).
(t) B o n d- La der V A S will be a d mi nistere d i n o n Da y - 1, Da y 1 at 1, 3, 8, a n d 2 4 h o urs p ost d ose ( Da y 2), Da y 5, a n d (if a p plica ble) at Earl y Ter mi nati o n.
( u) 
 
( v) O pti o nal f or s u bjects i n Part 1, C o h orts 1 a n d 2: T he si n gle lea d E C G de vice will be use d d uri n g t he d osi n g peri o ds a n d f or a p pr o xi matel y t he first 3 da ys of t he 
was h o ut peri o d. T he s u bjects will be as ke d t o bri n g t he de vice t o t he u nit f or t he ne xt d osi n g peri o d.
 
.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y 
  
ct t o t h e a p pli c a bl e T er m s of U s e
l e
t a n d wil
a n d w
ad mi nistr
d mi nis
S S R S wil
S R S w
t Disc har g
t Disc ha
2), Da y 5,
), Da y 
e d d uri n g 
si n g peri o
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 2 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x B
Sc he d ule of St u d y Pr oce d ures P art 2 C o h orts 1 t o 4 ( he alt h y s u bjects o nl y)
Pr oce d ures
Scree n
i n g
Tre at me nt Peri o d
E T 
( a)
F oll o w -
u p 
Peri o d
Fi n al 
Visit
St u d y D a y
D a ys
-2 1 t o - 3
C hec k 
-i n
D a y - 2
D a y
- 1
D a y 
1
D a ys 
2- 3
D a y 
5
C hec k
-i n
D a y
7
D a y 
8
D a ys 
9- 1 0
C hec k
-i n
D a y
1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k
-i n
D a y
2 1
D a y 
2 2
D a y 
2 3
D a y 
2 4
D a y
2 6
S afet y 
P K 
F oll o w -
u p Visits 
( b)
St u d y 
C o m p -
leti o n
I nf or me d c o nse nt 
X
I ncl usi o n/e xcl usi o n 
criteria
X
X
De m o gra p hics 
(i ncl u di n g s m o ki n g 
stat us) a n d me dical 
hist or y
X
Me dicati o n hist or y
X
P h ysical 
e xa mi nati o n a n d 
ne ur ol o gical 
e xa mi nati o n (c)
X
X
X
X
X
X
X
X
X
X
Vital si g ns ( d)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hei g ht, wei g ht, a n d 
B MI (e)
X
X
X
X
X
X
C o nc o mita nt 
me dicati o ns 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C o nc urre nt me dical 
c o n diti o ns
X
X
X
1 2 -lea d E C G(f)
X
X
X
X
X
X
X
X
X
X
X
X
H olter E C G 
m o nit ori n g (f)
X
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x B Sc he d ule of St u d y Pr oce d ures P art 2  C o h orts 1 t o 4 ( he alt h y s u bjects o nl y) (c o nti n ue d)
Pr oce d ures
Scree n
i n g 
Tre at me nt Peri o d
E T 
( a)
F oll o w-
u p 
Peri o d
Fi n al 
Visit
St u d y D a y
D a ys
- 2 1 
t o - 3
C hec k-
i n
D a y - 2
D a y
- 1  
D a y 1
D a ys 
2- 3  
D a y 5
C hec k-
i n
D a y
7  
D a y 8
D a ys 
9- 1 0
C hec k-i n
D a y
1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k
-i n
D a y
2 1
D a y 
2 2
D a y 
2 3
D a y
2 4
D a y 
2 6
S afet y 
P K 
F oll o w-
u p Visits 
( b)
St u d y 
C o m p
-leti o n
Safet y la b orat or y 
c ollecti o ns ( g) 
X
X
 
X
X
 
X
 
X
X
 
X
X
 
X
X
X
X
X
e G F R ( h)
X
X
X
X
X
X
Uri ne, c oti ni ne, 
a n d dr u g scree n (i)
X
X
Ser u m pre g na nc y 
test ( h C G) (j)
X
X
X
X
X
X  
X
F S H ( k)
X
He patitis pa nel (l)  
X
Fecal c ollecti o n f o r
micr o bi o me 
a nal ysis ( p)
X
X
X
X
X
P K bl o o d 
c ollecti o n (r)
X
X
X
 
X
X
 
X
X
X
X
X
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k 
r n
k
T a k
le pa ge.
pa ge.
u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
n ue d)
n ue d)
li c
D a y 
D a y 
1 51 5
D aD
C h
C
h e
h e
bj e
t o h e
X
X
bj e
bj e
bj ej e
bj e
X
d s
n d
n d
n d
n d
l y n d
l yl yl y
nl y
e
u su su su su s
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x B Sc he d ule of St u d y Pr oce d ures P art 2 C o h orts 1 t o 4 ( he alt h y s u bjects o nl y) (c o nti n ue d)
Pr oce d ures 
Scree ni n g
Tre at me nt Peri o d
E T 
( a)
F oll o w- u
p Peri o d
Fi n al 
Visit
St u d y D a y
D a ys
- 2 1 t o - 3
C hec k 
-i n
D a y - 2
D a y
- 1  
D a y 1
D a ys 
2- 3  
D a y 5
C hec k-
i n
D a y
7  
D a y 8
D a ys 
9- 1 0
C hec k-i
n
D a y 1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k-
i n
D a y
2 1
D a y 
2 2
D a y 
2 3
D a y 
2 4
D a y
2 6
S afet y 
P K 
F oll o w-
u p Visits 
( b)
St u d y 
C o m p-l
eti o n
P K uri ne c ollecti o n 
(s)
X
X
 
X
X
 
X
X
X
 
X
 
X
T A K- 0 4 1/ place b o 
d osi n g (t)
X
X
X
X
C o nfi ne me nt ( u)
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X
P T E assess me nt  
X  
X  
X
A E
 
assess me nt
 
( v)
X
X
X
X
X
X
 
X
X
X
 
X
X
X
X
 
X
X
 
X
 
X
C- S S R S ( w)  
X  
X
X  
X  
X
X  
X
X  
X
X  
X  
X  
X
B o n d- La der V A S 
( x)
X
X
X
X
X
 
X
 
X
 
X
A p plicati o n of 
si n gle lea d E C G 
de vice ( y)
X
X
Re m o val of si n gle 
lea d E C G de vice 
( y)
X
X
X
F o ot n otes are o n t he f oll o wi n g pa ge.
Pr o p ert y of T a
n g pa ge
n g pa ge
n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
n ue d)
ue d)
li c
D a ysys
1 6-
1 6- 1 71 7
C hec k
hec k -
k
i n
i n
D a
a
b
ct
h e a
bj e
d
u b
X
d s
n d
X
a
nl y
nl y
nl y
nl y
nl y
X
X
o
s e
s e
s e
s e
l s e
X
l u
al
r c
m m e
o m
o m
o m
o m
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A E =a d verse e ve nt, B MI = b o d y mass i n de x, C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scale, D N A = de o x yri b o n ucleic aci d, e G F R = esti mate d gl o mer ular filtrati o n rate, E T = Earl y 
Ter mi nati o n, E C G =electr ocar di o gra m, F S H = f ollicle-sti m ulati n g h or m o ne, h C G = h u ma n c h ori o nic g o na d otr o pi n, P K = p har mac o ki netics,
P T E = pretreat me nt e ve nt, R N A = ri b o n u cleic aci d, V A S = vis ual a nal o g ue scale.
(a) 
 
( b) Safet y a n d P K F oll o w- u p Visits will occ ur starti n g fr o m 4 da ys after d osi n g ( Da y 2 6 ± 2 Da ys, 2 9 ± 2 da ys, 3 6 ± 2 da ys, 4 3 ± 2 da ys, 5 0 ± 2 da ys, 5 7 ± 2 da ys, a n d 6 4 ± 2 da ys) f or 
eac h c o h ort u ntil 6 wee ks after t he last d ose t o assess safet y a n d P K a n d w het her a n y c o nc o mita nt me dicati o ns were use d si nce di sc har ge o n Da y 2 4. If a b n or mal, cli nicall y si g nifica nt 
fi n di n gs are o bser ve d u p o n disc har ge, s u bjects ma y be br o u g ht bac k t o t he st u d y u nit f or re-e val uati o n per i n vesti gat or’s discreti o n.
(c) P h ysical e xa mi nati o ns a n d ne ur ol o gical e xa mi nati o ns will be ma de at Scree ni n g, Da y 1, Da ys 8, 1 5, a n d 2 2 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]) a n d at St u d y E xit 
( Da y 2 4) or Earl y Ter mi nati o n, at eac h safet y a n d P K F oll o w- u p Visit, a n d at t he Fi nal Visit.
( d) Vital si g ns will i ncl u de oral b o d y te m perat ure meas ure me nt, bl o o d press ure, res pirati o n rate, a n d p ulse ( beats per mi n ute). P ulse a n d bl o o d press ure will be meas ure d after 5 
mi n utes s u pi ne a n d a gai n at 1 a n d 3 mi n utes after sta n di n g f or all sc he d ule d ti me p oi nts. Vital si g ns will be rec or de d at Scree ni n g, C hec k-i n ( Da y - 2), Da y - 1, Da y 1 ( pre d ose [ wit hi n 
6 0 mi n utes pri or t o d osi n g]), a n d at 2, 8, 2 4, 3 6, a n d 4 8 h o urs p ost d ose), a n d Da ys 8, 1 5, a n d 2 2 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 2, 8, 2 4, 3 6, a n d 4 8 h o urs 
p ost d ose), at Earl y Ter mi nati o n, at eac h safet y a n d P K F oll o w- u p Visit, a n d at t he Fi nal Visit.
(e) Hei g ht a n d B MI will be meas ure d at Scree ni n g o nl y.
(f) Sta n dar d 1 2-lea d E C Gs will be r ec or de d at Scree ni n g, C hec k-i n ( Da y - 2); Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 2, 2 4, a n d 4 8 h o urs p os t d ose), a n d Da ys 8, 1 5, 
a n d 2 2 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d at 2, 2 4, a n d 4 8 h o urs p ost d ose); a n d at Earl y Ter mi nati o n. Si n gle E C Gs will be ta ke n at t hese ti me p oi nts. C o nti n u o us H olter 
E C G m o nit ori n g will be c o n d ucte d fr o m Da y - 1 u ntil 2 4 h o urs p ost d ose o n Da y 1. Tri plicate 1 2-lea d E C Gs will be e xtracte d fr o m t he H- 1 2 flas h car d a p pr o xi matel y 1 mi n ute a part 
fr o m o ne a n ot her (f or eac h ti me p oi nt, tri plicate E C Gs wit h 1 0 sec. e xtracti o n) at t he f oll o wi n g ti me p oi nts: Da y - 1 ( 2 3, 2 2, 20, 1 6, 1 2 h o ur bef ore d osi n g), a n d Da y 1 i m me diatel y 
bef ore d osi n g [ 0 hr, wit hi n 4 5 mi n of d osi n g], a n d at 1, 2, 4, 8, 1 2, a n d 2 4 h o urs p ost d ose. A wi n d o w of ± 1 0 mi n utes ar o u n d eac h  sc he d ule d ti me p oi nt ca n be utilize d i n or der f or t he 
ce ntral rea der t o o btai n t he necessar y E C Gs.
( g) C ollecti o ns f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis tests will occ ur u p o n risi n g after a n a p pr o xi mate 8- h o ur o ver ni g ht fast at Scree ni n g, C hec k-i n ( Da y - 2, 7, 1 4, a n d 2 1), 
Da ys 1, 8, 1 5, a n d 2 2 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]), a n d Da y 2 4 ( St u d y E xit), or Earl y Ter mi nati o n, at eac h wee kl y safet y a n d P K F oll o w- u p Visit, a n d at t he Fi nal 
Visit.
( h) e G F R: T he bl o o d re q uire d f or t he e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples o n Da ys - 2, 1, 7, 1 4, 2 1, a n d at eac h safet y a n d P K F oll o w- u p Visit.
(i) Uri ne c oti ni ne a n d dr u g scree ns ma y be re peate d as nee de d at t he i n vesti gat or’s discreti o n.
(j) Ser u m pre g na nc y tests f or fe male s u bjects o nl y will be d o ne at Scree ni n g, Da y - 2 a n d o n Da y 2 4 ( St u d y E xit), or Earl y Ter mi n ati o n, a n d at t he Fi nal Visit.
( k) A n F S H le vel will be o btai ne d f or p ost me n o pa usal w o me n ( defi ne d as c o nti n u o us a me n orr hea of at least 2 years).
(l) He patitis pa nel, i ncl u di n g H Bs A g a n d a nti- H C V.
( m) 
 
( n) T w o 2. 5 m L w h ole bl o o d sa m ples will be c ollecte d f or R N A p har mac o ge n o mic a nal ysis at eac h of t hese ti me p oi nts: o n Da y 1 pred ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), at 2 4 
h o urs p ost d ose, a n d o n  Da y 2 2 (a p pr o xi matel y 8 h o urs p ost d ose) fr o m eac h s u bject i n C o h orts 1- 4.
( o)
 
 
( p) Feces will c ollecte d fr o m s u bjects i n Part 2 C o h orts 1- 4 a n d f or e x pl orat or y a nal ysis of g ut micr o bi o me a p pr o xi matel y 1 wee k pri or t o A d missi o n, o n Da y - 1, Da y 9 ( o ne da y after 
Da y 8 d osi n g), Da y 2 3 ( o ne da y after Da y 2 2 d osi n g), a n d at Earl y Ter mi nati o n if t his occ urs pri or t o Da y 2 2. S u bjects will be pr o vi de d wit h a fecal sa m ple c ollecti o n kit a n d 
i nstr ucti o ns at t he Scree ni n g Visit, sa m ple t o be c ollecte d a p pr o xi matel y 1 wee k pri or t o a d missi o n t o t he u nit a n d t o be ret urne d w he n a d mitte d t o t he u n it o n Da y - 1. F or t he sa m ple 
Pr o p ert y of T a 
r 
c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e  
li 
bl e T er m s of U s e
l e
sti mate d gl
te d
tics,
ics,
, 4 3 ± 2 da
 4 3 ± 2
d si nce dis
i nce d
at or’s discr
or’s d
pre d ose [ w
re d ose 
( beats per 
( beats p
be rec or de
rec or d
d ose [ wi
se [ wit hi
t
wit hi n 6 0 
wit hi n 6
a n d at Earl
n d at E
plicate 1 2
cate 1 2 l
e f oll o wi n g
l o wi
ost d ose. A
st d ose
cc ur u p o n r
ur u p o n
Da y 2 4 ( S
Da y 2 4 (
e d as part o
d as par
t t he i n ves
t he i n v
ne at Scree
e at Scr
me n ( defi n
me n ( de
c ollecte d f o
le
el y 8 h o ur
h o
s u bjects i n
s u bjec
ne da y afte
ne da y af
ni n g Visit
i n g Vis
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 2 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
c ollecti o ns sc he d ule d d uri n g c o nfi ne me nt ( Da ys - 1, 9, a n d 2 3) a ± 1 da y wi n d o w is per mitte d i n or der t o c oi nci de wit h t he s u bjec t’s n or mal patter n of b o wel m o ve me nts or if t here is 
a c o nflict wit h ot her st u d y pr oce d ures. T he date a n d a p pr o xi mate ti me of act ual sa m ple c ollecti o n s h o ul d be rec or de d. As s u bjec ts’ b o wel m o ve me nt patter ns s h o w si g nifica nt 
i nter-s u bject varia bilit y a n d ma y be f urt her altere d b y c ha n ges i n diet a n d / or p h ysical acti vit y d uri n g t he resi de ntial sta y, if a s u bject w h o has c o nse nte d t o t his pr oce d ure d oes n ot 
pr o vi de a sa m ple t his will n ot be c o nsi dere d t o be a pr ot oc ol de viati o n. T he reas o n f or missi n g t he sa m ple s h o ul d be n ote d. F ul l details of sa m ple c ollecti o n will be pr o vi de d i n t he 
La b orat or y Ma n ual. Partici pati o n i n t he c ollecti o n f or fecal sa m ples f or e x pl orat or y micr o bi o me a nal ysis is v ol u ntar y a n d is s u bject t o se parate i nf or me d c o nse nt.
( q) 
 
 
 
 
 
(r) P K bl o o d sa m ples f or t he deter mi nati o n of T A K- 0 4 1 c o nce ntrati o ns i n plas ma will be c ollecte d o n Da y 1 pre d ose ( wit hi n 6 0 min utes pri or t o d ose) a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, 1 2, 
2 4, 4 8, a n d 9 6 h o urs p ost d ose ( o n Da y 5), Da ys 8 a n d 1 5 pre d ose ( wit hi n 6 0 mi n utes pri or t o d osi n g), 1, 2, a n d 4 h o ur p ost d ose,  a n d Da y 2 2 pre d ose ( wit hi n 6 0 mi n utes pri or t o d ose) 
a n d at 0. 5, 1, 1. 5, 2, 3, 4, 8, 1 2, 2 4, a n d 4 8 h o urs p ost d ose, a n d at eac h safet y a n d P K F oll o w- U p Visit ( Da ys 2 6, 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4).
(s) Uri ne sa m ples f or t he deter mi nati o n of T A K- 0 4 1 c o nce ntrati o ns i n uri ne will be c ollecte d pre d ose o n Da y - 1 t hr o u g h Da y 3 t o  j ust bef ore d osi n g (- 1 2 t o 0 h o urs) a n d p ost d ose at 
( 0 t o 6 h o urs), ( 6 t o 1 2 h o urs), ( 1 2 t o 2 4 h o urs), ( 2 4 t o 4 8 h o urs) i nter vals a n d Da y 2 2 pre d ose (- 1 2 t o 0 h o urs) a n d p ost d ose at ( 0 t o 6 h o urs), ( 6 t o 1 2 h o urs), ( 1 2 t o 2 4 h o urs), a n d ( 2 4 
t o 4 8 h o urs) i nter vals. Te n- milliliter ali q u ots s h o ul d be ta ke n fr o m t he uri ne c ollecti o ns o n Da ys 1 a n d 2 2 ( pre d ose a n d 1 2- 2 4 h o urs p ost d ose) f or meas ure me nt of 
6 β - h ydr o x yc ortis ol/c ortis ol rati o t o assess C Y P 3 A 4 i n d ucti o n.
(t) S u bjects will be a d mi nistere d T A K- 0 4 1/ matc hi n g place b o at a p pr o xi matel y 0 8 0 0 h o urs f oll o wi n g a fast of at least 8 h o ur a n d will c o nti n ue t o fast f or a n a d diti o nal 4 h o urs 
p ost d ose. S u bjects ma y c o ns u me water a d li bit u m wit h t he e xce pti o n of 1 h o ur bef ore a n d 1 h o ur after dr u g a d mi nistrati o n. 
( u) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3, fr o m Da y 7 t o Da y 1 0, fr o m Da y 1 4 t o Da y 1 7, a nd fr o m Da y 2 1 t o Da y 2 4 (f or at least 4 8 h o urs after 
eac h d ose) f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge.
( v) A Es will be ca pt ure d fr o m t he first d ose of st u d y dr u g u ntil t he Fi nal Visit.
( w) C- S S R S: T he Scree ni n g/ Baseli ne C- S S R S will be a d mi nistere d at Scree ni n g a n d t he Si nce Last Visit C- S S R S will be a d mi nistere d at C hec k-i n o n Da y - 2; Da ys 3 ( Disc har ge), 5, 
7 ( C hec k-i n), 1 0 ( Disc har ge), 1 4 ( C hec k-i n), 1 7 ( Disc har ge), 2 1 ( C hec k-i n) a n d 2 4 ( Fi nal Disc har ge), Earl y Ter mi nati o n, a n d F oll o w- u p Visits as a p pr o priate (if cli nicall y si g nifica nt 
at Disc har ge).
( x) B o n d- La der V A S will be a d mi nistere d o n Da y - 1; Da ys 1, 8, 1 5, a n d 2 2 at 1, 3, 8, a n d 2 4 h o urs p ost d ose; Da y 2 4, a n d (if a p p lica ble) at Earl y Ter mi nati o n.
( y) O pti o nal f or s u bjects i n Part 2, C o h orts 3 a n d 4: T he si n gle lea d E C G de vice will be w or n c o nti n u o usl y fr o m Da y - 1 t o Da y 8. T he de vices will be r e-a p plie d o n Da y 2 1 of t he st u d y 
a n d will be w or n c o nti n u o usl y u ntil s u bjects ret ur n t o t he u nit f or t he first f oll o w- u p visit. De vices will be re m o ve d if s u bje cts ter mi nate t he st u d y earl y.
(z) 
 
Pr o p ert y of T a k e d a: F or 
c o m m er ci al u s e o nl y a n d s u bj 
e a p pli c a bl e T er m s of U s e
l e
mal patter n
al patter
o wel m o v
o wel m o
ect w h o ha
t w h o 
l details o
details o f
s u bject t o 
ject t o
y 1 pre d os
1 pre d o
1, 2, a n d 4
2, a n d
Visit ( Da ys
it ( Da y
e d ose o n D
d ose o n
(-1 2 t o 0 h
2 t o 
n Da ys 1 a
Da ys
0 h o urs f ol
urs f o
ef ore a n d 1
ore a n
fr o m Da y
r o m D
Visit.
Visit.
Scree ni n g
cree ni n
hec k
ec k-i n) a n
i n)
, 8, 1 5, a n
8, 1 5, a
gle lea d E
le lea d
he u nit f or
nit f o
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 3 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x C
Sc he d ule of St u d y Pr oce d ures P art 3 ( T a blet F or m ul ati o n – Rel ati ve Bi o a v ail a bilit y a n d F o o d Effect)
Scree ni n g
Tre at me nt Peri o d
E arl y 
Ter mi n ati o n 
( a)
F oll o w - u
p ( b )
St u d y D a y
-2 8 t o -2
-1
1 t o 5
1 9 ( ± 2)
Sc he d ule d Ti me ( h)
Pre -d o
se D a y 
1
0
0. 2 5
0. 5
1
1. 5
2
3
4
6
8
1 2
2 4
3 6
4 8
7 2
9 6
A d mi nistr ati ve Pr oce d ures
I nf or me d C o nse nt
X
I ncl usi o n/ E xcl usi o n 
Criteria
X  
X  
X
Me dical 
Hist or y/ De m o gra p hic
s
X
Pri or a n d 
C o nc o mita nt 
Me dicati o n Re vie w
X
X
--------------------------------------------C o nti n u o us Re vie w -----------------------------------------------------
Cli nic Pr oce d ures/ Assess me nts
F ull P h ysical 
E xa mi nati o n (c)
X
X(c )
X(c)
X
X  
X  
X
B o d y Mass I n de x ( d)
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 3 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x C
Sc he d ule of St u d y Pr oce d ures P art 3 ( T a blet F or m ul ati o n – Rel ati ve Bi o a v ail a bilit y a n d F o o d Effect) (c o nti n ue d)
Scree ni n g
Tre at me nt Peri o d
E arl y 
Ter mi n ati o n 
( b)
F oll o w - u
p ( a)
St u d y D a y
-2 8 t o -2
-1
1 t o 5
1 9 ( ± 2)
Sc he d ule d Ti me
Pre -d o
se D a y 
1
0
0. 2 5
0. 5
1
1. 5
2
3
4
6
8
1 2
2 4
3 6
4 8
7 2
9 6
T A K -0 4 1 A d mi nistrati
o n (e)
X
Se mi -rec u m be nt Vital 
Si g ns ( H R, S B P a n d 
D B P) (f)
X
X
X  
X
X
X
X  
X
Vital Si g ns 
(res pirat or y rate a n d 
te m perat ure) (f)
X
X
X  
X
X
X
X  
X
Sta n dar d 1 2 -lea d 
E C Gs ( g)
X  
X  
X
X
X
X  
X
C -S S R S ( h)
X
X
X
X
X
X
X
A d verse E ve nts 
M o nit ori n g (i)
X  
X  
X ----------------------------C o nti n u o us M o nit ori n g -----------------------------------------------------X
X  
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x C Sc he d ule of St u d y Pr oce d ures P art 3 ( T a blet F or m ul ati o n –  Rel ati ve Bi o a v ail a bilit y a n d F o o d Effect) (c o nti n ue d)
Scree ni n g
Tre at me nt Peri o d
E arl y 
Ter mi n ati o n
F oll o w- u
p
St u d y D a y 
- 2 8 t o - 2 
- 1
1 t o 5
1 9 ( ± 2)
Sc he d ule d Ti me 
( H o urs)
Pre- d o
se D a y 
1
0 
0. 2 5 
0. 5 
1 
1. 5 
2 
3 
4 
6 
8 
1 2 
2 4 
3 6 
4 8 
7 2 
9 6
L a b or at or y Pr oce d ures/ Assess me nts
He mat ol o g y (j)  
X  
X(j)
X
X
X
Uri nal ysis (j)
X  
X(j)
X
X
X
Ser u m C he mistr y (j)  
X  
X(j)
X
X
X
Uri ne Dr u g Scree n 
( k)
X
X( k)
X
He patitis Scree n (l)  
X
H u ma n 
i m m u n o deficie nc y 
vir us ( HI V) Scree n 
X
β h C G ( pre g na nc y) 
( m)
X
X
X
Ser u m F S H ( n)  
X
X
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n 
er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
it y 
it y a n d 
a n d
li c
a p
2 42 4
h e
ct o t
e
bj e ct ctctct
bjbjbj e
u bj
u b
u b
u b
d
u b
d s
d
n d
y a d
l yy
o n y
o n
o n
o n
s
o
l u
ci a
er c
e c
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x C Sc he d ule of St u d y Pr oce d ures P art 3 ( T a blet F or m ul ati o n –  Rel ati ve Bi o a v ail a bilit y a n d F o o d Effect) (c o nti n ue d) 
Scree ni n g
Tre at me nt Peri o d
E arl y 
Ter mi n ati o n
F oll o w- u
p
St u d y D a y
- 2 8 t o - 2 
- 1
1 t o 5
1 9 ( ± 2)
Sc he d ule d Ti me
H o urs
Pre- d o
se D a y 
1
0 
0. 2 5 
0. 5 
1 
1. 5 
2 
3 
4 
6 
8 
1 2 
2 4 
3 6 
4 8 
7 2 
9 6
P h ar m ac o ki netics E v al u ati o ns
Bl o o d Sa m ple f or P K 
T A K- 0 4 1 ( p)
X
 
X
 
X
X
X
 
X
X
X
 
X
X
X
 
X
X
X
X
 
X
X
 
X
Ot her
C o nfi ne me nt ( q)
  X                                                                                                                                                      X
A E =a d verse e ve nt, B MI = b o d y mass i n de x, C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scale, D N A = de o x yri b o n ucleic aci d, e G F R = esti mate d gl o mer ular filtrati o n rate, E T = Earl y 
Ter mi nati o n, E C G =electr ocar di o gra m, F S H = f ollicle-sti m ulati n g h or m o ne, h C G = h u ma n c h ori o nic g o na d otr o pi n, P K = p har mac o ki netics, 
, 
P T E = pretreat me nt e ve nt, R N A = ri b o n u cleic aci d, V A S = vis ual a nal o g ue scale.
(a) W he n earl y ter mi nati o n occ urs, P K bl o o d sa m ples s h o ul d be c ollecte d.
( b) A Safet y a n d P K F oll o w- u p Visit will 2 wee ks da ys after disc har ge t o assess safet y a n d P K a n d w het her a n y c o nc o mita nt me dicati o ns were use d. T his will be t he fi nal sc he d ule d 
st u d y visit.
(c) P h ysical a n d ne ur ol o gical e xa mi nati o ns will be t h or o u g h, a n d su bse q ue nt e xa mi nati o ns l o o ki n g f or a b n or mal c ha n ge fr o m Scree ni n g. Pre d ose e xa mi nati o ns o n Da y 1 ma y be d o ne 
o n Da y - 1.
( d) Hei g ht a n d B MI will be meas ure d at Scree ni n g o nl y.
(e) S u bjects will be a d mi nistere d a si n gle T A K- 0 4 1 4 0 m g i m me diate release ta blet at a p pr o xi matel y 0 8 0 0 h o urs, f oll o wi n g eit her  a 1 0- h o ur fast or 3 0 mi n after starti n g i n gesti o n of 
a hi g h cal orie a n d hi g h fat meal. S u bjects will c o nti n ue t o fast f or a n a d diti o nal 4 h o urs p ost d ose a n d ma y c o ns u me water a d li bit u m wit h t he e xce pti o n of 1 h o ur bef ore a n d 1 h o ur 
after dr u g a d mi nistrati o n. Sta n dar d meals will be a d mi nistere d at a p pr o xi matel y H o ur 4 (l u nc h), H o ur 7 (s nac k), H o ur 1 0 ( di n ner) a n d H o ur 1 3 (s nac k) h o urs p ost d ose.
(f) Vital si g ns will i ncl u de oral b o d y te m perat ure meas ure me nt, bl o o d press ure, res pirati o n rate, a n d p ulse ( beats per mi n ute). P ulse a n d bl o o d press ure will be meas ure d after 5 
mi n utes s u pi ne a n d a gai n at 1 a n d 3 mi n utes after sta n di n g f or all sc he d ule d ti me p oi nts.
( g) Sta n dar d 1 2-lea d E C Gs will be o n  Da y 1 ( pre d ose [ wit hi n 6 0 mi n utes pri or t o d osi n g]). 
( h) C- S S R S: T he Scree ni n g/ Baseli ne C- S S R S will be a d mi nistere d at Scree ni n g a n d t he Si nce Last Visit C- S S R S will be a d mi nistere d  o n all ot her visits.
(i) A Es will be ca pt ure d fr o m t he first d ose of st u d y dr u g a n d will c o nti n ue u ntil t he Fi nal Visit.
(j) C ollecti o ns f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis para meters will occ ur u p o n risi n g after a fast of at least 8 h ours. C ollecti o n o n Da y 1 pri or t o d osi n g ca n be perf or me d 
alter nati vel y o n Da y - 1.
( k) Uri ne c oti ni ne a n d dr u g scree n ma y be re peate d at t he j u d ge me nt of t he i n vesti gat or.
(l) He patitis pa nel i ncl u des H Bs A g a n d a nti- H C V 
( m) Bl o o d will be c ollecte d fr o m fe male s u bjects o nl y f or pre g na nc y tests.
( n) A n F S H le vel will be o btai ne d f or p ost me n o pa usal w o me n ( defi ne d as c o nti n u o us a me n orr hea of at least 2 years).
( o) 
 
Pr o p ert y  
a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
it y 
it y a n d 
a n d
li c
a p
2 42 4
h e
ct o t
e
j e ct 
ctctct
X
X
j e c
e c
u bj e
d s us u
               
         
d 
a
cale, D N A
ale, D N
a n c h ori o ni
c h ori o n
s safet y a n
afet y a
e nt e xa mi n
nt e xa m
diate relea
ate rel
t f or a n a d
f or a n a
ere d at a p p
d at a p
ure me nt, bl
me nt, 
n di n g
di n g f or 
f
d ose [ wit hi
se [ wit
will be a d m
ill be a
of st u d y dr
of st u d y
mistr y, a n
istr y, a
ma y be re p
a y be r
A g a n d a nt
A g a n d a
o m fe male
m fe ma
btai ne d f or
ne d f
n d
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
 
( p) P K bl o o d sa m ples f or t he deter mi nati o n of T A K- 0 4 1 plas ma c o nce ntrati o ns will be c ollecte d o n Da y 1 ( pre d ose [ wit hi n 6 0 mi n u tes pri or t o d ose]) a n d at ot her sc he d ule d ti mes.
( q) S u bjects will be c o nfi ne d t o t he st u d y u nit fr o m Da y - 1 u ntil 4 8 h o urs after d osi n g.  O n Da y 1, s u bjects ra n d o mize d fe d will start t o i n gest a hi g h-fat hi g h cal orie brea kfast wit hi n 
3 0 mi n pri or t o d osi n g, a n d s u bjects ra n d o mize d fasti n g will c o nti n ue t heir mi ni m u m 1 0 h o ur o ver ni g ht fast u ntil d ose a d mi nistr ati o n. All s u bjects will ha ve n o f o o d, dri n k ( ot her t ha n 
water) a n d n o me dicati o n after d ose a d mi nistrati o n u ntil l u nc h 4 h o urs later.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli 
l e T er m s of U s e
l e
es pri or t o
es pr
rt t o i n gest
t o i n ge
ati o n. All s
i o n. All
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 3 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x D
Sc he d ule of St u d y Pr oce d ures P art 4 Scree ni n g T hr o u g h D a y 2 4/ E T 
Pr oce d ures
Scree ni n g
E T 
St u d y D a y
D a ys
- 3 5 t o - 3
C hec k 
-i n
D a y - 2
D a y
- 1
D a y 1
D a ys 
2 - 3
D a y 5
C hec k -
i n
D a y
7
D a y 8
D a ys 
9- 1 0
C hec k -
i n
D a y
1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k -
i n
D a y
2 1
D a y 
2 2
D a y
2 3- 2 4
E T (a)
I nf or me d c o nse nt 
X
I ncl usi o n/e xcl usi o n 
criteria
X
X
De m o gra p hics 
(i ncl u di n g s m o ki n g 
stat us) a n d me dical 
hist or y
X
Me dicati o n hist or y
X
P h ysical e xa mi nati o n 
a n d ne ur ol o gical 
assess me nts ( b)
X
X
X
X
X
X
X
Vital si g ns (c)
X
X
X
X
X
X
X
X
X
X
X
X
Hei g ht, wei g ht, a n d 
B MI ( d)
X
X
X
C o nc o mita nt 
me dicati o ns 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
C o nc urre nt me dical 
c o n diti o ns
X
X
1 2 -lea d E C G(e)
X
X
X
X
X
X
X
X
X
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x D Sc he d ule of St u d y Pr oce d ures P art 4 : Scree ni n g T hr o u g h D a y 2 4/ E T (c o nti n ue d)
Pr oce d ures
Scree n
i n g
St u d y D a y
D a ys
- 3 5
t o - 3
C hec k 
-i n
D a y - 2
D a y
- 1  
D a y 1
D a ys 
2- 3  
D a y 5
C hec k-
i n
D a y 7  
D a y 8
D a ys 
9- 1 0
C hec k-
i n
D a y 1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k-
i n
D a y 2 1
D a y 
2 2  
D a y 2 3- 2 4
E T (a)
Safet y la b orat or y 
c ollecti o ns (f)
X
X
X
 
X
X
X
X
X
X
X
X
A nti ps yc h otic me dicati o n 
le vel
X
X
e G F R ( g)
X
X
X
X
X
Uri ne, a n d dr u g scree n ( h)
X
X
X
X
X
X
Ser u m a nti ps yc h otic 
me dicati o n le vel
X
X
Ser u m pre g na nc y test ( h C G) 
(i)
X
X
X
X
F S H (j)
X
He patitis pa nel ( k)
X
Fecal c ollecti o n f or 
micr o bi o me a nal ysis ( o)
X
X
X
X
X
Uri ne c ollecti o n f or 
6 β h y dr o x yc ortis ol / 
c ortis ol rati o ( q)
X ( q)
X( q)
P K bl o o d c ollecti o n (r)
X (r)  
X (r)  
X (r)
X (r)
X (r)
X (r)  
X (r)  
X
F o ot n otes are o n last ta ble pa ge.
Pr o p ert y of T a k e d a: F 
n- 
l u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
)
li c
D a y 
D a y 
1 51 5
D
a p
o
e
X
X
t o
t o
t oot o
e c
bj
s u
d
n d
a n
nl y
n
o n
s
n
s e
u su
n
e d
e d
e d
k e d
e
ge.
ge.
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x  D Sc he d ule of St u d y Pr oce d ures P art 4: Scree ni n g T hr o u g h Da y 2 4/ E T (c o nti n ue d)
Pr oce d ures
Scree ni n
g
St u d y D a y
D a ys
- 3 5 t o - 3
C hec k 
-i n
D a y - 2
D a y
- 1
D a y 
1
D a ys 
2- 3
D a y 
5
C hec k-
i n
D a y
7
D a y 
8
D a ys 
9- 1 0
C hec k-
i n
D a y 1 4
D a y 
1 5
D a ys 
1 6- 1 7
C hec k-
i n
D a y
2 1
D a y 
2 2
D a y 
2 3- 2 4
E T ( a)
T A K- 0 4 1/ place b o 
d osi n g (s)
X
X
X
X
C o nfi ne me nt (t)
X  
X  
X  
X
X  
X  
X  
X  
X  
X  
X  
X  
X
P T E assess me nt
X  
X  
X
A E assess me nt ( u)
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X 
MI NI
X
P A N S S
X
X
X
X
X
C- S S R S ( v)
X  
X
X  
X  
X
X  
X
X  
X
X  
X 
B o n d- La der V A S ( w)
X
X ( w)
F o ot n otes are o n t he f oll o wi n g pa ge.
Pr o p ert y of T a k e d a: F o 
- c oc o
 o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
li c
hec k
ec k-
k
i n
i n
D a y 1
D a y
a p
bj e
o t
a
bj e
bj e
bj e
bj e
X
X
d s
d
n d
X
a
l y
nl yl yl yl y
o
C CI
C CI
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A E =a d verse e ve nt, 
, B MI = b o d y mass i n de x, 
– Se verit y, C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scale, D N A = de o x yri b o n ucleic aci d, e G F R = esti mate d gl o mer ular 
filtrati o n rate, E T = Earl y Ter mi nati o n, E C G =electr ocar di o gra m, F S H = f ollicle-sti m ulati n g h or m o ne, h C G = h u ma n c h ori o nic g o na d otr o pi n, MI NI = Mi ni I nter nati o nal 
Ne ur o ps yc hiatric I nter vie w, P A N S S = P ositi ve a n d Ne gati ve S y n dr o me Scale, P K = p har mac o ki netics, 
), P T E = pretreat me nt e ve nt, R N A = ri bo n ucleic aci d, 
, V A S = vis ual a nal o g ue scale.
(a) W he n earl y ter mi nati o n occ urs o n a n o n- P K bl o o d c ollecti o n da y, P K bl o o d a n d uri ne sa m ples s h o ul d be c ollecte d. If earl y ter mi nati o n occ urs o n t he da y of a sc he d ule d 
e x pl orat or y bi o mar ker sa m ple ( bl o o d, uri ne, st o ol) t he sa m ple s h o ul d be c ollecte d
( b) Scree ni n g p h ysical a n d ne ur ol o gical e xa mi nati o ns will be t h or o u g h. S u bjects wit h e vi de nce of cli nicall y si g nifica nt e xtra p yra mi dal s y m pt o ms as meas ure d b y a S A S sc ore > 6, or 
e vi de nce of de pressi o n as meas ure d b y a C D S S sc ore > 9 will be e xcl u de d fr o m t he st u d y. P h ysical a n d ne ur ol o gical pre d ose e xa mi n ati o ns pre d ose e xa mi nati o ns will be c o n d ucte d 
wit hi n 6 0 mi n utes pri or t o d osi n g o n all d osi n g da ys, a n d s u bse q ue nt e xa mi nati o ns l o o ki n g f or a b n or mal c ha n ge fr o m Scree ni n g.
(c) Vital si g ns will i ncl u de oral b o d y te m perat ure meas ure me nt, bl o o d press ure, res pirati o n rate, a n d p ulse ( beats per mi n ute). P ulse a n d bl o o d press ure will be meas ure d after 5 
mi n utes s u pi ne a n d a gai n at 1 a n d 3 mi n utes after sta n di n g f or all sc he d ule d ti me p oi nts. Vital si g ns will be rec or de d o n all d o si n g da ys wit hi n 6 0 mi n utes pri or t o d osi n g, a n d at 2, 8, 
2 4, 3 6, a n d 4 8 h o urs p ost d ose.
( d) Hei g ht a n d b o d y wei g ht a n d B MI will be meas ure d at Scree ni n g o nl y. All ot her assess me nts will be b o d y wei g ht o nl y.
(e) Sta n dar d 1 2-lea d E C Gs will be rec or de d o n all d osi n g da ys wit hi n 6 0 mi n utes pri or t o d osi n g a n d at 2, 2 4, a n d 4 8 h o urs p ost d o se. Si n gle E C Gs will be ta ke n at t hese ti me p oi nts. 
(f) C ollecti o ns f or he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis tests will occ ur u p o n risi n g after a n a p pr o xi mate 8- h o ur o ver ni g ht fast wit hi n 6 0 mi n utes pri or t o d osi n g o n all d osi n g 
da ys.
( g) e G F R: T he bl o o d re q uire d f or t he e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples 
( h) Uri ne dr u g scree ns ma y be re peate d as nee de d at t he i n vesti gat or’s discreti o n.
(i)
 .
(j) A n F S H le vel will be o btai ne d f or p ost me n o pa usal w o me n ( defi ne d as c o nti n u o us a me n orr hea of at least 2 years).
( k) He patitis pa nel, i ncl u di n g H Bs A g a n d a nti- H C V.
(l)
 
( m)
 
( n) 
 
 
 
.
( o) Feces will be c ollecte d fr o m s u bjects i n Part 2 C o h orts 1- 4 f or e x pl orat or y a nal ysis of g ut. S u bjects will be pr o vi de d wit h a fecal sa m ple c ollecti o n kit a n d i nstr ucti o ns at t he 
Scree ni n g Visit, sa m ple t o be c ollecte d a p pr o xi matel y 1 wee k pri or t o a d missi o n t o t he u nit a n d t o be ret ur ne d w he n a d mitte d t o  t he u nit o n Da y - 1. F or t he sa m ple c ollecti o ns 
sc he d ule d d uri n g c o nfi ne me nt ( Da ys - 1, 9, a n d 2 3) a ± 1 da y wi n d o w is per mitte d i n or der t o c oi nci de wit h t he s u bject’s n or mal pa tter n of b o wel m o ve me nts or if t here is a c o nflict 
wit h ot her st u d y pr oce d ures. T he date a n d a p pr o xi mate ti me of act ual sa m ple c ollecti o n s h o ul d be rec or de d. As s u bjects’ b o wel  m o ve me nt patter ns s h o w si g nifica nt i nter-s u bject 
varia bilit y a n d ma y be f urt her altere d b y c ha n ges i n diet a n d / or p h ysical acti vit y d uri n g t he resi de ntial sta y, if a s u bject  w h o has c o nse nte d t o t his pr o ce d ure d oes n ot pr o vi de a sa m ple 
t his will n ot be c o nsi dere d t o be a pr ot oc ol de viati o n. T he reas o n f or missi n g t he sa m ple s h o ul d be n ote d. F ull details of sa m ple c ollecti o n will be pr o vi de d i n t he La b orat or y Ma n ual. 
Partici pati o n i n t he c ollecti o n f or fecal sa m ples f or e x pl orat or y micr o bi o me a nal ysis is v ol u ntar y a n d is s u bject t o se parate i n f or me d c o nse nt.
( p)
 
 
 
C o h orts
C o h ort
i matel y 1 
matel y 
a n d 2 3) a ±
a n d 2 3) 
d a p pr o xi m
a p pr o x
b y c ha n ges
b y c ha n
r ot oc ol de
oc ol d
r fecal sa m
r fecal sa
u s e o nl y a n d s u bj e ct t o t h e a p pli 
l e T er m s of U s e
l e
ucleic aci d
clei
d otr o pi n, 
tr o pi n M
), , P T E = pr
P T E = p
earl y ter m
earl y te
a nt e xtra p y
nt e xt
ical pre d o
al pre d
ge fr o m S
e fr o m 
( beats per 
( beats p
be rec or de
rec or d
ill be b o d y
be b o d
g a n d at
n d at 2, 
fter a n a p p
er a n a p
t y la b orat o
y la b orat
n u o us a m
n u o us 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 3 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
( q) Uri ne sa m ples will be c ollecte d o n Da y 1 a n d Da y 2 2 ( pre d ose a n d 1 2- 2 4 h o urs p ost d ose) f or meas ure me nt of 6β  h y dr o x yc ortis ol / c ortis ol rati o t o assess C Y P 3 A 4 i n d ucti o n. 
Te n- milliliter ali q u ots s h o ul d be ta ke n fr o m t he uri ne c ollecti o ns.
(r) P K bl o o d sa m ples f or t he deter mi nati o n of T A K- 0 4 1 c o nce ntrati o ns i n plas ma will be c ollecte d wit hi n 6 0 mi n utes pri or t o d ose o n all d osi n g da ys a n d o n Da y 1 at 0. 5, 1, 1. 5, 2, 
3, 4, 8, 1 2, 2 4, 4 8, a n d 9 6 h o urs p ost d ose ( o n Da y 5), at 1, 2, a n d 4 h o urs p ost d ose o n Da ys 8 a n d 1 5, a n d 0. 5, 1, 1. 5, 2, 3, 4,  8, 1 2, 2 4, a n d 4 8 h o urs p ost d ose o n Da y 2 2, a n d o n all 
F oll o w- u p visits.
(s) S u bjects will be a d mi nistere d T A K- 0 4 1/ matc hi n g place b o at a p pr o xi matel y 0 8 0 0 h o urs f oll o wi n g a fast of at least 8 h o urs a n d will c o nti n ue t o fast f or a n a d diti o nal 4 h o urs 
p ost d ose. S u bjects  ma y c o ns u me water a d li bit u m wit h t he e xce pti o n of 1 h o ur bef ore a n d 1 h o ur after dr u g a d mi nistrati o n. 
(t) S u bjects will be re q uire d t o re mai n i n t he st u d y u nit fr o m Da y - 2 t o Da y 3, fr o m Da y 7 t o Da y 1 0, fr o m Da y 1 4 t o Da y 1 7, a nd fr o m Da y 2 1 t o Da y 2 4 (f or at least 4 8 h o urs after 
eac h d ose) f or safet y, P K, a n d all st u d y assess me nts bef ore disc har ge.
( u) A Es will be ca pt ure d fr o m t he first d ose of st u d y dr u g u ntil t he Fi nal Visit.
( v) C- S S R S: T he Scree ni n g/ Baseli ne C- S S R S will be a d mi nistere d at Scree ni n g a n d t he Si nce Last Visit C- S S R S will be a d mi nistered at C hec k-i n o n Da y - 2; Da ys 3 ( Disc har ge), 7 
( C hec k-i n), 1 0 ( Disc har ge), 1 4 ( C hec k-i n), 1 7 ( Disc har ge), 2 1 ( C hec k-i n), a n d 2 4 ( Fi nal Disc har ge), Earl y Ter mi nati o n, a n d F oll o w- u p Visits as a p pr o priate (if cli nicall y si g nifica nt 
at Disc har ge).
( w)  V A S is assesse d o n 1, 8, 1 5 a n d 2 4 h o urs fr o m d osi n g o n Da y 1 5.
( x)
 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e  
 a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
ortis ol
tis ol / c oc
or t o d ose 
or t o d o
3, 4, 8, 1 2
4, 8, 
least 8 h o u
east 8 h
d mi nistrati
mi nistra
Da y 1 4 t o 
Da y 1 4
t Visit C
Visit C -S
r ge), Earl y
ge), Ear
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 4 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x E Sc he d ule of St u d y Pr oce d ures P art 4: F oll o w- U p a n d Fi n al Visit
Pr oce d ures
F oll o w- U p Peri o d 
Fi n al Visit
St u d y C o m pleti o n
St u d y D a y
D a y 2 6  
D a y 2 9  
D a y 3 6
± 2
D a y 4 3
± 2
D a y 5 0
± 2
D a y 5 7
± 2
D a y 6 4
± 2
D a y 7 0
± 2
C o nc o mita nt me dicati o ns
X  
X 
X
X
X
X
X
 
X
P h ysical e xa mi nati o n a n d ne ur ol o gical 
assess me nts (a)
X
1 2-lea d E C G
X
Safet y la b orat or y c ollecti o ns
X  
X
X
X
X
X
X
 
X
Ser u m a nti ps yc h otic me dicati o n le vel
X
e G F R ( b)
X
X
Uri ne, a n d dr u g scree n (c)
X
X
Ser u m pre g na nc y test ( h C G)
X
Fecal c ollecti o n f or micr o bi o me a nal ysis (f)
X
P K bl o o d c ollecti o n 
X  
X
X
X
X
X
X
 
X  
A E  
a
ssessm en t 
X
X
X
X
X
X
X
 
X
P A N S S
X
X
X
C -S S R S  
(
h )
X
X
X
X
X
X
X
 
X
B o n d- La der V A S
X
Pr o p ert y of T a k 
 F  
m m ee
X
m ee
X
m m
X
F
l y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
l e
pli
D a y 5 7
D a y
± 2
a
o t
o t
o
t t oo
bj e
u b
s
n d
a
l y
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 4 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A E =a d verse e ve nt, 
, 
, 
C- S S R S = C ol u m bia- S uici de Se verit y Rati n g Scale, e G F R = esti mate d gl o mer ular filtrati o n rate, E C G =electr ocar di o gra m, h C G = h u ma n c h or i o nic g o na d otr o pi n, P A N S S = P ositi ve a n d 
Ne gati ve S y n dr o me Scale, P K = p har mac o ki netic, 
, 
, V A S = vis ual a nal o g ue scale.
(a) T hese p h ysical a n d ne ur ol o gical e xa mi nati o ns will l o o k f or a b n or mal c ha n ge fr o m Scree ni n g.
( b) e G F R: T he blo o d re q uire d f or t he e G F R sa m ple will be c ollecte d as part of t he safet y la b orat or y sa m ples.
(c) Uri ne dr u g scree ns ma y be re peate d as nee de d at t he i n vesti gat or’s discreti o n.
( d) T w o 2. 5 m L w h ole bl o o d sa m ples will be c ollecte d f or R N A p har mac o ge n o mic a nal ysis fr o m eac h s u bject.
(e) 
 
.
(f) If a s u bject w h o has c o nse nte d t o t his pr oce d ure d oes n ot pr o vi de a fecal sa m ple t his will n ot be c o nsi dere d t o be a pr ot ocol de viati o n. T he reas o n f or missi n g t he sa m ple s h o ul d be 
n ote d. F ull details of sa m ple c ollecti o n will be pr o vi de d i n t he La b orat or y Ma n ual. Partici pati o n i n t he c ollecti o n f or fecal s a m ples f or e x pl orat or y micr o bi o me a nal ysis is v ol u ntar y 
a n d is s u bject t o se parate i nf or me d c o nse nt.
( g)
 
( h) C- S S R S: T he Si nce Last Visit C- S S R S will be a d mi nistere d at F oll o w- u p Visits as a p pr o priate (if cli nicall y si g nifica nt at Disc har ge).
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d 
j e 
h e a p pli 
l e T er m s of U s e
l e
n c h ori o nic
c h o
vis ual a nal
ual a n
.
t o be a pr o
ecti o n f or 
ti o n f
ate (if cli n
e (if cl
C CI
C CI
C CI
C CI
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x F
Res p o nsi bilities of t he I n vesti g at or
Cli nical researc h st u dies s p o ns ore d b y  t he s p o ns or are s u bject t o I C H G C P a n d all t he a p plica ble 
l ocal la ws a n d re g ulat i ons. T h e res p o nsi bilit ies i m p ose d b y t he F D A are s u m marize d i n t he 
“ State me nt of I n vesti gat or” ( F or m F D A 1 5 7 2), w hic h m ust be c o m plete d a n d si g ne d bef ore t he 
i n vesti gat or ma y p artici pate i n t his st u d y.
T he i n vest i gat or a grees t o ass u me t he f oll owi n g res p o nsi bilit ies b y si g ni n g a F or m F D A 1 5 7 2:
1.
C o n d uct t he st u d y  in acc or da nce wit h t he pr ot oc ol.
2.
Pers o nall y c o n d uct or s u per vise t he staff w h o will assist i n t he pr ot oc ol.
3.
E ns ure t hat st u d y  relate d pr oce d ures, i ncl u di n g st u d y s pecific ( n o nr o utine/ n o nsta n dar d pa nel) 
scree ni n g assess me nts are N O T perf or me d o n p ote nt ial s u bjects, pri or t o t he recei pt of writte n 
a p pr o val fr o m r ele va nt g o ver ni n g b o dies/a ut h orit ies.
4.
E ns ure t hat all c o llea g ues a n d e m pl oyees assist i n g i n t he c o n d uct of t he st u d y are i nf or me d of 
t hese o bli gat i ons.
5.
Sec ure pri or a p pr o val o f the st u d y a n d a n y c ha n ges b y a n a p pr o priate I R B/I E C t hat c o nf or m t o 
2 1 C F R Part 5 6, I C H, a n d l ocal re g ulat or y  re q uire me nts.
6.
E ns ure t hat t he I R B/I E C will be res p o nsi ble f or i nit ial re vie w, c o nti n ui n g re vie w, a n d a p pr o val 
of  t he pr ot oc ol. Pr o m ptl y re p ort t o t he I R B/I E C all c ha n ges i n researc h act i vity a n d all 
a nt ici pate d ris ks t o s u bjects. Ma ke at least yearl y re p orts o n t he pr o gress of t he st u d y t o t he 
I R B/I E C, a n d iss ue a fi nal re p ort wit hi n 3 m o nt hs of st u d y c o mplet i on.
7.
E ns ur e t hat re q uire me nts f or i nf or me d c o nse nt, as o utli ne d i n 2 1 C F R Part 5 0, I C H, a n d l ocal 
re g ulat i ons, are m et.
8.
O btai n vali d i nf or me d c o nse nt fr o m eac h s u bject w h o partici pates i n t he st u d y , a n d d oc u me nt 
t he date of c o nse nt i n t he s u bject’s me dical c hart. Va li d i nf or me d c o nse nt is t he m ost c urre nt 
versi o n a p pr o ve d b y t he I R B/I E C. Eac h i nf or me d c o nse nt f or m s h o ul d c o ntai n a s u bject 
a ut h orizat i on sect i on t hat descri bes t he uses a n d discl os ures of a s u bject’s pers o nal 
i nf or mat i on ( i ncl u di n g pers o nal health i nf or mat i on) t hat will ta ke place i n c o n nect i on wit h t he 
st u d y. If a n i nf or me d c o nse nt f or m d oes n ot i ncl u de s uc h a s u bject a ut h orizati o n, t he n t he 
i n vesti gat or m ust o btai n a se parate s u bject a ut h orizati o n f or m fr o m eac h s u bject or t he 
s u bject’s le gall y acce ptable re prese ntati ve.
9.
Pre pare a n d mai ntai n a de q uate case hist ories of all pers o ns e ntere d i nt o t he st u d y , i nclu di n g 
e C R Fs, h os pital rec or ds, la b orat or y res ults, etc, a n d mai ntai n t hese data f or a mi ni m u m of 
2 years f o ll owi n g n otificat i on b y t he s p o ns or t hat all i n vesti gati ons ha ve bee n disc o nt i n ue d or 
t hat t he re g ulat or y a ut h orit y has a p pr o ve d t he mar keti n g a p plicat i on. T he i n vest i gat or s h o ul d 
c o ntact a n d recei ve writte n a p pr o val fr o m t he s p o ns or bef ore dis p osi n g o f a n y s uc h 
d oc u m e nts.
1 0. All o w p ossi ble i ns pecti o n a n d c o p yi n g b y t he re g ulat or y  a ut h orit y of G C P-s pecifie d esse ntial 
d oc u m e nts.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 1. Mai ntai n c urre nt rec or ds of t he recei pt, a d mi nistrati o n, a n d dis p osit i on of s p o ns or -s u p plie d 
dr u gs, a n d ret ur n all u n use d s p o ns or -s u p plie d dr u gs t o t he s p o ns or. 
1 2. Re p ort a d vers e reactio ns t o t he s p o ns or pr o m pt l y. I n t he e ve nt of a n S A E, n otif y t he s p o ns or 
wi t hi n 2 4 h o urs. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x G
Ele me nts of t he S u bject I nf or me d C o nse nt
I n see ki n g i nf or me d c o nse nt, t he f oll owi n g i nf or mati o n s hall be pr o vi de d t o eac h s u bject:
1.
A state me nt t hat t he st u d y  in v o l ves researc h.
2.
A n e x pla nat i on of t he p ur p oses of t he researc h.
3.
T he e x pecte d d urati o n of t he s u bject’s partici pat i on.
4.
A descri pt i on of t he pr oce d ures t o be f o ll owe d, i ncl u di n g i n vasi ve pr oce d ures.
5.
T he i de nt ificatio n of  a n y pr oce d ures t hat are e x peri me ntal.
6.
T he est i mate d n u m ber of s u bjects i n v ol ve d i n t he st u d y.
7.
A descri pt i on of t he s u bject’s res p o nsi bilit ies.
8.
A descri pt i on of t he c o n d uct of t he st u d y .
9.
A state me nt descri bi n g t he treat me nt(s) a n d t he pr o ba bilit y f or ra n d o m assi g n me nt t o eac h 
treat me nt.
1 0. A descri pt i on of t he p ossi ble si de effects of t he treat me nt t hat t he s u bject ma y recei ve.
1 1. A descri pt i on of a n y  reas o na bl y foreseea ble ri s ks or disc o mforts t o t he s u bject a n d, w he n 
a p plica ble, t o a n e m br yo, f et us, or nursi n g i nfa nt.
1 2. A descri pt i on of a n y  be nefits t o t he s u bject or t o ot hers t hat reas o na bl y ma y be e x pecte d fr o m 
t he researc h. W he n t here is n o i nte n de d cli nical be nefit t o t he s u bject, t he s u bject s h o ul d be 
ma de a ware of t his.
1 3. Di s clos ures o f a p pr o priate alter nati ve pr oce d ures or c o urses of treat me nt, if a n y, t hat mi g ht be 
a d va nta ge o us t o t he s u bject a n d t heir i m p orta nt p ote nt ial ris ks a n d be nefits.
1 4. A state me nt descri bi n g t he e xte nt t o w hic h c o nfi de nt iality of  rec or ds ide ntif yi n g t he s u bject 
will be mai ntai ne d , a n d a n ote of t he p ossi bility t hat re g ulat or y a ge ncies, a u dit or(s), I R B/I E C, 
a n d t he m o nit or ma y i ns pect t he rec or ds. B y  si g ni n g a writte n i nf or me d c o nse nt f or m, t he 
s u bject or t he s u bject’s le gall y acce pta ble re prese ntati ve is a ut h orizi n g s uc h access.
1 5. F or researc h i n v ol vi n g m ore t ha n mi ni mal ris k, a n e x pla nat i on as t o w het her a n y c o m pe nsati o n 
a n d a n e x pla nat i on as t o w het her a n y me dical treat me nts are a vaila ble if i nj ur y occ urs a n d, if s o, 
w hat t he y  c o nsist of or w here f urt her i nf or mati on ma y be o btai ne d.
1 6. T he a nt ici pate d pr orate d pa y me nt(s), if a n y, t o t he s u bject f or partici pati n g i n t he st u d y.
1 7. T he a nt ici pate d e x pe nses, if a n y, t o t he s u bject f or partici pat i n g i n t he st u d y.
1 8. A n e x pla nat i on of w h o m t o c o ntact f or a ns wers t o perti ne nt q uesti o ns a b o ut t he r esearc h 
(in vest i gat or), s u bject’s ri g hts, a n d I R B/I E C a n d w h om t o c o ntact in t he e ve nt of a 
researc h-r elate d i njur y t o t he s u bject.
1 9. A state me nt t hat partici pati o n is v o l unt ar y, t hat ref usal t o partici pate will i n v ol ve n o pe nalty o r 
l oss of be nefits t o w hich t he s u bject ot her wise is e ntit le d, a n d t hat t he s u bject ma y disc o nti n ue 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
parti ci pat i on at a n y  ti me wit ho ut pe nal t y or loss of be nefits t o w hic h t he s u bject is ot her wise 
e nt itle d.
2 0. T he c o nse q ue nces of a s u bject’s decisi o n t o wi t hdra w fr o m  t he researc h a n d pr oce d ures f or 
or derl y ter mi nat i on of part ici pati on b y t he s u bject.
2 1. A state me nt t hat t he s u bject or t he s u bject’s le gall y acce pta ble re prese ntati ve will be i nf or me d 
i n a ti mel y ma n ner if i nf or mat i on bec o mes a vaila ble t hat ma y be rele va nt t o t he s u bject’s 
wi lli n g ness t o c o nti n ue partici pati on i n t he st u d y.
2 2. A state me nt t hat res ults of p har mac o ge n o mic a nal ysis will n ot be discl ose d t o a n i n di vi d ual, 
u nless pre vaili n g la ws re q uire t he s p o ns or t o d o s o.
2 3. T he f oreseea ble circ u msta nces or reas o ns u n der w hic h t he s u b ject’s partici pati on i n t he st u d y 
ma y be ter mi nate d.
2 4. A wr itte n s u bject a ut h orizati o n (either c o ntai ne d wit hi n t he i nf or me d c o nse nt f or m or pr o vi de d 
as a se parate d oc u me nt) descri bi n g t o t he s u bject t he c o nte m plate d a n d per missi ble uses a n d 
di s clos ures of t he s u bject’s pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mat i on) f or 
p ur p oses of c o n d uct i n g t he st u d y. T he s u bject a ut h orizati on m u st c o ntai n t he f oll owi n g 
state me nts re gar di n g t he uses a n d discl os ures of t he s u bject’s pers o nal i nf or mat i on:
a)
t hat pers o nal i nf or mat i on ( i ncl u di n g pers o nal health i nf or mati o n) ma y be pr ocesse d b y 
or tra nsferre d t o ot her parties i n ot her c o u ntries f or cli nical researc h a n d safet y 
re p orti n g p ur p oses, i ncl u di n g, wit h o ut li mitati on, t o t he f o ll owi n g: ( 1) Ta ke da, its 
affiliates, a n d lice nsi n g part ners; ( 2) b usi ness part ners assisti n g Ta ke da, its affiliates, 
a n d lice nsi n g part ners; ( 3) re g ulat or y a ge ncies a n d ot her healt h a ut h orities; a n d 
( 4) I R Bs/I E Cs;
b)
it is p ossi ble t hat pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati o n) ma y be 
pr ocesse d a n d tra nsferre d t o c o u ntries t hat d o n ot ha ve data pr otecti o n la ws t hat offer 
s u bjects t he sa me le vel of pr otecti o n as t he data pr otecti o n la ws wit hi n t his c o u ntr y; 
h o we ver, Ta ke da will ma ke e ver y  effort t o kee p y o ur pers o nal  inf or m at i on 
c o nfi de nt ial, a n d yo ur na me will n ot be di sclos e d o utside t he u nit u nless re q uire d b y 
la w;
c)
t hat pers o nal i nf or mati o n (i ncl u di n g pers o nal healt h i nf or mati on) m a y be a d de d t o 
Ta ke da’s researc h data bases f or p ur p oses of de vel o pi n g a better u n dersta n di n g of  t he 
safety a n d effect i ve ness of t he st u d y me dicat i on(s), st u d yi n g ot her t hera pies f or 
pati e nts, de vel o pi n g a better u n dersta n di n g of disease, a n d i m pr o vi n g t he efficie nc y of 
f ut ure cli nical st u dies;
d)
t hat s u bjects a gree n ot t o restrict t he use a n d disclos ure of t hei r pers o nal inf or mat i on 
(incl u di n g pers o nal healt h i nf or mati on) u p o n wit h dra wal fr o m t he st u d y t o t he e xte nt 
t hat t he restricte d use or discl o s ure of s uc h i nf or mati o n ma y i m pact t he scie ntific 
i nte grit y of t he researc h; a n d
e)
t hat t he s u bject’s ide nt ity will re mai n c o nfi de nt ial i n t he e ve nt t hat st u d y res ults are 
p u blis he d.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
2 5. Fe male s u bjects of c hil d beari n g p ote ntial are e xcl u de d fr o m t his st u d y. Re g ular pre g na nc y 
tests will be perf or me d t hr o u g h o ut t he st u d y for all fe male s u bjects. If a s u bject is f ou n d t o be 
pre g na nt d uri n g st u d y, st u d y me dicati o n will be disc o nti n ue d a n d t he i n vest i gat or will offer t he 
s u bject t he c h oice t o recei ve u n bli n de d treat me nt i nf or mati on.
2 6. Male s u bjects m ust use a de q uate c o ntrace pti o n (as defi ne d i n t he i nf or me d c o nse nt) f r o m 
Scree ni n g a n d t hr o u g h o ut t he d urati o n of t he st u d y. If the part ner or wife of t he s u bject is f o u n d 
t o be pre g na nt d uri n g t he st u d y, t he i n vesti gat or will offer t he s u bject t he c h oice t o recei ve 
u n bli n de d treat me nt i nf or mat i on.
2 7. A st ate me nt t hat cli nical trial i nf or mati on fr o m t his trial will be p u blicl y discl o se d i n a p u blicl y 
accessi ble we bsite, s uc h as Cli nical Trials. g o v.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x H
I n vesti g at or C o nse nt t o Use of Pers o n al I nf or m ati o n
Ta ke da will c o llect a n d retai n pers o nal i nf or mati o n of i n vest i gat or, i ncl u di n g his or her na me, 
a d dress, a n d ot her pers o nall y i de ntifia ble i nf or mat i o n. I n a d diti on, i n vest i gat or’s pers o nal 
i nf or mat i on ma y be tra nsferre d t o ot her parties l ocate d i n c o u ntries t hr o u g h o ut t he w orl d (e g, t he
U nite d Ki n g d o m, U nite d States, a n d Ja pa n), i ncl u di n g t he f oll o wi n g:

Ta ke da, its affiliates, a n d lice nsi n g part ners.

B usi ness part ners assist i n g Ta ke da, its affiliates, a n d lice nsi n g part ners.

Re g ulat or y  a ge ncies a n d ot her healt h a ut h orities.

I R Bs a n d I E Cs.
I n vesti gat or’s pers o nal i nf or mati on ma y be retai ne d, pr ocesse d, a n d tra nsferre d b y  Ta ke da a n d 
t hese ot her parties f or researc h p ur p oses i ncl u di n g t he f o ll owi n g:

Assess me nt of t he s uita bilit y of i n vest i gat or f or t he st u d y a n d/ or ot her cli nical st u dies.

Ma na ge me nt, m o nit ori n g, i ns pect i on, a n d a u dit of t he st u d y .

A nal ysis, re vie w, a n d verificat i on of t he st u d y  res ults.

S af et y re p ortin g a n d p har mac o vi gila nce relat i n g t o t he st u d y.

Pre parati o n a n d s u b missi o n of re g ulat or y  fili n gs, c orres p o n de nce, a n d c o m m u nicat i ons t o 
re g ulat or y a ge ncies relat i n g t o t he st u d y.

Pre parati o n a n d s u b missi o n of re g ulat or y  fili n gs, c orres p o n de nce, a n d c o m m u nicati ons t o 
re g ulat or y a ge ncies relati n g t o ot her me dicati o ns use d i n ot her cli nical st u dies t hat ma y c o ntai n 
t he sa me c he mica l c om p o u n d prese nt i n t he st u d y me dicat i on.

I ns pecti ons a n d i n vest i gati ons b y re g ulat or y  a ut h orities relati n g t o t he st u d y.

Self -i ns pecti on a n d i nter nal a u dit wit hi n Ta ke da, its affiliates, a n d lice nsi n g part ners.

Arc hi vi n g a n d a u dit of st u d y  rec or ds.

P os ti n g i n vesti gat or site c o ntact i nf or mati on, st u d y details a n d res ults o n p u blicl y accessi ble 
cli nical trial re gistries, data bases, a n d we bsites.
I n vesti gat or’s pers o nal i nf or mati on ma y be tra nsferre d t o ot her c o u ntries t hat d o n ot ha ve data 
pr otecti o n la ws t hat offer t he sa me le vel of pr otecti o n as data pr otecti o n la ws i n i n vest i gat or’s o w n 
c o u ntr y.
I n vesti gat or ac k n o wle d ges a n d c o nse nts t o t he use of his or her pers o nal i nf or mati o n b y Ta ke da 
a n d ot her parties f or t he p ur p oses descri be d a b o ve.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
A p pe n di x I
Det aile d Descri pti o n of A me n d me nts t o Te xt
T his d oc u me nt descri bes c ha n ges i n refere nce t o Pr ot oc ol I nc or p orati n g A me n d me nt N o. 0 5.
T he pri mar y  secti ons of  t he pr ot oc ol affecte d b y t he c ha n ges i n A me n d me nt N o. 0 5 are i n dicate d. 
T he c orres p o n di n g te xt has bee n re vise d t hr o u g h o ut t he pr ot oc ol. 
C h a n ge  1 : A d de d Part 3 st u d y desi g n, wit h p o p ulati o n, f or m ulat i on, d osi n g, f o o d effect re gi me n, 
a n d c o n fi ne me nt
T he pri mar y  c ha n ge occ urs i n Secti o n  6. 1. 3 Part 3: Si n gle D ose: Healt h y S u bjects Rel at i ve 
Bi oa vaila blit y a n d F o o d Effect St u d y
A d de d Te xt 
a n d ta bles:
P art 3 is a p h ase 1, r a n d o mize d, o pe n- l a bel, si n gle-d ose, si n gle -ce nter, p ar allel 
desi g n st u d y. T o e v al u ate t he or al bi o a v ail a bilit y of t he rece ntl y de vel o pe d 
T A K -0 4 1 t a blet f or m ul ati o n rel ati ve t o t he or al s us pe nsi o n a n d effect of f o o d 
o n t he P K of t he t a blet f or m ul ati o n, he alt h y s u bjects will be r a n d o mize d t o 
recei ve o n D a y 1 a si n gle 4 0 m g d ose of T A K -0 4 1 ( as a si n gle 4 0 m g t a blet) after 
eit her at le ast 1 0 -h o urs of o ver ni g ht f ast or 3 0 mi n utes after st arti n g i n gesti o n 
of a hi g h -f at, hi g h-c al orie bre a kf ast. Bl o o d s a m ples will be c ollecte d o ver 
9 6 h o urs p ost -d ose t o me as ure T A K -0 4 1 pl as m a c o nce ntr ati o ns. 
T he c o h ort will be r a n d o mize d w here 9 s u bjects will recei ve T A K -0 4 1 i n t he 
f aste d st ate a n d 9 s u bjects t o recei ve i n t he fe d st ate. T he st u d y p o p ul ati o n f or 
P art 3 will be c o m p ose d of a p pr o xi m atel y 1 8 he alt h y s u bjects r a n d o mize d i n a 
1: 1 r ati o t o recei ve T A K -0 4 1 i n t he f aste d st ate or i n t he fe d st ate. 
S u bjects w h o s atisf y t he Scree ni n g e v al u ati o n a n d selecti o n criteri a m a y be 
e nr olle d i n t he st u d y. O n D a y 1, eli gi ble s u bjects will be r a n d o mize d t o recei ve 
T A K -0 4 1 as o ne 4 0 m g i m me di ate rele ase t a blet a d mi nistere d or all y after 
eit her a n at le ast 1 0 - h o urs of o ver ni g ht f ast (i ncl u di n g n o me dic ati o ns) or 3 0 
mi n utes after st arti n g i n gesti o n of a hi g h -f at, hi g h-c al orie bre a kf ast 
( a p pr o xi m atel y 8 0 0-1 0 0 0 c al ories wit h a p pr o xi m atel y 5 0 % fr o m f at), a n d will 
be re q ui re d t o re m ai n i n t he st u d y u nit f or at le ast a n a d diti o n al 4 8 h o urs after 
d osi n g f or s afet y a n d P K, wit h a d diti o n al visits f or P K a n d s afet y assess me nts 
o n D a y 4 a n d 5 a n d a fi n al F oll o w -u p visit o n D a y 1 7 -2 1. 
O ver all, f or he alt h y s u bjects, P art 3 of t he st u d y will c o nsist of a Scree ni n g 
Visit ( D a ys -2 8 t o -2), a pre d ose C hec k -i n D a y f or all s u bjects ( D a y -1) d uri n g 
w hic h b aseli ne assess me nts will be c o n d ucte d, a n d a si n gle or al d ose 
a d mi nistr ati o n ( D a ys 1) f oll o wi n g w hic h all s u bjects will u n der g o 
st u d y-s pecific assess me nts. S u bjects fr o m P art 3 will be re q uire d t o re m ai n i n 
t he st u d y u nit u ntil a mi ni m u m 4 8 h o urs after t he first d ose f or s afet y, P K, a n d 
st u d y assess me nts bef ore disc h ar ge. S u bjects will be re q uire d t o ret ur n t o t he 
st u d y u nit f or s afet y a nd P K assess me nts, a n d f or a fi n al F oll o w -u p visit t h at 
c o m pletes t he st u d y a p pr o xi m atel y 1 8 d a ys after d osi n g. T he sc he d ule f or P art 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 4 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
3 is s h o w n i n A p pe n di x C.
R ati o n ale f or C h a n ge: T o a d d t o t he st u d y d esig n t o assess t he relat i ve bi oa vaila bilit y a n d f o o d
effect o n t he P K of t he T A K-0 4 1 ta bl et for m ulat i on.
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  2. 0 S T U D Y S U M M A R Y

Secti o n  4. 2 Rati o nale f or t he Pr o p ose d St u d y

Secti o n 6. 1. 6 D o se Escalati o n
C h a n ge  2 : A d de d Part 4 st u d y desi g n wit h sta ble sc hiz o p hre nic p o p ulat i on, d ose le vels, d osi n g 
da ys a n d c o nfi ne me nt da ys.
T he p rimar y  c ha n ge occ urs i n Secti o n 6. 1. 4 Part 4 : Si n gle D ose: S u bjects wit h Sc hiz o p hre nia
A d de d te xt 
a n d ta bles:
P a r t 4: Si n gle D ose: S u bjects wit h Sc hiz o p hre ni a
P art 4 will c o nsist of a d o u ble -bli n d, wee kl y d osi n g, p ar allel gr o u p desi g n. 
T we nt y -f o ur s u bjects wit h st a ble sc hiz o p hre ni a will be e nr olle d. T he 2 4 
s u bjects are c o nsi dere d a de q u ate t o e x pl ore t he p h ar m ac ol o gic all y acti ve 
e x p os ure r a n ge i n s u bjects wit h st a ble sc hiz o p hre ni a. T he s u bjects will be 
r a n d o ml y assi g ne d t o recei ve T A K - 0 4 1 or pl ace b o i n a r ati o of 2: 1. S u bjects 
will recei ve a n i niti al l o a di n g d ose of T A K- 0 4 1 o n D a y 1 f oll o we d b y a 
m ai nte n a nce d ose t h at will be h alf t he i niti al d ose o n D a ys 8, 1 5, a n d 2 2 or will 
recei ve pl ace b o o n all st u d y d osi n g d a ys. P art 4 m a y c o m me nce o nl y after at 
le ast 2 1 d a ys of s afet y, t oler a bilit y, a n d a v ail a ble P K d at a h a ve bee n c ollecte d 
at t he e q ui v ale nt d ose c o h ort i n he alt h y s u bjects i n P art 2.
T he d ose le vels f or P art 4 will be b ase d o n e mer gi n g s afet y/t oler a bilit y a n d 
a v ail a ble P K d at a of t he s a me d ose i n he alt h y s u bjects fr o m P art 2. D ose 
esc al ati o n will be b ase d o n a s p o ns or re vie w of at le ast 2 1 d a ys of s afet y, 
t oler a bilit y, a n d a v ail a ble P K d ata fr o m t he prece di n g c o h ort. T he hi g hest 
pl a n ne d l o a di n g d ose i n P art 4 will n ot e xcee d t he hi g hest d ose e v al u ate d, 
dee me d s afe, a n d well t oler ate d i n P art 2. S u bjects i n P art 4 will be 
a d mi nistere d a si n gle T A K -0 4 1 l o a di n g d ose or pl ace b o o n D a y 1 a n d wee kl y 
m ai nte n a nce d oses o n D a ys 8, 1 5 a n d 2 2. T he 2 4 s u bjects will be r a n d o mize d 
wit h 1 6 acti ve : 8 pl ace b o. 
O ver all, P art 4 of t he st u d y will c o nsist of a Scree ni n g Visit ( D a ys -3 5 t o -3), a 
pre d ose C hec k -i n D a y f or all s u bjects ( D a ys -2) d uri n g w hic h s o me b aseli ne 
assess me nts will be c o n d ucte d, D a y -1 d uri n g w hic h ot her b aseli ne assess me nts 
will be c o n d ucte d, a n d 2 2 d a ys of tre at me nt w he n all s u bjects will be d ose d o n 
D a ys 1, 8, 1 5, a n d 2 2 as well as u n der g oi n g w he n all s u bjects will u n der g o 
st u d y-s pecific assess me nts. After 4 wee ks of d osi n g, s u bjects will ret ur n f or 
f oll o w-u p st u d y -s pecific assess me nts o n D a ys 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
S u bjects will be re q uire d t o re m ai n i n t he st u d y u nit fr o m D a y - 2 t o D a y 3 ( 4 8 
h o urs after t he first d ose) f or s afet y, P K, a n d all st u d y assess me nts bef ore 
disc h ar ge. S u bjects will ret ur n o n D a y 5 f or a s afet y a n d P K assess me nt. 
S u bjects will ret ur n o n D a y 7 t o o bt ai n s afet y l a b or at or y tests bef ore recei vi n g 
t he sec o n d d ose o n D a y 8. S u bjects will re m ai n i n t he st u d y u nit fr o m D a y 7 t o 
D a y 1 0 ( 4 8 h o urs after t he sec o n d d ose). S u bjects will ret ur n o n D a y 1 4 t o 
o bt ai n s afet y l a b or at or y tests bef ore recei vi n g t he t hir d d ose o n D a y 1 5. 
S u bjects will re m ai n i n t he st u d y u nit fr o m D a y 1 4 t o D a y 1 7 ( 4 8 h o urs after 
t he t hir d d ose). S u bjects will ret ur n o n D a y 2 1 t o o bt ai n s afet y l a b or at or y tests 
bef ore recei vi n g t he t hir d d ose o n D a y 2 2. S u bjects will re m ai n i n t he st u d y 
u nit fr o m D a y 2 1 t o D a y 2 4 ( 4 8 h o urs after t he f o urt h d ose). After disc h ar ge o n 
D a y 2 4, s u bjects will ret ur n t o t he cli nic o n D a ys 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4 f or 
s afet y a n d P K f oll o w u p visits. T he fi n al visit t h at c o m pletes t he st u d y will 
occ ur 1 2 t o 1 6 d a ys after t he l ast s afet y a n d P K f oll o w- u p visit. T he sc he d ule 
f or P art 4 is s h o w n bel o w.
B o n d- L a der vis u al a n al o g sc ales will be perf or me d o n D a ys - 1, 1, 8, 1 5, a n d 
D a y 2 2 at 1, 3, 8, a n d 2 4 h o urs p ost d ose, D a y 2 4, a n d (if a p plic a ble) at E arl y 
R ati o n ale f or C h a n ge: T o e x pl ore t he safet y, t olera bilit y, a n d P K of T A K- 0 4 1 as a d d- o n t hera p y 
t o a nti ps yc h otics i n s u bjects f or w h o m t o date t here are n o a p pr o ve d dr u gs a d dressi n g ne gati ve 
s y m pt o ms or c o g niti ve i m p air ment ass ociate d wit h  sc hiz o p hre nia.
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
Secti o n  4. 2 Rati o nale f or t he Pr o p ose d St u d y
!
Secti o n  6. 1. 6  D ose Escalati o n
Pr o p ert y of T a k e d a: 
o wi n g s
wi n g
Secti
Secti o no
!
Sec
S
!
a: F or n
h a n ge
n ge
cs i n s u b
cs i n s u
r c o g nit
c o g ni
a: 
n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
i vi n g 
i vi n g 
D a y 7 t o
a y 7 t
y 1 4 t o 
1 4 t o
D a y 1 5. 
y 1 5.
4 8 h o ur
8 h o u
et y l a b or
y l a b
e m ai n i n
m ai n 
d ose). Af
ose). 
, 3 6, 4 3, 
3 6, 4 3
t c o m ple
c o m p
K f oll o w
f oll o
perf or m
perf or
se, D a y
e, D a
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
C h a n ge  3: A d de d o bjecti ves a n d e n d p oi nts f or Parts 3 a n d 4.
T he pri mar y c ha n ge occ urs i n Secti o n  5. 1 St u d y O bjecti ve a n d E n d p oi nts
A me n de d or 
ne w w or di n g:
Pri m ar y O bjecti ve
T o e val uate t he safet y a n d t olera bilit y of T A K- 0 4 1 f oll o wi n g
!
F oll o wi n g or al si n gle a n d m ulti ple d oses i n healt h y s u bjects ( P arts 1, 2, a n d 3).
!
As a d d- o n t her a p y t o a nti ps yc h otics i n s u bjects wit h st a ble sc hiz o p hre ni a 
( P art 4).
T o assess t he or al bi o a v ail a bilit y i n he alt h y s u bjects of T A K – 0 4 1 a d mi nistere d 
as a 4 0 m g i m me di ate rele ase t a blet f or m ul ati o n i n t he f aste d st ate c o m p are d 
t o 4 0 m g or al s us pe nsi o n f or m ul ati o n i n t he f aste d st ate ( P art 3).
T o assess t he effect of f o o d o n t he p h ar m ac o ki netics of 4 0 m g i m me di ate 
rele ase t a blet f o r m ul ati o n of T A K – 0 4 1 i n he alt h y s u bjects ( P art 3).
Sec o n d ar y O bjecti ve
T o e val uate t he P K of T A K- 0 4 1
!
A d mi nistere d u n der f asti n g c o n diti o ns f oll o wi n g oral si n gle a n d m ulti ple 
d oses i n healt h y s u bjects ( P arts 1 a n d 2).
!
As a d d- o n t her a p y t o a nti ps yc h otics i n s u bjects wit h st a ble sc hiz o p hre ni a 
( P art 4).
E x pl or at or y O bjecti ves
Pr o p ert y of T a k e
r ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
ts 1, 2, a
 1, 2,
le sc hiz o
sc hi
T A K
T A K – 0
t he f aste
he f as
e d st ate 
d st ate
ki netics 
netics
he alt h y 
e alt h y
g c o n dit
c o n di
( P arts 1
P arts 
o a nti ps
o a nti p
ti ves
i ves
m
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Pri m ar y E n d p oi nts
T he pri mar y e n d p oi nt f or all p arts of t his st u d y is t he c o m p osite of safet y varia bles 
t o deter mi ne t he safet y a n d t olera bilit y of oral si n gle a n d m ulti ple d oses of 
T A K- 0 4 1 as well as d ose- li miti n g effects of T A K- 0 4 1. T he f oll o wi n g safet y 
para meters will be a nal yze d f or e ac h of t he st u d y p arts as t he n u m ber a n d 
perce nta ge of s u bjects w h o:
!
e x perie nce E x perie nce at least 1 treat me nt-e mer ge nt a d verse e ve nt ( T E A E).
!
disc o nti n ue Disc o nti n ue d ue t o a n a d verse e ve nt ( A E).
!
meet Meet t he mar ke dl y a b n or mal criteria f or safet y la b orat or y tests at least 
o nce p ost d ose.
!
meet Meet t he mar ke dl y a b n or mal criteria f or vital si g n meas ure me nts at least 
o nce p ost d ose.
!
meet Meet t he mar ke dl y a b n or mal criteria f or 1 2-lea d E C G para meters at least 
o nce p ost d ose.
!
e x perie nce E x perie nce cli nicall y si g nifica nt a b n or mal c ha n ges i n c o nti n u o us 
1 2-lea d E C G  meas ure me nts at least o nce p ost d ose (e xce pt P art 3).
T he pri m ar y e n d p oi nts als o i ncl u de t he T A K- 0 4 1 pl as m a P K p ar a meters f or 
P art 3, m a xi m u m o bser ve d c o nce ntr ati o n ( C m a x ) a n d are a u n der t he pl as m a 
c o nce ntr ati o n-ti me c ur ve fr o m ti me 0 t o 9 6 h o urs ( A U C 9 6).
Sec o n d ar y E n d p oi nts
T he sec o n dar y e n d p oi nts c o nsists e n d p oi nt c o nsist of sta n dar d P K varia bles t o 
deter mi ne dr u g e x p os ure at eac h d ose i n e ac h of t he st u d y p arts. T he f oll o wi n g P K 
para meters f or T A K- 0 4 1 will be a nal yze d as sec o n dar y e n d p oi nts:
!
C ma x : ma xi m u m o bser ve d plas ma c o nce ntrati o n ( P arts 1, 2 a n d 4 o nl y).
!
tma x : ti me t o Cma x .
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t
he c o
e c o m pm
n gle a n d
n gle a n
T A K
A K -0 4 1
0 4
he st u d y 
e st u d
treat m
reat m
e t o a n a
t o a n a
y a b n or m
a b n o
mar ke dl y
ar ke dl
e.
et t h
t he ma
e m
p ost d ose
st d os
x perie nc
erie n
1 21 2 -lea d
lea
T he p
T he 
P ar
P a
s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
!
A U C 2 4: area u n der t he plas ma c o nce ntrati on-ti me c ur ve fr o m ti me 0 t o 2 4 h o urs.
!
A U C tA U C 9 6: are a u n der t he pl as m a c o nce ntr ati o n-ti me c ur ve fr o m ti me 0 
t o 9 6 h o urs ( P arts 1, 2 a n d 4 o nl y).
!
A U C l ast: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o t he ti me 
of t h e last q ua ntifia ble c o nce ntrati o n.
!
A U C ∞: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t o i nfi nit y 
( P art 1 o nl y).
!
A U C τ: area u n der t he plas ma c o nce ntrati o n-ti me c ur ve d uri n g a d osi n g i nter val, 
w here ta u ( τ) is t he le n gt h of t he d osi n g i nter val ( PartP arts 2 a n d 4 o nl y).
!
t1/ 2z: ter mi nal dis p ositi o n p hase half-life.
E x pl or at or y E n d p oi nts
Pr o p ert y of T a k e
t t o t h e a p pli c a bl e T er m s of U s e
t hh e ti me
e ti m
me 0 t o i n
0 t o 
uri n g a d
n g a 
P art
P art s 2 
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 5 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
R ati o n ale f or C h a n ge: t o assess t he oral bi oa vaila bilit y a n d f o o d effect o n t he P K of t he 4 0- m g 
T A K- 0 4 1 i m me diate release ta blet a n d t o assess its safet y  a n d t olera bilit y as a d d- o n t hera p y i n 
s u bjects wit h sta ble sc hiz o p hre nia i n Part 4.
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  5. 2 E n d p oi nts f or Part 1 a n d Part 2 a n d Part 3 ( Healt h y S u bjects) a n d P art 4 ( S u bjects 
wit h Sc hiz o p hre nia)
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x C Sc he d ule of St u d y Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relati ve 
Bi oa vaila bilit y a n d F o o d Effect)
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
C h a n ge  4: A d de d t he j ustificati o n f or t he pr o p ose d st u d y desi g n d ose a n d e n d p oi nts f or Part 3.
T he pri mar y c ha n ge occ urs i n Secti o n  6. 2. 1 J ustificati o n f or St u d y Desi g n, D ose, a n d E n d p oi nts
A d de d te xt:
T he pri m ar y o bjecti ve of P art 3 t he st u d y is t o deter mi ne t he or al 
bi o a v ail a bilit y of T A K- 0 4 1 i n he alt h y s u bjects a d mi nistere d as a 4 0 m g 
i m me di ate rele ase t a blet f or m ul ati o n i n t he f aste d st ate c o m p are d t o 4 0 m g 
or al s us pe nsi o n f or m ul ati o n i n t he f aste d st ate a n d t o esti m ate t he effect of 
f o o d o n t he p h a m ac o ki netics of a si n gle d ose of 4 0 m g i m me di ate rele ase 
t a blet f or m ul ati o n of T A K- 0 4 1 i n he alt h y s u bjects. 
R ati o n ale f or C h a n ge: t o e x pl ore t he safet y, t olera bilit y, a n d P K of T A K- 0 4 1 as a d d- o n 
t hera p y t o sta ble sc hiz o p hre nia s u bjects at d oses t hat will be base d o n e mer gi n g 
safet y/t olera bilit y a n d a vaila ble P K data of t he sa me d ose i n healt h y s u bjects fr o m Part 2. 
E x pl or at or y e n d p oi nts will assess t he effect of T A K- 0 4 1 o n i m pr o vi n g t he ne gati ve s y m pt o ms, 
a n d/ or c o g niti ve i m pair me nt, a n d/ or a n he d o nia d o mai ns ass ociate d wit h sc hiz o p hre nia
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n 5. 2 E n d p oi nts f or Part 1 a n d Part 2 a n d Part 3 ( Healt h y S u bjects) a n d Part 4 ( S u bjects 
Pr o p ert y of T a
R ati o n a
R ati o n
t h
t hera
er
T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h
ct o n t h
o n t
a bili
bili t y
t y
i
a
y
h
3 ( Heal
( Hea
res Part 3
s Par
r oce d ure
oce d u
d y Pr oce
Pr oc
y
j e c
catat i oi on n f
m e
c urs i n S
rs i n 
o m
pri m ar y 
ri m ar
o a v ail a b
v ail a
i m me di
m me d
or al s
or a
f o o
f o
n
sa
T a
s of U s e
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 5 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
wi t h Sc hiz o p hre nia)

Secti o n  2. 0 S T U D Y S U M M A R Y

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)
C h a n ge  5 : A d de d t he j ust ificati on f or t he pr o p ose d st u d y desi g n d ose a n d e n d p oi nts for Part 4.
T he pri mar y  c ha n ge occ urs i n Secti o n 6. 2 J ustificati o n f or St u d y Desi g n, D ose, a n d E n d p oi nts
A d de d
w or di n g:
T he hi g hest pl a n ne d l o a di n g d ose i n P art 4 will n ot e xcee d t he hi g hest d ose 
e v al u ate d, dee me d s afe, a n d well t oler ate d i n P art 1 a n d P art 2. T he hi g hest 
pr o p ose d wee kl y m ai nte n a nce d ose will h a ve a pre dicte d me a n a ver a ge 
c o nce ntr ati o n d uri n g a d osi n g i nter v al, at ste a d y st ate ( C a v,ss) bel o w t he Ca v,ss
o bser ve d at t he N O A E L d ose of 3 0 m g/ k g/ d a y i n t he m ale a n d fe m ale d o gs 
fr o m t he 1 3-wee k t o xic ol o g y st u d y.
R ati o n ale f or C h a n ge: e x pl ore t he safet y,  t olera bilit y,  a n d P K of T A K-0 4 1 as a d d -o n t hera p y  
t o sta ble sc hiz o p hre nia s u bjects at d oses t hat will be base d o n e mer gi n g safet y/ t olera bilit y a n d 
a vaila ble P K data of t he sa me d ose i n healt h y s u bjects fr o m Part 2. E x pl orat or y e n d p oi nts will 
assess t he effect of T A K- 0 4 1 o n i m pr o vi n g t he ne gati ve s y m pt o ms, a n d/ or c o g niti ve 
i m pair me nt, a nd/ or a n he d o nia d o mai ns ass ociate d wit h sc hiz o p hre nia
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  2. 0 S T U D Y S U M M A R Y

Secti o n  5. 2 E n d p oi nts f or Part 1 a n d Part 2 a n d Part 3 ( Healt h y S u bjects) a n d Part 4 ( S u bjects 
wi t h Sc hiz o p hre nia)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
C h a n ge  6 : A d de d i ncl usi o n a n d e xcl usi o n cri t eria for Part 3 a n d 4.
T he pri mar y  c ha n ge occ urs i n Secti o n  7. 2 E xcl usi o n Cri t eria
A me n de d or 
ne w w or di n g:
N ote: S u bjects wit h sc hiz o p hre ni a w h o meet a n y of t he criteri a liste d 
bel o w wit h t he e xce pti o n of N u m ber 9, a n d 1 4 will als o n ot q u alif y f or 
e ntr y i nt o t he st u d y. F or criteri a t h at are als o re prese nte d i n Secti o n 7. 2. 2
f or s u bjects wit h sc hiz o p hre ni a, t h ose criteri a s u perse de t he criteri a i n t his 
secti o n ( Secti o n 7. 2. 1.
A n y s u bject w h o meets a n y  of t he f oll owi n g cri teria will n ot q ualif y for e ntr y  
i nto t he st u d y : 
1.
T he s u bject has recei ve d a n y i n vest i gati onal c o m p o u n d wit hi n 3 0 da ys pri or 
t o t he first d ose of st u d y dr u g, or d ue t o t he half-life of t he i n vesti gati onal 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 5 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
dr u g is li kel y  t o still ha ve detecta ble plas ma le vels of t hat c o m p o u n d.
2.
S u bject T he s u bject is a n i m me diate fa mil y me m ber, st u d y site e m pl oyee, 
or is i n a de pe n de nt relat i ons hi p wit h a st u d y site e m plo y ee w h o is i n v o l ve d 
i n t he c o n d uct of t his st u d y (e g, s p o use, pare nt, c hil d, si bli n g) or ma y 
c o nse nt u n der d uress.
3.
T he s u bject has a k n o w n h y perse nsit i vity t o a n y  c o m p o ne nt of t he 
f or mulat i on of T A K - 0 4 1.
4.
T he s u bject has a p osit i ve uri ne/ bl o o d dr u g result  f or dr u gs of a b use 
( defi ne d as a n y illicit dr u g use) at Scree ni n g or Da y - 1.
5.
S u bject has a hist or y  of dr u g a b use ( defi ne d as a n y illicit dr u g use) or a 
hist or y  of alc o h ol a b use ( defi ne d as 4 or m ore alc o h olic be vera ges per da y) 
wi t hi n 1 year prior t o t he Scree ni n g Visit or is u n willi n g t o a bstai n fr om 
alc o h o l a n d dr u gs t hr o u g h o ut t he st u d y.
5.
S u bject T he s u bject has ta ke n a n y e xcl u de d me dicati o n, s u p ple me nts, or 
f oo d pr o d ucts d uri n g t he ti me peri o ds liste d i n t he E xcl u de d Me dicat i ons 
a n d Dietar y Pr o d uct s ( T a ble 7 a f or he alt h y s u bjects a n d T a ble 7 b f or 
s u bjects wit h sc hiz o p hre ni a i n Secti o n 7. 3 ) or is u n a ble t o refr ai n fr o m 
or a ntici p ates t he use of a n y me dic ati o n (e xce pt t h ose prescri be d) as 
descri be d i n ( T a ble 7 a f or he alt h y s u bjects a n d T a ble 7 b f or s u bjects 
wit h sc hiz o p hre ni a i n Secti o n 7. 3).
6.
T he s u bject is l act ose i nt oler a nt ( P art 3 o nl y).
7.
If fe male, t he s u bject is of c hil d beari n g p ote ntial (e g, pre me n o pa usal, n ot 
sterilize d).
8.
If male, t he s u bject i nte n ds t o d o nate s per m d uri n g t he c o urse of t his st u d y  
or f or 1 4 5 da y s (ie, 9 0 da ys after 5 half-li ves) ha ve ela pse d si nce t he last 
d ose of st u d y  dr u g.
9.
S u bject T he s u bject has e vi de nce of c urre nt acti ve car di o vasc ular, ce ntral 
ner v o us s yste m, he pat o biliar y  disease i ncl u di n g hist or y of biliar y tree 
di s or ders, gallst o nes, e n d osc o pic retr o gra de c h o lan gi o c h o lan gi o 
pa ncreat o gra p h y  ( E R C P), a n d/ or c h olec ystect o m y, he mat o p oietic disease, 
re nal d ysf u ncti o n, meta b olic or e n d ocri ne d ysf u ncti on, seri o us aller g y , 
ast h ma, h y p o xe mia, h y perte nsi o n, seiz ures, or aller gic s ki n ras h. T here is 
a n y fi n di n g i n t he s u bject’s me dical hist or y, p h ysical e xa mi nat i on, or safet y 
la b orat or y test res ults (i nclu di n g ele vate d A L P, ele vate d bilir u bi n, ele vate d 
G G T, or ele vate d 5’- n ucle oti dase) t hat i n t he j u d g me nt of t he pri nci pal 
i n vesti gat or re prese nts a reas o na ble s us pici on o f a disease t hat w o ul d 
c o ntrai n dicate ta ki n g T A K- 0 4 1, or t hat mi g ht i nterfere wit h t he c o n d uct of 
t he st u d y. T his i ncl u des, b ut is n ot li mite d t o, pe ptic ulcer disease, 
c h o lestasis, seiz ure dis or ders, a n d car diac arr h yth mias.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 5 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
1 0. S u bject T he s u bject has c urre nt or rece nt ( wit hi n 6 m o nt hs) gastr oi ntesti nal 
di sease t hat w o ul d be e x pecte d t o i nfl ue nce t he a bs or pti o n of dr u gs (ie, a 
hist or y  of mala bs or ptio n, es o p ha geal refl u x, pe ptic ulcer disease, er osi ve 
es o p ha git is, fre q ue nt [m o re t ha n o nce per wee k] occ urre nce of heart b ur n, or 
a n y s ur gical i nter ve nt i on).
1 1. S u bject H a d m aj or s ur ger y, or d o n ate d or l ost 1 u nit of bl o o d 
( a p pr o xi m atel y 5 0 0 m L) wit hi n 4 wee ks pri or t o Scree ni n g.
1 2. T he s u bject has a hist or y  of ca ncer, e xce pt basal cell carci n o ma t hat has 
bee n i n re missi o n f or at least 5 years prior t o Da y  1.
1 3. S u bject T he s u bject has a p osit i ve test res ult f or he patitis B s urface a nti ge n 
( H Bs A g), he patitis C vir us ( H C V) a nt i b o d y at Scree ni n g or a k n o w n hist or y 
of  h u ma n i m m u n o deficie nc y vir us ( HI V) i nfecti on.
1 4. S u bject T he s u bject has use d nic oti ne -c o ntai ni n g pr o d ucts (i ncl u di n g b ut 
n ot li mite d t o ci garettes, pi pes, ci gars, c he wi n g t o bacc o, nic oti ne patc h or 
nic oti ne g u m) wit hi n 2 1 da ys pri or t o C hec k -i n o n Da y -1. C oti ni ne test is 
p osi tive at Scree ni n g or Da y  - 1.
1 5. T he s u bject has p o or peri p heral ve n o us access.
1 6. S u bject has d o nate d or l ost 4 5 0 m L or m ore of his or her bl o o d v ol u me 
(incl u di n g plas ma p heresis), or T he s u bject ha d a tra nsf usi o n of a n y bl o o d 
pr o d uct wit hi n 3 0 da ys pri or t o Da y  1.
1 7. S u bject T he s u bject has a Scree ni n g or C hec k -i n a b n or mal (cli nicall y 
sig nifica nt) E C G. E ntr y  of a n y s u bject wit h a n a b n or mal ( n ot cli nicall y 
sig nifica nt) E C G m ust be a p pr o ve d, a n d d oc u me nte d b y  si g nat ure of t he 
pri nci pal i n vesti gat or or a me dicall y  q ualifie d s u b-i n vesti gat or.
1 8. T he s u bject has a s ustai ne d vit al si g ns resti n g heart rate o utsi de t he ra n ge 4 0 
t o 1 0 0 beats per mi n ute ( b p m), c o nfir me d o n re peat testi n g wit hi n a 
ma xi m u m o f 3 0 mi n utes, at Scree ni n g or C hec k -i n.
1 9. T he s u bject has a Q T i nter val wit h Fri dericia c orrecti o n met h o d ( Q Tc F) 
> 4 5 0 ms or P R o utsi de t he ra n ge 1 2 0 t o 2 2 0 ms, c o nfir me d o n re peat testi n g 
wi t hi n a ma xi m u m of 3 0 mi n utes, at t he Scree ni n g Visit or C hec k -i n.
2 0. S u bject T he s u bject has a b n or mal Scree ni n g or C hec k -i n lab orat or y  v alues 
( > U L N f or t he res pecti ve ser u m c he mistries) of A L T, A S T, T BI LI, A L P, 
G G T, 5’ n ucle oti dase ( Scree ni n g o nl y) a n d/ or a b n or mal uri ne os m o lality,  
c o nfir me d u p o n re peat testi n g.
2 1. T he s u bject has a cli nicall y si g nifica nt hist or y of hea d i nj ur y or tra u ma 
ass oci ate d wit h l oss of c o nsci o us ness f or > 1 5 mi n utes .
2 2. T he s u b ject has a is c o nsi dere d b y t he i n vesti g at or t o be at i m mi ne nt ris k 
of  s uici de acc or di n g t o t he i n vest i gat or’sor s u bi n vesti gat or’s cli nical 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 5 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
j u d g me nt (e g, per C-S S R S) i nj ur y t o self, ot hers, or has ma d e a s uici de 
atte mpt i np r o pert y, or s u bjects w h o wit hi n t he p ast ye ar pri or t o 
Scree ni n g h a ve atte m pte d s uici de. S u bjects w h o h a ve p ositi ve a ns wers 
o n ite m 4 or 5 o n t he C -S S R S ( b ase d o n t he p ast ye ar) pri or t o 
r a n d o miz ati o n are e xcl u de d.
2 3. S u bject T he s u bject has a hist or y  of si g nifica nt s ki n reacti o ns 
( h y perse nsitivit y) t o a d hesi ves, metals or plastic; t his criteri o n a p plies o nl y  
t o s u bjects partici pati n g i n t he st u d y of t he t w o weara ble di gital de vices.
2 4. T he s u bject is u ns uit a ble f or i ncl usi o n i n t he tri al i n t he o pi ni o n of t he 
i n vesti g at or or s p o ns or.
S u bjects wit h sc hiz o p hre ni a o nl y
N ote: S u bjects wit h sc hiz o p hre ni a m ust n ot meet a n y of t he criteri a liste d 
i n Secti o n 7. 2. 1 f or he alt h y s u bjects wit h t he e xce pti o n of N u m ber 9 a n d 
1 4, as well t he criteri a liste d bel o w. T he criteri a liste d bel o w s u perse de t he 
criteri a i n Secti o n 7. 2. 1.
All e ntr y criteri a, i ncl u di n g test res ults, nee d t o be c o nfir me d pri or t o 
r a n d o miz ati o n.
A n y s u bject wit h sc hiz o p hre ni a w h o meets a n y of t he f oll o wi n g criteri a 
will n ot q u alif y f or e ntr y i nt o t he st u d y: 
1.
T he s u bject h as a n u n detect a ble le vel of b aseli ne a nti ps yc h otic 
me dic ati o n at Scree ni n g.
2.
T he s u bject h as a lifeti me di a g n osis of sc hiz o affecti ve dis or der; a 
lifeti me di a g n osis of bi p ol ar dis or der; or a lifeti me di a g n osis of 
o bsessi ve c o m p ulsi ve dis or der b ase d o n t he MI NI c o m bi ne d wit h t he 
ge ner al ps yc hi atric e v al u ati o n. As a n e xce pti o n, s u bjects wit h a 
hist oric al pri or lifeti me di a g n osis of sc hiz o affecti ve dis or der m a y be 
e nr olle d i n t he st u d y wit h s p o ns or or desi g nee a p pr o v al pr o vi de d t h at 
t he pri nci p al i n vesti g at or c a n attest t h at t he s u bject’s o ver all hist or y 
a n d c urre nt cli nic al prese nt ati o n a n d hist or y is m ost c o nsiste nt wit h 
sc hiz o p hre ni a, n ot sc hiz o affecti ve dis or der.
3.
T he s u bject h as a rece nt ( wit hi n t he l ast 6 m o nt hs) di a g n osis of p a nic 
dis or der, de pressi ve e pis o de, or ot her c o m or bi d ps yc hi atric c o n diti o ns 
re q uiri n g cli nic al atte nti o n b ase d o n t he MI NI f or D S M -5 a n d t he 
ge ner al ps yc hi atric e v al u ati o n.
4.
T he s u bject h as a hist or y of dr u g a b use ( defi ne d as a n y illicit dr u g use) 
or a hist or y of alc o h ol a b use ( defi ne d as 4 or m ore alc o h olic be ver a ges 
per d a y) wit hi n 1 ye ar pri or t o t he Scree ni n g Visit or is u n willi n g t o 
a gree t o a bst ai n fr o m alc o h ol a n d dr u gs t hr o u g h o ut t he st u d y. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 5 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
5.
T he s u bject h as a di a g n osis of s u bst a nce use dis or der ( wit h t he 
e xce pti o n of nic oti ne de pe n de nce) wit hi n t he pr ece di n g 6 m o nt hs b ase d 
o n t he MI NI f or D S M -5 a n d t he ge ner al ps yc hi atric e v al u ati o n.
6.
T he s u bject h as e vi de nce or hist or y of c urre nt cli nic all y si g nific a nt 
c ar di o v asc ul ar dise ase, i ncl u di n g u nc o ntr olle d h y perte nsi o n (st a n di n g 
or s u pi ne di ast olic bl o o d press ure > 9 0 m m H g a n d/ or st a n di n g or 
s u pi ne s yst olic bl o o d press ure > 1 4 5 m m H g, wit h or wit h o ut 
tre at me nt), s y m pt o m atic isc he mic he art dise ase, u nc o m pe ns ate d he art 
f ail ure or rece nt ( p ast 1 2 m o nt hs) ac ute m y oc ar di al i nf arcti o n or 
b y p ass s ur ger y. C o ntr olle d ess e nti al h y perte nsi o n, n o n -cli nic all y 
si g nific a nt si n us br a d yc ar di a a n d si n us t ac h yc ar di a will n ot be 
c o nsi dere d si g nific a nt me dic al ill nesses a n d w o ul d n ot e xcl u de a 
s u bject fr o m t he st u d y. Ot her well -c o ntr olle d me dic al ill nesses m a y be 
per mitte d t h at d o n o t i ncre ase he p atic ris ks or ot her s afet y ris ks t o t he 
s u bject's p artici p ati o n i n t he j u d ge me nt of t he i n vesti g at or i n 
c o ns ult ati o n wit h t he s p o ns or or desi g nee.
7.
T he s u bject h as e vi de nce of cli nic all y si g nific a nt e xtr a p yr a mi d al 
s y m pt o ms as me as ure d b y a Si ms o n-A n g us Sc ale ( S A S) sc ore > 6.
8.
T he s u bject h as e vi de nce of de pressi o n as me as ure d b y a C al g ar y 
De pressi o n Sc ore ( C D S S) sc ore > 9.
9.
T he s u bject h as recei ve d T A K -0 4 1 i n a pre vi o us cli nic al st u d y; or h as 
pre vi o usl y or is c urre ntl y p artici p ati n g i n t his st u d y; h as recei ve d 
tre at me nt wit h ot her e x peri me nt al t her a pies wit hi n t he prece di n g 6 0 
d a ys or < 5 h alf -li ves pri or t o r a n d o miz ati o n, w hic he ver is l o n ger; h as 
p artici p ate d i n 2 or m ore cli nic al st u dies wit hi n 1 2 m o nt hs pri or t o 
Scree ni n g; or h as p artici p ate d i n a cli nic al st u d y f or a ps yc hi atric 
c o n diti o n t h at is e xcl usi o n ar y per t his pr ot oc ol.
R ati o n ale f or C h a n ge: select a healt h y p o p ulat i on c o nsiste nt wit h t he F D A bi oa vaila bilit y a n d 
f oo d effect g ui da nce i n Part 3 a n d t o select a sta ble sc hiz o p hre nia p o p ul at i on t o assess safet y a n d  
t olera bilit y as a n a d d -o n t hera p y  t o a ntips yc h oti cs i n Part 4
C h a n ge  7 : A d de d e xcl u de d me dicati o ns, dietar y pr o d ucts a n d st u d y c o ntr ol of diet, fl ui d a n d 
acti vit y c o ntr ol for Parts 3 a n d 4.
T he pri mar y  c ha n ge occ urs i n Secti o n 7. 4 Di et, Fl uid, a n d Act i vity C o ntr ol
A me n de d or 
ne w 
w or di n g:
Diet, Fl ui d, a n d Acti vit y C o ntr ol
S u bjects will be c o nfi ne d t o t he u nit f or t he d urati o n of eac h treat me nt peri o d i n 
Parts 1 , 2, 3 a n d 2 P art 4 as descri be d i n A p pe n di x A, A p pe n di x B, A p pe n di x C, 
A p pe n di x D a n d A p pe n di x E res pecti vel y . I nS u bjects fr o m Part 1 s u bjects 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 6 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
arewill be re q uire d t o re mai n i n t he st u d y u nit d uri n g eac h treat me nt perio d f r o m 
C hec k -i n, Da y 1 f or si n gle d ose a d mi nistrati o n, a n d wit h C o h orts 1 - 5 at  least 9 6 
h o urs p ost d ose f or a t otal c o nfi ne me nt peri o d f or eac h treat me nt peri o d of 5 da ys. 
S u bjects fr o m Part 2 C o h orts 1 t o 4, a n d P art 1 C o h orts 1 a n d 2, will be re q uire d 
t o re mai n i n t he st u d y u nit fr o m D a y -2 t o Da y 3, Da ys 7 t o 1 0, Da y 1 4 t o Da y 1 7, 
a n d Da y 2 1 t o Da y 2 4 ( 4 8 h o urs after t heeac h d ose i n Part 2) f or safet y,  P K, a n d all 
st u d y assess me nts bef ore disc har ge. I n a d dit i on, s u bjects will ret ur n t o t he cli nic 
o n Da y s 5, 2 6, 2 9, 3 6, 4 3, 5 0, 5 7, a n d 6 4 f or safety a n d P K f o ll ow u p visit s. 
S u bjects wit h sc hiz o p hre ni a ( P art 4) will als o u n der g o p art -s pecific 
assess me nts o n D a ys 2 9 a n d 4 3. A Fi nal Vis it that c o m pletes t he st u d y will occ ur 
1 2 t o 1 6 da y s after t he last safet y a n d P K F ollo w -u p Visit. O n t he da ys of d osi n g, 
s u bjects will be a d mi nistere d T A K-0 4 1/ matc he d place b o at a p pr o xi matel y 0 8 0 0 
h o urs f o ll owi n g a fast of at least 8 h o urs a n d will c o nti n ue t o fast f or a n a d diti o nal 
4 h o urs p ost d ose. 
S u bjects fr o m st u d y P arts 1, 2 a n d 4 ma y c o ns u me water a d li bit u m wit h t he 
e xce pti o n o f 1 h our bef ore a n d 1 h o ur after dr u g a d mi nistrati o n. T he meal start a n d 
st o p ti mes a n d t he a m o u nt c o ns u me d will be rec or de d i n t he so urce d oc u m e nt a n d 
a p pr o priate electr o nic case re p ort f or m (e C R F) pa ge f or all meals ser ve d o n t he 
d osi n g da ys. D uri n g c o nfi ne me nt o n n o n d osi n g da ys, s u bjects will be gi ve n 3 
meals a n d a n e ve ni n g s nac k eac h c o ntai ni n g a p pr o xi matel y 3 0 % fat (relat i ve to t he
t otal c alori es). Brea kfast will n ot be ser ve d o n d osi n g da ys.
S u bjects fr o m all st u d y p arts s h o uld re mai n u pri g ht (seate d, sta n di n g, or 
a m b ulat or y) for 4 h o urs f oll o wi n g d ose a d mi nistrati o n, e xce pt as necessitate d b y  
t he occ urre nce of  a n A E / or st u d y pr oce d ure (e g, o btai ni n g 1 2 -lea d E C G). S u bjects 
s h o uld r ef r ai n fr o m stre n u o us e xercise fr om 7 2 h o urs bef ore C hec k -i n ( Da y - 2)
a n d t hr o u g h o ut t he e ntire c o urse of t he st u d y.
P art 3 Diet a n d Fl ui d C o ntr ol
S u bjects i n P art 3 will be re q uire d t o re m ai n i n t he st u d y u nit f or a 
c o nfi ne me nt peri o d of 3 d a ys. T he s u bjects will be r a n d o mize d f or T A K - 0 4 1 
i m me di ate rele ase t a blet a d mi nistr ati o n at a p pr o xi m atel y 0 8 0 0 h o urs eit her 
f oll o wi n g a n o ver ni g ht f ast ( n o f o o d, n o dri n k ot her t h a n w ater, n o 
me dic ati o ns) of at le a st 1 0 h o urs or 3 0 mi n utes after st arti n g i n gesti o n of a 
hi g h -f at, hi g h-c al orie bre a kf ast as descri be d i n 2 0 0 2 F D A F o o d -Effect 
G ui d a nce (t he me al c o m p ositi o n s h o ul d deri ve of a p pr o xi m atel y 1 5 0, 2 5 0, 
a n d 5 0 0 t o 6 0 0 c al ories fr o m pr otei n, c ar b o h y dr ate, a n d f a t, res pecti vel y, i n 
t ot al of a p pr o xi m atel y 8 0 0 t o 1 0 0 0 c al ories). 
Per F D A g ui d a nce, s u bjects will be ser ve d t he st a n d ar d F D A bre a kf ast t o be 
i n geste d a n d c o m pletel y c o ns u me d o ver 3 0 mi n utes. T A K-0 4 1 4 0 m g t a blet 
s h o ul d be a d mi nistere d i m me di atel y after bre a kf ast wit h a gl ass of w ater.
S u bstit uti o ns t o t he c o nte nts of t his hi g h -f at, hi g h-c al orie me al c a n be m a de 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 6 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
as l o n g as t he s a me me al is ser ve d t o all s u bjects a n d a n utriti o nist at t he site 
e ns ures t h at t he test me al pr o vi des a si mil ar a m o u nt of c al ories fr o m pr otei n, 
c ar b o h y dr ates a n d f at a n d h as c o m p ar a ble me al v ol u me a n d visc osit y. T he 
cli nic al site will d oc u me nt t he a m o u nt of pr otei n c ar b o h y dr ates a n d f at a n d 
t ot al c al orie c o nte nt of t he test me al f or t he st u d y file a n d pr o vi de a c o p y t o 
t he s p o ns or. The d ate a n d ti me of t he me al will als o be rec or de d o n t he e C R F.
F asti n g s u bjects will als o be a d mi nistere d t he 4 0 m g t a blet wit h a gl ass of 
w ater. B ot h f asti n g a n d fe d s u bjects will h a ve n o f o o d, n o dri n ks (e xce pt 
w ater) a n d n o me dic ati o ns f or 4 h o urs after d ose a d mi nistr ati o n.
R ati o n ale f or C h a n ge: t o pr o vide a heal t hy s u bject p o p ulatio n i n Part 3 c o nsiste nt wit h F D A 
bi oa vaila bilit y a n d f o o d effect g ui da nce i n Part 3 o n diet, fl ui d a n d acti vit y a n d m e dicat i on 
c o ntr ol in Part 4.
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  7. 3 E xcl u de d Me dicati o ns a n d Di et ar y Pr o d ucts

Secti o n  7. 2 E xcl usi o n Criteria

Secti o n  2. 0 S T U D Y S U M M A R Y

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
C h a n ge  8 : A d de d T A K -0 4 1 ta bl et for m ulat i on t o st u d y  me dicat i on f or Part 3 a n d 
ma n ufact uri n g, pac ka gi n g, la beli n g, dis pe nsi n g a n d ra n d o mizat i on t o i ncl u de Part 3 a n d 4.
T he pri mar y  c ha n ge occ urs i n Secti o n  8. 1. 1 D o sa ge F or m, Ma n ufact uri n g, Pac ka gi n g, a n d 
La beli n g
A me n de d or 
ne w 
w or di n g:
T he T A K -0 4 1 oral cr ystalli ne s us pe nsi on will be use d i n t his st u d y . P arts 1, 2 a n d 
4 . T he T A K-0 4 1 cr y stalli ne dr u g s u bsta nce ( mille d) will be la bele d i n a n 
o pe n -label fas hio n  a n d c om p o u n de d i nt o oral s us pe nsi o ns t hat will be la bele d i n a 
bli n de d fas hi o n f or t hir d part y dispe nsi n g. A n u n bli n de d p har macist will ma na ge 
a n d pre pare d oses as nee de d t hr o u g h o ut t he st u d y . T he oral s us pe nsio n s will 
c o ntai n 5 t o 1 6 0 m g of T A K-0 4 1 per d ose. C o m p o u n di n g i nstr ucti o ns will be 
pr o vi de d t o t he cli nical site usi n g t he c o m p o u n di n g w or ks heet or a si milar 
d oc u m e nt .
1 6. 1. 2. 2. 1 I n vesti gati o nal Dr u g
T he oral  s us pe nsio n  c o ntai ni n g cr ystalli ne T A K-0 4 1 ( mille d) will be pre pare d at 
t he sit e b y wei g hi n g a n a p pr o priate a m o u nt of cr ystalli ne T A K-0 4 1 ( mille d) i nt o a 
d osi n g b ottl e a n d mi xi n g wit h 7 0 m L of 0. 5 % T wee n 8 0 i n 0. 5 % met h ylcell ul o se 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
ve hicle ( T wee n/ M C ve hicle). T he c o m p ositi o n of t he T wee n/ M C ve hicle is i n 
Ta ble 8. a.  T he c o m p ositi o n of cr yst alli ne T A K- 0 4 1 or al s us pe nsi o n is liste d i n 
Ta ble 8. b.
T he T A K- 0 4 1 4 0 m g t a blet will be use d i n t his st u d y f or P art 3. T he t a blet 
f or m ul ati o n is desi g ne d f or i m me di ate dr u g rele ase
 
. T he t a blets 
are r o u n d a n d fil m c o ate d. 
S p o ns or- S u p plie d Dr u g
F or P arts 1, 2, a n d 4, t he T A K- 0 4 1 cr ystalli ne dr u g s u bsta nce ( mille d) will be 
s u p plie d i n a p o w der f or m, i n a p pr o priate pac ka gi n g, a n d eac h c o ntai ner will bear a 
si n gle pa nel la bel t hat i ncl u des all perti ne nt st u d y i nf or mati o n.
T he T A K- 0 4 1 4 0 m g i m me di ate rele ase t a blet will be use d i n t his st u d y f or 
he alt h y s u bjects i n P art 3. T he t a blets are p ac k a ge d i n a m ber gl ass b ottles. 
E ac h b ottle will c o nt ai n a l a bel t h at i ncl u des perti ne nt st u d y i nf or m ati o n a n d 
c a uti o n st ate me nts.
St or a ge
I n vesti gati o nal dr u g  m ust be ke pt i n a n a p pr o priate, li mite d-access, sec ure place 
u ntil it is use d or ret ur ne d t o t he s p o ns or or desi g nee f or destr ucti o n. 
I n vesti gati o nal dr u g  m ust be st ore d u n der t he c o n diti o ns s pecifie d o n t he la bel, a n d 
r e mai n i n t he ori gi nal c o ntai ner u ntil dis pe nse d.
T A K- 0 4 1 cr ystalli ne dr u g s u bsta nce ( mille d) is a n d 4 0 m g t a blets are st ore d at 
c o ntr olle d r o o m te m perat ure ( 2 0°- 2 5° C wit h e xc ursi o ns all o we d fr o m 1 5°- 3 0° C).
D ose a n d Re gi me n
T he pla n ne d i nitial d ose of T A K- 0 4 1 f or Part 1 S R D C o h ort 1 Peri o d 1 is 5 m g. 
D oses f or s u bse q ue nt peri o ds/c o h orts will be deter mi ne d base d o n t he a vaila ble 
safet y, t olera bilit y, a n d P K data fr o m t he prece di n g peri o d/c o h ort. T he d oses will 
be a d mi nistere d t o t he s u bjects b y t he i n vesti gat or or t he i n vesti gat or’s desi g nee. 
S u bjects will recei ve t he d oses b y dri n ki n g t he e ntire s us pe nsi o n fr o m t he d osi n g 
b ottle. T he d osi n g b ottle will t he n be ri nse d wit h 3 5 m L of water a n d t he ri nse will 
be a d mi nistere d i n t he sa me ma n ner as t he s us pe nsi o n. T he ri nse a n d 
a d mi nistrati o n will be re peate d o ne m ore ti me.
Eli gi ble s u bjects i n P art 3 will be r a n d o mize d t o recei ve a si n gle d ose of 
T A K- 0 4 1 as o ne 4 0 m g t a blet a d mi nistere d or all y after eit her a n o ver ni g ht 
f ast of at le ast 1 0 h o urs or 3 0 mi n utes after st arti n g i n gesti o n of a hi g h-f at a n d 
hi g h- c al orie bre a kf ast as rec o m me n de d i n t he 2 0 0 2 F D A F o o d- Effect 
G ui d a nce [ 3] (t he me al s h o ul d deri ve of a p pr o xi m atel y 1 5 0, 2 5 0 a n d 5 0 0 t o 6 0 0 
c al ories fr o m pr otei n, c ar b o h y dr ate a n d f at, res pecti vel y, i n t ot al of 
a p pr o xi m atel y 1 0 0 0 c al ories). T he t a blet m ust be a d mi nistere d wit h a gl ass o f 
w ater ( a p pr o xi m atel y 2 4 0 m L). It s h o ul d be s w all o we d as a w h ole a n d n ot be 
t 
t a blets 
t a bl
ce ( mille
e ( mill
ac h c o nt
ac h c o
m atat i oi on.n
ill be us
be 
c k a ge d i
c k a ge d
es perti n
s perti
i n a n a p p
n a n a
e s p o ns o
p o n
st ore d u
t ore d
tai ner u n
tai ner u
dr u g s u b
r u g s u
m perat u
perat
i me n
me n
e d i ni
i nititi
i al
f or s u bse
r s u b
y, t ol
t olera
e
e a d mi ni
e a d mi n
S u bject
S u bje
b ott
b o
b
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
m a ni p ul ate d i n a n y w a y.
R ati o n ale f or C h a n ge: t o pr o vi de d osa ge f or m, ma n ufact uri n g, pac ka gi n g a n d la beli n g 
i nf or mati o n a n d ra n d omizati o n f or t he T A K- 0 4 1 i m me diate release ta blet i n Part 3
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  8. 2 I n vesti gati o nal Dr u g Assi g n me nt a n d Dis pe nsi n g Pr oce d ures
C h a n ge  9: A d de d hei g ht wei g ht a n d B MI t o Part 3 a n d 4, wit h Part 4 s u bjects ha ve a n i ncrease d 
u p per li mit f or B MI of 4 0. 5 k g/ m 2.
T he pri mar y c ha n ge occ urs i n Secti o n  7. 1. 1  Healt h y s u bjects a n d s u bjects wit h sc hiz o p hre nia.
A me n de d or 
ne w 
w or di n g:
T he s u bject wei g hs at least 4 5 k g ( 9 9 l b) a n d has a b o d y mass i n de x ( B MI) fr o m 1 8 
u p t o 3 2 k g/ m 2 f or he alt h y s u bjects a n d u p t o 4 0. 5 k g/ m2 f or s u bjects wit h 
sc hiz o p hre ni a, i ncl usi ve at Scree ni n g.
R ati o n ale f or C h a n ge: t o pr o vi de a n acce pta ble B MI ra n ge f or e nr oll me nt of s u bjects wit h 
sta ble sc hiz o p hre nia i n Part 4
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
C h a n ge  1 0: A d de d c o g niti ve a n d ot her ps yc h iatric/ ne ur ol o gical assess me nts t o Part 4.
T he pri mar y c ha n ge occ urs i n Secti o n 9. 1. 1 7  Ot her Ps yc hiatric/ Ne ur ol o gical Rati n g Scales
Ne w 
Secti o n:
S u bjects wit h sc hiz o p hre ni a ( P art 4) will als o recei ve t he MI NI,  
 
 A tri al m a n u al descri bi n g 
t he pr oce d ures t o be use d wit h t hese assess me nts will be s u p plie d t o t he site. 
T hese assess me nts will be a d mi nistere d acc or di n g t o t he sc he d ule s h o w n i n 
A p pe n di x D/ E. T he assess me nts are briefl y descri be d bel o w:
MI NI I nter n ati o n al Ne ur o psyc hi atric I ntervie w
T he MI NI I nter n ati o n al Ne ur o ps yc hi atric I nter vie w ( MI NI) is a s h ort 
str uct ure d di a g n ostic i nter vie w de vel o pe d j oi ntl y b y ps yc hi atrists a n d 
cli nici a ns i n t he U nite d St ates a n d E ur o pe f or D S M-I V a n d I nter n ati o n al 
Cl assific ati o n of Dise ases 1 0t h Re visi o n ps yc hi atric dis or ders wit h a n 
a d mi nistr ati o n ti me of a p pr o xi m atel y 1 5  mi n utes, it w as desi g ne d t o meet t he 
nee d f or a s h ort b ut acc ur ate str uct ure d ps yc hi atric i nter vie w f or m ultice nter 
cli nic al tri als a n d e pi de mi ol o g y st u dies. T he cli nici a n res p o nsi ble f or t he 
s u bject m ust a d mi nister t he MI NI[ 2 0- 2 2].
Pr o p ert y of T a k e d a: F or n 
o m
wit h sc h
sc
pr oce d u
oce
hese ass
hese as
A p pe n
A p pe
o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
T er
a ve a n i n
ve a n 
c a
ts wit h s
ts wit h 
a p
y mass i n
mass i
k g/ m
k g/ m 2 f
t h
n ge f or e n
e f or 
bj
d ures Pa
ures 
oce d ure
ce d ur
a n
d ot her 
ot her p
ci a
i n Secti
Sect o
m e
MIM
o m
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
Pr o p ert y of T a k e
of U s e
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
R ati o n ale f or C h a n ge: t o pr o vi de Part 4 assess me nt of safet y a n d of c o g niti ve f u ncti o n a n d 
ot her ps yc hiatric/ ne ur ol o gical rati n g scales t o i ncl u de meas ure effect of a d d- o n T A K- 0 4 1 
a d mi nistrati o n o n i m pr o vi n g ne gati ve s y m pt o ms ass ociate d wit h sc hiz o p hre nia
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  9. 1. 1 3 B o n d- La der Vis u al A nal o g ue Scale
Secti o n 9. 1. 1 5 P A N S S
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
C h a n ge  1 1: A d de d statistical a nal ysis f or Part 3 a n d Part 4.
T he pri mar y c ha n ge occ urs i n Secti o n  1 3. 1. 3 P harmac o ki netic A nal ysis
A me n de d or 
ne w 
w or di n g:
C o nce ntrati o ns of T A K- 0 4 1 i n plas ma will be s u m marize d b y d ose o ver eac h 
sc he d ule d sa m pli n g ti me usi n g descri pti ve statistics f or si n gle ( Part 1) a n d m ulti pl e 
d oses ( Part 2). e ac h st u d y p art . A m o u nt of T A K- 0 4 1 e xcrete d i n uri ne will be 
s u m marize d b y d ose o ver eac h sc he d ule d sa m pli n g i nter val usi n g descri pti ve 
statistics f or si n gle ( Part 1) a n d m ulti ple d ose ( Part 2).e ac h st u d y p art . I n di vi d ual 
P K data will be prese nte d i n a data listi n g. P K para meters of T A K- 0 4 1 will be 
s u m marize d b y d ose usi n g descri pti ve statistics f or si n gle( Part 1) a n d m ulti ple d ose 
( Part 2). eac h st u d y part. D ose pr o p orti o nalit y will be assesse d gra p hicall y 
( d ose- n or malize d C ma x a n d A U C vers us d ose). i n P art 1 a n d P art 2. T o assess 
d ose pr o p orti o nalit y of si n gle d osi n g ( Part 1), a p o wer m o del will be use d. T he 
m o d el will i ncl u de t he nat ural l o g-tra nsf or me d A U C a n d C
ma x as res p o nse varia ble 
a n d t he nat ural l o g-tr a nsf or me d d ose [l n( d ose)] as a c o nti n u o us c o variate. N o 
f or mal statistic al c o m paris o ns will be c o n d ucte d. F or Part 2, d ose pr o p orti o nalit y 
will be assesse d usi n g a n a nal ysis of varia nce ( A N O V A) m o del se paratel y f or 
d ose- n or malize d A U C a n d C ma x o n Da y 2 2. Treat me nt wit h tre at me nt (as a 
cate g orical varia ble, will be ) as a fi xe d effect. T he d ose- n or malize d para meters 
will be nat ural l o g-tra nsf or me d pri or t o t he a nal ysis. All treat me nt differe nces a n d 
c orres p o n di n g t w o-si d e d 9 0 % CIs will be e xtracte d fr o m t he m o d el, 
bac k-tra nsf or me d, a n d e x presse d as ce ntral val ue rati os.
T he effect of f o o d o n T A K- 0 4 1 e x p os ure will be e v al u ate d i n P art 3 usi n g a n 
A N O V A o n t he n at ur al l o g-tr a nsf or me d T A K- 0 4 1 C
m a x a n d  A U C 9 6 wit h 
re gi me n ( hi g h-f at vs. f aste d) as a fi xe d effect. T he L S me a n differe nce bet wee n 
re gi me ns a n d t he c orres p o n di n g t w o-si de d 9 0 % CI will be e xtr acte d fr o m t he 
m o del, b ac k-tr a nsf or me d, a n d e x presse d as ce ntr al v al ue r ati os of T A K- 0 4 1 
e x p os ure after t he hi g h-f at me al vers us t he f aste d st ate. 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d
will be 
will b
cri pti ve s
i pti ve
A m o u nt 
o u nt 
h sc he d u
sc he d
a n d m u
a n d m
u s
e d i n a da
e d i n a d
usi n g de
si n g d
y part. D
part
y
e d C
d C ma x
m
i o nalit
o nalit y
ll i ncl u de
ncl u d
e nat ural
nat ur
m al statis
stat
will be as
will be
d ose
d os -n
cate
ca
n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
u g h Da y
g h Da
a n d Fi n
a n d Fi
r
e c
ki net
i netic 
ic A
u
n d
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he rel ati ve bi o a v ail a bilit y of T A K- 0 4 1 a d mi nistere d as a 4 0 m g i m me di ate 
rele ase t a blet f or m ul ati o n c o m p are d t o t he 4 0 m g or al s us pe nsi o n f or m ul ati o n 
i n t he f aste d st ate will als o be assesse d usi n g a n A N O V A m o del. S u bjects 
a d mi nistere d t he 4 0 m g or al s us pe nsi o n i n P art 1 a n d P art 2 ( D a y 1 d at a o nl y) 
will be p o ole d t o get her a n d tre ate d as t he refere nce re gi me n f or t his a n al ysis; 
s u bjects tre ate d wit h t he T A K- 0 4 1 4 0 m g t a blet f or m ul ati o n u n der t he f aste d 
c o n diti o n i n P art 3 will be t he test re gi me n. T he A N O V A will be perf or me d o n 
t he n at ur al l o g-tr a nsf or me d D a y 1 T A K- 0 4 1 Cm a x a n d  A U C 9 6 wit h re gi me n as a 
fi xe d effect. T he L S me a n differe nce bet wee n re gi me ns a n d t he c orres p o n di n g 
t w o-si de d 9 0 % CI will be e xtr acte d fr o m t he m o del, b ac k-tr a nsf or me d, a n d 
e x presse d as ce ntr al v al ue r ati os.
R ati o n ale f or C h a n ge: t o pr o vi de statistical a nal ysis f or Part 3 effect of f o o d o n T A K- 0 4 1 
e x p os ure a n d t he relati ve bi oa vaila bilit y of T A K- 0 4 1 a d mi nistere d as a 4 0 m g i m me diate release 
ta blet f or m ulati o n c o m pare d t o t he 4 0 m g oral s us pe nsi o n i n Part 1 a n d Part 2 ( Da y 1 o nl y), as 
well as e x pl orat or y a nal ysis i n Part 4.
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
Secti o n 1 3. 1. 4 E x pl orat or y A nal yses
Secti o n  1 3. 1. 5 Safet y A nal ysis
!
Secti o n  2. 0 S T U D Y S U M M A R Y
C h a n ge  1 2: A d de d p har mac o ge n o mic sa m ple c ollecti o ns f or Part 3 a n d 4.
Rati o nale: t o s u bject D N A a n d R N A w hic h ma y pr o vi de
T he pri mar y c ha n ge occ urs i n Secti o n  9. 1. 1 8 P harmac o ge n o mic Sa m ple C o llecti o n
A me n de d or 
ne w 
w or di n g:
P h ar m ac o ge n o mic S a m ple C ollecti o n
Pr o p ert y of T a k e
o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
nl y) 
nl y) 
al ysis; 
ysis; 
he f aste d
e f as
rf or me d
or me
h re gi me
re gi m
he c orre
e c orr
tr a nsf or
a nsf o
ct of f o o
ct of f o
d as a 4 0 
as a 4
art 1 a n d
art 1 a
t h
s u
c sa m ple
sa m p
N A w hic
A w h
u s
n Secti
Secti o
e
n o mic
n o m
m
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
R ati o n ale f or C h a n ge:
 
Pr o p ert y f
R atiat
f
of U s e
C CI
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 6 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:
Secti o n  9. 1. 1. 1 P har mac o ge n o mic I nf or me d C o nse nt Pr oce d ure
Secti o n  2. 0 S T U D Y S U M M A R Y

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
C h a n ge  1 3 : A d de d P K para meters a n d P K bl o o d c ollect i ons f or Part 3 a n d 4 a n d P K uri ne 
c ollect i ons f or Part 4.
T he pri mar y  c ha n ge occ urs i n Secti o n 9. 1. 1 9 P har mac o ki net ic Sa m ple C ollecti on
I nitial 
w or di n g:
La b orat or y  Ma n ual.
A me n de d or 
ne w 
w or di n g:
P h ar m ac o ki netic S a m ple C ollecti o n
C ollecti o n of Pl as m a f or P h ar m ac oki netic S a m pli n g
Bl o o d sa mples ( o ne 4 -m L sa m ple per sc he d ule d t i me) f or P K a nal ysis of T A K-0 4 1 
a n d its meta b olites (if p ossi ble) will be c ollecte d i nt o c hille d Vac utai ners 
c o ntai ni n g a ntic oa g ula nt K 2E D T A acc or di n g t o t he sc he d ules f or Parts 1 a n d 2 i n 
A p pe n di x A a n d A p pe n di x B, res pecti vel y . Pl ace b o sa mples will  not be a nal yze d 
b y t he bi oa nal yt ical la b orat or y e xce pt 2 sa mp les per s u bject recei vi n g place b o, 1 
pre d ose a n d t he ot her ar o u n d t he e x pecte d ti me at w hic h C ma x occ urre d (as 
e mer gi n g fr o m t he act ual meas ure me nt of t he sa m ples of t he first d ose gr o u p) t o 
e ns ure fr o m a safet y pers pect i ve t hat n o a d diti onal s u bjects c o ul d ha ve bee n o n 
acti ve treat me nt . I nstr ucti o ns f or sa m ple pr ocessi n g a n d s hi p me nt will be pr o vi de d 
i n t o t he site i n t he La b orat or y Ma n ual.
S eri al blo o d s a m pl es f or deter mi nati o n o f T A K -0 4 1 i n Part 1 will be c ollecte d 
acc or di n g t o Ta ble 9.c a n d Ta ble 9. d a nd i n A p pe n di x A.
Seri al bl o o d s a m ples f or deter mi n ati o n of T A K -0 4 1 i n P art 3 will be c ollecte d 
acc or di n g t o A p pe n di x C .
Base d o n e mer gi n g P K data fr o m pre vi o us c o h orts, t he act ual ti mes ma y c ha n ge 
b ut t he n u m ber of sa m ples will re mai n t he sa me. All eff orts will be ma de t o o btai n 
t he P K sa m ples at t he e xact n o mi nal t i me relati ve t o d osi n g. W he n t he ti mi n g of 
safety meas ure me nt s c oi nci des wit h a P K bl o o d c ollecti on, t he or der s h o ul d be 
safety assess me nts f oll o we d b y P K bl o o d sa m ple c ollect i on at t he n o mi nal t i me. 
T he act ual  ti mes of sa m ple c ollecti on will be rec or de d o n t he s o urce d oc u me nts 
a n d e C R F.
S a m pli n g ti me p oi nts ma y  be a dj uste d base d o n t he preli mi nar y e mer gi n g P K data 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 6 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
c ollecte d fr o m pri or peri o d/c o h ort(s), b ut t he t otal n u m ber of sa m ples c ollecte d per 
s u bject s h o ul d n ot e xcee d t he pla n ne d n u m ber.
C ollecti o n of Uri ne f or P h ar m ac oki netic S a m pli n g
S erial uri ne sa m ples f or deter mi nati o n of T A K- 0 4 1 i n Part 1 will be c ollecte d 
acc or di n g t o A p pe n di x  A.
S erial uri ne sa m ples f or deter mi nati o n of T A K- 0 4 1 i n Part 2 will be c ollecte d 
acc or di n g t o  A p pe n di x B.
I n Part 2 a n d P art 4 o nl y, 1 0 m L ali q u ots s h o ul d be ta ke n fr o m t he uri ne 
c ollecti o ns o n Da ys  1 a n d 2 2 ( pre d ose a n d 1 2 t o 2 4 h o urs p ost d ose) f or 
meas ure me nt of 6 β - h y dr o x yc ortis ol/c ortis ol r ati o t o assess C Y P 3 A 4 i n d ucti o n.
W he n Earl y Ter mi nati o n occ urs o n a n o n- P K bl o o d c ollecti o n da y, P K bl o o d a n d 
uri ne sa m ples s h o ul d be c ollect e d.
Uri ne sa m ples f or s u bjects ra n d o mize d t o place b o will n ot be a nal yze d.
Uri ne v ol u me will be rec or de d wit hi n 2 h o urs of t he e n d of t he c ollecti o n peri o d. 
I nstr ucti o ns f or sa m ple pr ocessi n g a n d s hi p me nt will be pr o vi de d t o t he site i n t he 
La b orat or y Ma n ual.
R ati o n ale f or C h a n ge: t o a d d P K c ollecti o n a n d para meters f or t he f o o d effect a n d 
bi oa vaila blit y c o m paris o n i n healt h y s u bjects f or Part 3 as well as pr o vi de P K pr ofile f or 
T A K- 0 4 1 i n t he sta ble sc hiz o p hre nic s u bjects i n Part 4
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  9. 1. 2 0 P harmac o ki netic Para meters
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x C Sc he d ule of St u d y Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relati ve 
Bi oa vaila bilit y a n d F o o d Effect)
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
C h a n ge  1 4: Re vise d t he st u d y-s pecific d ose escalati o n a n d st o p pi n g r ule f or Part 1 a n d Part 2.
T he pri mar y c ha n ge occ urs i n Secti o n  6. 3. 2 St u d y- S pecific D ose Escalati o n a n d Sto p pi n g R ules.
A me n de d or 
ne w 
w or di n g:
S pecific D ose Esc al ati o n a n d St o p pi n g R ules
1.  D ose escalati o n bet wee n c o h orts a n d wit hi n a c o h ort will be deci de d after 
eit her a f ull- bli n de d ( Part 1, C o h orts 1 a n d 2) or a s p o ns or partial u n bli n de d 
( Part 1, C o h orts 3 t o 5, a n d Part 2, C o h ort 1 o n war ds, w here certai n s p o ns or 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al  
y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
d 
ollecte d
llecte
m t h
t he uri
e ur
ost d ose) 
st d ose
s C Y P 3
C Y P
ollect
ollect i oi
ce b o wil
b o wi
o urs of t
urs of
s hi p me n
hi p me
lect
ect i on
h y y s u bje
s u bj
hre nic s u
e nic s
o c o ntai n
c o ntai
mac o ki n
ac o k
U D Y S U
D Y 
C Sc he d
Sc h
la bilit
a bili y
pe n di x 
e n di x D
A p pe n d
A p pe n
m
C h a n
C h
f T
T
y
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
staff n ot directl y i n v ol ve d with t he t reat me nt or e val uati on ma y be u n bli n de d t o 
t he treat me nt or i nter ve nt i on) re vie w of at le ast 2 1 da ys of safet y,  t olera bilit y,  
a n d a vaila ble P K data fr o m t he pre vi o us d ose. T he selecti on o f eac h s u bse q ue nt 
d ose will be ma de j o i ntl y a n d a gree d u p o n b y t he s p o ns or a n d t he pri nci pal 
i n vesti gat or/ desi g nee a n d after caref ul e val uati on of all a vaila b le data fr o m 
pre vi o us d oses.
2.
D ose escalat i on will be st o p pe d at a d ose le vel (ie, o ne escalat i on ste p) bel o w 
t he d ose t hat is pre dicte d t o gi ve a T A K- 0 4 1 A U C 2 4 or C a v,ss C m a x t hat e xcee ds 
t he mea n A U C 2 4, ss or C a vC m a x ,ss ( Part 1) or C ma x a n d A U C 2 4 C a v,ss t h at 
e xcee ds C a v,ss ( Part 2) at t he N O A E L d ose of 3 0 m g/ k g/ da y in t he m ale a n d 
fe male d o gs fr om t he 1 3 wee k t o xic o l og y  st u d y.
3.
Escal at i on will st o p o nce t he ma xi m u m t olerate d d ose has bee n reac he d or 
pre vi o usl y defi ne d t o xic o ki net ic e x p os ure li mits are met.
4.
D ose esc alat i on ma y n ot pr ocee d if a n y o f t he f o ll owi n g occ ur at t he pre vi o us 
d ose c o h ort, alt h o u g h d osi n g ma y be res u me d at a l o wer d ose i n t he s u bse q ue nt  
c o h ort:
a)
Si g nifica nt st u d y  dr u g-r elate d a d verse e ve nts of se vere i nte nsit y i n 
≥3 s u bjects.
b)
O ne or m o re s u bjects e x perie nce cli nicall y si g nifica nt E C G 
a b n or malities or effects o n vital si g ns i n dicat i n g d ose-li miti n g 
i ntol era nce.
c)
O ne o rf m o re s u bjects e x perie nce cli nicall y si g nifica nt c ha n ges i n 
ne ur o l ogi cal assess me nts i n dicati n g d ose-li miti n g i nt olera nce.
d)
O ne or m ore s u bjects i n a c o h ort e x perie nces a st u d y  dr u g-r elate d 
serio us a d verse e ve nt ( S A E).
e)
O ne or m ore s u bjects has a b n or mal li ver f u nct i on tests as descri be d i n 
Secti o n  6. 3. 1 t hat ca n be c o nsi dere d relate d t o st u d y dr u g.
f)
S u bject e x perie nces a n y of t he Ta ke da Me dical Si g nifica nt E ve nts 
(Ta ble 1 0 . a) t hat ca n be c o nsi dere d relate d t o st u d y dr u g.
5.
Wit hi n eac h d ose le vel, if at least 1 s u bject de vel o ps a d ose -li miti n g t o xicit y 
( D L T) liste d i n Ta ble 6.j w hic h is c o nfir me d b y  re peat test if a p plica ble, n o 
f urt her d osi n g will occ ur i n t hat s u bject if t he s u bject has recei ve d T A K- 0 4 1.
Defi niti o n of D L Ts
T o xicit y
Defi niti o n
Le u k o pe nia
T otal le u k oc yte c o u nt < 2 5 0 0 cells/ m m 3 ( 2. 5 x 1 09/ L)
Ne utr o pe nia
A bs ol ute ne utr o p hil c o u nt < 1 5 0 0/ m m 3 ( 1. 5 x 1 09/ L)
T hr o m b oc yt o pe nia
Platelet c o u nt < 1 0 0 x 1 0 9/ L
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
L y m p h o pe nia
L y m p h oc y te c o u nt < 1 0 0 0 cells/ m m3 ( 1 x 1 09/ L)
A ne mia
Re d bl o o d cell c o u nt < 3. 5 x 1 0 1 2/ L ( me n) or < 3. 0 x 1 01 2/ L ( w o me n)
L o w He m o gl o bi n
He m o gl o bi n < 1 1 g/ d L ( me n) or < 1 0. 5 g/ d L ( w o me n)
Se vere I nfecti o n 
Seri o us i nfecti o n re q uiri n g h os pitalizati o n, i ntra ve n o us a nti bi otics, 
s yste mic a ntif u n gal or a nti viral i nter ve nti o n
Q Tc
Q Tc > 5 0 0 msec
6.
After re vie w of t he safet y data a n d disc ussi o n/a gree m e nt bet wee n t he 
i n vesti gat or a n d Ta ke da, t he sa me d ose ma y be gi ve n a gai n or a l o wer d ose 
ma y be gi ve n i n s u bse q ue nt peri o ds/c o h ort t o i ncrease data wit hi n t he d ose 
ra n ge.
7.
T he d ose i ncre me nts a n d pla n ne d d oses ma y be c ha n ge d as t he st u d y  
pr o gresses de pe n de nt u p o n e mer gi n g P K, safet y , a n d t olera bilit y data. A n y 
decisi o n t o al ter t he pla n ne d d ose sc he me a n d t he decisi o n o n w hic h d oses t o 
use will be ma de j o i ntl y a n d a gree d u p o n b y t he i n vesti gat or a n d Ta ke da after 
caref ul e val uati o n o f all a vaila ble data.
8.
S h o ul d si g nific a nt a d verse e ve nts occ ur, a n y decisi o n t o res u me d osi n g at t he 
c urre nt d ose le vel or t o escalate t he d ose will be ma de j o i ntl y b y t he 
i n vesti gat or a n d Ta ke da after caref ul e val uati on o f all availa ble data a n d will be 
c o m m u nicate d t o t he I nst itut i onal Re vie w B oar d (I R B).
R ati o n ale f or C h a n ge: U p date d d ose escalat i on st o p pi n g r ule u p date d t o i nc or p orate stea d y 
state Cma x a n d stea d y state C a v
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  6. 1. 4 ( D ose Escalati on)
C h a n ge  1 5 : A d de d e xcl usi o n cri t eria for rece nt maj or s ur ger y or d o natio n or l oss of bl o o d.
T he pri mar y  c ha n ge occ urs i n Secti o n 7. 2 E xcl usi o n Cri t eria
A me n de d or 
ne w
w or di n g:
H a d m aj or s ur ger y, or d o n ate d or l ost 1 u nit of bl o o d ( a p pr o xi m atel y 5 0 0 
m L) wit hi n 4 wee ks pri or t o Scree ni n g.
R ati o n ale f or C h a n ge: N o w e xcl u de s u bjects t hat are rec o veri n g fr o m rece nt maj or s ur ger y , 
d o n ate d blo o d or e x perie nce d bl o o d l oss, as a n a d dit i onal safety meas ure d uri n g scree ni n g
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
C h a n ge  1 6 : Re vise d e xcl usi o n f or cli nicall y si g nifica nt hist or y or hea d i nj ur y or tra u ma t o 
i ncl u de l oss of c o nsci o us ness f or greater t ha n 1 5 mi n utes.
T he pri mar y  c ha n ge occ urs i n Secti o n 7. 2 E xcl usi o n Cri t eria
I nitial 
w or di n g:
T he s u bject has a cli nicall y si g nifica nt hist or y of  hea d i nj ur y or tra u ma.
A me n de d or 
ne w 
w or di n g:
T he s u bject has a cli nicall y si g nifica nt hist or y of hea d i nj ur y or tra u ma ass oci ate d 
wit h l oss of c o nsci o us ness f or > 1 5 mi n utes.
R ati o n ale f or C h a n ge: A d de d detail t o se verit y of t he hea d i nj ur y  or tra u ma i n a p pl yi n g 
e xcl usi o n
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

S E C TI O N  2. 0 S T U D Y S U M M A R Y
C h a n ge  1 7 : U p date d e xcl usi o n la n g ua ge o n ris k of s uici de c o nsi dere d b y t he i n vesti gat or, 
i ncl u di n g s pecific C-S S R S res ul ts.
T he pri mar y  c ha n ge occ urs i n Secti o n  7. 2. 1 Heal t h y s u bjects
I nitial 
w or di n g:
T he s u bject has a ris k of s uici de acc or di n g t o t he i n vesti gat or’s or 
s u b-i n vesti gat or’s cli nical j u d g me nt (e g, per C-S S R S) or has ma de a s uici de 
atte mpt i n t he pre vi o us 6 m o nt hs fr o m Scree ni n g.
A me n de d or 
ne w 
w or di n g:
T he s u bject has a is c o nsi dere d b y t he i n vesti g at or t o be at i m mi ne nt ris k of 
s uicid e acc or di n g t o t he i n vest i gat or’s or s u b-i n vesti gat or’s cli nical j u d g me nt (e g, 
per C -S S R S i nj ur y t o self, ot hers, or has ma de a s uici de atte m pt i n p r o pert y, or 
s u bjects w h o wit hi n t he pre vi o us si x m o nt hs fr om p ast ye ar pri or t o Scree ni n g 
h a ve atte m pte d s uici de. S u bjects w h o h a ve p ositi ve a ns wers o n ite m 4 or 5 o n 
t he C-S S R S ( b ase d o n t he p ast ye ar) pri or t o r a n d o miz ati o n are e xcl u de d.
R ati o n ale f or C h a n ge: t o detail s pecific a ns wers o n t he C-S S R S pri or t o ra n d o mizat i on as 
e xcl usi o n cri teria a n d t o pr o vide ti mi n g of  assess me nts f or Part 3 a n d 4.
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  2. 0 S T U D Y S U M M A R Y

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
C h a n ge  1 8 : A d de d u ns uita ble f or i ncl usi o n i n t he o pi ni on of t he i n vest i gat or or s p o ns or as a n 
e xcl usi o n cri t erio n.
T he pri mar y  c ha n ge occ urs i n Secti o n  7. 2. 1 Heal t h y s u bjects
A me n de d or 
ne w 
w or di n g:
E xcl usi o n cri t eria 2 4: T he s u bject is u ns uit a ble f or i ncl usi o n i n t he tri al i n t he 
o pi ni o n of t he i n vesti g at or or s p o ns or .
R ati o n ale f or C h a n ge: t o e ns ure i n t he o pi ni o n of t he i n vesti gat or t hat t he s u bjects are n ot 
e x p ose d t o a n u nacce pta ble le vel of ris k, or if t he s u bject ma y n ot be a ble t o f o ll ow or c o m plete 
t he st u d y pr oce d ures
C h a n ge  1 9 : Detaile d s pecific ne ur o l ogi cal e xa mi natio ns, a n d c o m bi ne d a s part of p h ysical 
e xa mi nat i on, wi t h re q uire d assess me nt as n ot cli nicall y si g nifica nt ( N C S) or cli nicall y 
sig nifica nt ( C S).
T he pri mar y  c ha n ge occ urs i n Secti o n  9. 1. 3 P h ysical E xa mi nat i on Pr oce d ure a n d Ne ur ol o gical 
E xa mi nat i on
I nitial 
w or di n g:
A p h ysical e xa mi nat i on will c o nsist of t he f o ll owi n g b o d y  s yste ms: ( 1) e yes; ( 2) 
ears, n ose, t hr oat; ( 3) car di o vasc ular s yste m; ( 4) res pirat or y s yste m; ( 5) 
gastr oi ntesti nal s yste m; ( 6) d er m at olo gi c s yste m; ( 7) e xtre mit ies; ( 8) 
m usc ul os keletal s yste m; ( 9) ner v o us s yste m; ( 1 0) l y m p h n o des; a n d ( 1 1) ot her.
Ne ur ol o gi cal assess me nts will be i ncl u de d i n t he 1 1 s yst e m assess me nts of  t he 
p h ysical e xa mi nat i on a n d will mai nl y c o nsist of tests of se ns or y  a n d mot or 
f u ncti ons (e g, refle xes, c o or di nat i on, a n d gait). T he B o n d -La der vis ual a nal o g ue 
scale ( V A S) ( Secti o n 9. 1. 1 3 ) a n d t he C- S S R S ( Secti o n 9. 1. 1 4 ) will als o be 
a d mi nistere d.
A n y a b n or mal fi n di n g o n a pretreat me nt p h ysic al e xa mi nati on assess me nt m ust be 
assesse d as N ot Cli nicall y Si g nifica nt ( N C S) or Cli nicall y Si g nifica nt ( C S) b y t he 
i n vesti gat or a n d rec or de d i n t he s o urce d oc u me nt a n d e C R F. All C S 
fi n di n gs/c ha n ges will be rec or de d as a P T E or c o nc urre nt me dical c o n diti on i n t he 
s o urce d oc u me nt a n d o n t he a p pr o priate e C R F descri be d i n Secti on  1 0. 0 or Secti o n 
9. 1. 8 .
O n s u bse q ue nt e xa mi nat i ons, a n y  a b n or mal c ha n ge fr o m t he pretreat me nt p h ysical 
e xa mi nat i on assess me nt occ urri n g i m me diatel y pri or t o t he start of t he 
i n vesti gati onal dr u g ( Da y -1) m ust be assesse d as N C S or C S b y t he i n vest i gat or a n d 
rec or de d i n t he s o urce d oc u me nt a n d e C R F. A n y C S c ha n ge or ne w dia g n osis as a 
res ult of a C S c ha n ge, as deter mi ne d b y t he i n vesti gat or, will be rec or de d as a n A E 
i n s o urce d oc u me ntati o n a n d o n t he P T E/ A E e C R F descri be d i n Secti on 1 0. 0 .
A me n de d 
or ne w 
P h ysical E xa mi nat i on Pr oce d ure a n d Ne ur ol o gic al E x a mi n ati o n
A p h ysical e xa mi nat i on will c o nsist of t he f o ll owi n g b o d y  s yste ms: ( 1) e yes; ( 2) 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 7 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
w or di n g: 
ears, n ose, t hr oat; ( 3) car di o vasc ular s yste m; ( 4) res pirat or y s yste m; ( 5) 
gastr oi ntesti nal s yste m; ( 6) der mat ol o gic s yste m; ( 7) e xtre mities; ( 8) 
m usc ul os keletal s yste m; ( 9) ner v o us s yste m; ( 1 0) l y m p h n o des; a n d ( 1 1) ot her.
Ne ur ol o gical As p art of t he p h ysic al e x a mi n ati o n, ne ur ol o gic al assess me nts will 
be i ncl u de d i n t he 1 1 s yste m asess me nts of t he p h ysical e xa mi nati o n o n t he 
Ne ur ol o gic al E x a m e C R F a n d  will mai nl y c o nsist of tests of se ns or y a n d m ot or 
f u ncti o ns (e g, refle xes, c o or di nati o n, a n d gait).i ncl u de ( 1) B asic Me nt al St at us; 
( 2) Cr a ni al ner ves II- XII; ( 3) M ot or e x a mi n ati o n; ( 4) Dee p Te n d o n Refle xes; 
( 5) Se ns or y e x a mi n ati o n; ( 6) Cere bell ar f u ncti o n. T he B o n d- La der vis ual 
a nal o g ue scale ( V A S) ( Secti o n  9. 1. 1 3) a n d t he C- S S R S ( Secti o n 9. 1. 1 4) will als o be 
a d mi nistere d.
A n y a b n or mal fi n di n g o n a pretreat me nt p h ysical e xa mi nati o n assess me nt 
(i ncl u di n g ne ur ol o gic al) m ust be assesse d as N ot Cli nicall y Si g nifica nt ( N C S) or 
Cli nicall y Si g nifica nt ( C S) b y t he i n vesti gat or a n d rec or de d i n t he s o urce d oc u me nt 
a n d e C R F. All C S fi n di n gs/c ha n ges will be rec or de d as a P T E or c o nc urre nt me dical 
c o n diti o n i n t he s o urce d oc u me nt a n d o n t he a p pr o priate e C R F descri be d i n Secti o n 
1 0. 0 or Secti o n  9. 1. 8.
O n s u bse q ue nt e xa mi nati o ns, a n y a b n or mal  c ha n ge fr o m t he pretreat me nt p h ysical 
e xa mi nati o n (i ncl u di n g ne ur ol o gical) assess me nt occ urri n g i m me diatel y pri or t o t he 
start of t he i n vesti gati o nal dr u g ( Da y - 1) m ust be assesse d as N C S or C S b y t he 
i n vesti gat or a n d rec or de d i n t he s o urce d oc u me nt a n d e C R F. A n y C S c ha n ge or ne w 
dia g n osis as a res ult of a C S c ha n ge, as deter mi ne d b y t he i n vesti gat or, will be 
rec or de d as a n A E i n s o urce d oc u me ntati o n a n d o n t he P T E/ A E e C R F descri be d i n 
Secti o n 1 0. 0.
R ati o n ale f or C h a n ge: T o pr o vi de cli nical assess me nt of si g nifica nce of t he ne ur ol o gical 
e xa mi nati o ns
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  1 3. 1. 5 Safet y A nal ysis
C h a n ge  2 0: U p date d weara ble de vice ti mi n g of place me nt a n d re m o val f or Part 2 a n d a d de d t o 
Part 4.
T he pri mar y c ha n ge occ urs i n Secti o n  9. 1. 6  Weara ble De vice Pr oce d ure.
Pr o p ert 
a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
will 
will 
d m ot or 
d m ot or
bl e
t al St at u
t al St at
d o n Ref
o n Re
La der vis
der v
o n 9. 1. 1 4
9. 1. 1
mi nat
mi nat i oi on
Cli nicall y
li nica
d rec or d
d rec o
or de d as
r de d as
e a p pr o p
a p pr o
n or m
n or m al 
cal) asse
al) asse
g ( Da y
( Da yy
n t he s o ur
he s o
C S c ha n
C S c ha
s o urce d
o urce 
o pr o vi d
pr o vi
m
o ns als o
ns als
1. 5
1. 5 Safe
Sa
n
0 : : U p da
U p d
F o
he pri mar
pri m
k e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 7 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
R ati o n ale f or C h a n ge: T o u p date t he ti mi n g of t he place me nt a n d re m o val of t he weara ble 
de vices.
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  4. 2 Rati o nale f or t he Pr o p ose d St u d y
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x B: Sc he d ule of St u d y Pr oce d ures Part 2 C o h orts 1 t o 4 ( healt h y s u bjects o nl y)
!
A p pe n di x C Sc he d ule of St u d y Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relati ve 
Bi oa vaila bilit y a n d F o o d Effect)
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
Pr o p ert y of T a k e d a: F or 
g sect
g sect i oi on
n 4 . 2
. 2 R
ecectitio no n 2
A p pe
A p p
!
r n o n-
ge:: T o 
T o
A
r
f U s e
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
C h a n ge  2 1 : A d de d la b orat or y sa m ple c ollecti o ns a n d bl o o d sa m pli n g v o l umes f or Part 3 a n d 4
T he pri mar y  c ha n ge occ urs i n Secti o n  9. 5 Bl o o d V ol u me
A me n de d or 
ne w 
w or di n g:
A p pr o xi m ate Bl o o d V ol u me f or P art 3
T he m a xi m u m v ol u me of bl o o d c ollecte d f or a s u bject i n P art 3 i n a n y si n gle 
d a y is a p pr o xi m atel y 5 5 m L. T he t ot al v ol u me of bl o o d f or e ac h s u bject i n 
P art 3 is a p pr o xi m atel y 1 5 9 m L. Direct ve ni p u nct ure or i n d welli n g c at heter 
m a y be use d f or bl o o d c ollecti o n.
A p pr o xi m ate Bl o o d V ol u me f or P art 4
T he m a xi m u m v ol u me of bl o o d c ollecte d o n a n y si n gle d a y is a p pr o xi m atel y 
1 0 8 m L. T he t ot al v ol u me of bl o o d t o be c ollecte d fr o m e ac h s u bject i n P art 4 
is a p pr o xi m atel y 4 5 5 m L, a n d will be t a ke n o ver a peri o d of 2. 5 m o nt h s. 
Direct ve ni p u nct ure or i n d welli n g c at heter m a y be use d f or bl o o d c ollecti o n.
R ati o n ale f or C h a n ge: t o i ncl u de Part 3 a n d 4 i n cli nical la b orat or y a n d P K blo o d s a m pli n g 
pr oce d ures, a n d u p date bl o o d sa m pli n g i n Part 1 a n d 2.
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  9. 1. 9 Pr oce d ures f or Cli nical La b orat or y Sa m ples

Secti o n  9. 1. 1 9 P har mac o ki net ic Sa m ple C ollecti on

Secti o n 2. 0 S T U D Y S U M M A R Y

A p pe n di x A Sc he d ule o f St u d y  Pr oce d ures Part 1

A p pe n di x B : Sc he d ule of St u d y  Pr oce d ures Part 2 C o h orts 1 t o 4 ( healt h y s u bjects o nl y)

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
C h a n ge  2 2 : A d de d c o ntrace pti o n, a v oi da nce pr oce d ures a n d pre g na nc y state me nts t o Part 3 a n d 
4.
T he pri mar y  c ha n ge occ urs i n Secti o n 9. 1. 1 0 C o ntrace pti o n a n d Pre g na nc y A v o i da nce 
Pr oce d ure
A me n de d 
or ne w 
w or di n g:
I n a d diti on t o a ne gati ve ser u m h C G pre g na nc y test at Scree ni n g, fe male s u bjects 
als o m ust ha ve a ne gat i ve ser u m h C G pre g na nc y test o n Da y - 1 a n d St u d y E xit/ Earl y 
Ter mi nat i on ( Parts 1 a n d 2).f or all st u d y p arts.
R ati o n ale f or C h a n ge: U p date pr oce d ures a n d state me nts t o i ncl u de Part 3 a n d 4 s u bjects .
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)

A p pe n di x D Sc he d ule o f St u d y  Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y  2 4/ E T

A p pe n di x E Sc he d ule of St u d y  Pr oce d ures Part 4: F oll o w-U p a n d Fi nal Visit
C h a n ge  2 3 : A d de d E C G assess me nts t o Part 3 a n d 4 a n d re m o ve d tri plicate para meter 
assess me nts fr o m H o lter E C G i n part 2.
T he pri mar y  c ha n ge occ urs i n Secti o n  9. 1. 1 2 E C G Pr oce d ure
A me n de d or 
ne w 
w or di n g:
A st a n dar d 1 2-lea d E C G will be rec or de d. T he i n vesti gat or ( or a q ualifie d o bser ver 
at t he i n vesti gati o nal site) will i nter pret t he E C G usi n g o ne of t he f o ll owi n g 
categ ori es: wit hi n n or mal li mits, a b n or mal b ut n ot cli nicall y si g nifica nt, or 
a b n or mal a n d cli nicall y si g nifica nt. T he f o ll owi n g para m eters will be rec or de d o n 
t he e C R F fr o m t he s u bject’s E C G trace: heart rate, P R i nter val, Q T i nter val, Q R S 
i nter val, a n d Q T c, a n d Q Tc F.
All st atio nar y  1 2-lea d E C G mac hi nes will be s u p plie d b y t he site. S u bjects s h o ul d 
be i n a s u pi ne p ositi on f oll owi n g a n a p pr o xi mate 1 0 -mi n ute rest peri o d f or E C G 
rec or di n gs. S h o ul d tec h nical diffic ulties occ ur d uri n g rec or di n g of t he E C G, a 
reas o na ble atte mpt s h o ul d be m a de t o re peat t he E C G s h ortl y after t he faile d 
atte mpt.
E C G res ul ts (i ncl u di n g electr o nic traci n g) will be ca pt ure d electr o nicall y a n d 
re vie we d i n t he site’s electr o nic s o urce data s yste m, Cli n Base, a n d n ot pri nte d. 
E C Gs ca n be pri n te d if nee de d.
E C Gs will be a d mi nistere d acc or di n g t o t he sc he d ules s h o w n i n Ta ble 9. b bel o w, 
a n d i n A p pe n di x A ( Part 1) a n d A p pe n di x B ( Part 2).i n all st u d y p arts as s h o w n 
i n A p pe n di x A, B, C a n d D/ E. Si n gle E C Gs will be ta ke n at all t i me p oi nts.
C o nti n u o us 1 2 -lea d H olter E C G m o nit ori n g will als o be c o n d ucte d i n Part 2 o nl y 
fr om D a y  -1 u ntil 2 4 h o urs p ost d ose o n Da y  1. Tri plicate 1 2-lea d E C Gs will be 
e xtracte d fr o m t he H -1 2 flas h car d a p pr o xi matel y 1 mi n ute a part fr o m o ne a n ot her 
(f or eac h ti me p oi nt, tri plicate E C Gs wit h 1 0 sec. e xtracti o n) at t he f oll owi n g ti me 
p oi nts: Da y  -1 ( 2 3, 2 2, 2 0, 1 6, 1 2 h o ur bef ore d osi n g), a n d Da y 1 i m me diatel y 
bef ore d osi n g [ 0 hr, wi t hi n 4 5 mi n of d osi n g], a n d at 1, 2, 4, 8, 1 2, a n d 2 4 h o urs 
p ost d ose. A wi n d o w of ± 1 0 mi n utes ar o u n d eac h sc he d ule d t i me p oi nt ca n be 
utilize d i n or der f or t he ce ntral rea der t o o btai n t he necessar y E C Gs. H ol t er 
rec or di n gs will be als o st ore d b y Ta ke da, use d f or a d diti onal a nal yses, a n d ma y be 
se nt t o a ce ntral E C G a nal ysis la b orat or y for retr os pecti ve e x pert re vie w a n d 
esti mat i on of E C G i nter vals at a n a p pr o priate ti me f or t he T A K -0 4 1 pr o gra m  
d uri n g or after c o m plet i on of t he prese nt st u d y
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 7 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
E C G M o nit ori n g ( P art 2, He alt hy S u bject C o h orts)
T o e ns ure hi g h -q ualit y d ata rec or di n g, pri or t o electr o de place me nt, t he a nat o mical 
sites must be pre pare d t o all o w f or pr o per s ki n/electr o de i nterface. A n y hair o n t he 
electr o de sit es must be s ha ve n. A n y oils, l oti o ns, or dea d s ki n s h o ul d be re m o ve d 
fr om t he electr o de sites usi n g a n a brasi ve alc o h o l pre p pa d desi g ne d f or t his 
p ur p ose. A n i n deli ble s ki n mar ker m ust be use d t o mar k t he e xact electr o de 
pl ace me nt site s o t hat t he electr o de p osit i ons will re mai n c o nsta nt t hr o u g h o ut eac h 
treat me nt perio d. T he el ectr o des s h o uld al wa ys be attac he d t o t he H olter 
c o n necti n g ca ble pri or t o s ki n place me nt.
All H o lter rec or di n gs will be o btai ne d o n 1 0 0 0 s ps flas h car ds usi n g a 1 2 -lea d 
H ol ter rec or der. T he flas h car ds will be c o uriere d t o t he ce ntral car diac c ore 
la b orator y . Alter nati vel y, H olter rec or di n gs will be di gitall y tra ns mitte d t o t he 
ce ntral car diac c ore la b orat or y, as a p pr o priate.
Eac h 1 2 -lea d H olter E C G ac q uisit i on w i n d o w will be a p pr o xi matel y 1 0 mi n utes i n 
d urati o n, fr o m w hic h car diac data a nal ysis la b orat or y will e xtract 1 0 -sec o n d E C Gs 
i n triplicate. T his wi n d o w will be prece de d b y  1 0 mi n utes of q uiet s u pi ne rest.
Tri plicate para m eter esti mates will be deri ve d fr o m t he E C G traces at eac h 
n o mi nal t i me p oi nt, i ncl u di n g heart rate, R R i nter val, P R i nter val, Q T i nter val, 
Q R S i nter val, Q Tc F, Q T i nter val wit h Bazett c orrecti o n ( Q Tc B), a n d T a n d U 
wa ve m or p h o l og y , as a p pr opri ate. Ot her ti me p oi nts ma y als o be retr os pecti vel y 
assesse d if cli nical o bser vat i ons or fi n di n gs re q uire f urt her i n vesti gat i on.
S u bjects will be s u per vise d w hile re mai ni n g at rest, q uiet, a wa ke, a n d i n a s u pi ne 
p osi tio n f r o m at least 1 0 mi n utes pri or t o t he be gi n ni n g of eac h E C G e xtracti o n 
ti me p oi nt a n d will re mai n q uiet, a wa ke, m oti o nless, a n d s u pi ne f or at least 1 0 
mi n utes after t he be gi n ni n g o f eac h E C G e xtracti o n ti me p o i nt.
E C Gs deri ve d fr o m H o lter m o nit ori n g are n ot i nte n de d t o be a nal yze d f or rea l-time 
safety m o nit ori n g b ut m a y be use d f or f ut ure retr os pecti ve E C G a nal yses, u nless 
a n earlier a nal ysis is warra nte d b y e mer gi n g safety i nf or mat i on.
R ati o n ale f or C h a n ge: t o i ncl u de Part 3 a n d 4 i n E C G assess me nts a n d t o u p date Part 2 H olter 
E C G assess me nt ( Part 2 ( Healt h y S u bjects)
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n 9. 1. 1 2. 1 H ol ter E C G M o nit ori n g ( Part 2, Healt h y S u bject Co h orts)

Secti o n  2. 0 S T U D Y S U M M A R Y

A p pe n di x B : Sc he d ule of St u d y  Pr oce d ures Part 2 C o h orts 1 t o 4 ( healt h y s u bjects o nl y)

A p pe n di x C Sc he d ule of St u d y  Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relat i ve 
Bi oa vaila bilit y a n d F o o d Effect)
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 7 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
C h a n ge  2 4: A d de d o pti o nal e x pl orat or y bi o mar ker sa m ple c ollecti o n t o Part 4.
T he pri mar y c ha n ge occ urs i n Secti o n  9. 1. 2 2 E x pl orat or y Bi o mar ker Sa m ple C ollecti o n
A me n de d or 
ne w 
w or di n g:
E x pl or at or y Bi o m ar ker S a m ple C ollecti o n
R ati o n ale f or C h a n ge: t he bi o mar ker- base d dee p c haracterizati o n is e x pl orat or y researc h a n d 
will hel p i n t he desi g n of f ut ure st u dies
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  4. 2 Rati o nale f or t he Pr o p ose d St u d y
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
Secti o n  6. 1. 2 Part 2 M ulti ple- Risi n g D ose: Healt h y S u bjects
!
Secti o n  6. 1. 4 Part 4: Si n gle D ose: S u bjects wit h Sc hiz o p hre nia
!
Secti o n  9. 5 Bl o o d V ol u me
!
A p pe n di x D Sc he d ule of St u d y Pr oce d ures Part 4 Scree ni n g T hr o u g h Da y 2 4/ E T
!
A p pe n di x E Sc he d ule of St u d y Pr oce d ures Part 4: F oll o w- U p a n d Fi nal Visit
Pr o p ert y of T a k e d a: F o
wi n gn g sect
se
ctiio no n 4. 2
4
Secti
Secti o
!
Se
!
F or n o
a n ge:
n ge: t
desi g n o
desi g n
o
F o
bl e T er m s of U s e
n
T e
bl
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 0 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
C h a n ge  2 5 : U p date d t he n o ncli nical i nf or mat i on o n T A K - 0 4 1
T he p rimar y  c ha n ge occ urs i n Secti o n 4. 1 .
A me n de d or 
ne w 
w or di n g:
Be ha vi oral res p o nses were e xa mi ne d i n 2 differe nt m o use m o dels e x hi biti n g s ocia l 
i nteracti on deficits: t he Bal b/c m o del a n d t he 
p ol yi n osi nic: ol yc yt i d ylicp ol yc yti d ylic aci d ( p ol y [I: C]) m o del. I n b ot h m o dels, 0. 1 
m g/ k g T A K -0 4 1, d ose d ei t her ac utel y or s u bc hr o nicall y ( 1 5 da ys of treat me nt), 
mit i gate d t he s ocial deficits t hat were eit her nat urall y occ urri n g ( Bal b/c) or 
p har mac o l ogi call y e v o ke d b y t he i nfla m mat or y sti m ul us ( p ol y [I/ C]). M ore o ver, 
hal o peri d o l, a d opa mi ne D 2 rece pt or a nta g o nist, di d n ot pr o vi de t hera pe utic be nefit  
as a sta n d-al o ne treat me nt i n t he p ol y (I: C) m o del a n d di d n ot a br o gate t he efficac y 
ass ociat e d wit h T A K-0 4 1. F urt her m ore, t he c o g niti ve deficit s ass ociate d wit h 
s u bc hr o nic p he nc ycli di ne ( P C P) treat me nt i n a rat set s hift i n g tas k were 
sig nifica nt l y atte n uate d b y i ncreasi n g d oses of T A K-0 4 1 f r o m 0. 3 t o 3 m g/ k g with 
4 h o ur s of pretreat me nt. T his res ult c o m pare d fa v ora bl y t o ris peri d o ne, a sec o n d 
ge nerat i on a nti ps yc h otic treat me nt. Acc or di n gl y, t he a vaila ble e x peri me ntal 
e vi de nce s u p p orts t he use of T A K-0 4 1, a G P R 1 3 9 a g o nist, as a p ote ntial treat me nt 
f or t he ne gati ve s y m pt o ms (i ncl u di n g a m oti vati on,  a n he d o nia, a n d as ociality) a n d 
c o g nitive i m pair me nt ass ociate d wit h sc hiz o p hre nia, a de bilitati n g dis or der wit h 
hi g h u n met me dical nee d.
T he P K pr o perties of T A K -0 4 1 ha ve bee n c haracterize d i n vitr o a n d i n 
S pra g ue -Da wl e y rats a n d bea gle d o gs after oral ( P O) or i ntra ve n o us (I V) 
a d mi nistrati o n. P har mac o ki net ic e val uati o ns were c o n d ucte d i n rats a n d d o gs 
beca use t hese were t he maj or s pecies use d i n t he t o xic o l og y  pr o gra m.
T A K -0 4 1 was a bs or be d after P O a d mi nistrati o n t o rats a n d d o gs, wit h pea k plas ma 
c o nce ntrati o ns ge nerall y occ urri n g wit hi n 4 t o 8 h o urs p ost d ose i n rats a n d 0. 5 t o 2 
h o urs p ost d ose i n d o gs. T he plas ma cleara nce of T A K -0 4 1 was l o w i n rats a n d 
m o derate t o hi g h i n d o gs ( ~ 4 a n d ~ 1 1 m L/ mi n/ k g, res pecti vel y ). T he ter mi nal 
eli mi nati on half -life (t1/ 2) of T A K-0 4 1 after P O a d mi nistrati o n was 1. 5 t o 2. 8 h o urs 
i n d o gs, a n d u n defi ne d i n rats beca use of a p o orl y defi ne d ter mi nal p hase o bser ve d 
i n t his s pecies. T he oral bi oa vaila bility of  T A K-0 4 1 was hi g h ( 9 0. 8 % t o 9 4. 2 % i n 
rats; i n d o gs, t he d ose -n or m alize d P O e x p os ures were greater t ha n o bser ve d after 
I V d osi n g, res ulti n g i n re p orte d bi oa vaila bility y p u p t o 1 0 0 % or greater. 
A bs or pti o n was n ot li kel y  mo d ulate d b y  P-gl yc o pr otei n ( P - g p), beca use T A K-0 4 1 
ha d a l o w P -g p effl u x rati o ( 0. 4), as de m o nstrate d i n L L C -P K 1 -M D R 1 cells, 
i n dicati n g t hat T A K-0 4 1 is n ot li kel y a s u bstrate f or P -g p. T A K -0 4 1 ( 1 a n d 1 0 µ M) 
pl as ma pr otei n bi n di n g was 9 5. 9 %, 9 5. 4 t o 9 6. 5 %, 9 6. 8 t o 9 7. 3 %, 9 5. 3 t o 9 5. 4 %, 
a n d 9 6. 8 t o 9 7. 1 % i n plas ma fr o m mice (teste d at 1 0 µ M o nl y), rats, d o gs, 
m o n ke ys, a n d h u ma ns, res pecti vel y. Re d bl o o d cell: plas ma rati os of T A K -0 4 1 at 
0. 1, 1, a n d 1 0 µ M were a p p r o xi matel y 0. 8, 0. 8, a n d 1. 1 i n rats; 0. 4, 0. 4, a n d 1. 0 i n 
d o gs; a n d 0. 7, 0. 6, a n d 0. 8 i n h uma ns, res pecti vel y. T A K -0 4 1 s h o we d n o i n hi bit or y 
effect o n t he Bile Salt E x p ort P u m p tra ns p orter i n rat a n d h u ma n vesicles u p t o 2 0 0 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 1 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
µ M a n d a m o derate i n hi bit or y  effect i n d o g vesicles (I C 5 0 ~ 7 2 µ M).
I n vitr o meta b olis m st u dies with he pat ic micr os o mes a n d he pat oc ytes fr om h u ma n 
d o n ors s h o we d trace a m o u nts of a fe w meta b olites i nclu di n g o xi dat i ve 
N- deal k ylat i on t o f or m a n a mi de meta b olite a n d o xi dat i ons at t he o x o be n z otriazi ne 
m o iety t o f or m p osit i onal is o meric str uct ures. S u bse q ue nt gl uc ur o ni dat i on of t hese 
o xi dat i ve is omer ic str uct ures yiel de d t heir c orres p o n di n g gl uc ur o ni de c o nj u gate 
meta b o lites. I n a d dit i on t o t hese meta b o lites, a glutat hi o ne c o nj u gate of T A K - 0 4 1 
a n d o ne of its d o w nstrea m meta b o lites, a c ystei ne c o nj u gate, were als o detecte d i n 
rat a n d d o g he pat oc ytes. N o h u ma n-s pecific meta b olites were o bser ve d. A n 
e val uat i on of t he c y t o c hr o me P-4 5 0 e nz y mes ( C Y Ps) res p o nsi ble f or t he 
meta b o lis m of T A K-0 4 1 has n ot yet  bee n c o n d ucte d. Gl utat hi o ne-a d d uct -deri ve d 
t hiol  meta b o lites t hr o u g h t he -l yase pat h wa y is si g nifica nt i n d o g ( hi g her rate of 
meta b o lis m a n d lac k of N-acet ylat i on det o xificat i on pat h wa y). Preli mi nar y h u ma n 
i n vitr o a n d i n vi v o data s u g gest si milar meta b o lic pat h wa ys b ut t o a m uc h lesser 
e xte nt. T he f or mat i on of N -acet ylc ystei ne c o nj u gate was o bser ve d i n h u ma n as 
e vi de nt of N -acet ylat i on det o xificat i on pat h wa y . I n rat, h o we ver, gl uc ur o ni dati on 
pat h wa y  see ms t o be pre d o mi na nt.
A n assess me nt of c y t o c hr o me P- 4 5 0 e nz y me ( C Y P) i n d uct i on was c o n d ucte d i n 
c ult ure d h u ma n he pat oc ytes, a n d i n d uctio n of  C Y P 2 B 6 a n d C Y P 3 A 4 messe n ger 
R N A ( m R N A) was o bser ve d. Treat me nt of c ult ure d h u ma n he pat oc ytes wit h u p t o 
1 0 µ M T A K -0 4 1 ha d litt le or n o effect o n C Y P 1 A 2 m R N A le vels, w hile treat me nt 
wi t h u p t o 1 0 µ M T A K-0 4 1 ca use d c o nce ntrati o n -de pe n de nt i ncreases o f > 2. 0-f ol d 
a n d > 2 0 % of t he p osit i ve c o ntr ol i n C Y P 2 B 6 a n d C Y P 3 A 4 m R N A le vels, 
res pecti vel y, i n all c ult ures teste d. T h us, T A K-0 4 1 was a mil d i n d ucer of C Y P 2 B 6 
a n d C Y P 3 A 4 mR N A i n vitr o a n d C Y P i n d uct i on base d D DI p ote ntial is c o nsi dere d 
l ow. T A K -0 4 1 s h o we d n o re versi ble i n hi biti o n of C Y P 3 A 4/ 5 acti vities at 
c o nce ntr ati o ns r a n gi n g u p t o 1 0 0 M wit h a n I C 5 0 > 1 0 0 M.
I n t he 
C Y P 3 A 4/ 5 ti me -de pe n de nt i n acti v ati o n ( T DI) st u d y, t he p erce nt a ge of 
acti vit y re m ai ni n g i n s a m ples prei nc u b ate d wit h T A K- 0 4 1 s h o we d n o ti me -, 
c o nce ntr ati o n -, or N A D P H-de pe n de nt C Y P 3 A 4/ 5 l oss of acti vit y. T hese d at a 
s u g gest t h at p ote nti al re versi ble i n hi biti o n a n d T DI of C Y P 3 A 4/ 5 b y 
T A K -0 4 1 are u nli kel y.
Uri nar y e xcret i on of T A K -0 4 1 was i n vest i gate d i n d o gs after a si n gle I V d ose. 
After I V a d mi nistrati o n t o 3 d o gs, T A K -0 4 1 was detecta ble i n d o g uri ne, b ut at l o w 
le vels. T he a m o u nt of  T A K-0 4 1 e xcrete d u nc ha n ge d i nt o d o g uri ne wit hi n 2 4 h o urs 
ra n ge d fr om a p pr o xi mat el y 0. 0 0 9 % t o 0. 0 1 5 7 % wit h mea n rec o ver y of 0. 0 1 3 5 % of 
t he gi ve n d ose. 
A c o m pre he nsi ve series of n o ncli nical safet y st u dies ( G o o d La b orat or y Pr a ctices 
[ G L P]) ha ve bee n c o n d ucte d wit h T A K-0 4 1 t o s u p p ort earl y  hu ma n st u di es 
i ncl u di n g: h E R G, electr ocar di o gra ph y i n d o gs, res pirat or y a n d C N S i n rats, ge net ic 
t o xicit y st u dies ( A mes, i n vitr o micr o n ucle us, i n vi v o micr o n ucle us), a n d i n vitr o 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 2 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
p h ot ot o xi cit y. A n effect of T A K-0 4 1 was first o bser ve d at 1 µ M i n t he h u ma n 
et her - à-g o -g o – relate d ge ne ( h E R G) assa y (I C5 0 > 3 µ M); h o we ver, n o c ha n ges i n 
E C G para meters were o bser ve d i n t he i n vi v o d o g car di o vasc ular ( C V) or 4 -wee k 
re peat-d ose t o xicit y st u d y at 1 2 5 m g/ k g. I n t he d o g C V st u d y, a n i ncrease i n 
s yst olic bl o o d press ure ( 1 0 %) res ult i n g i n i ncreases i n mea n arterial a n d p ulse 
press ures wit h o ut a n y ass ociate d c ha n ges i n heart rate at 0. 5 t o 6. 2 5 h o urs p ost d ose 
at 1 2 5 mg/ k g was o bser ve d. A di mi nis he d tre n d n ot of bi ol o gical si g nifica nce 
occ urre d at 1 5 m g/ k g wit h n o effect o bser ve d at 5 m g/ k g. I n a d dit i on, dail y 
re peat- d ose t o xicit y st u dies of 4-wee k a n d 1 3 -wee k d urati o n ha ve bee n c o n d ucte d 
i n rats a n d d o gs. T he or al  d ose le vels i n t he 4-wee k t o xicit y st u d y  i n rats were 5, 3 0, 
a n d 2 0 0 m g/ k g/ da y ( males) a n d 3, 1 0, a n d 2 0 0 m g/ k g/ da y (fe males). I n t he 
1 3- wee k re peat -d ose t o xic ity st u d y i n rats, t he oral d ose le vels were 1 0, 4 0 a n d 2 0 0 
m g/ k g/ da y  in males a n d 2, 1 0, a n d 2 0 0 m g/ k g/ da y  in fe males. I n t he 4- a n d 
1 3- wee k t o xicit y st u dies i n d o gs, d osa ges were 5, 1 5, 5 0, a n d 1 2 5 m g/ k g/ da y f or 
t he 4-wee k st u d y  a n d 1 5, 3 0 a n d 6 0 m g/ k g/ da y i n t he 1 3-wee k st u d y . T he 
n o -o bser ve d -a d verse-effect le v el ( N O A E L) i n t he rat t o xicity st u dies was t he 
ma xi m u m feasi ble d ose of 2 0 0 m g/ k g/ da y. T he N O A E L i n t he d o g t o xicit y st u di es 
was 1 5 m g/ k g/ da y i n males a n d 5 0 m g/ k g/ da y i n fe males f or t he 4-wee k st u d y. T he 
N O A E L was 3 0 m g/ k g/ da y f or b ot h males a n d fe males i n t he 1 3 -wee k d o g t o xicit y 
st u d y, beca use of mor bi di t y attri b ute d t o he patic c h olestasis a n d re nal t u b ule 
de ge nerati o n c o nsi dere d sec o n dar y  t o he patic c ha n ges at 6 0 m g/ k g/ da y, w hic h le d 
t o e ut ha nasia of 2 d o gs at Da y  8 5. T hese a ni mals ha ve ele vate d A L T, A S T, bile 
acids, B U N, creati ni ne, G G T, P H O S, a n d T BI LI bef ore e ut ha nasia, a n d i ncreases 
i n A L P a n d C H O L as earl y  as Da y 1 4. T his fi n di n g was mo ni t or a ble, base d o n 
pl as ma c he mistr y c ha n ges at all d ose levels a n d as earl y as Da y 1 4 i n t he hi g h d ose 
gr o u p, w hi c h prece de d cli nical si g ns. After a 4 -wee k treat me nt -free peri o d, t here 
was n o e vi de nce of rec o ver y of biliar y h y per plasia, m ult i-n ucleate d cells, or mi xe d 
cell i nfiltrate a n d si n gle cell he pat ic necr osis; h o we ver, ele vat i ons i n plas ma 
c he mistr y val ues were lar gel y re versi ble (tre n di n g d o w n of ele vate d li ver f u ncti o n 
tests at all d ose le vels i n t he rec o ver y gr o u p d o gs).
D ue t o t his fi n di n g of c h o lest atic li ver i nj ur y bei n g mo ni t ora ble, partiall y 
re versi ble, a n d o bser ve d i n d o gs b ut n ot rats, t he selecte d d oses are pr ojecte d t o be
res ult i n plas ma e x p os ures of T A K- 0 4 1 b el o w t h ose ass ociate d wit h t he N O A E L i n 
t he d o g 1 3 -wee k t o xic o l og y  st u d y. F urt her i nf or matio n f r o m t he n o ncli nical 
st u dies, s u m marize d a b o ve, ca n be f o u n d i n t he c urre nt I n vest i gat or’s Br oc h ure. 
O verall, t he n o ncli nical P K a n d safet y pac ka ge s u m marize d herei n pr o vi de s u p p ort 
f or t he cli nical e val uati on of T A K - 0 4 1.
R ati o n ale f or C h a n ge: T o u p date t he n o ncli nical i nf or mat i on relate d t o t he stu d y.
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 3 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  2. 0 S T U D Y S U M M A R Y
C h a n ge  2 6 : U p date d P K a nal ysis f or all sa m ple parts.
T he pri mar y  c ha n ge occ urs i n Secti o n Part  1 3. 1. 3 P har mac o ki net ic A nal ysis
A me n de d or 
ne w 
w or di n g:
P h ar m ac o ki netic A n al ysis
C o nce ntrati o ns of T A K- 0 4 1 i n plas ma will be s u m marize d b y d ose o ver eac h 
sc he d ule d sa m pli n g ti me usi n g descri pt i ve statistics f or si n gle ( Part 1) a n d m ulti ple 
d oses ( Part 2). e ac h st u d y p art. A m o u nt of T A K -0 4 1 e xcrete d i n uri ne will be 
s u m marize d b y d ose o ver eac h sc he d ule d sa m pli n g i nter val usi n g descri pti ve 
statistics f or si n gle ( Part 1) a n d m ulti ple d ose ( Part 2).e ac h st u d y p art. I n di vi d ual 
P K data will be prese nte d i n a data list i n g. P K para meters of T A K-0 4 1 will be 
s u m marize d b y d ose usi n g descri pti ve statistics f or si n gle ( Part 1) a n d m ulti ple 
d ose ( Part 2). e ac h st u d y p art . D ose pr o p orti o nality will be assesse d gra p hicall y 
( d ose-n or m alize d C ma x a n d A U C vers us d ose ).) i n P art 1 a n d P art 2. T o assess 
d ose pr o p orti o nalit y of si n gle d osi n g ( Part 1), a p o wer m o del will be use d. T he 
m o d el  will i ncl u de t he nat ural l o g-tra nsf or me d A U C a n d Cma x as res p o nse varia ble 
a n d t he nat ural l o g -tra nsf or me d d ose [l n( d ose)] as a c o nti n u o us c o variate. N o 
f or mal statistic al c o m par is o ns will be c o n d ucte d. F or Part 2, d ose pr o p orti o nality 
will be assesse d usi n g a n a nal ysis o f varia nce ( A N O V A) m o del se paratel y  for 
d ose -n or m alize d A U C a n d C ma x o n Da y 2 2. Treat me nt, wit h tre at me nt ( as a 
cate g orical varia ble, will be) as a fi xe d effect. T he d ose -n or m alize d para meters 
will be nat ural l o g -tra nsf or me d pri or t o t he a nal ysis. All treat me nt differe nces a n d 
c orres p o n di n g t w o -si de d 9 0 % CIs will be e xtracte d fr o m t he mo d el , 
bac k -tra nsf or me d, a n d e x presse d as ce ntral val ue rati os.
T he effect of f o o d o n T A K -0 4 1 e x p os ure will be e v al u ate d i n P art 3 usi n g a n 
A N O V A o n t he n at ur al l o g -tr a nsf or me d T A K-0 4 1 C m a x a n d A U C 9 6 wit h 
re gi me n ( hi g h -f at vs. f aste d) as a fi xe d effect. T he L S me a n differe nce bet wee n 
re gi me ns a n d t he c orres p o n di n g t w o -si de d 9 0 % CI will be e xtr acte d fr o m t he 
m o del, b ac k -tr a nsf or me d, a n d e x presse d as ce ntr al v al ue r ati os of T A K- 0 4 1 
e x p os ure after t he hi g h- f at me al vers us t he f aste d st ate. 
T he rel ati ve bi o a v ail a bilit y of T A K -0 4 1 a d mi nistere d as a 4 0 m g i m me di ate 
rele ase t a blet f or m ul ati o n c o m p are d t o t he 4 0 m g or al s us pe nsi o n f or m ul ati o n 
i n t he f aste d st ate will als o be assesse d usi n g a n A N O V A m o del. S u bjects 
a d mi nistere d t he 4 0 m g or al s us pe nsi o n i n P art 1 a n d P art 2 ( D a y 1 d at a o nl y) 
will be p o ole d t o get her a n d tre ate d as t he refere nce re gi me n f or t his a n al ysis; 
s u bjects tre ate d wit h t he T A K-0 4 1 4 0 m g t a blet f or m ul ati o n u n der t he f aste d 
c o n diti o n i n P art 3 will be t he test re gi me n. T he A N O V A will be perf or me d o n 
t he n at ur al l o g-tr a nsf or me d D a y 1 T A K-0 4 1 C m a x a n d A U C 9 6 wit h re gi me n as a 
fi xe d effect. T he L S me a n differe nce bet wee n re gi me ns a n d t he c orres p o n di n g 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 8 4 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
t w o-si de d 9 0 % CI will be e xtr acte d fr o m t he m o del, b ac k-tr a nsf or me d, a n d 
e x presse d as ce ntr al v al ue r ati os.
R ati o n ale f or C h a n ge: t o pr o vi de statistic al a nal ysis of Part 3 pri mar y P K e n d p oi nts a n d Part 4 
e x pl orat or y P K data
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
Secti o n  2. 0 S T U D Y S U M M A R Y
C h a n ge  2 7: A d de d P D a nal ysis set f or Part 4 o nl y
T he pri mar y c ha n ge occ urs i n Secti o n 1 3. 1. 4 E x pl orat or y A nal yses
I nitial 
w or di n g:
I n di vi d ual res ults of B L- V A S, C- S S R S, a n d  
 assess me nts will be liste d.
A me n de d 
or ne w 
w or di n g:
I n di vi d ual res ults of B L- V A S, C- S S R S, a n d  
assess me nts will be liste d.
Pr o p ert y of T a k e
j e c
assess
asses
j ect t o t h e a p pli c a bl e T er m s of U s e
4 
T
li c
a p
s me nts w
me nts
t h
e c
C CI
C CI
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 8 5 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
R ati o n ale f or  C h a n ge: T o pr o vi de statistic al basis f or t he Part 4 e x pl orat or y o bjecti ves.
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  2. 0 S T U D Y S U M M A R Y
!
A p pe n di x C Sc he d ule of St u d y Pr oce d ures Part 3 ( Ta blet F or m ulati o n – Relati ve 
Bi oa vaila bilit y a n d F o o d Effect)
C h a n ge  2 8: U p date d safet y a nal ysis.
T he pri mar y c ha n ge occ urs i n Secti o n  1 3. 1. 5 Safet y A nal ysis
I nitial 
w or di n g:
S afet y A n al ysis
S afet y data will be prese nte d b y T A K- 0 4 1 d ose a n d place b o f or eac h part.
T E A Es will be s u m marize d b y place b o, eac h T A K- 0 4 1 d ose le vel, a n d T A K- 0 4 1 
o verall f or Part 1 a n d Part 2.
Cli nical la b orat or y varia bles, vital si g ns, a n d E C G para meters will be s u m marize d 
wit h descri pti ve statistics f or baseli ne,  p ost d ose, a n d c ha n ge fr o m baseli ne t o 
p ost d ose val ues b y d ose. I n Part 2, c o nti n u o us H olter E C G m o nit ori n g para meters 
will be e xtracte d i n tri plicate a n d t he a vera ge of t he 3 val ues at eac h ti me p oi nt will 
be calc ulate d a n d use d f or all statistical a nal yses a n d s u m maries. U nc orrecte d a n d 
c orrecte d Q T i nter vals, P R, a n d Q R S i nter vals a n d heart rate, as well as t heir 
c ha n ges fr o m baseli ne will be s u m marize d at eac h ti me p oi nt. T he n u m ber a n d 
p erce nta ge of s u bjects wit h p ost d ose val ues meeti n g Ta ke da’s criteria f or mar ke dl y 
a b n or mal val ues f or cli nical la b orat or y varia bles, vital si g ns, a n d E C G para meters 
will be prese nte d b y d ose. Ne ur ol o gical assess me nts will be j u d ge d n or mal, 
a b n or mal, C S or N C S. All s u m maries will be perf or me d b y p o ole d place b o wit hi n 
c o h ort a n d T A K- 0 4 1 d ose le vel. P h ysical e xa mi nati o n fi n di n gs will be prese nte d i n 
Pr o p ert y of T a k e d a: F or n o n- c o m m e
is
a will be
will b
s will be
will b
rall f or P
all f or
Cli nical
Cli nic
wiw t h
t h
i h
p o
m er ci al u s e o nl y a n d s u
e Part 4
Part 
es Part 3
Par
d s
u s
ecti o n
cti o n 1 3
ci a
m e
 of U s e
C CI

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 6 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
data list i n gs.
All A Es will be c o de d usi n g Me d D R A. Data will be s u m marize d usi n g preferre d 
t er m a n d pri mar y s yste m or ga n class.
A me n de d or 
ne w 
w or di n g:
S afet y A n al ysis
S af et y data will be prese nte d b y  T A K-0 4 1 d ose a n d place b o f or eac h part.
T E A Es will be s u m marize d b y place b o, eac h T A K -0 4 1 d ose le vel, a n d T A K - 0 4 1 
o verall f or Part 1 a n d Part 2 e ac h st u d y p art .
Cli nical la b orat or y  varia bles, vital si g ns, a n d E C G para meters will be s u m marize d 
wi t h descri pti ve statistics f or baseli ne, p ost d ose, a n d c ha n ge fr o m baseli ne t o 
p ost d ose val ues b y d ose . a n d sc he d ule d ti me p oi nt f or e ac h st u d y p art. I n Part 2, 
c o nti n u o us H olter E C G m o nit ori n g para meters will be e xtracte d i n tri plicate a n d 
t he a vera ge of t he 3 val ues at eac h ti me p o i nt will be calc ulate d a n d use d f or all 
statistical a nal yses a n d s u m maries. U nc orrecte d a n d c orrecte d Q T i nter vals, P R, 
a n d Q R S i nter vals a n d heart rate, as well as t heir c ha n ges fr o m baseli ne will be 
s u m marize d at eac h sc he d ule d ti me p oi nt.
P ote nti al Q T pr ol o n g ati o n will be assesse d usi n g t he H olter E C G 
me as ure me nts i n P art 2. A li ne ar mi xe d effect m o del f or re pe ate d me as ures 
will be use d. T he res p o nse v ari a ble i n t he m o del will be t he c h a n ge fr o m t he 
ti me-m atc he d b aseli ne i n t he a ver a ge of t he tri plic ate c orrecte d Q T i nter v als 
( Q Tc). T he ti me-m atc he d b aseli nes will c o me fr o m t he E C Gs t a ke n o n D a y -1 
( 2 3, 2 2, 2 0, 1 6, a n d 1 2 h o urs bef ore d osi n g). T he m o del will i ncl u de tre at me nt, 
ti me ( as a c ate g oric al v ari a ble), a n d t he tre at me nt-b y -ti me i nter acti o n as 
fi xe d effects, s u bject as a r a n d o m effect, b aseli ne as a c o v ari ate, a n d t he 
b ase li ne-b y -ti me i nter acti o n as a n a d diti o n al fi xe d effect. T he L S me a n 
c h a n ge fr o m ti me -m atc he d b aseli ne f or e ac h tre at me nt a n d t he ass oci ate d 
st a n d ar d err or a n d t w o-si de d 9 5 % CI will be e xtr acte d f or e ac h tre at me nt at 
e ac h ti me p oi nt, as well as differe nces f r o m pl ace b o a n d ass oci ate d st a n d ar d 
err ors, t w o- si de d 9 5 % CIs, a n d p-v al ues.
A se p ar ate li ne ar mi xe d effects m o del will be use d t o assess t he rel ati o ns hi p 
bet wee n t he c h a n ge fr o m ti me -m atc he d b aseli ne i n Q Tc a n d T A K -0 4 1 
e x p os ure i n P art 2. T he res p o nse v ari a ble i n t he m o del will be t he c h a n ge 
fr o m ti me-m atc he d b aseli ne i n Q Tc. T he m o del will i ncl u de T A K -0 4 1 pl as m a 
c o nce ntr ati o n ( as a c o nti n u o us v ari a ble) as a fi xe d effect a n d s u bject as a 
r a n d o m effect. Pl ace b o s u bjects will be i ncl u de d i n t he a n al ysis wit h a pl as m a 
c o nce ntr ati o n of 0. T he esti m ate d re gressi o n li ne a n d t he 9 0 % c o nfi de nce 
b a n d f or t he re gressi o n li ne will be e xtr acte d fr o m t he m o del. T he 
rel ati o ns hi p bet wee n t he c h a n ge fr o m ti me -m atc he d b aseli ne i n Q Tc a n d 
T A K -0 4 1 pl as m a c o nce ntr ati o n will als o be e x a mi ne d gr a p hic all y usi n g a 
sc atter pl ot. T he re gressi o n li ne a n d 9 0 % co nfi de nce b a n d f or t he re gressi o n 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K -0 4 1
St u d y N o. T A K -0 4 1 -1 0 0 1
P a ge 1 8 7 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
li ne esti m ate d fr o m t he m o del will be o verl ai d o nt o t he sc atter pl ot.
T he n u m ber a n d perce nta ge of s u bjects wit h p ost d ose val ues meeti n g Ta ke da’s 
criteria f or mar ke dl y a b n or mal v alu es f or cli nical  la b orat or y varia bles, vital si g ns, 
a n d E C G para meters will be prese nte d b y d ose. Ne ur ol o gical assess me nts will be 
j u d ge d n or mal, a b n or mal, C S or N C S. All s u m maries will be perf or me d b y p o ole d 
pl ace b o wit hi n c o h ort a n d T A K-0 4 1 d ose le vel. P h ysical e xa mi nat i on fi n di n gs will 
be prese n te d i n data listi n gs. I n di vi d u al res ults of B L-V A S a n d t he C -S S R S will 
be liste d.
All A Es will be c o de d usi n g Me d D R A. Data will be s u m marize d usi n g preferre d 
t er m a n d pri mar y s yste m or ga n class.
R ati o n ale f or C h a n ge: t o u p date t he safet y a nal ysis t hat will be use d f or t he m o difie d st u d y 
desi g n.
T he f o ll owi n g sect i ons als o c o ntai n t his c ha n ge:

Secti o n  2. 0 S T U D Y S U M M A R Y
C h a n ge  2 9 : U p date d sa m ple size deter mi nati o n f or t he st u d y .
T he pri mar y  c ha n ge occ urs i n Secti o n 1 3. 3 Deter mi nat i on of Sa m ple Size .
I nitial 
w or di n g:
Deter mi n ati o n of S a m ple Size
T he sa m ple size c h ose n o f 8 s u bjects per c o h ort ( 6 acti ve: 2 place b o) i n Part 1 
C o h orts 1 -5 a n d Part 2 C o h orts 1 -4 is base d u p o n prece de nts of ot her 
first-i n-h u ma n trials rat her t ha n a f or mal assess me nt of statist ical p o wer. T his 
sa m ple size is c o nsi dere d s ufficie nt f or i n vest i gati n g t he o bject i ves of t he st u d y a n d 
c haracterizi n g a n y p ot e ntial effects o n safet y para meters.
F or Part 3, wit h a sa m ple size of 1 6 s u bjects ( 8 per re gi me n), ass u mi n g a c oefficie nt 
of  variati on ( %) f or t he C ma x of  T A K-0 4 1 of 1 3. 8 %, a t w o -si de d 9 0 % c o nfi de nce 
i nter val for t he differe nce i n l o g -tra nsf or me d C ma x bet wee n fe d a n d faste d will 
e xte n d n o m ore t ha n 0. 1 3 fr o m t he o bser ve d mea n differe nce. As a n e xa m ple, if t he 
o bser ve d rat i o bet wee n t he t w o re gi me ns is 1.5, re prese nt i n g a 5 0 % i ncrease i n 
e x p os ure d ue t o f o o d, t he n t he c o nfi de nce i nter val f or t he tr ue rati o will e xte n d 
fr om 1. 3 2 t o 1. 7 1. Si milarl y , if t he o bser ve d ratio is 1. 0, re prese nt i n g n o effect of 
f oo d, t he n t he c o nfi de nce i nter val f or t he tr ue rati o will e xte n d fr o m 0. 8 8 t o 1. 1 4. 
T he e x pecte d varia bilit y i n t he A U C9 6 of  T A K-0 4 1 is lar ger t ha n i n C ma x . I n a 
w orst -case sce nari o, ass u mi n g a c oefficie nt of variati o n ( %) f or A U C 9 6 of  2 6. 8 %, 
t he c o nfi de nce i nter val will e xte n d n o m ore t ha n 0. 2 5 fr o m t he o bser ve d mea n 
differe nce. If t he o bser ve d rat i o bet wee n t he t w o re gi me ns is 1. 5, re prese nti n g a 
5 0 % i ncrease i n e x p os ure d ue t o f o o d, t he n t he c o nfi de nce i nter val f or t he A U C 9 6 
r atio will  e xte n d fr o m 1. 1 7 t o 1. 9 3. If t he o bser ve d rati o is 1. 0, re prese nti n g n o
effect of f o o d, t he n t he c o nfi de nce i nter val will e xte n d fr o m 0. 7 8 t o 1. 2 8. Ta ke n 
t o get her, t hese res ults are c o nsi dere d t o re prese nt a de q uate precisi on f or t he 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 8 8 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
esti mate d f o o d effect. T he ass u me d varia bilit y i n C ma x a n d A U C 9 6 are esti mates 
fr o m t he c o m plete d c o h orts i n Part 1 of t his st u d y. T o acc o u nt f or p ote ntial 
disc o nti n uati o ns, 1 8 s u bjects ( 9 per re gi me n) will be e nr olle d.
S u bjects w h o dr o p o ut f or n o n-safet y reas o ns ma y be re place d o n a case- b y-case 
b asis at t he discreti o n of t he s p o ns or i n c o ns ultati o n wit h t he i n vesti gat or. S u bjects 
w h o re place dr o p o uts will be all ocate d t o t he sa me C o h ort as t he s u bject t he y 
r e place. S u bjects w h o dr o p o ut f or safet y reas o ns will n ot be re place d.
A me n de d or 
ne w 
w or di n g:
Deter mi n ati o n of S a m ple Size
T he sa m ple size c h ose n of 8 s u bjects per c o h ort ( 6 acti ve: 2 place b o) i n Parts P art 1 
C o h orts 1- 5 a n d P art 2 C o h orts 1- 4 is base d u p o n prece de nts of ot her 
first-i n- h u ma n trials rat her t ha n a f or mal assess me nt of statistical p o wer. T his 
sa m ple size is c o nsi dere d s ufficie nt f or i n vesti gati n g t he o bjecti ves of t he st u d y a n d
c haracterizi n g a n y p ot e ntial effects o n safet y para meters.
F or P art 3, wit h a s a m ple size of 1 6 s u bjects ( 8 per re gi me n), ass u mi n g a 
c oefficie nt of v ari ati o n ( %) f or t he C m a x of T A K- 0 4 1 of 1 3. 8 %, a t w o-si de d 
9 0 % c o nfi de nce i nter v al f or t he differe nce i n l o g-tr a nsf or me d C m a x bet wee n 
fe d a n d f aste d will e xte n d n o m ore t h a n 0. 1 3 fr o m t he o bser ve d me a n 
differe nce. As a n e x a m ple, if t he o bser ve d r ati o bet wee n t he t w o re gi me ns is 
1. 5, re prese nti n g a 5 0 % i ncre ase i n e x p os ure d ue t o f o o d, t he n t he c o nfi de nce 
i nter v al f or t he tr ue r ati o will e xte n d fr o m 1. 3 2 t o 1. 7 1. Si mil arl y, if t he 
o bser ve d r ati o is 1. 0, re prese nti n g n o effect of f o o d, t he n t he c o nfi de nce 
i nter v al f or t he tr ue r ati o will e xte n d fr o m 0. 8 8 t o 1. 1 4. T he e x pecte d 
v ari a bilit y i n t he A U C 9 6 of T A K- 0 4 1 is l ar ger t h a n i n C m a x . I n a w orst-c ase 
sce n ari o, ass u mi n g a c oefficie nt of v ari ati o n ( %) f or A U C 9 6 of 2 6. 8 %, t he 
c o nfi de nce i nter v al will e xte n d n o m ore t h a n 0. 2 5 fr o m t he o bser ve d me a n 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e 
saf
s p o ns o
p o ns
ll be all o
be al
dr o p o u
dr o p o
f S a m pl
S a m p
ize c h ose
ze c h o
- 5 a n d 
a n d P
h u ma n t
u ma
ple size i
e size
haracteri
haracter
F or P
F or
c oe
c o
er c
s of U s e
C CI

T A K- 0 4 1
St u d y N o. T A K- 0 4 1- 1 0 0 1
P a ge 1 8 9 of 1 8 9
Pr ot oc ol I nc or p or ati n g A me n d me nt N o. 0 5
0 3 J ul y 2 0 1 8
differe nce. If t he o bser ve d r ati o bet wee n t he t w o re gi me ns is 1. 5, re prese nti n g 
a 5 0 % i ncre ase i n e x p os ure d ue t o f o o d, t he n t he c o nfi de nce i nter v al f or t he 
A U C 9 6 r ati o will e xte n d fr o m 1. 1 7 t o 1. 9 3. If t he o bser ve d r ati o is 1. 0, 
re prese nti n g n o effect of f o o d, t he n t he c o nfi de nce i nter v al will e xte n d fr o m 
0. 7 8 t o 1. 2 8. T a ke n t o get her, t hese res ults are c o nsi dere d t o re prese nt 
a de q u ate precisi o n f or t he esti m ate d f o o d effect. T he ass u me d v ari a bilit y i n 
C m a x a n d A U C 9 6 are esti m ates fr o m t he c o m plete d c o h orts i n P art 1 of t his 
st u d y. T o acc o u nt f or p ote nti al disc o nti n u ati o ns, 1 8 s u bjects ( 9 per re gi me n) 
will be e nr olle d.
S u bjects w h o dr o p o ut f or n o n-safet y reas o ns ma y be re place d o n a case- b y-case 
b asis at t he discreti o n of t he s p o ns or i n c o ns ultati o n wit h t he i n vesti gat or. S u bjects 
w h o re place dr o p o uts will be all ocate d t o t he sa me C o h ort as t he s u bject t he y 
r e place. S u bjects w h o dr o p o ut f or safet y reas o ns will n ot be re place d.
R ati o n ale f or C h a n ge: Pr o vi de d sa m ple s ize deter mi nati o n f or t he Part 3 oral bi oa vaila bilit y of 
t he T A K- 0 4 1 ta blet f or m ulati o n relati ve t o t he oral s us pe nsi o n, a n d t he effect of f o o d o n t he 
T A K- 0 4 1 ta blet f or m ulati o n; a n d f or t he 
 
T he f oll o wi n g secti o ns als o c o ntai n t his c ha n ge:
!
Secti o n  2. 0 S T U D Y S U M M A R Y
Pr o p ert y
 a k e d a:
 
F o
f or C h a
f or C
K -0 4 1 ta
0 4 1 t
-0 4 1 ta b
0 4 1 t
F or n o n- c
w h o dr
o d
t he disc
e di
re place 
e plac
plpl ace. S u
ace. 
F o
T h
pli c a bl e T er m s of U s e
m 
ilit y i n 
it y i
1 of t his
of t h
per re gi
er re g
C CI
C CI

Si g ne 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 ‘ U T C’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e
bl e T
ate 
ate 
a bl
H H: m m ‘ U
H: m m 
e T
a b
P P D